Stroke Alert

On Episode 29 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the June 2023 issue of Stroke: “Prevalence and Procedural Risk of Intracranial Atherosclerotic Stenosis Coexisting With Unruptured Intracranial Aneurysm” and “Adolescent Hypertension Is Associated With Stroke in Young Adulthood: A Nationwide Cohort of 1.9 Million Adolescents.” She also interviews Dr. Darren B. Orbach about his article "Transuterine Ultrasound-Guided Fetal Embolization of Vein of Galen Malformation, Eliminating Postnatal Pathophysiology."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230530.62217

On Episode 28 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the May 2023 issue of Stroke: “Decreased Estimated Glomerular Filtration Rate and Proteinuria and Long-Term Outcomes After Ischemic Stroke: A Longitudinal Observational Cohort Study” and “Stroke Prevention and Treatment in People With Type 2 Diabetes: Is There a Role for GLP-1 (Glucagon-Like Peptide-1) Analogues?” She also interviews Drs. Kanishk Kaushik and Marieke J.H. Wermer about their article “Iatrogenic Cerebral Amyloid Angiopathy Post Neurosurgery: Frequency, Clinical Profile, Radiological Features, and Outcome.”

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230501.274417

On Episode 27 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the April 2023 issue of Stroke: “Association Between Hospital-Documented Atrial Fibrillation and Central Retinal Artery Occlusion” and “Early Stroke and Mortality After Percutaneous Left Atrial Appendage Occlusion in Patients With Atrial Fibrillation.” She also interviews Drs. Wenting Zhang and Jun Chen about their article “Poststroke Intravenous Transplantation of Human Mesenchymal Stem Cells Improves Brain Repair Dynamics and Functional Outcomes in Aged Mice.”

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230407.897078

On Episode 26 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the March 2023 issue of Stroke: “Tenecteplase Treatment and Thrombus Characteristics Associated With Early Reperfusion” and “Dual Antiplatelet Therapy With Cilostazol for Secondary Prevention in Lacunar Stroke.” She also interviews Dr. Mitchell Elkind about the life and the legacy of Dr. Ralph L. Sacco, Stroke’s Editor-in-Chief, who died January 17, 2023.

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230308.776720

On Episode 25 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the February 2023 issue of Stroke: “Early Antiplatelet Resumption and the Risks of Major Bleeding After Intracerebral Hemorrhage” and “Using Noncontrast Computed Tomography to Improve Prediction of Intracerebral Hemorrhage Expansion.” She also interviews Dr. Lauren H. Sansing about her article “Role of Inflammatory Processes in Hemorrhagic Stroke.”

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230203.583057.

On Episode 24 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the January 2023 issue of Stroke: “Covert Brain Infarction as a Risk Factor for Stroke Recurrence in Patients With Atrial Fibrillation” and “Subarachnoid Hemorrhage During Pregnancy and Puerperium.” She also interviews Dr. Georgios Tsivgoulis about his article “Clinical, Neuroimaging, and Genetic Markers in Cerebral Amyloid Angiopathy-Related Inflammation: A Systematic Review and Meta-Analysis.”

Dr. Negar Asdaghi:         Let's start with some questions.

1) When during pregnancy is an intracranial aneurysm at the highest risk of rupture?

2) What does the presence of covert brain infarcts mean in the setting of atrial fibrillation?

3) And, finally, how is the inflammatory form of cerebral amyloid angiopathy different from the classic CAA form, and why is it important to differentiate between the two?

We'll be answering these questions and much more in today's podcast. We're covering the latest in cerebrovascular disorders, and this is the best in Stroke. Stay with us.

Welcome back to another issue of the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. Together with my co-editors, Drs. Nastajjia Krementz and Eric Goldstein, here's our article selection for the month of January. Symptomatic intracerebral hemorrhage is a feared complication of reperfusion therapies in acute stroke, so there's a lot of interest in looking for predictors of development of this complication, especially when you're making decisions for pursuing endovascular therapy. For many years now, we've known about some of these predictors, such as presence of a large infarct core and high blood glucose levels. But in the recent years, other radiographic markers of tissue viability, such as a poor collateral status and unfavorable venous outflow profile, have been shown to be predictors of post-reperfusion hemorrhagic transformation.

In this issue of the journal, we learn about another imaging marker that can potentially predict parenchymal hemorrhage occurrence post-endovascular therapy, which is high hypoperfusion intensity ratio, or HIR, as measured by perfusion imaging. What is HIR? It's a long name for a simple ratio that can easily be measured by dividing the volume of tissue with Tmax delay of over 10 seconds to the volume of tissue with Tmax delays of over 6 seconds. Simply put, Tmax 10 divided by Tmax 6. These volumes, as you know, are typically provided to us by almost all post-processing perfusion softwares, and so this ratio can be easily calculated in the acute setting. So, in this paper led by Dr. Tobias Faizy from University Medical Center in Hamburg and colleagues, we learned that higher hypoperfusion intensity ratios are strongly associated with parenchymal hemorrhage occurrence after endovascular therapy. So, in summary, HIR, that is a quantitative ratio, can be used as a marker to risk stratify patients that are undergoing endovascular therapy in terms of helping us predicting the risk of development of intracerebral hemorrhage after reperfusion therapies.

In a separate study in this issue of the journal, we read a very interesting paper titled "Anti-Epileptic Drug Target Perturbation and Intracranial Aneurysm Risk." How are intracranial aneurysms even related to anti-epileptic drugs? Well, first of all, it's been known for a long time based on genome-wide association studies that there are multiple common genes that are associated with increased risk of intracranial aneurysm development. Now, some of the largest genetic studies to date have shown pleiotropy between genetic causes of development of intracranial aneurysms and genes encoding targets for anti-epileptic drugs. Now that's a fascinating finding because finding commonalities between these genes may help find new treatment targets for intracranial aneurysms.

So, in this paper in this issue of the journal, the investigators from the University Medical Center in Utrecht found an association in the expression of anti-epileptic drug target gene CNNM2 and intracranial aneurysm risk. They found that certain anti-epileptic drugs, such as phenytoin, valproic acid, and carbamazepine, that are expected to lower CNNM2 levels in the blood may subsequently lead to a lower risk of development of intracranial aneurysms. And, of course, a reasonable follow-up study to this would be to investigate whether persons exposed to these anti-epileptic drugs have indeed a lower risk of unruptured intracranial aneurysms and subarachnoid hemorrhage, and how variation in CNNM2 expression can lead to development of aneurysms. Bottom line, CNNM2 may be a relevant drug target for treatment of cerebral aneurysms. As always, I encourage you to review these papers in detail in addition to listening to our podcast today. My guest on the podcast today is the Chairman of Neurology at the University of Athens, Dr. Georgios Tsivgoulis. He joins me all the way from Greece to talk about cerebral amyloid angiopathy-related inflammation, or CAA-ri. He's a remarkable researcher, and I can say with absolute confidence that we cannot find a better summary of this very tough topic elsewhere. He ends the interview with an intriguing account of the early description of dementia in Greek mythology. But first, with these two articles.

What are covert brain infarcts, or CBIs? Are these the John Wick or the James Bond of the stroke world? After all, they operate undercover. They're ominous and attack without warning. That's probably why they're also called silent infarcts. Now, whatever we call them, we need to know how prevalent they are and what does their presence actually mean. Let's dive into this topic. For at least two centuries, if not longer, we've known about covert brain infarcts. Early description of these lesions is credited to Amédée Dechambre, a medical intern at Salpêtrière Hospital in Paris who noted that there are strokes that can cause symptoms like hemiplegia, but also strokes that are asymptomatic, or so he thought at the time. In the modern times, while we agree with our pathology forefathers that CBIs are different from symptomatic strokes, we also know that they are not entirely asymptomatic. The symptoms can be subtle and tend to sneak up on the patient, but what is clear is that amassing of covert brain infarcts results in an overall decline in cerebrovascular reserve of the brain.

With the advent of neuroimaging, we now know that CBIs are age-dependent and prevalent, seen in almost 10 to 30% of even healthy adults, but much more prevalent in those with vascular risk factors, and they can be caused by nearly the entire spectrum of neurovascular disease, including large vessel, small vessel disorders, cardioembolism, and others. Now, how do these covert infarcts catch up in those with atrial fibrillation? Neuroimaging studies have shown that patients with A-fib, especially those untreated, have a higher percentage of embolic-appearing CBIs, and conversely, those with embolic formed pattern of CBIs are more likely to have undiagnosed A-fib. So the question is, what's the significance of CBI in those with confirmed A-fib? In this issue of the journal, Dr. Do Yeon Kim from Seoul National University and colleagues help us answer this question using the EAST-AF, which stands for East Asian Ischemic Stroke Patients With Atrial Fibrillation Study.

So, the paper included over 1300 patients with A-fib and first-ever stroke without a prior history of TIA or stroke. And then they categorized these patients into those who had evidence of CBI on neuroimaging and those who didn't. So, what did they find? Forty-two percent of patients with A-fib and first-ever stroke had evidence of covert brain infarcts on neuroimaging. Let's think about it for a moment. These patients presented with what was thought to be their first-ever stroke, not knowing they already had some in their brain. Now, what makes things really worse is that over a quarter of these subjects had more than just one covert infarct. Not surprisingly, those with CBI tended to be older, had higher blood pressure, and had worse white matter hyperintensity burden. This is kind of expected and also not expected was the fact that most of these covert infarcts were actually embolic in pattern.

Over 60% of them were embolic. Another 14% of cases had combined embolic and non-embolic-appearing CBIs. Now, overall, the one-year incidence of ischemic stroke and all-cause mortality was higher in those that had CBIs at baseline. When they started looking at the specific patterns of CBIs, those embolic-appearing CBIs had a threefold higher risk of recurrent ischemic stroke, whereas those with non-embolic-appearing covert infarcts had oddly a higher all-cause mortality rate but not recurrent ischemic stroke. And finally, just briefly, the authors noted that the addition of CBIs to the classic CHA2DS2-VASc score didn't meaningfully otherwise statistically improve the scoring metrics, so they left it at that. So, the take-home message is that 42% of A-fib patients presenting with first-ever stroke actually had prior strokes without even knowing based on this study. And most of these strokes were embolic-appearing, and these covert brain infarcts can be used as predictors of future clinical strokes in this population.

Strokes should be the last thing to worry about when we think of pregnancy. In the United States, around 30 in 100,000 women, unfortunately, experienced a stroke during pregnancy, and between 6 to 8 in 100,000 deliveries are complicated by subarachnoid hemorrhage. What's the most common cause of pregnancy-associated subarachnoid hemorrhage? In the general population, close to 80% of subarachnoid hemorrhage cases are aneurysmal. Is this true for the pregnant population as well? And importantly, what's the contemporary incidence trend, risk factors, and outcomes of pregnancy-related subarachnoid hemorrhage? In this issue of the journal, Dr. Korhonen and Petra [Ijäs] and their colleagues from the Departments of Neurology and Obstetrics and Gynecology at Helsinki University Hospital will give us the answers to some of these questions through a nationwide population-based study in Finland. So, they looked at over one and a half million pregnant women who gave birth during a 30-year time period between 1987 to 2016.

Subarachnoid hemorrhage was identified through appropriate ICD codes and then further adjudicated based on confirmatory information, including neuroimaging and data from lumbar puncture. A total of 57 cases of pregnancy-related subarachnoid hemorrhage was identified in this paper. The mean age of women was 33, ranging from 23 to 45, and the clinical presentation was typical for subarachnoid hemorrhage, including thunderclap headache and mild neurological symptoms. So, what did they find? So, first off, in terms of general observations, the overall incidence rate of pregnancy-related subarachnoid hemorrhage in this study was 3 over 100,000 deliveries. This is almost half the incidence rate reported from the nationwide registries in the United States. Seventy-seven percent of pregnancy-related subarachnoid hemorrhage cases were aneurysmal, so very similar to the general population. The other 23% were non-aneurysmal cases, but it's important to note that 40% of those non-aneurysmal cases also had vascular etiologies, so etiologies such as moyamoya syndrome, postpartum angiopathy, AVM, to name a few. Like non-pregnant patients with subarachnoid hemorrhage, the aneurysmal cases were sicker patients in general. They had a lower GCS at presentation, higher Hunt and Hess scores, and required more ICU admissions. The next finding is very important because it actually shows that development of subarachnoid hemorrhage during pregnancy significantly impacted obstetrical care. A total of 66% of women with subarachnoid hemorrhage during pregnancy ended up having a C-section and a high percentage of these cesarean sections were actually elective. This is in contrast with subarachnoid hemorrhages in the postpartum period where 67% of women had spontaneous vaginal deliveries. The other important finding of the paper was really highlighting the differences between pregnancy-related aneurysmal versus non-aneurysmal subarachnoid hemorrhages. We already talked about how, in general, aneurysmal cases had more severe neurological presentations, so, not surprisingly, they also had worse outcomes with a mortality rate of 16% for the aneurysmal subarachnoid hemorrhage cases, and only 68% of women with pregnancy-related aneurysmal subarachnoid hemorrhage reached a favorable outcome, which was defined in this study as modified Rankin Scale of 0 to 2. Other important differences included the fact that the incidence of aneurysmal subarachnoid hemorrhage increased towards the end of pregnancy and was highest in the third trimester.

This ties in with the findings from prior studies all indicating that rupture of an aneurysm is most common in the third trimester. By contrast, the incidence of non-aneurysmal subarachnoid hemorrhage peaked in the second trimester in this study. And finally, in terms of risk factors, first let's talk about age. The incidence rate of pregnancy-associated subarachnoid hemorrhage increased with age of the mother. So, in this study, there were no cases noted amongst women aged below 20 years of age to an incident rate of 12 per 100,000 deliveries among women aged 40 years or over. So that's a fourfold increase from the overall incidence rate of pregnancy-related subarachnoid hemorrhage, and very important point that we learned from this paper. Apart from age, smoking beyond 12 weeks of gestation and hypertension were also independent factors associated with pregnancy-related subarachnoid hemorrhage. So, overall, hypertension, smoking are bad and are significant risk factors for pregnancy-related subarachnoid hemorrhage. And if we have to remember just one thing from this paper, let it be this one: The rupture of an aneurysm is most common in the third trimester of pregnancy.

Cerebral amyloid angiopathy, or CAA, is an important cause of intracranial hemorrhage and refers to deposition of β-amyloid fibrils in the wall of the small- and medium-sized cerebral blood vessels, mostly involving cortical and leptomeningeal arteries. It is believed that the deposition of β-amyloid results in architectural disruption of the blood vessels, which then leads to perivascular leakage. That's the pathophysiological mechanism behind the development of cerebral microbleeds. And this process, of course, can cause frank vascular rupture resulting in cortical intracerebral hemorrhage or development of high-convexity subarachnoid hemorrhages. It is important to note that varying amounts of perivascular inflammation, that is inflammation surrounding β-amyloid-laden blood vessels, may be present in some CAA cases, rendering them the designation of inflammation-related CAA. However, frank vasculitic destruction of the vessel wall, such as what is found in amyloid-β-related angiitis, or ABRA, and primary angiitis of the central nervous system, is usually absent in most CAA-related inflammation cases.

How these entities are best defined, diagnosed, and treated is subject of intense research. In this issue of the journal, in the study titled "Clinical, Neuroimaging, and Genetic Markers in CAA-Related Inflammation," Dr. Georgios Tsivgoulis and colleagues take us through a systematic review and meta-analysis of published studies of patients with CAA-related inflammation. I am joined today by Dr. Tsivgoulis himself to discuss this paper. He's a Professor of Neurology and Chairman of the Second Department of Neurology at the University of Athens School of Medicine. Dr. Tsivgoulis is the residency program director and the director of cerebrovascular fellowship program with extensive research and expertise in the field of stroke. Good morning, Georgios, and welcome to our podcast.

Dr. Georgios Tsivgoulis: Good morning, Negar. I'm delighted to be here and delighted to present our findings, on behalf of all our co-authors.

Dr. Negar Asdaghi:         Thank you very much for being here and congrats again on the paper. So, Georgios, let's start with this interest that's going on with using clinical and radiographic features to make the diagnosis of CAA-related inflammation in contrast to moving ahead and performing brain biopsy. Can you please start us off with a brief review of the newly proposed clinico-radiographic criteria for this condition, please?

Dr. Georgios Tsivgoulis: Yes. As you mentioned, Negar, CAA-ri is a distinct, however, rare subset of cerebral amyloid angiopathy. Firstly, Greenberg and the Boston group published in Neurology in 2007 a paper highlighting that a diagnosis of a probable CAA-ri patient could be made on the basis of characteristic clinical and neuroimaging findings without requiring a biopsy. Following this observation, Chung and colleagues in 2010, in a seminal paper in JNNP, proposed the first diagnostic criteria for probable and definite CAA-ri. For the definite diagnosis, besides the typical clinical presentation with headache, encephalopathy, focal neurological signs and seizures, and the characteristic neuroimaging findings with T2 or FLAIR hyperintense asymmetric white matter lesions complicated with microbleeds and leptomeningeal or parenchymal gadolinium enhancement, and histopathological confirmation with amyloid deposition within cortical leptomeningeal vessels associated with perivascular, transmural or intramural inflammation was also required. The latest criteria developed in 2015 by Auriel and colleagues that were published in JAMA Neurology using a validation study modified the current criteria for the diagnosis of CAA-ri.

In this paper, the author supported the use of empirical immunosuppressive therapy, avoiding brain biopsy, for patients meeting the criteria proposed for probable CAA-ri. They suggested that a brain biopsy should be considered in empirically treated patients who failed to respond to corticosteroid therapy within three weeks. The criteria by Auriel and colleagues are widely applicable in everyday clinical practice, and we also use this criteria for the inclusion of studies in our current meta-analysis. I would like to highlight for our audience that the latest criteria for CAA-ri were published in 2015 by Auriel and colleagues. However, these are different for the criteria for cerebral amyloid angiopathy than the latest criteria were published in 2022 in Lancet Neurology, OK?

Dr. Negar Asdaghi:         Georgios, that was a great start for this interview. You had mentioned a lot of information here. I just want to highlight what you just said. So, we are using for this meta-analysis, the latest criteria in CAA-related inflammation published in JAMA by Auriel and colleagues. That's slightly different than, we're not referring to the 2022 criteria of cerebral amyloid angiopathy. It's an important distinction. We're going to talk about this a little more as we go through the interview, but I want to come back to your current paper and start from there. Can you please tell us about the importance of this paper, why doing a meta-analysis was important in your view, and tell us a little bit about the studies that were included in your paper?

Dr. Georgios Tsivgoulis: Yes, thank you for that question. CAA-ri is an increasingly recognized entity since the recent diagnostic criteria by Auriel and colleagues published in 2015. In collaboration with the greater availability of the high-resolution MR, we can have now a reliable non-invasive diagnosis of possible or probable CAA-ri, avoiding the risk of brain biopsy. However, I need to highlight that the early diagnosis remains a great challenge for the clinicians and neurologists. Searching the literature, we observe that there is scarce data regarding the prevalence of the distinct clinical, neuroimaging, and genetic markers among patients diagnosed with CAA-ri. We believe that pooling all this information in the current meta-analysis would be very helpful for every clinician, increasing a comprehensive understanding of this rare cerebrovascular disorder. Consequently, we conducted this meta-analysis including 21 studies that recruited a total of 378 patients with CAA-ri. Our study involved only 4 prospective and 17 retrospective hospital-based cohorts of patients diagnosed with CAA-ri based on autopsy or biopsy or on the recent Auriel diagnostic criteria that do not require autopsy or biopsy. Due to limited data in the literature regarding this entity, we had to include only small cohort studies with at least five patients in our meta-analysis. We excluded case reports and case series with less than five patients. This is, by far, the largest available sample of CAA-ri patients in the literature.

Dr. Negar Asdaghi:         OK, great. So, let me just recap this, more so for myself. So, we have 21 studies, and you excluded studies that included less than 5 patients. So, practically speaking, case reports.

Dr. Georgios Tsivgoulis: Yes, and single-case reports.

Dr. Negar Asdaghi:         Yes. And practically speaking, of the total number of patients that are included in this meta-analysis, you have 378 cases, and basically the diagnosis of CAA-related inflammation was either based on the newly proposed criteria or based on biopsy-confirmed or autopsy cases.

Dr. Georgios Tsivgoulis: Which is the standard criteria.

Dr. Negar Asdaghi:         So, now, I'm dying to ask you about these clinical and radiographic characteristics of patients with CAA-related inflammation in this meta-analysis.

Dr. Georgios Tsivgoulis: The mean age of patients in the included studies was approximately 72 years old, and there was no obvious gender predominance. Fifty-two percent of the patients were of female sex. In our study, 70% of the included patients presented with cognitive decline, which was the most common neurological manifestation, while 50% of the total sample had focal neurological signs and 54% encephalopathy presentation. Symptoms such as headache and seizures were less common, 37 and 31% respectively. With regard to the radiological findings, hyperintense T2 FLAIR white matter lesions were very, very common in 98% of our patients, and they were also complicated with lobar cerebral microbleeds, with a prevalence of 96%, and these two were, by far, the most prevalent neuroimaging findings, that white matter hyperintensities coupled with a cerebral microbleed. The pooled prevalence rates of gadolinium-enhanced lesions was 54%, and also the prevalence of cortical superficial siderosis was 51%, which is also very high in this cohort of patients with CAA-ri.

Dr. Negar Asdaghi:         OK. So many of the features Georgios said, you mentioned, from presence of white matter hyperintense lesions on T2 FLAIR to presence of cortical microbleeds or superficial siderosis, these features are also seen in patients with cerebral amyloid angiopathy. What are some of the important differentiating features between the two conditions?

Dr. Georgios Tsivgoulis: Yes, this is an excellent clinical question. First of all, the lower age threshold for CAA-ri is 40 years old, whereas in cerebral amyloid angiopathy, the lower age threshold is 50 years. So, patients who are younger than 50 years can be diagnosed with CAA-ri, but they cannot be diagnosed with CAA. Another issue is that comparing the result of this meta-analysis with another recent meta-analysis focusing on CAA, on cerebral amyloid angiopathy, that our international multi-collaborative group published in Stroke in 2002, we also evaluated the presence of clinical phenotypes and radiological markers among patients with cerebral amyloid angiopathy. We have documented that transient focal neurological episodes are much more common in patients with cerebral amyloid angiopathy in contrast to patients with CAA-ri. These episodes, which are called TFNEs, transient focal neurological episodes, are attributed to cortical subarachnoid hemorrhage or cortical superficial siderosis.

So, I think this is another important clinical distinction. The most important, however, differentiating features between the two entities are neuroimaging markers, in specific, in particular, T2 FLAIR hyperintense unifocal or multifocal lesions with mass effect. These are the most prevalent neuroimaging features among patients with CAA-ri, but they're very seldomly described in patients with cerebral amyloid angiopathy, in patients with CAA. Another characteristic neuroimaging finding very indicative of the inflammation is the leptomeningeal or parenchymal gadolinium enhancement. This finding has been very rarely described in patients with non-inflammatory cerebral amyloid angiopathy. So, the clinical distinction is not so solid. However, the neuroimaging distinction would provide us with very strong information that can help us differentiate these two conditions.

Dr. Negar Asdaghi:         Excellent points, I have to say, golden points, not just excellent points. I'm going to try to recap this and see if I understood it correctly. So, for our listeners, we have two conditions that potentially have many common points. One is the cerebral amyloid angiopathy, and the second one, which is obviously the subject of this interview, is cerebral amyloid angiopathy-related inflammation. The most important differentiating factors between the two are actually the neuroimaging features, as Georgios mentioned. So, the first feature that was mentioned is presence of T2 FLAIR hyperintense lesions. Some of them are large and have actually mass effects. This feature is rarely seen in patients with CAA, and it's an important radiographic factor that is seen in patients with CAA-related inflammation. The second distinguishing feature was leptomeningeal enhancement, again, rarely seen in non-inflammatory CAA, but was seen in a significant proportion of patients with CAA-related inflammation. These were the neuroimaging features. You also mentioned two other factors. The median age of CAA-related inflammation was lower than CAA. That can be helpful. And also the entity of transient focal neurological episodes, or TFNE, is rarely seen in inflammatory cases of CAA, whereas it is described in cases with cerebral amyloid angiopathy and mostly related to development of either cortical subarachnoid hemorrhage or cortical superficial siderosis. I think I got this all, correct?

Dr. Georgios Tsivgoulis: Excellent.

Dr. Negar Asdaghi:         All right, so let's come now to the genetics of CAA. The apolipoprotein E gene is associated with the presence of amyloid angiopathy and development of lobar intracerebral hemorrhage, and we've learned about this in cases with cerebral amyloid angiopathy. Is there an association with ApoE, and did you find anything in this meta-analysis?

Dr. Georgios Tsivgoulis: Another very exciting question. In 2007, there was a first report that the apolipoprotein ε4 homozygosity may be considered a risk factor for CAA-ri, and there was a strong correlation reporting a high prevalence of 77% of this apolipoprotein ε4 alleles among patients with CAA-ri. To justify this correlation, the hypothesis was that an underlying pathogenic mechanism, which increases the amyloid-β deposition and has a pro-inflammatory effect, may be suspected as the cause of this disorder. The largest, however, prospective cohort of CAA-ri patients conducted by Antolini and colleagues and was published in 2021 in Neurology, reported a much lower prevalence of apolipoprotein ε4 carriers accounting for 37%, 23% heterozygotes and 14% homozygotes. So, we also documented a pool prevalence of apolipoprotein ε4 homozygosity of 34%. So, we did not confirm the initial finding of 77%. However, in our meta-analysis, the homozygosity was 34%, and we need to have a cautious interpretation of these results because data is limited, and we need larger future population-based studies and in larger cohorts to evaluate the prevalence rate of these specific genetic markers. So, we can confirm an association between apolipoprotein ε4 homozygosity, however not as strong as originally reported in 2007.

Dr. Negar Asdaghi:         OK. So, Georgios, thank you. And again, very important factor to keep in mind for our clinicians listening in. Unfortunately, based on what you mentioned, we don't have yet a genetic marker to, for sure, tell us if we're dealing with CAA-related inflammation, yes or no, as you mentioned. Just to recap, earlier on, there was studies to suggest a very strong association between apolipoprotein ε4 homozygosity and CAA-related inflammation. But later on, this was not confirmed by subsequent studies, and in your meta-analysis, you found 34% ApoE ε4 homozygosity amongst patients with CAA-related inflammation and could not confirm that original high association. OK, so with all of that, it's a lot of information. I have to go to the next question regarding controversies involving the levels of Aβ40, Aβ42, and P-tau proteins in CSF in the setting of CAA-related inflammation. Can you please tell us more about these biomarkers?

Dr. Georgios Tsivgoulis: Yes. The overlap of Alzheimer's disease and CAA can be attributed to the coexistence of some degree of cerebrovascular amyloid deposition and amyloid plaque pathology, which is very common. And, of course, the evaluation of amyloid and tau proteins in CSF is of high significance for the prognosis and the evolution of CAA patients. In our previous review, we have summarized the literature and noticed that CSF concentrations of Aβ40 and, secondarily, Aβ42 were much lower in patients with cerebral amyloid angiopathy compared with Alzheimer's disease. Total tau and phospho-tau CSF levels were comparable to healthy controls in CAA and lower than patients with Alzheimer's disease. Moving now to CAA-ri, there were scarce data about these biomarkers amongst CAA-ri patients. The majority of the relevant studies have found relatively low levels of Aβ42 and Aβ40 in the CSF and high levels of P-tau. In the present meta-analysis, the pooled means of biomarker levels were based on the findings of only two studies with heterogeneity, and these limit substantially the validity of our observations. However, they confirm the previous reports indicating, as I said before, but I would like to repeat, low levels of Aβ42 and Aβ40 in the CSF and high levels of P-tau.

Dr. Negar Asdaghi:         Perfect. So, thank you, Georgios. I'm going to recap what you said. So, we're talking about CSF biomarkers, and first what you mentioned is going back to the original studies concentrated on using these biomarkers as ways of differentiating between cerebral amyloid angiopathy and Alzheimer's disease. And very briefly, to recap what you said, in general, the levels of Aβ40 and, secondarily, Aβ42 was found to be much lower than the Alzheimer's levels in patients with CAA. Now coming to the inflammatory form of CAA, what you mentioned and what you found in this meta-analysis, practically speaking, confirmed that the levels of Aβ40 and Aβ42 in CSF are low and the levels of P-tau are high in this condition as well. So, one thing I want to ask as a secondary question to that is, that it sounds like these biomarkers are more or less similar in CAA and CAA -related inflammation, not that different. Is that correct?

Dr. Georgios Tsivgoulis: It's absolutely correct. And I would also like to highlight a major limitation of the meta-analysis that we had available data from only two studies to pool the mean of these CSF biomarker levels. So, these results need to be acknowledged with caution, and we would love to repeat our meta-analysis after the publication of more studies and prospective cohorts measuring the CSF biomarkers in patients with CAA-ri.

Dr. Negar Asdaghi:         OK. So, again, important to note, as you mentioned, that there's heterogeneity in data because of just paucity of information on this, but as we stand today, the biomarkers won't really help us in terms of differentiating between the two conditions that are CAA or CAA-related inflammation. And so, I think I've learned a lot from this interview myself, but I think we have to just talk briefly about the available therapies for CAA-related inflammation.

Dr. Georgios Tsivgoulis: Yes. In our meta-analysis, we sought to summarize the available information regarding different therapeutic strategies and outcomes among CAA-ri patients. Our results supported our clinical experience indicating that corticosteroids represent the first-line treatment in these patients' outlook. Steroids have been associated with clinical and radiological improvement of the primary disease episode and decreased risk of subsequent relapses in patients with CAA-ri. Additional immunosuppressive therapies, including cyclophosphamide, mycophenolate mofetil, azathioprine, IVIG, or rituximab, have been also reported as adjunct therapies in selected cases with a more severe course of the disease. However, this is another limitation that needs to be acknowledged. That data regarding the treatment and the outcomes are limited and heterogeneous, which prevented us from drawing robust conclusions using a meta-analytical approach. And we believe that we need future cohort studies with prospective data validation in order to generate a proposal for a therapeutic algorithm management in these cases.

Dr. Negar Asdaghi:         Thank you, Georgios. So, we have a condition that is now being more and more recognized. We now have criteria based on clinical and radiographic presentation features of patients that might help us with this diagnosis to differentiate it from cerebral amyloid angiopathy. And in terms of therapies, the idea is that the most studied drug is really just first-line therapy, that's corticosteroids. And then there's positive data regarding use of all other forms of immunosuppression, including, as you mentioned, cyclophosphamide, rituximab, and oral agents such as mycophenolate mofetil or azathioprine. We have limited information about those, but I want to highlight something you actually mentioned earlier on in the interview, which is the field is moving towards making these diagnoses based on clinical features and radiographic features that you had highlighted and actually giving patients immunosuppression early on and only move on to a biopsy if the patient had failed these therapies for a period of time, which you mentioned three weeks. So, I think it's important for us as clinicians to keep this evolving criterion and recommendations in mind. And before we end, I want to ask you a hypothetical question, Georgios. In your opinion, what's an ideal randomized trial for CAA-related inflammation in the future?

Dr. Georgios Tsivgoulis: I think before going to the randomized, the ideal randomized trial for CAA-ri, and designing this trial, we need much more information regarding the underlying pathophysiological mechanisms. There are many unanswered questions. What is the diagnostic value of CSF biomarkers such as amyloid, we discussed earlier, and tau protein? And, of course, what is the value of CSF and the amyloid-β autoantibodies, if there is any? What is the value of genetic markers such as apolipoprotein E genotype and a correlation with the co-existing inflammation in CAA-ri? However, I don't want to defer this question. So, a typical answer would be that with regard to the ideal patients, we would want a young patient without comorbidities after the first manifestation of CAA-ri who has shown a good clinical and radiological response to corticosteroids in order to define the best second-line therapy. However, before answering all these questions in a clinical trial, if we can, I think that we need to understand the CSF and genetic biomarkers in order to uncover mechanisms regarding pathophysiology that can help us to design more targeted clinical trials studying novel disease-modifying treatments.

Dr. Negar Asdaghi:         Thank you.

Dr. Georgios, it's been a pleasure having you on the podcast, and I can say we've learned a lot. We look forward to having you back here and talk about that hypothetical randomized trial, and I'm sure one day hopefully will happen in our lifetime. Thank you for being here.

Dr. Georgios Tsivgoulis: Thank you. Thank you for having me. It was a pleasure.

Dr. Negar Asdaghi:         Thank you.

Homer, the legendary Greek poet, described a case of dementia in his seminal work, The Odyssey, in the late eighth century before Christ. He described the cognitive decline of Odysseus's father, King Laertes. The detailed account of the king's mental decline, loss of short-term memory with retention of long-term memory combined with his depression and despair over the loss of his son, is dramatically accurate for a nearly 3,000-year-old description of dementia. Before I ended the interview, I had to use this opportunity to ask Georgios about lessons learned from ancient Greeks and this seemingly timeless disease.

Dr. Georgios Tsivgoulis: Thank you for this question. King Laertes was indeed Odysseus's father, and it's a great paradigm describing dementia. However, the ancient history of dementia may be separated according to the Greek philosopher Posidonius in two periods. The first period is called dementia appearing due to old age, which is called in Greek, eros. And the second one is dementia appearing in other ages and mainly due to other reasons, called morosis. Posidonius of Rhodes was a Greek stoic philosopher of the second first century BC who strongly believed and suggested that morosis, which is that dementia appearing in younger ages due to other disorders, should be treated immediately after its onset. So, if I would like to end this podcast, I would just suggest that CAA-ri could be classified as morosis according to Posidonius. And what we could learn is that the early diagnosis is essential since the prompt initiation of corticosteroids should not be unreasonably delayed.

Dr. Negar Asdaghi:         And this concludes our podcast for the January 2023 issue of Stroke. Please be sure to check this month's table of contents for the full list of publications, including a series of Focused Updates on post-stroke neurological recovery, from management of post-stroke attention deficit, neglect and apraxia to post-stroke memory decline. And with this, we end the start of our 2023 podcast series. Like all new things, a new beginning can come with new directions, and sometimes a new direction is all that we need. After all, as the legend has it, it was a direction of that falling apple back in the year 1666 that gave Isaac Newton the idea of the universal law of gravitation. Now, Isaac Newton has, without a doubt, given science some of its biggest discoveries in mathematics, physics, and astronomy. But most may not know that Newton had a pretty rough start in life.

A January-born premature baby, he was thought not to survive the first few days of life. Newton had a difficult childhood, and at the age of 16, he was pulled out of school by his family and forced to become a farmer, a job he didn't like and he was miserably bad at. So, as we start a new year, let's remember that even the smartest people are not good at everything, and it does take time to find one's passion in life. Now, while things may not always be clear, what is clear is that a great way to find that center of gravity is, as always, staying alert with Stroke Alert.

This podcast is produced by Wolters Kluwer and supported by the editorial team of Stroke. Our Stroke Alert podcast and production staff includes Danielle Cross, Eric Goldstein, Nastajjia Krementz, Ishara Ratnayaka, Erinn Cain, Rebecca Seastrong, and Negar Asdaghi. This program is copyright of the American Heart Association, 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 23 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the December 2022 issue of Stroke: “Direct, Indirect, and Combined Extracranial-to-Intracranial Bypass for Adult Moyamoya Disease” and “Contemporary Incidence and Burden of Cerebral Venous Sinus Thrombosis in Children of the United States.” She also interviews Drs. Koji Tanaka and Andrew Demchuk about article “Significance of Baseline Ischemic Core Volume on Stroke Outcome After EVT in Patients Age ≥75 Years.”

Dr. Negar Asdaghi:         Let's start with some questions.

1) Is direct bypass better than indirect bypass in preventing the future risk of vascular events in adult patients with moyamoya disease?

2) What is the contemporary incidence of cerebral venous sinus thrombosis in the pediatric population?

3) And finally, is endovascular therapy beneficial for patients presenting with a large ischemic core?

We have the answers and much more in today's podcast. You're listening to the Stroke Alert Podcast, and this is the best in Stroke. Stay with us.

Welcome back to another issue of the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. In our final podcast for the year, I'm thrilled to announce that Drs. Nastajjia Krementz and Eric Goldstein have joined our podcast as assistant editors to help us cover the latest and the best in the field of cerebrovascular disorder. And together, here's our article selection to close the year.

As part of our Advances in Stroke, in the article titled "Focus on Anticoagulation for Valvular Heart Disease With and Without Atrial Fibrillation," we get an update on current evidence from randomized controlled trials on the use of direct oral anticoagulants or vitamin K antagonists in patients with valvular heart disease that are mechanical valves, moderate to severe mitral stenosis, or bioprosthetic valves from the perspective of stroke physicians.

What that means is that data from randomized trials was analyzed based on whether the patient had a prior history of stroke or TIA. In this review, we learned that direct oral anticoagulants may be used in patients with bioprosthetic valves who have atrial fibrillation, although DOACs have never been shown to be superior over vitamin K antagonists. We also learned that vitamin K antagonists should be used in patients with rheumatic moderate to severe mitral valve stenosis or patients with mechanical valves with or without atrial fibrillation and, of course, sometimes during the first few months after either surgical or transcatheter aortic valve replacement in patients without atrial fibrillation. And finally, patients with bioprosthetic valves without AFib don't have any other indications to be treated with anticoagulants should be treated with antiplatelet monotherapy in the long run.

In a separate article in this issue of the journal, from Dr. Yang and colleagues from China, we learn about the pathophysiology of radiation-induced brain injury with special attention to radiation-induced vasculopathy. These investigators show that hyperactivity of notch signaling pathway that in normal state is essential in vascular morphogenesis and maintenance of arterial identity actually results in abnormal accumulation and disturbance of vascular smooth muscle cells, resulting in arterial muscularization and arterial dysfunction seen in radiation-induced vasculopathy. What's interesting is that inhibition of the notch signaling pathway in their study resulted not only in a measurable reduction in radiation induced vasculopathy, but also an overall improvement in radiation-induced brain injury as measured by the cognitive function of the mice exposed to radiation in their study. This study takes us a step closer to possible therapeutic options for radiation-induced vasculopathy and radiation-induced brain injury using compounds that can potentially inhibit the notch signaling pathway.

As always, I encourage you to review these articles in detail in addition to listening to our podcast. For our interview today, I have a special guest who's not only a prominent researcher and a pioneer in the field of acute stroke therapies, but also, he's an experienced educator who has trained many of the current leaders in the field of vascular neurology and has been influential in shaping the careers of many vascular neurology fellows over the years. Take a listen.

Dr. Andrew Demchuk:   I've had the privilege of training fellows. I've been the director since 2004, and we've trained close to 100 fellows in Calgary over 20-some years now. Really, it's frankly an honor and privilege to be able to do that. These individuals come from all over the world. They're here to dedicate themselves to learning a subspecialty really, really well, and it's just a fantastic experience to interact with them all and all their cultures to help them learn those things, and doing it in a fun, enjoyable, comprehensive way.

Dr. Negar Asdaghi:         And those are the words of Dr. Andrew Demchuk, who's incidentally my own vascular fellowship director as well. Andrew joins me all the way from Canada to talk about his latest paper on the very hot topic of outcomes of endovascular therapy in patients presenting with a large ischemic core. And true to form, he's accompanied by one of his current vascular fellows. The interview is definitely worth the wait after we review these two articles.

Most of us have heard of the term "moyamoya." First described in Japan in 1950s, the term refers to occlusion or stenosis of the terminal portion of the internal carotid artery and is associated with dilated collateral vessels of the proximal middle cerebral artery. These collaterals have a hazy appearance on angiography resembling the puff of smoke, which is Japanese for "moyamoya." Moyamoya is categorized into two broad categories of moyamoya syndrome and moyamoya disease. Syndrome refers to the situations where the occlusion occurs due to another condition. Conditions such as Down syndrome, sickle cell disease, neurofibromatosis type one have all been recognized as associated with moyamoya syndrome. Of course, moyamoya syndrome can occur due to a secondary insult to the blood vessels, anything from radiation vasculopathy, as we reviewed earlier in the podcast, to autoimmune vasculitis, or even good old advanced intracranial atherosclerosis involving the distal ICA region can cause moyamoya syndrome.

Now, in contrast to moyamoya syndrome, the term "moyamoya disease" is reserved for individuals with no vascular risk factors or known moyamoya predisposing conditions other than, of course, some potential genetic factors. The most recognized genetic association for moyamoya disease is polymorphism in the ring finger protein 213, or RNF213, gene on chromosome 17. But we also have to keep in mind that the majority of moyamoya disease patients have no identified genetic abnormalities. So, moyamoya is truly a complex condition, and the physicians have to navigate the many possible etiologies that may cause or be associated with this condition. But when it comes to treatment options, we're really limited here.

Antiplatelets are generally used and have been shown to reduce mortality in both moyamoya disease and syndrome, and especially cilostazol, which is the favorite antiplatelet therapy of our own assistant editor, Eric, has been shown to be significantly associated with increased survival rate in patients with moyamoya disease. Eric really wanted me to talk about a recently published study out of Korea, which included over 9,000 patients, and that showed that patients treated with cilostazol had a better survival rate than any other antiplatelet therapies. Apart from antiplatelet therapies, medical treatment includes optimizing all other vascular risk factors, which, as we mentioned, are rarely present in this population.

So, it all comes down to most cases, at some point, needing surgical treatment, with bypass surgery being the most commonly surgical intervention for this population. Three flavors of bypass are used: indirect, direct, or combination of the two. Indirect bypasses are kind of like long-term investments where the surgeon moves vascular tissue to the surface of the brain in hopes of promoting angiogenesis. Several procedures, such as performing multiple burr holes, pial synangiosis, dural inversion, or omental transposition, among other methods, are used.

And broadly speaking, we can think of indirect procedures as angiogenesis-dependent methods, the effect of which takes months to recognize and, in general, are thought to be more efficacious in the pediatric population than the adult population. The direct bypass, in contrast, commonly referred to as extracranial-to-intracranial, or ECIC, bypass, is more of an immediate reward where the surgeon stitches a vessel directly from a donor extracranial branch, typically the superficial temporal artery, to a recipient artery, typically the middle cerebral artery, to provide a direct anastomosis between the two vessels. There are technical variations, of course, especially with regards to the number of donors and recipient arteries used, but essentially this method is an angiogenesis-independent method that results in a quicker revascularization, but it's unclear if this strategy is long lasting. A combination of direct and indirect bypass can also be used.

So, the question is, which method is better, especially in the adult population? In this issue of the journal, in the study titled "Direct, Indirect, and Combined ECIC Bypass for Adult Moyamoya Disease," Dr. Nickalus Khan and colleagues report on a meta-analysis and systematic review of those with adult moyamoya disease who underwent either direct, indirect, or a combination bypass. The main study question was whether there's a difference in the rates of early ischemic or hemorrhagic strokes, defined as strokes occurring within 30 days of bypass, or late strokes, defined as strokes occurring after 30 days of bypass, in this population when comparing the different surgical techniques. They also compared the "favorable" outcome rate; however, this outcome was defined in each study between the various broad techniques of direct, indirect, and combined bypass.

So, with that, let's take a very quick look at their methodology. They screened more than 4,000 articles and identified 143 articles for their pooled analysis, the majority of articles being from Eastern Asian-based regions, and they had close to 4,000 combined, 4,000 direct, and 4,000 indirect bypass procedures for this analysis. And they had an average follow-up of over three and a half years. So, this is a great sample size for this large, pooled analysis.

But they also performed a smaller meta-analysis where they were much more stringent with article selection, excluding pediatric papers, excluding articles containing only one surgical modality, or articles with insufficient outcome data. So, for that meta-analysis, they only had 43 articles qualified and were included in that meta-analysis. So, what did they find? In the larger pooled analysis, a significant benefit in favor of both direct and combined bypass techniques were noted in reduction of early and late ischemic strokes and late intracerebral hemorrhage. Also, a higher rate of that sort of vague favorable outcome was noted with both the direct or combined methods as compared to when indirect bypass techniques were used alone.

So, everything in the large, pooled analysis pointed towards the direct bypass or combined technique performing better than all indirect bypass techniques, with only one exception, which was a lower incidence of early intracerebral hemorrhage rate in indirect bypass cases. So, that's one point to keep in mind. The second point was when they compared combined techniques to direct bypass. Overall, these procedures had more or less the same outcomes with the exception that the rate of late ischemic stroke was lower in the combined group than the direct bypass group.

So, this is sort of the overall summary of what they found in that large, pooled analysis. When they were much more stringent with their selection criteria, focusing on the smaller meta-analysis portion of the study, what they found was that in the short term, there were no differences in outcomes of any type of stroke between any of these methods. So, basically, people, regardless of the type of bypasses they received, did the same with regards to the risk of intracerebral hemorrhage and ischemic stroke recurrence within the first 30 days after the bypass.

But for the late stroke outcomes, whether ischemic or hemorrhagic, those with indirect bypass were nearly twofold more likely to develop late stroke after 30 days compared to those who've undergone the direct bypass. A similar pattern was found comparing combined bypass versus indirect bypass, in general, beyond the 30 days, with combined bypass doing better. Comparing direct versus combined bypass showed no difference regardless of timeframe.

So, in summary, overall, it appears that combined or direct bypasses may be the best surgical strategies for treatment of adult patients with moyamoya disease. This study, of course, has many limitations, as does any meta-analysis, but most importantly, the authors focused on moyamoya disease in their analysis. It is presumed, but really unclear if patients with moyamoya syndrome would respond similarly to these different techniques. So, the question is, what surgical procedure are you using at your institution for treatment of adult moyamoya disease patients? And, of course, Eric wanted me to ask if your antiplatelet of choice is cilostazol for this population, yes or no. Leave us your comments, and let us know.

Venous sinus thrombosis, or CVST, is a less common form of stroke most commonly affecting women and young individuals. In our past podcast, we've covered many aspects of CVST, especially when it comes to therapy with anticoagulation, anticoagulant of choice, and duration of therapy. In the October podcast, we reviewed a systematic review and meta-analysis comparing direct oral anticoagulants to vitamin K antagonists in the adult patients with CVST. But there are many aspects of this disease that we have not yet covered. For instance, you may ask, how common is this relatively uncommon condition? In the adult population, the incidence of CVST varies depending on the age of individuals studied, and ranges between 1.3 to 2.7 per 100,000 in women between the ages of 31 to 50, which is the adult population at highest risk for this disease. But the incidence of CVST, for instance, in the pediatric population is largely unknown.

Some studies suggested an incidence rate of 0.67 per 100,000 in the pediatric population. That's roughly less than half the incidence rate in young female adults, but these reports are from the 1990s and are likely very outdated. Nowadays, many of the pediatric conditions, especially infectious conditions, that can predispose children to CVST are more readily diagnosed and treated. On the other hand, we now perform a lot more imaging than 30 years ago. Our neuroimaging modalities are more accurate, so we are more likely to diagnose CVST than before.

So, the question is, what is the contemporary incidence of pediatric cerebral venous sinus thrombosis? In this issue of the journal, in the study titled "Contemporary Incidence and Burden of Cerebral Venous Sinus Thrombosis in Children of the United States," Dr. Fadar Otite and colleagues conducted a retrospective analysis of the New York State Inpatient Database, or SID, from 2006 to 2018, and the National Kids Inpatient Database, referred to as KID, from 2006 to 2019, for all hospitalized CVST cases.

KID is the largest publicly-available pediatric inpatient care database in the United States, containing about 3 million pediatric discharges. They included over 700 hospitalized CVST cases from the SID database and 6,100 hospitalizations from the national KID database for the current analysis. And here's what they found. Number one, in terms of significant risk factors associated with CVST, congenital circulatory system anomalies, infections, head trauma, dehydration, and anemia were amongst the top CVST risk factors in the pediatric population. So that's very good to know. Number two, in terms of presentation, seizures were the most common presentation among all pediatric age groups, with close to half of infants with CVST presenting with seizures. Number three, in terms of outcomes, the rate of mortality was twice higher in the infants group as compared to all other age groups. And finally, the overall incidence of CVST, which was the main question of the paper, in this population was 1.1 per 100,000 per year, with a peak incidence during infancy of 6.4 per 100,000 per year.

Interestingly, incident admissions also increased annually by 3.8% throughout the study period, which was close to 15 years in this paper. And the national burden of hospitalization dramatically and exponentially grew during the study period. So, here are the top three points from this study. Point one: Girls included less than half of all admissions nationally and statewide, and the overall burden of CVST was higher in boys than girls. That's a dramatic difference between the pediatric and adult populations. Point two: Incidence of CVST in infants was higher than five times that of other age groups at 6.4 per 100,000 compared to overall incidence in children, which was 1.1 per 100,000 people per year. Mortality was also two times higher in infants than in any other age group. And finally, point 3, incident admissions and national burden of hospitalization have dramatically increased over time, but it remains unclear whether true incidence has been on the rise or if simply more cases are recognized nowadays due to heightened awareness of this condition and our advanced neuroimaging capabilities.

This study, of course, has some limitations. Data was only obtained on patients admitted, so many patients that may have had CVST but not admitted are not captured in this database. So, in summary, CVST can have catastrophic consequences in children and lead to long-term neurological deficits. Having a high clinical suspicion and early recognition remain crucial for prompt treatment and improved outcomes in this population.

Dr. Negar Asdaghi:         Endovascular treatment, or EVT, is an effective method to achieve recanalization and to improve clinical outcomes in ischemic stroke patients with a target vessel occlusion. Both advanced age and having a large infarct volume at the time of presentation are negative predictors of beneficial outcomes post-EVT. Despite this, the neurological benefits of EVT seem to persist across the spectrum of age, and the same has been observed for a range of ischemic core volumes. But it's important to note that, in general, patients presenting with large ischemic core volumes were excluded from the original thrombectomy studies, and currently there's several ongoing trials to determine whether EVT is beneficial for the large core population.

Now, the question that everyone is interested in answering is whether there is an actual ischemic core volume beyond which endovascular therapy is either futile or potentially even harmful, and if this magic futile core volume is the same for all patients, or does it differ depending on the age and other factors.

In a previous podcast, in an interview with Dr. Osama Zaidat, we learned about that important interaction between the presenting ischemic core volume as measured by ASPECTS score and advanced age in an analysis of patients enrolled in the STRATIS registry. In that study, no one over the age of 75 achieved functional independence post-EVT if the presenting ASPECTS score was under 5 regardless of the angiographic outcomes. In that interview, we also discussed the limitations of STRATIS registry as a non-randomized, single-arm study, and the issues surrounding using ASPECTS score to define ischemic core. In today's podcast, we're going to revisit the important interaction between the presenting ischemic core volume and age while reviewing a pooled analysis of seven endovascular clinical trials in the paper titled "Significance of Baseline Ischemic Core Volume on Stroke Outcome After Endovascular Therapy in Patients Age 75 Years or Older."

I'm delighted to be joined today by the first and senior authors of this paper, Drs. Koji Tanaka and Andrew Demchuk. Dr. Tanaka is an Assistant Professor of Neurology at Kyushu University in Japan. With his experience working at the leading center for conducting stroke clinical trials in Osaka, he has now joined the Calgary Stroke Program as a research fellow. And he's accompanied today by his fellowship director, Dr. Demchuk. Dr. Demchuk, of course, needs no introduction to our Stroke readership and our podcast audience. He's a Professor of Neurology at the University of Calgary Cumming School of Medicine. He's a stroke neurologist and a leader in the field of cerebrovascular research who has been involved in multiple clinical studies and randomized trials, including the seminal studies that led to the approval of EVT as the standard of care for treatment of stroke. And, of course, he's a very special guest of this podcast this morning as he was my very own fellowship director. Top of the morning to you both, Andrew and Koji. Welcome to the podcast.

Dr. Andrew Demchuk:   Thanks, Negar. It's great to be here.

Dr. Koji Tanaka:               Thank you very much for your invitation. That is a great honor to be here.

Dr. Negar Asdaghi:         Thank you both. Andrew, let's start with you. Can you please provide us some background on the pooled analysis and the HERMES collaboration, please?

Dr. Andrew Demchuk:   Yeah, HERMES is a really, it's been a really fun journey. Years back, when these trials all came out roughly at the same time, right? There was a real quick succession of trials, the MR CLEAN trial was obviously first, and ESCAPE and others quickly followed it. It became very clear to us that it just made total sense to collaborate. And so we got together as a group and decided we will pool the data. We'll do it in a very careful scientific way with basically an independent statistical analysis, and develop a core imaging lab, and really actually share the workload amongst us.

I remember one of the really interesting tidbits about HERMES is when we got together, in order, I think, to really build trust in the group, one of the important things we decided early was we were going to have a snake draft. If you don't know what a snake draft is, Negar, it's essentially where you take turns selecting a topic through each of the trials. So, every trialist got an opportunity to pick a topic, and we just went down the list until everyone had their turn, and then we'd start over again and do it again. And I think that really worked very well to be as democratic as possible with this, and as fair. And it really allowed for a lot to get done because whoever was motivated in the collaboration was able to do an analysis.

Dr. Negar Asdaghi:         So, what a great summary of this collaboration. So, it's true collaboration between the trialists that basically gave us those seven original randomized trials. Andrew, can I just stay with you, and can you tell us a little bit about the patient population that were enrolled in those trials?

Dr. Andrew Demchuk:   Yeah, I think one of the important things to know, and I think a limitation for any kind of analysis like this, is the trials generally were small core trials, right? I mean there are some, MR CLEAN was certainly a more generalized population, but many other trials, including ESCAPE, I mean the "S" and the "C" in ESCAPE is "small core," right? And so a lot of these trials were small core. So, we don't have a lot of data in larger core patients. But, as you can imagine when you do core lab analysis, you realize that some of the stroke patients weren't as small core as we thought they were when we enrolled them. So, there is some sufficient data to hypothesize. I would consider this paper very much hypothesis-generating. So, yeah, it is a limitation to be considered here. I mean, our sample size isn't very large in the big core patients.

Dr. Negar Asdaghi:         Perfect. Thank you, Andrew. So, again, a recap for our listeners, that we are looking at pooled analysis of seven original trials of thrombectomy, but keeping in mind that those patients that were enrolled in the trials had, generally speaking, small presenting ischemic core. So, now, Koji, on to you. Can you walk us please through the current study, and what was the premise of it, and who was actually included in this study?

Dr. Koji Tanaka:               Yes. In this study, we aimed to evaluate association between baseline ischemic core volume and the benefit of endovascular therapy over the best medical treatment on functional outcomes. Patients were categorized age over 75 years, and less than 75 years old. The primary outcome of interest was a modified Rankin Scale of three or less, and we included 899 patients who underwent this baseline ischemic core volume measurement, which corresponds to 51% of our patients in the HERMES collaboration dataset.

Dr. Negar Asdaghi:         All right. So, just a quick recap of what you said. Thank you for this. So, we have 899 patients. Those patients were all included in the HERMES collaboration, but, of course, these are patients in whom we had presenting ischemic core measurements. And that will get me, actually, Koji, to my second question. Can you please walk us through how you did analysis of ischemic core volume measurements in this study?

Dr. Koji Tanaka:               In this study, ischemic core volume was measured by CT perfusion in 591 patients and by diffusion-weighted imaging in 309 patients. We defined the ischemic core volume as a relative cerebral blood flow of less than 30% in CT perfusion and diffusion coefficient of less than 620 square micrometers per second in diffusion-weighted imaging. Previous studies showed ASPECTS moderately correlate with ischemic core volume in both CT perfusion and diffusion-weighted imaging. For example, ASPECTS of eight can be considered as ischemic core volume of 20 milliliters. But underlying [inaudible 00:28:21] were different between CT perfusion and diffusion-weighted imaging, and previous studies suggested CT perfusion occasionally overestimates the ischemic core volume was on diffusion-weighted imaging. In this study, the results did not change when analyzing CT perfusion and diffusion-weighted imaging separately.

Dr. Andrew Demchuk:   Yeah, that's a really important point Koji makes, is that because we had sort of a, not quite a 50/50 split, we had a 60/40 split of CTP and DWI, we did analyze them separately, and the odds ratios of treatment effect were pretty similar at different core thresholds. So, they're fairly similar when you separate them out, but obviously the methodology is a little different between a CTP and a diffusion. And to Koji's point, he's absolutely right, the CTP has a tendency to slightly overestimate core when you compare to diffusion.

Dr. Negar Asdaghi:         Yeah, and thank you. I think you already sort of alluded to what I was going to ask you and Koji, because, in reality, we have different ways of measuring core. We have the ASPECTS score, which is just a quick and dirty way of estimating or guesstimating core, and then we have CT perfusion, and we also have diffusion that sometimes is available to us, but not always. And the question is, in the heat of it, how we're going to measure the volume. With post-processing softwares, with CT perfusion, we get a quick potential ischemic core volume, but we don't have that capability with diffusion even if we did get diffusion.

So, I think it's important to know that what Koji mentioned, an ASPECTS of eight can, more or less, in a quick fashion, be thought of as about 20 cc of core. And the other point that Koji raised was that CTP, again, this is sort of ballpark, can tend to overestimate ischemic core if you were to compare that with diffusion-weighted data. So, with that, now we have a study in which we have core volumes, and we're going to look at outcomes from endovascular thrombectomies compared to best medical management and see whether there is a correlation or interaction between ischemic core presentation, especially age. So, my next question would be to Andrew, can you walk us please through the main findings of the paper?

Dr. Andrew Demchuk:   The whole goal of this paper was really to understand, are there thresholds in the older patients? When we looked at overall, and Bruce Campbell and the team wrote an important paper with HERMES and the CTP cohort overall, and the sort of message there was if you looked at shift analysis, there wasn't actually a core threshold found at all in HERMES for lack of benefit. There was a benefit across all the core volumes, but, of course, that's all ages. So, we were really interested in looking at the older patients because we felt there's more likelihood the core volume will matter in the elderly than in the younger patient. We know the younger population, it benefits overwhelmingly with EVT, it's hard to even find a core volume threshold. So, that was a premise.

Essentially, we had 247 patients over 75 in the overall cohort, of which 98 had EVT. So, it was a decent population, and not a huge sample, but a decent sample. And so we looked at various things. The first thing that was interesting we found was that infarct volumes, the average infarct volume to achieve an mRS three or less, was lower in the older patients, significantly lower, was 23.9 for younger patients under 75 and 10.7 for the older patients. You tend to have much smaller infarcts to achieve good outcome. And so that was kind of interesting, and I think that's been shown by others. Then we got into the weeds to try to figure out, OK, what are these thresholds? And if there's one figure that matters, Negar, you know me to always point out that there's always one figure or table in a paper that's kind of where the money is, where the real learning is, and that's Figure 2 on this paper in my opinion, beautiful figure with four figure A, B, C, and D. And it really sort of nicely highlights these issues and these cutoffs.

But what we saw is that in the older patients who received EVT, around 50 mils seemed to be a threshold to achieve zero three, you had to, to see treatment effect, you had to have a baseline infarct volume less than 50 mils for a zero three outcome advantage. For zero four, it was 85 mils. And then we looked at this issue of what we called futility, true futility. And that's a very controversial thing. What is futility, or how do you measure futility? And really, I think, we even had a debate about this as a HERMES group when we were designing the analysis, and we sort of landed on mRS five six. A 90% chance of mRS five six, right? That's quite the bar, right, to say true futility because some people argue mRS four is still not a horrible outcome. Culturally, that is an OK outcome in some situations.

But when we did use that five six 90% threshold, it was 132 mils. So, you're getting up to these really large volumes. But here's the catcher in the whole thing, and Koji will probably speak to this a bit more. I don't want to steal his thunder too much, but this issue of reperfusion seemed to matter in this. And we'll come back to that maybe with another question. Reperfusion matters a lot when you think about these thresholds.

Dr. Negar Asdaghi:         OK, so, Andrew, a lot of information, I don't know if I need a recap myself to recap, but basically what you mentioned is that for the older patients who received EVT, if we keep our eyes on the outcome of mRS of zero to three, it seems to be the magic core volume for that outcome post-endovascular therapy that it lands on the magic volume of 50 cc core. Did I get that right?

Dr. Andrew Demchuk:   That's correct.

Dr. Negar Asdaghi:         Then if you're still a bit more lenient with the definitions of what is favorable outcome, what outcomes we're looking at and so on, so forth, for an mRS of five to six, then when we talk about futility of endovascular thrombectomy, the volume that you mentioned, and again I want to ask you this, this volume is for elderly over the age of 75, is 130 mil.

Dr. Andrew Demchuk:   132, but yeah, absolutely. But there's a real catcher here, and we need to really emphasize the catcher in this.

Dr. Negar Asdaghi:         Okay. I will ask you one more question before I go to Koji, which I'm sure is going to tell us more about that catcher. Andrew, can you please tell us about the factor of time? I feel like that is something that we need to discuss, as well. Your study included patients early on in their stroke onset, but we're talking about an important interaction. The question is, do you think the results of this interaction would be different or impacted by the value of time?

Dr. Andrew Demchuk:   Hypothetically? It must, right? I think that that must be the case. We don't have any data specific to this. That would be an interesting Aurora analysis to do. Now, of course, the challenge with late window analysis is, we are really small core in our late window trials, we probably have even a much smaller proportion of large cores. So, to be able to even tackle that question in the late window is, I don't know if we have the data yet, to be honest. But it makes sense that you would expect the thresholds to be a bit lower the later you are in the window. But that is a hypothetical opinion.

Dr. Negar Asdaghi:         Right, so, I want to take that and come to Koji. I want to digress a little bit to Koji and see how we can understand the finding of this current analysis of this paper. So, small core patients early on into their onset, we're looking at the interaction between age and their core volume and coming up with numbers 50 cc for the elderly population. If you're looking at the outcome of zero to three or 132, as Andrew pointed out, for an MRS of much higher, four or five.

Dr. Andrew Demchuk:   Actually five, six, 90% chance of five, six. So, it's there. It's like almost everybody got five, six, took 132 mils to get there. So, it's like this extreme outcome.

Dr. Negar Asdaghi:         Right, so, exactly, and I have to correct it, again, mRS of five or six or dead or almost dead mRS basically.

Dr. Andrew Demchuk:   In 90% of patients.

Dr. Negar Asdaghi:         90% of patients. So, we have these important numbers here, and I want us to basically understand these numbers in these volumes in the context of the recently published RESCUE-Japan LIMIT study. Can you tell us a little bit about that study and how we can make sense of these volumes in the setting of that paper?

Dr. Koji Tanaka:               In the recent RESCUE-Japan LIMIT trial, the median ASPECTS was lower, and baseline ischemic core volume was greater than those in our study. And surprisingly, the median ischemic core volume in that trial was close to our threshold to predict less than 10% of patients achieve a modified Rankin Scale of four or less after endovascular therapy. We thought this is due to much higher complete reperfusion rate in HERMES patient. We have much interest in their additional analysis for outcomes in elderly patients by reperfusion status. This potential benefit of endovascular therapy in the area is promising for the future clinical trials.

Dr. Andrew Demchuk:   I think just to add to that, it was actually really interesting, Negar, because when we were analyzing all of this and then the trial came up and it was actually really nice because we're like, OK, how does our data relate to their data? And that's where Table 2 comes in, and it would almost be worth putting on the pod, whatever, I don't know if you have on your podcast website, you have one figure that you can sit there with as you listen to the podcast, because that would be the figure.

Dr. Negar Asdaghi:         We'll work on that Andrew, but tell us a little bit more because, really, when I read the trial results, the way I understand it is that people enrolled in RESCUE-Japan that were older than 75, and these are all large core patients, benefited more from endovascular therapy than their younger counterpart. How do I understand that? I don't know how to wrap my head around that finding.

Dr. Andrew Demchuk:   You want to try to answer that, and then I'll add?

Dr. Koji Tanaka:               As I mentioned previously, we want to know about the exact patient population just only for elderly patients, whether they have a exactly larger ischemic core volume or as well as their functional outcome. How many patients achieved modified Rankin Scale four or less or three or less, or more than five or six?

Dr. Andrew Demchuk:   Koji's point's very important. We actually don't have the breakdown of the mRS, so we don't know if they created a lot of fours, or threes, or what. So, that's one issue. But I think that the key to this whole thing is to understand that this is a 2022 trial. HERMES data is essentially a 2015 equivalent where we're looking at a number of clinical trials who roughly ended between 2014, 2016. So, the technology, the technique, the operators, are just at a different level back then than now. And quite frankly, EVT is an improving treatment. We probably don't even fully understand how much, I mean, we're just getting better at it. And I think what's happened here is the reperfusion rates have improved. And our HERMES reperfusion rates, remind me, Koji, I think they're about half, we think, in HERMES, than like the TICI 2bs, threes, are half in HERMES what they got in RESCUE-Japan LIMIT.

So, when you achieve successful reperfusion, what were the numbers here? TICI 3 was 43% in the Japan RESCUE LIMIT, and 8.6% in HERMES. Okay, TICI 3s were not ... Now that may be slight differences in core lab interpretation, but we were just starting to get good at 3s. We were getting a lot of 2bs and some 2cs, but we weren't getting a massive number of 3s back in 2015. Well, voilà, now we are, right? We're hitting home runs when we didn't before. And I think that has really shifted the goalposts on the large core. If you open the vessel, they can still do well if they're elderly, but you've got to really open that vessel. And in HERMES, we only did that in a small portion of patients. So, these thresholds are sort of representative of 2015 skill.

Dr. Negar Asdaghi:         Golden points, Andrew and Koji, both of you. I want to recap what you mentioned here. A note to all of our audience and listeners that we are looking at an analysis with RESCUE-Japan, an analysis of a 2022 study. And the patient population that were enrolled were also treated much later in terms of time than the patient population that was enrolled in the HERMES collaboration and in all of the trials that contributed to HERMES. So, we've got to remember that EVT is this fluid, ongoing, everyday-improving therapy, from our techniques to everything else, you know, how fast we get patients to the angiosuite. And the point that you raise, I want to repeat that, the percentage or the odds of achieving a perfect reperfusion was, in RESCUE-Japan, was 43% odds of TICI 3 reperfusion, whereas only 8.6%.

So, when we're talking about all of these predictive modeling or predictive factors that will tell us who's going to do well, who's not going to do well, it also is predicated on the angiographic success. And perhaps in the earlier trials or even the early study that we covered as part of the STRATIS registry, we put everybody, TICI 3s with TICI 2b or better, whereas nowadays we accept the best, TICI 3s, and maybe that improved percentage in the most recent trial, the RESCUE-Japan, really did what it had to be done for the elderly population to keep that in mind. And Andrew, before we end our interview, I want us to get your top two takeaway messages from this paper.

Dr. Andrew Demchuk:   Clearly, elderly patients do better when their strokes are smaller, that we know, compared to younger patients. But it's all about hitting the home run. It's all about hitting the home run. Figure 2C and 2D, you can see that if you achieve that high TICI score, a significant proportion of elderly patients potentially could still benefit, 30–40% reasonable outcomes with bigger cores if you get those high TICI scores. So, it is about hitting the home run in reperfusion in the elderly. You need to go for it, and hopefully you're successful, because if reperfusion isn't successful, then generally the outcomes are not ideal and they certainly worsen as the core volumes become larger, bigger.

Dr. Negar Asdaghi:         Before I ended the interview, given Andrew's tremendous experience as a longtime fellowship director and seeing that he was flanked by two of his fellows, one past, myself, and one present, Koji, I had to ask him one final question of what his philosophy is as an educator.

Dr. Andrew Demchuk:   I have a sort of philosophy on life with fellows. I always look for the special power in a fellow. I realized a long time ago we’re all, we’re not perfect, nobody’s perfect, I’m not perfect, but there’s usually a special power in people, and if you spend the time to get to know them, you identify that special power, and you really help harness it because you know that if they can harness it when they go back to their faculty job, they’re going to really contribute something special to their team, right? You can imagine six special powers from six different people in a team. Now you’ve got a real team, right? If you know what your power is, you know your limitations, but you know where your strengths you can add to the group, and that’s what we try to do here when we can. It’s not always, you know, special powers, you have to kind of seek them out. But they’re there in most people, and that’s really important for career down the line.

Dr. Negar Asdaghi:         And this concludes our podcast for the December 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including our very interesting Stroke Images series. In this month, we have a case of progressive cervical myelopathy secondary to a dural AV fistula supplied by the anterior inferior cerebellar artery. We also have a separate case of carotid rete mirabile imaged with a four-dimensional flow MRI study.

And with these cases, we bring our 2022 Stroke Alert Podcast series to an end. Over the past 12 months, we've ended our podcasts with various inspirational tales. From the moving account of the American runner Steve Prefontaine and the remarkable journey of the Syrian refugee and Olympian swimmer Yusra Mardini, to the discovery of positron and Commander Armstrong's landing on the moon, our podcast stories have but one thing in common, which is the story of human perseverance and consistency in the face of hardship. So, as we end 2022 to start 2023 anew, Andrew's comments on finding that special power in each of us resonate with our resolution to stay alert with Stroke Alert.

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 22 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the November 2022 issue of Stroke: “Estimating Perfusion Deficits in Acute Stroke Patients Without Perfusion Imaging” and “Five-Year Results of Coronary Artery Bypass Grafting With or Without Carotid Endarterectomy in Patients With Asymptomatic Carotid Artery Stenosis.” She also interviews Dr. George Ntaios about his article “Incidence of Stroke in Randomized Trials of COVID-19 Therapeutics.”

Dr. Negar Asdaghi:         Let's start with some questions.

1) What is the actual incidence of stroke after COVID-19?

2) In the setting of acute ischemic stroke, can the volume of ischemic penumbra be estimated with just a regular MRI study of the brain without any vascular or perfusion imaging?

3) And finally, can a patient with significant carotid stenosis go through coronary artery bypass graft surgery?

We're back here to answer these questions and bring us up to date with the latest in the world of cerebrovascular disorders. You're listening to the Stroke Alert Podcast, and this is the best in Stroke. Stay with us.

Welcome back to another issue of the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The November issue of Stroke is packed with a range of really exciting and exceedingly timely articles. As part of our Original Contributions in this issue of the journal, we have a post hoc analysis of the Treat Stroke to Target, or the TST, randomized trial by Dr. Pierre Amarenco and colleagues. We've talked about this trial in our past podcast, and the main study results that were published in New England Journal of Medicine in January of 2020. TST randomized patients with a recent stroke or TIA to either a low target of LDL cholesterol of less than 70 milligram per deciliter or a target LDL of 90 to 110. The main study showed that the low LDL target group had a significantly lower risk of subsequent cardiovascular events without increasing the risk of hemorrhagic stroke. So, from this, we know that achieving a low target LDL is possible and is actually better than the LDL target of 90 to 110 post-stroke.

But in the new paper, in this issue of the journal, in a post hoc analysis of the trial, the TST investigators showed that it's not just achieving that magic low target LDL of less than 70 that's important in a reduction of cerebrovascular disorders, but it's also how we achieve it that determines the future of vascular outcomes. So, in this analysis that compared patients on monostatin therapy to those treated with dual cholesterol-lowering agents, that would be a combination of statin and ezetimibe, and showed that in the low LDL target group, only those patients treated with dual therapy had a significant reduction of subsequent vascular events as compared to those in the higher LDL category.

But the same was not true for patients on statin monotherapy, even though they had all achieved a low target LDL. Think about this for a moment. Both groups, whether on statin monotherapy or on dual anti-cholesterol treatments, achieved the same low target of LDL, but only those on dual therapy had a lower risk of subsequent vascular events as compared to those that were in the higher LDL target group. Very thought-provoking study.

In a separate paper by Dr. Shin and colleagues out of Korea, we learned that survivors of tuberculosis, or TB, are at a significantly higher risk of ischemic stroke than their age- and risk factors–matched non-TB counterparts. The authors used data from the Korean National Health Insurance Services and studied over 200,000 cases diagnosed with TB between 2010 and 2017 and compared them to a pool of over one million non-TB cases for matching. And they found that the risk of ischemic stroke was 1.2 times greater among TB survivors compared to matched non-TB cases after adjusting for the usual confounders, health behavioral factors, and other comorbidities.

Now, why would TB increase the risk of stroke? The authors talk about the pro-inflammatory state of this condition, thrombocytosis, that is a known complication of chronic TB amongst other putative and less clear mechanisms. But what is clear is that findings from a large-scale population-based cohort such as the current study support an independent association between TB and ischemic stroke. As always, I encourage you to review these papers in addition to listening to our podcast today.

My guest on the podcast today, Dr. George Ntaios, joins me all the way from Greece to talk to us about the much discussed topic of the risk of stroke in the setting of COVID-19. Dr. Ntaios is the President of the Hellenic Stroke Organization and an experienced internist who has been fighting this pandemic in the front lines since the beginning. In an interview, he talks about his recently published paper, his experience, and the lessons learned on balancing scientific rigor against the urgency of COVID-19. But first, with these two articles.

In the setting of a target vessel occlusion in patients presenting with an acute ischemic stroke, distinguishing the ischemic core from the ischemic penumbra is of outmost importance. The success of all of our reperfusion therapies heavily lies on our ability to differentiate between the tissue that is already dead, which would be the ischemic core, from the tissue that is not dead yet but is going to die unless revascularization is achieved. That is the ischemic penumbra.

Over the past two to three decades, there's been lots of debate over how these entities of dead tissue versus going-to-die tissue are best defined, especially when we're making these distinctions under the pressure of time. We don't even agree on the best imaging modality to define them. Should we rely on CT-based imaging? Do we stop at CT, CT angiogram? Should we do single-phase CTA or multiphase CTA? When do we perform CT perfusion, and what perfusion parameters best define core and penumbra, or should we rely on MRI-based modalities altogether?

These questions have all been asked and extensively studied, which is why, as a field, I think, we have at least some agreements today on the basics of core and penumbra definitions. And I also think that overall we are becoming better at doing less imaging to be able to predict tissue outcomes in real time. And there's definitely a growing interest in trying to estimate tissue fate based on a single-imaging modality. So, I think you're going to find an Original Contribution in this issue of the journal, titled "Estimating Perfusion Deficits in Acute Stroke Patients Without Perfusion Imaging," really interesting.

In this paper, Dr. Richard Leigh from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, in Bethesda and colleagues evaluated patients with acute ischemic stroke enrolled between 2013 to 2014 in the NINDS Natural History of Stroke study. A little bit about the study: It enrolled stroke patients presenting to three hospitals in Washington, DC, and Maryland with serial MRI scans during the acute and subacute time period after ischemic stroke. For this particular paper, they included patients who received MRI and perfusion-weighted imaging and included only those who were thrombolized. That was their way of ensuring that all patients in their study were in the hyperacute stage of stroke.

They then looked at their MR imaging, specifically the fluid-attenuated inversion recovery, or FLAIR, images, for a presence of something called hyperintense vessels in the ischemic territory. Now, this is an audio-only podcast, so unless you're Googling FLAIR hyperintense vessels on MRI, to follow along, I have to take a bit of time explaining this entity. What do we mean by FLAIR hyperintense vessels? We are not just talking about the T2 hyperintense signal that's sometimes noticeable at the site of proximal occlusion. For example, in the setting of an M1 occlusion, we may be able to detect a T2 hyperintense signal at the site of M1 on FLAIR. That's not the point of this paper. The point is to look throughout the area supplied by that said target occlusion, in this case all of the MCA, and see whether there is hyperintense signal in all arteries in that potentially ischemic tissue and how the area delineated by these FLAIR hyperintense vessels could potentially correspond to the area of perfusion deficit on conventional perfusion imaging. It turns out that these hyperintense vessels actually map a pretty large area. So, this is the point of this study. The investigators developed a FLAIR hyperintense vessel scoring system and called it NIH, obviously, because this was a National Institutes of Health study, FHV, which stands for FLAIR hyperintense vessel, scoring system. And the score is based on presence of these hyperintense vessels in three vascular territories: ACA, MCA, or PCA.

Now, seeing that MCA is a larger territory, they had to further divide it into four sub-regions: frontal, insular, temporal, and parietal. So, in total, we have six regions now. Each of them would get a score of zero if there were no hyperintense vessels in them, and a score of two if there were three or more FLAIR hyperintense vessels in a single slice, or if there were three or more slices that contained FLAIR hyperintense vessels. And, of course, a score of one would be anything in between. So, we have six regions in total, each maximum getting two points, to give us a composite score of maximum 12 for this scoring system.

So, they wanted to see whether there's a correlation between the FLAIR hyperintense vessel score and the volume of perfusion deficits that is detected by conventional perfusion imaging, which is their main study result. But before we go there, it does seem like a lot of work to learn all these regions and count all these hyperintense vessels in these six regions and come up with an actual score. So, they had to do an interrater reliability to see how easy it is to score and how reliable are these scores. So, they had two independent reviewers for their study. On average, the scores of these two independent reviewers differed by one point for a κ of 0.31, which is quite a low interrater reliability.

But when they looked at a more liberal way of assessing interrater reliability, where partial credit was given, when the raters were at least close in their scoring, the κ improved to 0.65 for a moderate degree of agreement. So, what that means is that it's not easy to learn the score, and potentially I can give a score and another colleague can give a different score. So, we have to keep that in mind. But I want to emphasize that in the field of stroke neurology, we are kind of used to these poor interrater reliability agreements in general. For example, the interrater reliability of the ASPECTS score, a score that is commonly used in our day-to-day practice, and especially in the acute phase, we communicate the extent of early ischemic changes by using the ASPECTS score, has a pretty poor interrater reliability, especially in the first few hours after the ischemic stroke. So, we can make due with a κ of 0.65.

Now on to the results of this study. They had a total of 101 patients. Their median age was 73. The median FHV, which is that FLAIR hyperintense vessel score, in their entire cohort was four. And close to 80% of patients enrolled in their study had some perfusion abnormalities on their concurrent perfusion-weighted imaging. Now, briefly, they defined perfusion deficits as areas with delay in the relative time to peak map, or TTP maps, after applying a six-second threshold to these TTP maps. Of note, half of those patients with a perfusion deficit had a significant perfusion deficit, which meant that they had 15 cc or more of perfusion deficit.

OK, now on to the main study results. Number one, the score obtained by NIH FLAIR hyperintense score highly correlated with the volume of perfusion deficit. In fact, every one point increase on the NIH-FHV score was approximately equal to 12 cc of perfusion deficit. That's a really useful way of thinking about this score. Each score translated in 12 cc of perfusion deficit.

Number two, when they looked at the predictive ability of this score in predicting the presence of significant perfusion deficit, that is 15 cc or more of perfusion delay, the area under the curve was 0.9, which is quite high. This is quite reassuring that the FHV score was sensitive and specific in predicting the presence of significant perfusion deficit.

Next finding, how does this score do in predicting a significant mismatch? They calculated mismatch ratio by dividing the perfusion volume to that of ischemic core as measured by diffusion volume as it's done conventionally, and then did the same for the score with the exception that instead of using the perfusion volume, they actually used this score and divided it by diffusion volume. And it turns out that FLAIR hyperintense mismatch ratio had a strong predictive capability in predicting the mismatch ratio of 1.8.

So, in summary, if this score is validated in larger studies, it can potentially be used as a quick and dirty way of calculating the amount of perfusion deficit in the setting of target vessel occlusion. And, of course, it can also be used as a predictive way of presence of significant perfusion deficit, which is perfusion deficit of over 15 cc. This is all without the need to do actual perfusion imaging. Now, all we've got to do is to get comfortable with this scoring system and, of course, be able to multiply it by 12 to give us a quick guesstimate of the perfusion volume. And one final word on this is that I think the future of stroke imaging is not in doing more images, but to be able to extract more information from less imaging in the acute setting.

Stroke physicians were frequently consulted to see patients that are scheduled to undergo coronary artery bypass graft surgery, or CABG. The stroke consult would be for the optimal perioperative management of an often incidentally found carotid disease. Now, why do I say we were frequently consulted? Because at least anecdotally in my own practice, I feel that over the past decade, the number of these consults has substantially reduced. Why is that? Well, let's dive into this topic and review some of the literature.

First off, around 40% of patients who have active coronary artery disease and are scheduled to undergo CABG have concurrent carotid disease, and about 10% of CABG patients have evidence of hemodynamically significant carotid disease. And seeing that the risk factors for coronary artery disease are similar to those causing carotid disease, these high percentages are not surprising at all. But the question to ask is, can we put a patient with significant carotid disease through cardiac surgery? What is the perioperative risk of stroke in this situation? And importantly, should the carotid disease be surgically treated during carotid surgery? This is referred to as synchronous carotid endarterectomy, or CEA plus CABG. Or the carotid disease should be treated either surgically or endovascularly before CABG? We refer to this as staged carotid surgery or post-CABG. This is known as reverse staged carotid surgery. All of these questions are asked from the stroke physicians in that consult, and, like many of you, I have struggled to find the evidence to answer some of them. So, let's briefly review some of the current literature on this topic.

The CABACS trial, the acronym stands for the Coronary Artery Bypass Graft Surgery in Patients With Asymptomatic Carotid Stenosis, was a randomized controlled trial that included patients undergoing CABG who are found, exactly like that consult, to have an asymptomatic carotid disease of equal or greater than 70% stenosis. The carotid disease for this trial had to be amenable to carotid endarterectomy, or CEA, and the patients were randomized to either receive synchronous CEA plus CABG or just go through with the CABG alone. The trial started in 2010 and planned to enroll over a thousand patients, but was stopped, unfortunately, prematurely in 2014 due to slow recruitment and withdrawal of funding after only 129 patients were enrolled from 17 centers in Germany and Czech Republic.

The original study was published in this journal in 2017. So, what did it find? In their intention-to-treat analysis, the primary outcome of any stroke or death at 30 days was 18% in patients receiving synchronous CEA plus CABG as compared to only 9% in patients receiving isolated CABG. Ouch, a double risk of stroke in those who had concurrent surgical treatment of their carotid disease in addition to CABG. Now, this was an underpowered study, and the results should be understood in that context, but it really didn't appear that synchronous CEA plus CABG would decrease the rate of stroke in the first 30 days.

Now, how about the long-term outcomes of these patients? We know that asymptomatic carotid disease carries a cumulative annual risk of stroke, and it's important to see if the risk of subsequent stroke was lower downstream if the carotid was already fixed early on. So, in the current issue of the journal, the CABACS trial investigators, led by Dr. Stephan Knipp from the Department of Thoracic and Cardiovascular Surgery in Essen, Germany, and colleagues are back with the five-year results of this trial. How did synchronous CABG plus CEA do as compared to CABG alone? Well, by five years, the rate of stroke or death was 40% in the combined group and 35% in the CABG-only group. This was not a statistically significant difference.

Now, when they broke down the primary outcomes, the rate of death from any cause was similar in the two groups. By five years, the mortality rate was 25% in the combined group and 23% in the CABG-only group. And the same was true for the rate of nonfatal strokes. And also the cumulative rate of nonfatal strokes from year one to year five was similar between the two groups, which meant that the higher stroke risk early on in the CABG plus CEA group was not counterbalanced by decreased rate of stroke later on during the long-term follow-up.

And finally, they looked at the rate of disability-producing stroke. First of all, after the first year, no new disabling strokes were observed in either group. That's great news. However, in the early period, unfortunately, close to half of strokes that had happened after the combined CEA and CABG were disability-producing, and about a third of strokes that happened after CABG alone were also disability-producing. So, in summary, even though this study is quite underpowered, it appears that performing synchronous CEA plus CABG increases the preoperative morbidity and mortality in patients with asymptomatic carotid disease without providing any long-term benefits to these patients.

Coronaviruses are important human and animal pathogens. By now, I think it's safe to say that most of the population of the world has heard of at least one of the members of the coronavirus's family, which was first identified in late 2019 as the cause of a cluster of cases of pneumonia in Wuhan, China. In the early months of 2020, COVID-19, the disease caused by this novel coronavirus, would rapidly spread to involve much of the world. And on March 11 of the same year, the World Health Organization declared COVID-19 a pandemic. Today, over two and a half years have passed since that day, and an avalanche of scientific papers have since been published about COVID-19, not just in medicine, but in each and every imaginable field of life. Neurology's, of course, no exception.

The clinical presentation of COVID-19 largely depends on the severity of the disease and may range from a simple asymptomatic infection to a severe, lethal, multi-organ disease. In the world of neurology, a myriad of neurological symptoms, from loss of sense of taste and smell to headache, all the way to encephalopathy and seizures, have been reported in association with this disease. Early in the pandemic, some studies suggested that COVID-19 is indeed a risk factor for stroke. Like many severe infections, COVID-19 can potentially cause a prothrombotic state and can be associated with thromboembolic events. But most of these earlier studies were smaller observational studies that were completed in an inpatient setting, including those with severe COVID.

In fact, to date, we still don't have an accurate and reliable estimate of stroke incidence among patients with COVID-19. On the other hand, stroke is the second leading cause of death globally and the fifth cause of death in the US. In the United States, every 40 seconds, someone has a stroke, and every four minutes, someone dies of a stroke. So, I think the question that everyone should be asking is, has COVID-19 changed this statistic?

In this issue of the journal, in the study titled "Incidence of Stroke in Randomized Trials of COVID-19 Therapeutics: A Systematic Review and Meta-Analysis," Dr. Ntaios and colleagues aim to get us a step closer to answering this very important question. Dr. Ntaios is an Associate Professor of Medicine at the University of Thessaly in central Greece, and he's the current President of the Hellenic Stroke Organization. It is my great honor to have Dr. Ntaios today in our podcast to discuss this paper and all things stroke-related COVID-19. Good afternoon, George, and welcome to our podcast.

Dr. George Ntaios:          Thank you for the invitation, Negar, and for highlighting our work. It's a pleasure to be here with you today.

Dr. Negar Asdaghi:         Thank you for being here, and congrats on the paper. George, can you start us off by discussing the pathophysiological mechanisms through which COVID can potentially cause a stroke?

Dr. George Ntaios:          Well, one of the most attractive things about stroke, which makes it fascinating for all of us, is its complexity. So many different pathologies can cause stroke, and, quite frequently, identifying the actual cause of stroke can be really challenging. And in a similar way, the pathophysiological association between COVID and stroke seems to be, again, complex. Different pathways have been proposed. Internal, we talk about two broad mechanisms. One is the vascular inflammation and thrombosis, and the other is cardioembolism. And there are several pathways which are involved in vascular inflammation and thrombosis: activation of the complement, activation of the inflammasome, activation of thrombin, increased production of [inaudible 00:24:47] constriction, state of stress, platelet aggregation, vascular thrombosis.

So, collectively, this thromboinflammation could lead to damage of the neurovascular unit and consequently to stroke. And in a similar way, there are several cardiac pathologies which can cause stroke in a COVID patient, like acute left ventricular dysfunction, which can be caused, again, by several mechanisms, like coronary ischemia, stress-induced takotsubo cardiomyopathy, myocarditis inflammation, or also as a result of direct effect of the coronavirus at the myocardial cell. And, of course, we should not forget about atrial fibrillation, which seems to be more frequent in COVID patients.

So, we see that the proposed mechanisms behind the association between COVID and stroke, that is, vascular thromboinflammation on one hand, or cardioembolism on the other hand, are complex, but whether these derangements they have a clinically relevant effect or they are just biochemical derangements without any clinical effect is a debate. For example, the incidence of myocarditis in COVID is about 0.2%. That is, in every 500 COVID patients, you have one patient with myocarditis. But myocarditis has a very wide clinical spectrum ranging from subclinical elevation of myocardial enzymes to full and life-threatening disease. So, obviously, the incidence of severe myocarditis is even lower than 0.2%. And the same is true also for the incidence of myocarditis after COVID vaccination. The CDC estimates that one case of myocarditis occurs every 200,000 vaccinations, with the number being slightly higher in young men after the second dose. And this is extremely rare, and the huge majority of these myocarditis cases, they're mild.

So, this is about ischemic stroke. Now, with regard to hemorrhagic stroke and its association with COVID, again, it seems to be, again, very rare. The best estimate that we have comes from the Get With The Guidelines – Stroke Registry and is about 0.2% and involves mainly patients who are already on anticoagulants. So, they had already a risk factor for ICH. So, again, whether all these pathophysiologic derangements in COVID patients, they have a clinical meaningful association with stroke risk or not, I think it's a matter of debate.

Dr. Negar Asdaghi:         Wow, George, it was a simple question, but it seems like the answer was not that straightforward. Let me just recap some of the things you mentioned. So, first of all, the answer is not straightforward and depends on whether we're talking about ischemic stroke or hemorrhagic stroke. There seems to be a lot of connecting points, at least, so to speak, between COVID and either forms of stroke. But you touched on two major sort of broad mechanisms. One is the idea of vascular thromboinflammation that goes along the lines of many sort of hyperacute, hyperinflammatory processes that can occur, especially in the setting of severe COVID. You touched on activation of thrombin, complement activation, platelet aggregation, sort of an activation of that microvascular or vascular unit in a sense.

And then a second mechanism you touched on is the impact of COVID on the myocardium on sort of many different pathways. Again, you talked about acute left ventricular dysfunction, stress-induced myocarditis, and the impact of COVID on perhaps increasing the rate of atrial fibrillation. Again, these are all very complex associations, and some could be already present in a patient who is perhaps of an older age, and COVID is just a modifier of that risk factor that was already present in that particular person. And you also touched on how COVID can potentially increase the risk of hemorrhagic stroke, but the study seems to suggest that those patients already had risk factors for the same. And perhaps, again, COVID is a modifier of that risk factor.

All right, so with that information, a number of studies early on, especially, in the pandemic and later, some meta-analyses, have aimed to estimate the incident rate of stroke post-COVID. Can you please briefly tell us what were their findings, and how is your current paper and current meta-analysis different in terms of methodology from those earlier studies?

Dr. George Ntaios:          Yes. Well, it all started from this letter to the editor at the New England Journal of Medicine. It was published very early in the pandemic during the outbreak in New York. And in this letter, the authors had reported that within a period of two weeks, they had five young patients with COVID and large artery stroke, which they commented that it was much higher than their typical, actually their average, of 0.7 cases during a two-weeks period within the last year. And remember that back then, we knew literally nothing about COVID. So, this letter was really a huge, loud alert that something is going on here and that perhaps our hospitals would be flooded with COVID patients with stroke.

So, subsequently, several reports were published aiming to estimate the incidence of stroke in COVID. Rather contradictory with the incidence, estimates are ranging from as low as 0.5% to even 5%. However, these estimates could well be inaccurate. They were observational studies. Most of them were limited to the inpatient setting. Most of them were single-center studies. Most of them, if not all, were retrospective studies. So, there was really a high risk of registration and assessment bias, as well as reporting bias. And also remember that back then during the outbreak, people were really reluctant to visit the hospital, even if they had a serious condition like stroke, an urgent condition, which means that the real incidences could be even higher.

So, it was our feeling that these estimates were perhaps inaccurate. And there are also some meta-analyses of these studies which estimate that the incidence of stroke in COVID is about 1.5%. But, of course, any meta-analysis is as good as the studies it includes. So, we tried to find a way to have a more accurate estimate than these estimates. And we followed a different methodology. We studied randomized trials of COVID therapeutics, and we looked for strokes reported as adverse events or as outcome events. And the good thing about randomized trials is the rigorous assessment and reporting of outcomes in adverse events. So, we think, we believe, that this methodology provides a more reliable and a more robust estimate of stroke incidence in COVID patients.

Dr. Negar Asdaghi:         OK. George, it's very important what you just mentioned, so I wanted to recap for our listeners some of the things you mentioned. It all started with a letter to the editor of New England Journal of Medicine on a report of five young patients that had large vessel occlusion in the setting of COVID. And then, basically, the floodgates opened in terms of all these observational studies that basically reported the same. And subsequent to that, meta-analyses that were completed containing those observational studies predominantly gave us an incident rate of 0.5 to 5%. That's much, much higher than basically the non-COVID–associated incidence rate of stroke in the population-based studies, and basically suggested that COVID-19 is indeed a major risk factor for all types of stroke.

So, that's where it all started. And, as you alluded to, these numbers had to be reverified in bigger settings, more controlled setting. And you already answered my next question, which is the difference between those studies and prior meta-analyses to the current meta-analysis is that you basically took the simple question and started looking at it in a controlled setting of randomized trials. And you already answered this question of the methodology, but I want to recap. You took basically patients included in randomized trials of therapeutics for COVID-19, various therapies for COVID-19, and you did a meta-analysis to see what were the incident rate of stroke as an outcome in these trials.

So, with that, could you please tell us a little more about the population that you had in this meta-analysis in terms of their age, the types of therapies that these randomized trials had looked at, and the duration of the follow-up, please?

Dr. George Ntaios:          The follow-up included 77 randomized trials, which corresponds to more than 38,000 COVID patients. The mean age of these patients was about 55 years of age, and they were followed for an average of 23 days after study enrollment. With regard to the set strategy, I think it was not strict at all. I would rather say it was very liberal. We allowed trials of any drug in COVID patients of any age, of any severity, coming from any setting: outpatient, inpatient, either general ward or intensive care unit. And from any country. I don't think that we could achieve a wider inclusion than this strategy did. And the huge majority of patients, more than 95%, they were hospitalized patients. So, by definition, they had severe COVID disease. And the drugs studied in these trials included everything that was actually tried in COVID, including tocilizumab, IL-6R inhibitors, steroids, remdesivir, chloroquine, azithromycin, ritonavir, interferon, ivermectin, and many other drugs. So, I think we tried to include as many trials as possible.

Dr. Negar Asdaghi:         OK. So, let me see if I got it. You basically included 77 randomized trials. It is a younger population of patients in these trials, median aged 55. You had a total of over 38,000 patients. It's a great sample size for this meta-analysis. And importantly, the duration of follow-up is median of 23 days. And it's just about any treatments we've heard that have been tried for COVID, from dexamethasone to remdesivir and ivermectin. And a rigorous methodology. So, I think we're ready to hear the primary results of this meta-analysis. How many strokes happened in these patients?

Dr. George Ntaios:          In the overall population, that is both in the hospital and in the outpatient setting, there were totally 65 strokes in these 38,000 COVID patients, which corresponds to one stroke every 600 COVID patients or else an incident of only 0.16%, 0.16%. This is very low, much lower than the previous estimates. And, of note, all strokes occurred in hospitalized patients. There were no strokes at all in the ambulatory COVID patients. So, just to repeat the result, we just found that only one patient will have a stroke every 600 COVID patients who are either hospitalized or are ambulatory.

Dr. Negar Asdaghi:         OK. So, I need to have these numbers, I think, committed to memory, especially when we speak to family members and patients in the hospital. Ninety-five percent of the patient population of this meta-analysis were inpatient COVID. So, by definition, they must be sicker in terms of the severity of their COVID disease. Out of 38,000 patients, you had 65 events of stroke. So, these are very, very important numbers, a lot basically lower than the incidence rate reported from prior studies. So, I wanted to ask you about the sensitivity analysis that was done in the meta-analysis.

Dr. George Ntaios:          Yes. When we designed the analysis, we were expecting that we would find numbers was similar to those reported before. So, we thought that perhaps a sensitivity analysis would be able to increase the confidence and the robustness of the results. That's why we did this sensitivity analysis. However, it proved that the number of strokes, the number of outcome events was much lower than what expected. So, the power for those sensitivity analysis to show a meaningful conclusion was low. So, actually, that's why we don't comment at all on those sensitivity analysis because there were so few strokes to support such an analysis.

Dr. Negar Asdaghi:         OK. So, basically, you had a priori design the meta-analysis based on the assumption that the incidence rate of stroke would be a lot higher, but then later on, when the incidence rates was lower, then the sensitivity analysis didn't really give any meaningful data to us. So, I mean, I think we already talked about this, but I want to ask you, why do you think that the incidence rates were so much lower in your analysis than the prior meta-analysis?

Dr. George Ntaios:          I believe that our estimate is quite accurate. I think that the reports of stroke incidence published during the pandemic possibly overestimated the association. I think that the early concern that we all had in the beginning, that we would be flooded with strokes during the pandemic, was not confirmed. I think that we can support with decent confidence that stroke is a rare or perhaps very rare complication of COVID.

Dr. Negar Asdaghi:         Right. That's great news. That really is great news, and we take every bit of good news in these trying times. George, something that was not touched on in the paper, but I want to ask you and basically get your opinion on this matter, is a much talked about concept in the COVID literature of how COVID could potentially modify certain risk factors. There are much talk about how people with pre-existing diabetes or obesity can potentially develop more severe COVID and, hence, have more complications of COVID, including stroke. What is your clinical experience on this matter, and do you think there are certain predictors of development of COVID-associated stroke?

Dr. George Ntaios:          That's a very good point. For the last two years, I was involved in the hospitalization management of COVID patients. So, what we see is what is also described in the literature, that there are certain patient characteristics that predispose them to severe COVID. For example, obesity, for example, older age, pregnancy. Perhaps our analysis was not designed to respond to this question. The data available on the studies that were included, they could not support such an analysis. So, I cannot provide information from our study. But the fact that all strokes in our study, they occurred in hospitalized patients and none of them occurred in ambulatory patients, confirms what is known, that those strokes occurred in patients who, by definition, they have severe COVID disease. So, they confirm this putative association that perhaps severe COVID is associated with stroke rather than just mild COVID.

Dr. Negar Asdaghi:         All right. Thank you. And I just want to end with this simple question that I get asked often, and I want to see how you respond to patients or their loved ones when you're asked this question: "Doctor, did COVID give me a stroke?" How should we answer that question?

Dr. George Ntaios:          Yes. As we discussed, I think that stroke is a rather rare or perhaps very rare complication of stroke and certainly less frequent than we initially thought. And in those stroke patients who had already other pathologies which can cause stroke, I would be rather reluctant to attribute it to COVID. I would be perhaps more willing to do so in younger patients, but again, only after exhaustively looking for another cause, like PFO, dissection, etc.

I mean, the concern is that if we as the treating stroke physicians assume that the stroke is caused by COVID, then we might discourage patients from doing the necessary diagnostic workup to find the actual cause of stroke. And if it happens, then perhaps an underlying pathology may be missed, which means that the patient will remain vulnerable to stroke recurrence. So, in general, I'm rather very reluctant to say that the stroke is caused by COVID unless a really thorough diagnostic workup shows nothing else at all.

Dr. Negar Asdaghi:         All right. Very important message now to all practicing clinicians is don't stop at COVID. Don't just say simply, "Oh, this is COVID. COVID gave you a stroke." Keep looking for potential causes of stroke. Still do put that patient in the category of potentially ESUS or cryptogenic stroke if no other causes are found. And keep in mind that stroke is rare or, as George said, a very rare complication of COVID. Dr. George Ntaios, this is an exceedingly timely topic and a very important contribution to the field. Congratulations again on your paper, and thanks for taking the time to chatting with us today.

Dr. George Ntaios:          Thank you for the wonderful discussion, Negar, and for the focus of our work.

Dr. Negar Asdaghi:         Thank you.

And this concludes our podcast for the November 2022 issue of Stroke. As always, please be sure to check out the table of contents for the full list of publications, as we can only cover a fraction of the incredible science published in this journal each month. And don't forget to check our fantastic Literature Synopsis. In this month's issue, we read a short summary of the ACST-2 trial published in Lancet on the results of a randomized comparison of stenting versus endarterectomy in asymptomatic carotid disease patients with over 60% of carotid stenosis.

We also have the results of the CASSISS randomized trial, which was published in JAMA earlier this year, and it studied the effect of stenting plus maximal medical therapy versus maximum medical therapy alone on the risk of subsequent stroke and death in patients with symptomatic intracranial stenosis, either in the anterior or in the posterior circulation. CASSISS did not show that stenting was superior to maximum medical therapy, and sadly, these patients remain at a substantial risk of recurrent stroke despite being on best medical therapy.

But I wouldn't be too despondent about the future of interventional therapy for intracranial atherosclerotic disease. After all, we've come a long way since Dr. Charles Thomas Stent, an English dentist, started experimenting with products to advance the field of denture making around 1865. The work that Dr. Stent had started would be continued by his two sons, both dentists, to eventually make its way to products to create surgical tools. But it would be another 100 years before the first percutaneous coronary procedure was completed in 1964. And in honor of Dr. Stent's pioneering work, the device used to keep the coronaries open was named, you guessed it, stents.

Today's stroke care cannot be imagined without the use of various stents, and there's no doubt the future is promising for ways in which we will be able to safely treat intracranial atherosclerotic disease amongst all other vascular disorders. And what better way to keep our enthusiasm than staying alert with Stroke Alert.

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 21 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the October 2022 issue of Stroke: “Oral Contraceptives, Hormone Replacement Therapy, and Stroke Risk” and “Effectiveness and Safety of Antithrombotic Medication in Patients With Atrial Fibrillation and Intracranial Hemorrhage.” She also interviews Dr. Shadi Yaghi about his article “Direct Oral Anticoagulants Versus Vitamin K Antagonists in Cerebral Venous Thrombosis.”

Dr. Negar Asdaghi:         Let's start with some questions.

1) Do hormone replacement therapies or oral contraceptives increase the risk of stroke? And if yes, does the age of the individual or the duration of therapy modify this risk?

2) Should survivors of intracranial hemorrhage who have atrial fibrillation be treated with antithrombotic therapies for secondary prevention of stroke?

3) And finally, what is the anticoagulant of choice for treatment of cerebral venous sinus thrombosis?

We have the answers and much more in today's podcast as we continue to bring you the latest in cerebrovascular disorders. You're listening to the Stroke Alert Podcast, and this is the best in Stroke. Stay with us.

Welcome back to another amazing issue of the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine, and your host for the monthly Stroke Alert Podcast. The October issue of Stroke covers a number of timely topics. As part of our October Literature Synopsis, we have a nice paper by Dr. Farida Sohrabji and colleague, which summarizes three recently published animal studies to evaluate the association between small vessel ischemic injury and either development of Parkinsonism or the future risk of Parkinson's disease. These studies looked at how ischemia, specifically involving the lenticulostriate arteries, can modulate the nigrostriatal dopaminergic pathway and ultimately lead to Parkinsonism.

As part of our Original Contributions, we have the results of a small randomized trial out of Korea, which was led by Dr. Yun-Hee Kim from Sungkyunkwan University School of Medicine in Seoul, where we learned that doing 20 sessions of transcranial direct current stimulation for about 30 minutes for each session at home can improve post-stroke cognition. This was found to be specifically effective in patients with post-stroke moderate cognitive decline. Now, transcranial current stimulation can be given using a handheld device at home, and if truly proven safe and efficacious in larger studies, can dramatically change the landscape of stroke recovery in cognitive rehabilitation.

I encourage you to review these articles in addition to listening to our podcast today. Later in the podcast, I have the great pleasure of interviewing Dr. Shadi Yaghi from Brown University. Shadi will walk us through a systematic review and meta-analysis of published studies to compare the safety and efficacy of direct oral anticoagulants to that of vitamin K antagonists in patients with cerebral venous sinus thrombosis. Our devoted Stroke Alert Podcast listeners recall that we did cover this topic in our March podcast when we reviewed the results of ACTION-CVT, a multicenter international study that was led by none other than Shadi himself. I'm delighted to have him as a guest on my podcast today to talk more about the seminal study and all things cerebral venous sinus thrombosis. But first, with these two articles.

Millions of women worldwide use exogenous hormones, most commonly in the form of oral contraceptives and hormone replacement therapies. Despite the many different formulations of these drugs that are now available on the market, the two therapies are similar in that both combined oral contraceptives and hormone replacement therapies, or HRTs, contain various dosage of estrogen and progestin. Now, the principal difference between them being that the hormone contents of oral contraceptives are at high enough dosage to prevent ovulation, whereas hormone replacement therapies are considered more physiological as their aim is to return post-menopausal hormone levels to what they were before menopause. Well, by now, you must wonder how is any of this even relevant to vascular neurology? Well, the answer lies in the close relationship between hormonal therapies and stroke. But before we get to that, we have to review a few things.

First of all, it's long been known that the endogenous estrogen has strong and protective effects on the arteries. It promotes vasodilation and cell survival of the endothelial layer. It increases the endothelial mitochondrial efficiency and stimulates angiogenesis. In other words, endogenous estrogen is good for vascular health. And in fact, that's why we think that premenopausal women, in general, are at a lower risk of stroke as compared to their age and vascular risk factors–matched male counterparts. And to make things even better for estrogen, there's enough evidence to suggest that exogenous estrogen also does all of these good things for the endothelium. So, why are we even talking about an increased risk of stroke associated with use of hormonal therapies? The problem is, we have to remember that exogenous estrogen also does other things. It can increase the blood concentration of procoagulants, which, in turn, can increase the risk of thromboembolism, especially venous thrombosis. But there's still a lot of unknown on this topic. For instance, the majority of the prior research on the topic involves postmenopausal women using hormonal therapies.

Some of that research has actually suggested that HRTs may be protective against vascular events, while others showed the opposite. Well, we know that a majority of oral contraceptive users are actually much younger and use these medications premenopausal. So, there seems to be a lot of gaps in our current knowledge on the simple question of whether or not oral contraceptives and hormonal replacement therapies do, in fact, increase the risk of stroke or not. In the current issue of the journal, a group of researchers led by Drs. Therese Johansson, Torgny Karlsson, and Åsa Johansson from the Department of Immunology, Genetics and Pathology at Uppsala University in Sweden set out to fill some of these gaps with their study titled, "Oral Contraceptives, Hormone Replacement Therapy, and Risk of Stroke," as part of a large UK Biobank population-based cohort.

Just a bit about the UK Biobank. This was a large population-based cohort from 2006 to 2010 that included over 500,000 residents of the United Kingdom between the ages of 37 and 73. Participants at the time of enrollment would have extensive information collected from them through questionnaires, interviews, health records, physical measures, as well as some imaging and biological samples. Data on each participant was collected from the time of their birth all the way to the day of assessment, which is interesting, because the day of assessment would then count as the end of the follow-up for each participant. Now, for the current study, they included over 250,000 women of White race in whom information required for the study on whether or not they use hormonal therapies, duration of treatment, age at the time of exposure was available. And just a quick comment about their methodology. They analyzed their cohort once for oral contraceptive use and once for HRT use and compared each group to a reference group of either women who never used their set therapy or the number of years they contributed to the study prior to initiating that set treatment.

So, for instance, if a person started using oral contraceptives at the age of 21, all of the years that she contributed to the study before that age would count as non-exposed user years and were included in the control cohort. So now, on to their findings. A total of 3007 stroke diagnosis of any type were identified prior to the initial visit to the assessment center, which, as we mentioned, was the end of the follow-up in the study. Of these, 578 were ischemic strokes, 177 intracerebral hemorrhage, and 478 were subarachnoid hemorrhages. But as expected for any large cohort, over half of total strokes were self-reported as stroke of any type and could not be classified into any of the above subtypes. Now, let's look at the effects of oral contraceptives on the outcome of stroke. Overall of the women included in the study, 81% were classified as oral contraceptive users, while 19% reported never having used oral contraceptives at any point during the study. On the association between oral contraceptive use and the risk of stroke, at first glance, things looked OK. The hazard rates of any stroke for any stroke subtypes were not different between women who had used oral contraceptives as compared to those in the reference group.

That's great news. But when they looked deeper, they realized that the odds of development of any stroke was actually quite high during the first year after the initiation of oral contraceptives with hazard rate of 2.49 for any stroke, while there was no difference in hazard rates found during the remaining years of use and after discontinuation of oral contraceptive use. So, meaning that there was no lingering effects of oral contraceptives on increased risk of stroke after the first year or after discontinuing the medication. Now, on to HRTs. In total, 37% of women in the study had initiated HRTs at some point during the study, while 63% had never used this therapy. Here's the bad news. Overall, HRTs did increase the risk of stroke. An approximately 20% increase event rate of any stroke was noted among women who had initiated HRTs as compared to those who had not. When analyzing stroke subtypes, the use of HRTs was associated with increased risk of only the subarachnoid hemorrhage subtypes. We don't know why.

Diving deeper, in considering timing of HRT initiation, very similar to what was observed for the oral contraceptives, during the first year after starting the HRTs, the treatment group was twice more likely to suffer from any type of stroke, and the hazard rate was also increased for all three stroke subtypes that were available in the study. But, unlike oral contraceptives, the hazard rate of any stroke remains significantly high even after the first year of use, not just for those who continued HRTs, but sadly, even for those who discontinued the therapy. Though the risk remained high, the hazard ratio declined over time as we went further away from the first year when treatment was initiated. So, bottom line, if women had initiated HRTs at some point in their life, the hazard risk of any stroke increased significantly in the first year. That hazard risk did decline over time, but it always remained significantly higher than non–HRT users.

Now, what about timing of treatment in relation to the onset of menopause? Is the risk of stroke any different if women start on HRTs prior to or after their menopause? The answer is no. Initiation of HRTs was associated with an increased hazard rate of any stroke if it was started pre- or postmenopausal, but the risks were higher if the treatment was started prior to menopause. So, in summary, this large population-based cohort has truly given us some very important practical findings. We learned that both oral contraceptives and hormone replacement therapies do, in fact, increase the risk of stroke, an effect that was most notable in this study in the first year after initiation of both of these therapies, and in the case of oral contraceptives, was just actually limited to that one year alone. Why does this happen? I guess the easy answer is that these drugs, as we noted earlier, have an immediate prothrombotic effect, which gradually weakens over time.

That's one plausible explanation, but for instance, why HRTs increase the risk of subarachnoid hemorrhage is something we can't explain based on the prothrombotic effects of HRTs. So, we have to come back to the vessels, the impact of hormone therapies and estrogen specifically on the blood vessels, on the endothelial cells, the potential increase in blood pressure, especially early on in the course of treatment with these medications. And also, we have to think about the role these drugs may play in increasing inflammatory markers, providing a more suitable milieu for accelerated atherosclerosis, as to why these associations were noted in this study. And it's fair to say that we need more research on this topic in the future.

One challenging scenario that we commonly face in our daily practice is deciding whether or not we should resume antithrombotics in patients with atrial fibrillation who have survived an intracranial hemorrhage. The majority of intracranial hemorrhage survivors with atrial fibrillation actually have a very high CHA2DS2-VASc score, which means that they are actually at a very high risk of future ischemic stroke and systemic embolic events unless they're treated with anticoagulants. On the other hand, the risk of spontaneous intracranial bleeding is substantially higher in a person who has previously suffered from one, let alone if we treat them with anticoagulants. And to make matters worse, we have little evidence from the literature to guide us. So, in the current issue of the journal, in the study titled "Effectiveness and Safety of Antithrombotic Medication in Patients With Atrial Fibrillation and Intracranial Hemorrhage," a group of researchers from the UK led by Dr. Deirdre Lane, Professor of Medicine at the University of Liverpool, performed a much needed systematic review and meta-analysis of the available evidence on this subject.

I have to say that lately, it seems that we've been covering a few of these reviews in our podcasts, and we are just getting started. In fact, my next paper in today's episode is also a systematic review and meta-analysis. These papers are packed with details, a testament to the work needed to complete them, but I have to say that even summarizing these papers for a podcast has been a bit challenging. So, feel free to put me on pause, go get some coffee, and let's power through this one together. For their methods, they used the usual search engines looking for papers that included adults over the age of 18 with atrial fibrillation who had survived a non-traumatic spontaneous intracranial hemorrhage of any size, any type, and any location, be it lobar, brain stem, deep, cerebellar, subdural, epidural, or subarachnoid hemorrhage.

And very importantly, they included even those with evidence of microbleeds on neuroimaging. The intervention of interest was either long-term oral anticoagulation or antiplatelet therapy versus no antithrombotic use for the following three outcomes of interest: number one, recurrent thromboembolic events; number two, recurrent intracranial hemorrhage; and number three, all-cause mortality. Just a quick note that for this analysis, they excluded studies that looked at either short-term anticoagulation or non-oral anticoagulation use for any reason that was given to the patient other than for secondary prevention of stroke. For example, if a patient suffered from a pulmonary embolism and was treated with IV heparin or, for a short period of time after that, with oral anticoagulation, those patients or those studies were excluded from this meta-analysis. So, with this criteria, they pulled over 4,000 citations and abstracts, and finally included 20 papers that were published between 2015 and 2021 for a total of over 50,000 participants for this meta-analysis, very nice sample size.

Most of the papers included were observational cohorts, but in addition, we had two small randomized trials, and I want to take a moment and review these trials for our listeners. The first one was a small noninferiority pilot trial out of the UK, the SoSTART trial, that looked at any anticoagulant versus either antiplatelet therapy or no antithrombotics in this population, and the other trial was the Phase 2 trial, the APACHE-AF, that studied apixaban versus no anticoagulation after anticoagulant-associated intracerebral hemorrhage. A reminder that both of these trials were published in Lancet Neurology in 2021. And before we move on to the findings of the meta-analysis, it's worth noting that they had included a mix of patients, some were oral anticoagulant–naive, and some had developed their index intracranial hemorrhage while already on treatment with anticoagulants or antiplatelet therapies. OK, now on to their findings, as mentioned, we're going to review three outcomes of recurrent thromboembolism, recurrent intracranial hemorrhage, and all-cause death for the following three groups: group one, oral anticoagulant therapy versus no therapy; group two, oral anticoagulation therapy versus either antiplatelet treatment or no therapy; group three, comparing new oral anticoagulants versus warfarin.

So, for the first outcome of recurrent thromboembolic events in group one, when comparing oral anticoagulant therapy to no therapy, the study showed a significant reduction in thromboembolic events in favor of oral anticoagulation compared to no therapy. That's great news. Next, analysis of the studies that compared oral anticoagulation versus either antiplatelets or no therapy didn't show the same difference in prevention of embolic events in favor of either groups. Actually, no difference was noted between the two groups. Number three, now, in terms of comparing NOACs to warfarin, three studies had the information on this comparison, and they reported a significant reduction in the risk of thromboembolic events with NOAC as compared to warfarin. So, great news for oral anticoagulation overall, and especially for NOACs.

Now, on the next outcome. Our second outcome was a recurrent intracranial hemorrhage. Keeping in mind that they included some studies where the outcome was defined as any form of intracranial hemorrhage, meaning they included subdurals, epidurals, etc., and some studies only included the outcome of intracerebral hemorrhage. So, on to the first group, comparing oral anticoagulants to no therapy, the pooled estimate revealed no statistically significant difference between oral anticoagulant–treated patients to those who were not treated with any antithrombotics on the risk of recurrent intracranial hemorrhage. That's great news. Next, on our second group, for the same outcome of recurrent intracranial hemorrhage, comparing oral anticoagulants to either antiplatelet therapy or no treatment, they found that oral anticoagulation was associated with a higher risk of recurrent intracranial hemorrhage as compared to antiplatelets or no therapy. And finally, third group comparing new oral anticoagulants to warfarin for the same outcome, the risk of recurrent intracranial hemorrhage was significantly reduced in patients treated with NOACs as compared to warfarin. And now, we're finally on to our last outcome of the study, which is the outcome of all-cause mortality.

So, again back to group one, comparing oral anticoagulants to no therapy, this meta-analysis showed a significant reduction in all-cause mortality rate associated with oral anticoagulation. That's, again, great news. Next group, for the same outcome of mortality, comparing oral anticoagulants to either antiplatelet therapy or no treatment, they found no significant difference in the mortality rates between the two groups. And finally, comparing NOACs to warfarin, the pooled estimate showed that NOACs were associated with a significantly reduced risk of all-cause mortality. Amazing news for NOACs.

So, in summary, here's what we learned from this big study. Oral anticoagulation use after intracranial hemorrhage in patients with atrial fibrillation did significantly reduce the risk of thromboembolic events and all-cause mortality without significantly increasing the risk of recurrent intracranial hemorrhage. In general, new oral anticoagulants, or NOACs, are preferred to warfarin as they do prevent embolic events with a lower risk of recurrent intracranial hemorrhage. But, of course, we still have a lot more questions. For instance, would any of the outcomes mentioned above be different in patients with lobar intracerebral hemorrhage, a condition typically associated with amyloid angiopathy, which carries a high risk of development of intracerebral hemorrhage? Also, we have to keep in mind that the majority of the studies included in the meta-analysis were observational. So, there remains an urgent need for a larger randomized trial on this subject, and we have to stay tuned for more research.

Cerebral venous sinus thrombosis, or CVST, is an uncommon form of stroke resulting in headaches, seizure, or focal neurological symptoms due to either intracranial hemorrhage or venous ischemic infarcts. The rarity of the disease has made it difficult to study as part of randomized trials, so current treatment guidelines for CVST are consensus-based with much of the recommendations extrapolated from data on treatment of patients with systemic deep vein thrombosis. In general, based on the current evidence, the field agrees that a patient with CVST should be anticoagulated. The decision that is difficult and sometimes inappropriately delayed in the setting of acute hemorrhage in the brain. And not surprisingly, there's significant equipoise around the choice of anticoagulant, duration of therapy, and the role of heroic therapies, especially in the acute setting. Currently, there are a number of ongoing trials to address some of these issues. The direct oral anticoagulants present an attractive alternative to vitamin K antagonists for treatment of patients with CVST. This is partly because of their convenience of use.

But how do direct anticoagulants compare in safety and efficacy to the vitamin K antagonists in the setting of CVST is less known. In our March podcast, we reviewed the results of ACTION-CVT, which was a multicenter international study that compared the safety and efficacy profile of the direct oral anticoagulants to that of warfarin in routine practice. The study included over a thousand imaging-confirmed CVST patients from multiple centers in the US, Italy, Switzerland, and New Zealand. And if you missed it, no worries at all. We're here to review some of the results again, as in this issue of the journal, many of the ACTION-CVT investigators, led by Dr. Shadi Yaghi, present the results of a systematic review and meta-analysis comparing the safety and efficacy of DOACs, or direct oral anticoagulants, to that of vitamin K antagonists. I'm joined today by Dr. Yaghi himself to discuss ACTION-CVT and the current meta-analysis. Dr. Yaghi is a Director of Vascular Neurology at Lifespan and Co-Director of Comprehensive Stroke Center and a Director of Research at the Neurovascular Center at Rhode Island Hospital. Good afternoon, Shadi, and welcome to our podcast.

Dr. Shadi Yaghi:               Good afternoon, Dr. Asdaghi. Thank you so much for having me.

Dr. Negar Asdaghi:         Thank you. And please call me Negar. Congrats on the paper. Before we talk about the meta-analysis, can you please remind us of the results of ACTION-CVT and why the systematic review, in your opinion, was an important next step to that effort?

Dr. Shadi Yaghi:               Thank you so much for having me and for bringing up ACTION-CVT. So ACTION-CVT is a real-world multicenter international study that used real-world observational data to compare the safety and efficacy of direct oral anticoagulants to vitamin K antagonists in patients with cerebral venous thrombosis. The reason why we did ACTION-CVT was, as you know, cerebral venous thrombosis is a rare disease, and it's hard to have large studies that would be powered enough to compare the safety and efficacy of direct oral anticoagulants to vitamin K antagonists. So, most of the studies that were done are small, retrospective. There's one randomized controlled trial, but most of them are underpowered to detect the difference between the two groups. So, we decided to do a large-scale international multicenter study using real-world data to compare the safety and efficacy of both.

Dr. Negar Asdaghi:         OK, so we're glad you did. Let's start with the methodology of the current meta-analysis. Can you please give us an overview of the inclusion criteria for selection of the papers and the intervention and outcomes that you were interested in?

Dr. Shadi Yaghi:               Of course. So, this is a systematic review and meta-analysis that included studies comparing direct oral anticoagulants to vitamin K antagonists in patients with cerebral venous thrombosis. The studies needed to have the two groups included, the direct oral anticoagulants and vitamin K antagonists, and they need to include at least one of the outcomes in our study to compare this outcome between the two groups. In addition, we included articles published in English, and we also included papers that had five patients or more in each group.

Dr. Negar Asdaghi:         Perfect. So just recap for our listeners, in order to have been included in the meta-analysis, the paper had to have a reasonable number of patients, and you put that reasonable at the number five, and also they had to have at least one of the outcomes of interest reported in their papers. And those outcomes were either recurrent venous thromboembolism or recanalization rates. Right?

Dr. Shadi Yaghi:               Correct. Yes.

Dr. Negar Asdaghi:         Perfect. So with that, how many papers did you have to go through to come up with the current number of papers included?

Dr. Shadi Yaghi:               That's a great question. We had a little over 10,000 papers, and then we went through a screening process. We used this tool that was developed by Brown University. It's called Abstrackr, and what you do is, we did the search and using several databases like PubMed, Cochrane, and then we included all these studies. We uploaded them in Abstrackr, and Abstrackr was utilized to be able to review all these abstracts and select studies that may or will probably qualify and then go through the studies and details that would qualify. So, we had about 10,000 studies with the initial search, and we had two reviewers go through each abstract, and from these 10,665, we excluded 10,411, and that left us with 254 studies. And then we went through these 254 studies in details. And then finally, we had 19 studies included that met our inclusion/exclusion criteria. And these 19 studies included three randomized control trials and 16 observational studies.

Dr. Negar Asdaghi:         Incredible effort. So, three randomized trials in this meta-analysis and 16 observational studies. I think we're very ready to hear the primary outcomes.

Dr. Shadi Yaghi:               Yeah, so, the primary outcomes were recurrent venous thrombosis, and that included recurrent venous thromboembolism like peripheral DVTs or PEs, for example, and including recurrent cerebral venous thrombosis. And we know that most of the events are recurrent VTEs, not CVTs, like probably about two-thirds to three-quarters were VTEs, and a third to a quarter were CVT. And then the other efficacy outcome is venous recanalization on follow-up imaging. And we found that direct oral anticoagulants and warfarin were not significantly different in the primary efficacy outcomes.

Dr. Negar Asdaghi:         Thank you. I just want to repeat this for our listeners. So, you mentioned some important information here. First one was the fact that about three-quarters of recurrent events were actually systemic thromboembolic events rather than cerebral thromboembolism. So, an important outcome to keep in mind for our practicing physicians. And the fact that DOACs did the same as compared to vitamin K antagonist. So, I think you can already guess my next question, and that is, was there any compromise on the safety profile when using DOACs as compared to vitamin K antagonists in this meta-analysis?

Dr. Shadi Yaghi:               Thank you. That's a great question. In ACTION-CVT, we found that there was a lower risk of major hemorrhage with direct oral anticoagulants compared to vitamin K antagonists. In this systematic review and meta-analysis, we didn't find a significant difference, but there were fewer events in patients treated with direct oral anticoagulants versus vitamin K antagonists. This did not reach statistical significance, but if you look at the raw data, it's kind of along the same lines as ACTION-CVT, so the risk of major hemorrhage was about 3.5% with warfarin, and that was about 2% with direct oral anticoagulants.

Dr. Negar Asdaghi:         So, again, very important finding, and I want to repeat this for our listeners. So, important finding number one was that there was a superiority in favor of DOACs that you found in terms of a reduced risk of intracerebral hemorrhage in ACTION-CVT. You didn't find this superiority in the meta-analysis, but there was sort of a hint to perhaps lower risk of intracerebral hemorrhage in patients that were treated with DOACs. Did I get that right?

Dr. Shadi Yaghi:               Yes, that is correct, and in addition, also major hemorrhage in general, and that included also ICH.

Dr. Negar Asdaghi:         Oh, OK, so not just intracranial, but systemic hemorrhages as well. All right. Very good. So, I think my next question would be, why do you think that DOACs have a lower chance of causing hemorrhage?

Dr. Shadi Yaghi:               Yeah, that's a really good question. This is not unexpected with DOACs as opposed to vitamin K antagonists. We saw these same trends in patients with atrial fibrillation. We saw improved bleeding profiles with direct oral anticoagulants as compared to vitamin K antagonists. And the risks were along the same lines that we found in patients with cerebral venous thrombosis in ACTION-CVT. Also in the VTE trials as well, there was also reduced bleeding complications with direct oral anticoagulants as compared to vitamin K antagonists. So, it was kind of reassuring to see the same results in patients with cerebral venous thrombosis.

Dr. Negar Asdaghi:         Perfect, so kind of expected based on what we know from treatment of systemic conditions with DOACs. The next question I have for you is that in routine practice, treatment of cerebral venous sinus thrombosis almost always starts parenterally with either unfractionated heparin or low molecular weight heparin and then we switch to an oral agent. In the observational studies, did you find any differences in terms of timing of this switch or characteristics of the patients in whom vitamin K antagonists were chosen over direct oral anticoagulants?

Dr. Shadi Yaghi:               Thank you very much. Most of the studies did not report these details. I think the one study, off the top of my head, that does report the differences in characteristics between the two groups is RESPECT-CVT. That's the randomized controlled trial comparing dabigatran to vitamin K antagonists. In this study, there was a treatment with parenteral anticoagulation for several days, I think seven to 14 days, prior to transitioning to oral anticoagulation. And this is generally my practice. I typically would treat patients with at least seven days or so parenteral anticoagulation, and once they're clinically stable, then I would transition them to oral anticoagulation, either vitamin K antagonists or direct oral anticoagulant.

Dr. Negar Asdaghi:         And I think my next question is along the lines of this question as well. We have several direct oral anticoagulants now available on the market. What was the most common DOACs used for treatment of CVST in these studies, and did you note a preference for the use of any particular agent over others?

Dr. Shadi Yaghi:               Thank you so much for the question. Anti-Xa inhibitors were much more common than dabigatran, and the anti-Xa inhibitors most commonly used were apixaban and rivaroxaban. It's in line with what we saw in ACTION-CVT as well, although most of the randomized controlled trials or the largest randomized controlled trial, RESPECT-CVT, used dabigatran, but overall people have been using anti-Xa inhibitors, more particularly apixaban, which was also in line with what we saw in ACTION-CVT.

Dr. Negar Asdaghi:         But I think it's fair to say that we don't really have data on superiority of one over others. Is that fair?

Dr. Shadi Yaghi:               Yes, that is correct.

Dr. Negar Asdaghi:         OK, and so now, where are we at in terms of the future of studies on this topic? We have one ongoing randomized trial now?

Dr. Shadi Yaghi:               Yes, we have one randomized controlled trial ongoing, and this is the SECRET trial, and it's looking at rivaroxaban versus vitamin K antagonists in patients with cerebral venous thrombosis. There's another study, it's a prospective observational study that's called the DOAC-CVT study. It's an international study also looking at real-world data prospectively to see if there's a difference in outcomes between the two groups.

Dr. Negar Asdaghi:         So, we look forward to the results of those studies. Shadi, a follow-up question I have on this topic is, how long should a duration of therapy be in idiopathic cases of cerebral venous sinus thrombosis?

Dr. Shadi Yaghi:               Thank you so much for this question. So, it's unknown at this point for how long should we treat. The key things from the treatment are first achieving venous recanalization, and second is preventing another venous thromboembolic event from happening. So, regarding the venous recanalization, studies have shown that there's not a lot of recanalization beyond four months of treatment. So, a lot of the recanalization really happens early, and continuing anticoagulation beyond the six-months interval, for example, in order to achieve further venous recanalization probably has limited utility. And the second important reason why we treat patients with anticoagulation is also to reduce the risk of a recurrent venous thromboembolic event or cerebral venous thrombosis.

And for that, if it's a provoked CVT, then I think usually it's three to six months. If it's unprovoked, up to maybe six to 12 months or even longer, depending on the profile. And if there's a persistent provoking factor, such as cancer, antiphospholipid antibody syndrome, then the treatment is lifelong or until this condition subsides. There's a lot of controversy about the duration of treatment. The European guidelines were very helpful in identifying the duration of treatment. Hopefully, also, we have some guidelines or at least a scientific statement by the AHA that also doles details out and provides some guidance to practitioners.

Dr. Negar Asdaghi:         Shadi, what should be our top two takeaways from the current meta-analysis and also ACTION-CVT?

Dr. Shadi Yaghi:               So, really, the top two from ACTION-CVT and the meta-analysis are, first is direct oral anticoagulants have a comparable efficacy to vitamin K antagonists in terms of recurrent venous thrombosis and achieving venous recanalization on follow-up imaging. And then the second point is direct oral anticoagulants are probably safer than vitamin K antagonists. We have to keep in mind that this data is based mostly on observational studies. And, as we mentioned earlier, we need more randomized controlled trials to support these findings.

Dr. Negar Asdaghi:         Dr. Shadi Yaghi, it was a pleasure interviewing you on the podcast. Thank you very much for joining us, and we look forward to having you back on the podcast and reviewing this topic again in the future.

Dr. Shadi Yaghi:               Thank you so much. I appreciate you having me.

Dr. Negar Asdaghi:         Thank you.

And this concludes our podcast for the October 2022 issue of Stroke Please be sure to check out this month's table of contents for the full list of publications, including an important update from the European Stroke Organisation by Prof. Martin Dichgans.

I also want to draw your attention to this month's InterSECT paper, which is our International Stroke Early Career and Training section, to discuss the key topic of burnout and mental health amongst physicians, especially amongst neurologists and stroke neurologists. It's alarming to read in this article that neurology is one of the specialties with the highest reported rates of burnout syndrome, and stroke neurologists are at particularly higher risk than other neurological subspecialties. The article tackles some tough subjects, such as the barriers for physicians to seek help and important strategies to mitigate burnout and how to improve mental health in general. I think it's also timely to know that October is the Mental Health Awareness Month, and the theme for October 2022 is "Back to Basics." The basics of recognizing the burden of stress, anxiety, the burden of isolation and depression, not only on those who we take care of, but also on those who give care to us.

So, whether you're a stroke physician, a stroke caregiver, or whether you've been touched by this disease in some way or shape, please know that you are part of the stroke community and a part of our Stroke podcast family. Thank you for listening to us, and, as always, stay alert with Stroke Alert.

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 20 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the September 2022 issue of Stroke: “Transdural Revascularization by Multiple Burrhole After Erythropoietin in Stroke Patients With Cerebral Hypoperfusion” and “Silent Infarcts, White Matter Integrity, and Oxygen Metabolic Stress in Young Adults With and Without Sickle Cell Trait.” She also interviews Dr. Timo Uphaus about his article “Revacept, an Inhibitor of Platelet Adhesion in Symptomatic Carotid Stenosis.”

Dr. Negar Asdaghi:         Let's start with some questions.

1) Can performing multiple burrholes improve misery perfusion in patients with moyamoya disease? And if yes, how do the results compare to that of a direct EC-IC bypass surgery?

2) The glycoprotein VI antagonist Revacept provides lesion-directed thromboinhibition at the site of atherosclerotic plaque rupture without causing systemic platelet inhibition. In other words, it works where it should work without causing the systemic side effects of antiplatelet therapies. Is Revacept the future of carotid-related stroke treatment?

3) And finally, how should we counsel the family members of a patient with sickle cell anemia who are found to have sickle trait carrier state? Is sickle cell trait a risk factor for development of ischemic stroke?

              We're back here with the Stroke Alert Podcast to answer these questions and cover the latest in Stroke because, without a doubt, this is the best in Stroke. Stay with us.

              Welcome back to another issue of the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine, and your host for the monthly Stroke Alert Podcast.

              For the September 2022 issue of Stroke, we have a number of articles that I'd like to highlight. As part of our International Stroke Early Career and Training section, or the InterSECT series, we have an important article by Drs. Kathryn Hayward and Aaron Davis to discuss the importance of science visualization as a simple, but not a simplistic way to improve scientific communications with the public.

              The authors stress that the ability to communicate complex scientific information in an easily understandable format to those unfamiliar with the subject is not an obligation on the part of the scientists, rather, an opportunity for the scientific community to elevate knowledge translation for all.

              In a separate article in this issue of the journal, we learned that the presence of early venous filling, or EVF, post-endovascular thrombectomy, defined as presence of contrast opacification of any cerebral vein before the late arterial phase, is an important angiographic marker that has been associated with an increased risk of post-reperfusion hemorrhage and worse clinical outcomes.

              In an original contribution, Dr. Wagih Ben Hassen from the Department of Neuroradiology at Université de Paris and colleagues looked at the predictive ability of TAGE score to determine the odds of development of symptomatic intracerebral hemorrhage after thrombectomy. TAGE score, "T "for time from onset to successful recanalization of over 270 minutes, "A" for ASPECTS score either equal or less than five or ASPECTS of six to seven, "G" for blood glucose level of higher than seven millimole per liter, and "E" for EVF, or presence of early venous filling.

              The authors found that presence of each of these variables within the TAGE score were independently associated with increased odds of post-thrombectomy symptomatic intracerebral hemorrhage, and together, a higher TAGE score had a great prognostic value in predicting development of reperfusion hemorrhage.

              I encourage you to review these articles in detail in addition to listening to our podcast today. Later in the podcast, I have the great pleasure of interviewing Dr. Timo Uphaus from Johannes Gutenberg University in Mainz, Germany, on the results of a phase II clinical trial of symptomatic carotid stenosis patients treated with a novel glycoprotein VI inhibitor, Revacept. But first, with these two articles.

              Bypass surgery is often performed for treatment of cerebral hypoperfusion, typically in the setting of chronic cerebral arteriopathies, such as moyamoya disease, moyamoya syndrome, or non-moyamoya steno-occlusive disorders causing perfusion-dependent ischemia.

              In the adult population, the direct extracranial to intracranial bypass surgery, also referred to as EC-IC bypass, is the preferred procedure to improve cerebral perfusion as compared to all other currently performed indirect procedures.

              This is for many reasons, but one being that direct bypass can immediately improve cerebral blood flow, whereas the indirect methods rely on gradual collateralization and new angiogenesis, a process that's not only slow, but especially in the adult population, is often suboptimal, even if we can wait.

              On the other hand, a direct EC-IC bypass requires subspecialized surgical expertise in tertiary levels of stroke, neurosurgical, and neurointensive care, and the procedure could be challenging, especially if it's done in the setting of acute stroke where the patient is neurologically unstable.

              Cranial multiple burrhole surgery is a minimally invasive procedure that was actually incidentally discovered to improve transcranial angiogenesis in moyamoya disease.

              In 1984, a group of investigators from Japan reported their findings on a pediatric moyamoya case that had bilateral frontal burrholes for a completely different indication, which was drainage of an intraventricular hemorrhage, and three months later, unexpectedly, was found to have marked neurovascularization via the burrholes on the follow-up angiogram. Further experience over the next 30 years, mostly in children, would show that multiple burrholes truly have the potential to provide vascular ingrowth over the entire brain convexity in the ipsilateral hemisphere.

              Now, how does this even work? Well, performing burrholes can simply break the barrier, so to speak, between the intracranial space, where there is misery perfusion for whatever the etiology, be Moyamoya or atherosclerotic disease, and the extracranial vascular system that's already overactivated in this setting, and breaking the barrier and disruption of the meninges can stimulate transdural collateralization. But we have to keep in mind that this is not a secure and robust transdural anastomosis that, for example, a direct bypass provides.

              So, what do we know about the safety and efficacy of multiple burrhole surgery in the adult population? In this issue of the journal, Dr. Ji Man Hong from the Department of Neurology, School of Medicine, in Ajou University in South Korea and colleagues studied whether performing multiple burrholes, combined with high-dose systemic erythropoietin that's also known to enhance the angiogenetic potential of endothelial cells, improves cerebral perfusion in adult patients with perfusion-dependent acute ischemic stroke.

              So, let's look at their study. This was a single-center, prospective, randomized trial, which included 42 patients enrolled within two weeks from their acute ischemic stroke from an intracranial steno-occlusive disorder causing hypoperfusion. The median age of patients was 55 years of age, and median NIH Stroke Scale was under five at presentation. So, this is truly an adult population, obviously, median age was over 50, and a mild stroke population as expected for a bypass cohort. 26% of their cohort had a diagnosis of moyamoya disease, and over 70% had other steno-occlusive disorders, most likely occlusions related to atherosclerosis, although this we cannot know for sure because the exact etiology was not specified in the paper.

              Patients were randomized one-to-one to either receive multiple burrholes alone over the area of hemodynamic insufficiency under local anesthesia, or in combination with high-dose systemic erythropoietin, which was administered intravenously at 33,000 units per day for a total of a hundred thousand units administered over three consecutive days. So, everybody got surgery. The treatment group also got erythropoietin, and the control did not receive that. The two groups of patients were similar with regards to demographics, risk factors, stroke severity, and baseline perfusion parameters, and all received comparable stroke care. The primary outcome of the study was the rate of successful revascularization, which was determined on follow-up angiogram at six months.

              So, now, on to their findings. So, number one, on their follow-up angio at six months, the combined multiple burrhole and erythropoietin patients had a higher percentage of successful hemispheric and trans-burrhole revascularization rates as compared to those who just had received multiple burrholes. But we have to note that when we look at the details, the rate of excellent revascularization that was defined as improved angiographic reperfusion in greater than 66% of the affected area was only achieved in a third of patients, and only in 23% of multiple burrholes cases alone. Close to half of patients who received both multiple burrholes and erythropoietin had either poor or fair revascularization, which was defined as improvement in angiographic perfusion in less than 33% of the affected area. So, obviously, these are important numbers and percentages to keep in mind as we try to understand the results of the study.

              Next finding: In terms of perfusion imaging outcomes, the perfusion parameters were only available in half of their study population. On six months follow-up, the combined group had significant improvement in time-based perfusion parameters in the ipsilateral hemisphere. So, that included improvement in the mean transit time and time-to-peak maps, but not in the cerebral blood flow and cerebral blood volume maps.

              Next, in terms of adverse events, there were no significant differences between the two groups in terms of risk of hemorrhage or infarct recurrence and other adverse events. However, in general, a number of important complications were noted in their study, including procedure-related brain hemorrhage in 14% of patients in the combined group and 14% systemic complications in the erythropoietin treated group, which again deserves further assessment.

              And finally, I think one of the most important findings of the study was to evaluate serological biomarkers of angiogenesis, including matrix metalloproteinases 2 and 9, vascular endothelial growth factor, granulocyte colony stimulating factor, and interleukin 6. They compared these biomarkers at baseline and then remeasured them again at six months, and the most important finding was that the levels of MMP-9 were significantly increased in patients in whom successful revascularization was achieved, whereas these levels were similar at baseline if we went back and retrospectively divided the group into two groups of patients who would or would not receive successful revascularization at six months. MMP-9 is an important angiographic factor, but whether it can be used as a serological marker of complete revascularization remains to be seen.

              So, in summary, what we learned from the study is that the combination of multiple burrholes and erythropoietin therapy is potentially efficacious and possibly safe, though both of these outcomes need further confirmation in larger studies for patients with moyamoya disease and other steno-occlusive disorders causing perfusion dependence. And, in general, it's fair to say that combined approaches in revascularization therapies, be using two indirect approaches, such as the method we just reviewed today, or perhaps combining direct bypass with an indirect approach, may improve the overall revascularization success in this population and may be the way to move forward in the future.

              Sickle cell disease refers to an inherited group of hemoglobin disorders characterized by the presence of hemoglobin S either from homozygosity for the sickle mutation resulting in hemoglobin SS or compound heterozygosity with another beta-globin variant, for example, sickle beta thalassemia or hemoglobin SC disease. Now, as we know, even though this is a genetic hemoglobin problem, sickle cell disease creates a multi-system condition, and it's a major risk factor for stroke, with vaso-occlusive events accounting for much of its morbidity and mortality. Now, the question is, if sickle cell disease is a major risk factor for stroke, how about the much more common sickle cell trait carrier state? Sickle cell trait is about 20 times more common than sickle cell disease, is generally considered a benign condition, but some clinical events such as exercise-related injury, renal complications, and venous thromboembolism have been reported to occur more commonly in sickle trait carriers.

              If sickle trait is, in fact, a risk factor for ischemia, then it's conceivable that there would be similar, but perhaps to a milder extent, neuroimaging findings of sickle cell disease in individuals with this carrier state. In this issue of the journal, in the study titled "Silent Infarcts, White Matter Integrity, and Oxygen Metabolic Stress in Young Adults With and Without Sickle Cell Trait," Drs. Yan Wang and Andria Ford from the Department of Neurology at Washington University School of Medicine and colleagues report on the results of a prospective multimodal MRI study to measure various cerebrovascular structures, hemodynamic, metabolic functions, and silent infarct burden in young adults with and without sickle cell trait.

              So, the cohort composed of 49 healthy young adults without any known risk factors with either hemoglobin AA, which composed their control group with a total of 24 participants, or hemoglobin AS, which gave them their sickle trait cohort with 25 participants. The median age of their participants was 33 years of age, and the groups were matched in regards to age, sex, demographics, and baseline laboratory values, with the exception that the sickle trait group had a higher methemoglobin levels and creatinine concentration as compared to controls. All participants underwent various MR imaging, including ASL perfusion imaging with volumetric analysis and diffusion tensor imaging, and then they compared various values between control and sickle trait group.

              Now, let's look at their findings. Number one, as compared to control, participants with the carrier state had similar normalized whole brain gray and white matter volumes. What does normalized volume mean? Well, volume normalization is done in volumetric analysis to adjust for differences in the head size between different participants. So, so far, so good. No differences in size of white or gray matter in those patients who are sickle cell trait carriers.

              Next finding, using diffusion tensor imaging, they measured fractional anisotropy and mean diffusivity values for white matter tracts in both groups. Now, we've covered the meanings of fractional anisotropy and mean diffusivity in our podcast a number of times, but just a quick reminder. In general, when we have a structurally organized tissue, such as white matter tracts, the diffusion of hydrogen molecules is unidirectional in these tracts and, therefore, restricted in all other directions as white matter tract is intending to do so.

              Now, if we have a disruption to these tracts, for whatever the etiology, we can simply think of this disruption, allowing hydrogen molecules to now freely diffuse in various directions. And this would result in an increase in mean diffusivity values that is determined by diffusion tensor imaging, and a decrease in fractional anisotropy values. And I really want to stress that this is a very simplified formula to understand the values of FA and mean diffusivity for just the white matter tracts. But the damages to the gray matter actually creates differences in FA and mean diffusivity that are a bit different than what I just mentioned for the white matter tracts. Now, we have to keep this in mind if we're reviewing articles that deal with damages to other structures in the brain than the white matter tracts. Now, coming back to our study, for this study, comparing the FA and mean diffusivity values for the white matter tracts, it turns out that these values were similar between those with sickle trait and controlled individuals. So, also good news.

              Next, they examined regional white or gray matter or whole brain cerebral blood flow, oxygen extraction fraction, and cerebral metabolic oxygen demand, and similarly found no differences between control and healthy sickle trait carrier adults.

              Next finding, in terms of intracranial vascular imaging, there were two asymptomatic aneurysms found in this study, one in each cohort, and they found no differences in the two groups in terms of the prevalence of significant cerebral vasculopathy, which means equal or greater than 50% intracranial stenosis in either groups. So, also very, very good news so far.

              Finally, eight people in the control group and 11 people in the carrier group had evidence of silent cerebral ischemia. That is a high percentage. That means that the prevalence of silent ischemia was 33% in the control group versus 44% in the sickle trait group.

              This was not statistically different. It's interesting that the authors mentioned that the prevalence of silent ischemia was low, but I think it's actually alarming if we have a cohort of patients with a median age of 33 and found that one in three of them actually have evidence of silent ischemia on neuroimaging. But the good news is that the volumes of these lesions were exceedingly small, under 0.2 mL on volumetric analysis, and not different in size between the two groups. But when they did the analysis restricted to those who had silent ischemia, it turns out that these silent, incidentally found ischemic lesions were ever so slightly larger in those with sickle trait, as compared to the control cohort. The median volume of incidental silent ischemic lesions was 0.29 mL in sickle trait individuals as compared to 0.07 mL in control. So, very small differences, which may or may not become meaningful in larger cohorts.

              So, in summary, based on the best neuroimaging capabilities we have to date, we can conclude that unlike sickle cell disease, individuals with sickle trait do not seem to be at an accelerated risk of neurological injury if they are otherwise healthy. But we also have to keep in mind that somehow those incidental cerebral ischemic lesions were ever so slightly bigger in individuals with sickle trait than their control counterparts. And this finding also reminds us of other studies in the literature to suggest that sickle trait may not be a direct risk factor for ischemic stroke, but may be a modifier for increased ischemic risk. For example, in patients with diabetes, those with sickle trait have been found to be at a higher risk of ischemic events, or in the elderly population, individuals with APOE4 genotype have been shown to experience greater cognitive decline if they have sickle trait as compared to their age-matched individuals with the same genotype.

              So, the take-home message is that sickle trait is a benign condition, but may be a modifier of brain injury if it's combined with something else or other risk factors. So, it's safe to say that, as always, prevention and treatment of these risk factors are paramount in all, but especially in sickle carrier individuals, to maintain brain health.

              It's long been known that patients with carotid disease are at increased risk of first and recurrent ischemic events. The risk of carotid-associated ischemic stroke in each patient is dependent on a number of factors and traditionally predicted by two important pieces of information. Number one, the actual degree of carotid stenosis, and number two, whether or not that carotid artery has already caused an ischemic event, rendering them the designation of symptomatic as opposed to asymptomatic carotid disease. We've also known for some time now that in patients with symptomatic disease, the risk of recurrent stroke is up front. It's quite high, especially in the first two weeks after the index event. More recently, we've learned that there are other factors over and above the absolute degree of carotid stenosis that we should be paying attention to. Features such as plaque morphology, complex plaques with calcified segments of type of soft plaques, and the presence of intraluminal thrombi have all been associated with plaque instability. In these unstable or so-called "hot plaques," further embolization is thought to occur due to activation of circulating platelets by exposed collagen at the site of ruptured plaques.

              The presence of microembolic signals, as detected by transcranial Doppler studies, can assist with identifying these active plaques. What is the best antithrombotic regimen in the very hyperacute stage after presentation with acute ischemic stroke? Some of these decisions will depend on the type of presenting symptoms and whether the patient had received acute reperfusion therapies or not, but in routine practice, some patients are treated with dual antiplatelet therapy. Some are on monotherapy alone, especially if there are plans for endarterectomy, and this, in part, is influenced by the surgeon's practice patterns and so on. And some patients are actually treated with anticoagulation either alone or in combination with concurrent antiplatelet therapies. And, of course, we also have the intravenously administered options, the glycoprotein IIb/IIIa inhibitors and the glycoprotein VI antagonists, with growing potentials for usage in the acute setting of ischemic stroke, which are likely more and more to be used in the hyperacute stage of stroke.

              In this issue of the journal, in the study titled "Revacept, an Inhibitor of Platelet Adhesion in Symptomatic Carotid Stenosis," we learn about the role of Revacept, a glycoprotein VI antagonist, in patients with symptomatic carotid disease as part of a multicenter phase II randomized trial. I'm joined today by the first author of this randomized study, Dr. Timo Uphaus, all the way from Germany to learn about this newer class of antithrombotic agents and discuss the results of the trial. Dr. Uphaus is an Assistant Professor of Translational Neurology at the Johannes Gutenberg University in Mainz. He's one of the principal investigators of the Revacept randomized trial and is involved in multiple ongoing studies, including the prospective multi-centered German Stroke Registry to evaluate the safety and efficacy of endovascular thrombectomy in clinical practice and the prospective Gutenberg Stroke Study to evaluate biomarkers in patients undergoing endovascular therapy. Welcome to our podcast, Timo. Thank you so much for joining us.

Dr. Timo Uphaus:            Great to be with you. Thanks for the invitation.

Dr. Negar Asdaghi:         So, we'd like to learn more about Revacept first. How's this agent different from our usual antiplatelet agents?

Dr. Timo Uphaus:            Oh, the mechanism of action of Revacept is quite unique, as you already mentioned. In contrast to available agents mediating inhibition of platelet activation in the whole circulation, Revacept is solely inhibiting platelet function really at the site of the plaque rupture. And this is achieved by shielding the exposed collagen after plaque rupture to the bloodstream so that platelets aren't able to be activated at this subendothelial exposed collagen.

              And to really go in more mechanistic detail, Revacept is a fragment crystallizable region, also called FC fragment, fused to the glycoprotein VI, short GPVI receptor, which is an endogenous platelet collagen receptor. And this construct binds to the exposed collagen of unstable carotid plaque and acts as a physical barrier, reducing platelet activation, subsequent platelet binding, and aggregation on the carotid plaque. And this collagen-dependent, really, site-specific inhibition of platelet function might be as effective as available agents without side effects due to impairment of systemic platelet function, such as intracerebral hemorrhage. Concerning the administration route, Revacept is administered as an intravenous infusion of about 20 minutes, and, to go in more pharmacological details, Revacept exhibits a half-life of seven to 14 days and can also be administered several times in a row.

Dr. Negar Asdaghi:         So, Timo, that's a lot of information, and I'm going to try to summarize it for our listeners. This is a very interesting drug as it works differently than our usual antithrombotics. It's a site-specific antiplatelet agent. So, as you mentioned, it is administered intravenously, but even though it's systemically administered, it goes right where the action is, to the so-called unstable plaque, and prevents the adhesion of platelets to the underlying exposed collagen. So, now, this agent is a newer therapy for us in the field of stroke, but it's not so new for cardiologists. Can you please briefly tell us about the cardiac literature and the current applications of Revacept in patients with, say, acute myocardial infarction or coronary artery disease?

Dr. Timo Uphaus:            Well, we all know and experience that coronary and also carotid artery disease are commonly also linked in patients and can also occur simultaneously. And concerning the cardiac literature on Revacept, collagen-dependent platelet inhibition was recently also evaluated in patients with stable coronary artery disease undergoing elective PCI in the ISAR-PLASTER trial. And this was a phase II randomized clinical trial, including more than 300 patients who were allocated to receive either placebo or Revacept. And at the end, Revacept failed to show efficacy for the primary endpoint, which was a composite of death and also myocardial injury. Nonetheless, and this is an important point to mention, is that there were only few bleeding events within this trial and that there were no signs for increased bleeding rates after treatment with Revacept, which is always an issue when you're evaluating a new thrombocyte inhibition.

Dr. Negar Asdaghi:         So, just to recap, this agent has been recently studied and as part of a randomized trial in patients undergoing PCI with active coronary disease, and even though the primary results of the ISAR-PLASTER trial was neutral in terms of efficacy, did show us a signal towards safety in terms of bleeding, which is important. So, there seems to be a lot of action happening in the cardiology world. Now, moving from heart to brain, what did we know about the efficacy of Revacept in stroke prior to the current trial?

Dr. Timo Uphaus:            So, Revacept was really intensively studied in preclinical animal models, and these are also the basis for this trial now, phase II. And just to give you an example, what was studied in animal models so far, in animal model of a vascular atherosclerosis, Revacept dose twice weekly, over four weeks, was able to improve endothelial dysfunction and also vascular morphology on histology analyses. And importantly, within this study, no influence of Revacept on bleeding time alone, or also in combination with various antiplatelet drugs, could be observed. And another example is a study which made use of middle cerebral artery occlusion, and within this model, treatment with Revacept improved functional outcome, cerebral infarct size, and also edema formation compared to vehicle treatment. And Revacept also showed an effect on immune cell infiltration, which was demonstrated by reduced infiltration of macrophages within the CNS.

Dr. Negar Asdaghi:         So, just to recap, there seems to be a lot of positive signal for efficacy of Revacept in patients with an active plaque rupture, whether from the coronary literature or the preclinical studies in stroke, which brings us nicely now to your current study. Please tell us what kinds of patients were included in your trial and the inclusion criteria.

Dr. Timo Uphaus:            So, the Revacept/CS/02 study is, as we already mentioned, the first randomized trial examining GPVI inhibition in patients with stroke or symptomatic carotid artery disease as we did. And it is an international, randomized, placebo-control, double-blind, exploratory phase II study with three arm randomization and the treatment groups were placebo, 40 milligram Revacept, and also 120 milligram Revacept. So, we examined two treatment dosages. And who was enrolled in the study, in brief? 148 patients with recent symptomatic carotid artery disease were randomized to receive either high or low dose Revacept or placebo before they underwent then afterwards treatment of this ICA stenosis. It is important to mention that patient characteristics were balanced between these three treatment groups, and also that the treatment regimen was at the discretion of the treating physician, meaning the treatment regimen of the ICA stenosis, which could have been carotid endarterectomy, carotid angioplasty and stenting, and also best medical treatment.

              And moving on to inclusion criteria, the initial symptoms qualifying for symptomatic carotid artery disease had to be within the last 30 days prior to screening. And the grading of the ICA stenosis had to be at least 50% according to ECST criteria. And what is some of our pitfall of the study is that the initial study design only included those patients presenting with detection of microembolic signals, which were detected by transcranial Doppler examination at the screening examination. But due to the low percentage of patients who presented with MES at screening, this protocol had to be changed, and all patients in whom transcranial Doppler was possible were then, after this protocol changed, eligible for participation within the study.

              And what is the consequence of this protocol change? Well, that the primary efficacy endpoint of the study, which was reduction of microembolic signals after treatment, was no longer accessible, so that it was somehow switched to a number of new ischemic lesions on diffusion-weighted imaging and, therefore, the number of new DWI lesions detectable on MRI performed after the revascularization procedure compared to the MRI at screening served as new, now exploratory efficacy endpoint. And last, with regard to exclusion criteria, patients under dual antiplatelets or anticoagulation, or who received intravenous thrombolysis within the last 48 hours before screening, were eligible.

Dr. Negar Asdaghi:         Okay. So, a lot of information again, so I'm going to try to recap it. And also some changes that had to be done during the trial administration, as is always the case for practical reasons. So, we have a trial of symptomatic carotid artery patients. Symptomatic carotid artery defined as percentage of stenosis over 50% in patients that had a relevant TIA or stroke in the past 30 days prior to enrollment, where patients were enrolled into three arms of either placebo or receiving 40 milligram or 120 milligram of Revacept over 20 minutes infusion. And, as you mentioned, just a note that initially the trial only enrolled patients that had a positive microembolic signal as detected by transcranial Doppler, but over the course of the randomization in the trial, this was changed to anyone that had a TCD emboli detection studied prior to randomization. So, with that, I think we're ready to hear about the primary outcomes of the study.

Dr. Timo Uphaus:            Concerning this new exploratory efficacy end point, we were able to report a numerical reduction of new diffusion-weighted imaging lesions after treatment with 120 milligram Revacept. This effect was found to be significant within the main statistical analysis, which was a Poisson regression, but was not validated by respective sensitivity analysis, so that these findings at the end needs to be judged with caution. Nonetheless, we see a clear trend that number of new diffusion-weighted imaging lesions is decreased after treatment with 120 milligram Revacept.

              And concerning clinical outcomes, we assessed the combined safety and efficacy endpoint, which includes occurrence of ischemic stroke, transient ischemic attack, hemorrhagic stroke, as well as myocardial infarction or necessary coronary intervention deaths and any bleeding complications. And for this combined safety and efficacy endpoint, we observed a 45% risk reduction of the treatment with 120 milligram Revacept compared to placebo treatment over the course of the study. And with a 66% risk reduction, this effect was even more pronounced than the subgroup of patients with more than 70% ICA stenosis.

Dr. Negar Asdaghi:         All right. So, just to summarize, on the outcome of reduction of DWI positive lesions, there was a numeric reduction of the number of positive DWI lesions in patients that were enrolled to a higher dose of Revacept. That was not statistically significant in the Poisson regression analysis that you mentioned in the paper. So, this numeric reduction should be judged and needs to be further reevaluated in future studies, but obviously a very positive signal towards efficacy for Revacept. And the high dose Revacept seemed to reduce the combined primary safety and efficacy end points of the study, and that needs statistical analysis. So, very, very, very positive results. If I should say one more time, a very positive results for high dose Revacept in this study.

              So, now, moving on, you have discussed a number of subgroup analyses that were pre-specified in the trial. Can you please briefly tell us what we learned from the subgroup analysis? I guess you already alluded to it, over 70% stenosis carotid disease, but I'll let you take away the question.

Dr. Timo Uphaus:            Yeah, for sure. So, as you already mentioned, we analyzed subgroups, such as degree of ICA stenosis, prior statin treatment, and also different carotid interventions. And with regard to new diffusion-weighted imaging lesions on follow-up MRI, there were no effect of subgroups on the percentage of patients who suffered from new DWI lesions. However, the combined clinical safety and efficacy end point showed fewer outcome events after treatment with 120 milligram Revacept in the following subgroups: first, degree of ICA stenosis above 70%; second, patients with prior statin therapy; and last, but not least, patients undergoing carotid endarterectomy.

Dr. Negar Asdaghi:         So, again, a lot of signal for efficacy of high dose Revacept in these subgroup analyses, specifically for those with a higher grade of stenosis, which are truly the subgroup of patients with carotid disease that are at higher risk of imminent recurrent ischemic events, so, those people at a lower combined safety and efficacy end point, so combined risk of TIA, stroke, hemorrhagic events, as you mentioned. And also there seems to be an improvement or reduction in the total primary outcomes in patients that had plans for endarterectomy. And the way I read it was perhaps that in routine practice, these patients were less likely to be aggressively treated with, for instance, dual antiplatelet therapy, so they really needed that additional push to try to prevent the number of recurrent events until such time that they get their surgical treatment. So, I think we are going to see a lot more in the future on studies of these particular subgroups of patients. Now, just to end the interview, we have two more questions for you, Timo. What should be our top two take-away messages from your study?

Dr. Timo Uphaus:            So, I would say, take-home messages are, first, collagen-specific inhibition of GPVI through Revacept in patients with recently symptomatic carotid artery disease, in addition to standard of care medical treatment, is safe without any signs of increased bleeding rates. And second, Revacept showed a trend towards reduction of new ischemic lesions on diffusion-weighted MRI imaging, and altogether, I guess this paves the way for future phase III trials, not only in carotid artery disease, but probably in diseases with underlying rupture plaque embolization pathologies. And maybe I, at the end, I would add that change your primary efficacy endpoint wisely when you're studying a randomized trial.

Dr. Negar Asdaghi:         Right? So, a lot of important comments that you made. Very important comment on the site-specific therapies. We are used to giving drugs either intravenously or orally that affects just about everything systemically, has a systemic effect. And many of the adverse events of the drugs that we currently administer are because of those systemic side effects. Here, we have a new therapy that is very site-specific, so it goes right where the problem is. And I think the future of medicine, in general, will be the usage of therapies with such site-specific properties. So, more of that in the future, I'm sure. And you already answered the next question, which was whether there will be a phase III trial for Revacept. So, we look forward to the results of that future randomized trial. So, with that, Dr. Timo Uphaus, it was a pleasure interviewing you on the podcast today.

Dr. Timo Uphaus:            Thanks again for the invitation. It's been great talking to you.

Dr. Negar Asdaghi:         Thank you.

              And this concludes our podcast for the September 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including our Literature Synopsis on the latest developments in reperfusion therapies, covering the results of the newly published AcT randomized trial with a head-to-head comparison of tenecteplase to alteplase in treatment of patients with acute ischemic stroke, to the results of the CHOICE trial on the effects of intra-arterial alteplase following successful thrombectomy. The synopsis is sure a great way to keep updated on the latest in the field.

              And now, to end this podcast, I'd like to remind us that September 8 is the International Day of Literacy. Even today, though hard to believe, it's estimated that there are more than 750 million adults around the world who cannot read. Let's think about it for a second. Illiteracy impacts all aspects of life, but especially an individual's health. Studies have shown that people with inadequate literacy have less health-related knowledge, receive less preventative care, have poorer control of their chronic illnesses, and are hospitalized more frequently than others.

              But most may not know that illiteracy can also be acquired. How can we lose our ability to read and write? This concept is, of course, far too familiar for stroke neurologists, as a variety of stroke syndromes can cause alexia with agraphia, the very literal acquired illiteracy. So, as the world of education gathers on September 8 to celebrate the basic human right to literacy, in the world of vascular neurology, we celebrate stroke prevention and the right to keep our ability to read and write. And, of course, there's no better way to do so than staying alert with Stroke Alert.

              This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 19 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the August 2022 issue of Stroke: “Direct to Angiosuite Versus Conventional Imaging in Suspected Large Vessel Occlusion” and “Recurrent Ischemic Stroke and Bleeding in Patients With AF Who Suffered an Acute Stroke While on Treatment With NOACs.” She also interviews Dr. Alexander Nave about “Combined Oral Triglyceride and Glucose Tolerance Test After Acute Ischemic Stroke to Predict Recurrent Vascular Events.”

Dr. Negar Asdaghi:         Let's start with a few questions.

1) How much time do we actually save if we were to transfer all patients with suspected target vessel occlusion directly to the angiosuite and practically bypassing our current conventional imaging model?

2) What is the impact of an impaired metabolic state as measured by abnormal glucose and triglyceride tolerance tests on the risk of stroke recurrence in patients with ischemic stroke?

3) And finally, should we or should we not change the anticoagulant therapy of a patient with atrial fibrillation who suffered an ischemic stroke despite appropriate treatment with anticoagulation?

We have the answers to these questions and much more in today's podcast because this is the best in Stroke. Stay with us.

Dr. Negar Asdaghi:         Welcome back to another issue of the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The August 2022 issue of Stroke contains a range of really stimulating articles. We have an interesting study titled "Individual and Joint Effects of Influenza-Like Illness and Vaccinations on Stroke in the Young," led by Dr. Amelia Boehme and colleagues from Columbia University, with its accompanying editorial on how influenza-like illness is associated with increased risk of stroke in the young and middle-aged population while vaccinations of any type is protective of this risk. In a different paper, as part of a population-based study out of Scotland, Dr. Rustam Al-Shahi Salman from University of Edinburgh and colleagues report on a positive association between the use of beta-blockers, especially propranolol, and a lower risk of cerebral cavernous malformation, or CCM, associated intracranial hemorrhage. This study's findings are very interesting and quite important, and I encourage you to review the growing literature to suggest how beta-blockers may, in fact, reduce the risk of CCM-related hemorrhages through their anti-angiogenic properties.

Dr. Negar Asdaghi:         Later in the podcast, I have the great pleasure of interviewing Dr. Alexander Nave from Charité University Hospital in Berlin to discuss the relationship between having an impaired metabolic state in the setting of acute stroke and the risk of ischemic stroke recurrence, as we'll review the long-awaited results of the Berlin "Cream&Sugar" study, a very catchy title. But first, with these two articles.

Dr. Negar Asdaghi:         Time to successful endovascular reperfusion is an important predictor of clinical outcomes in patients with acute ischemic stroke related to a large vessel occlusion. And for years, we've known that the faster we're able to open the affected artery, the better the ischemic stroke outcomes are. Correspondingly, systems of care have adapted to various requirements of this so-called rapid workflow to ensure that all necessary pre-reperfusion steps are completed as fast as possible, preferably most in parallel to one another. And if any steps are unnecessary, they're bypassed altogether.

Dr. Negar Asdaghi:         Despite all these modifications to date, time from conventional imaging to angiosuite arrival remains both the longest and the most variable interval in the intra-hospital workflow prior to endovascular therapy. So, it's not surprising that many recent studies have evaluated whether the current model of hospital arrival, then transfer to the scanner for imaging, then transfer to the angiosuite for endovascular therapy, can be replaced by a simpler model where, based on clinical assessment, a patient with high likelihood of having a target vessel occlusion can directly be transferred to the angiosuite, where fast stroke imaging, including CT, CT angiogram, and CT perfusion, are completed on the angiotable using the flat panel imaging technology.

Dr. Negar Asdaghi:         If the patient is then found to be eligible to receive reperfusion therapies, including intravenous thrombolytics, they can receive the treatments and then proceed to endovascular thrombectomy without any further delays. So, in this issue of the journal, in the study titled "Direct to Angiosuite Versus Conventional Imaging in Suspected Large Vessel Occlusion," Dr. Raul Nogueira from Department of Neurology at Emory University and colleagues performed a systematic review and meta-analysis of published articles on this topic. So, they included seven articles for this analysis after pulling over 4000 articles using the common search engines for this meta-analysis. These articles included two single-centered European randomized controlled trials, one conducted in Germany, and the other one conducted in Spain, and five observational studies for a total of 1971 patients. The primary outcome was the odds of achieving favorable neurological recovery as defined by a modified Rankin Scale of zero to two at 90 days.

Dr. Negar Asdaghi:         Now, a few things to note: All studies reported door-to-puncture times, but not all reported door-to-reperfusion times or rate of successful reperfusion, and we know that these metrics are important in predicting the odds of safety and efficacy outcomes of endovascular therapy. And also it's important to note that not all details of the safety and efficacy outcome measures were reported in all of those seven studies. So, with that, here are the main findings of the meta-analysis. First off, amongst patients who were directly transferred to the angiosuite across these seven studies, the overall rate of false activation was 28%, meaning that after imaging assessment, 28% of those who were directly taken to the angiotable were not found to have a target occlusion, and as such, there was no need to further proceed to endovascular thrombectomy. And this is a practical finding of this meta-analysis as we deal with resource allocation and concerns of potentially overwhelming the neurointerventional teams.

Dr. Negar Asdaghi:         Now, moving on to the next finding of the study, the direct angio approach significantly reduced door-to-puncture times by a median of 30 minutes, and door-to-reperfusion times, when these metrics were available, by a median of 33 minutes as compared to the conventional imaging approach. So, bypassing conventional CT does translate into faster time metrics. These were, of course, expected findings of this meta-analysis, but nonetheless, important to quantify. But these faster time metrics did not improve the endovascular procedural outcomes, meaning that the direct to angio approach did not increase the odds of achieving a TICI 2b or better reperfusion, which is how successful reperfusion is defined, or the odds of achieving full reperfusion, meaning modified TICI 2c or greater reperfusion.

Dr. Negar Asdaghi:         So, it's great to get to the angiosuite fast, but that does not impact the procedural outcomes of endovascular therapy. Despite the above, the faster approach resulted in a significantly better functional independence outcome as measured by mRS Scale at 90 days, again emphasizing how important time is when it comes to endovascular outcomes. Now, the authors also performed a number of subgroup analysis in this meta-analysis, which I'd like to highlight some of them. We know that the impact of time on endovascular outcomes is more robust in the early time window. So, not surprisingly, when restricting the primary outcomes to those presenting within six hours from symptom onset, the favorable effect of direct to angio approach persisted in the early time window as well.

Dr. Negar Asdaghi:         Another important subgroup analysis was when restricting data to those patients who were transferred from a primary hospital to an endovascularly-capable center, the direct angio method didn't really have a significant impact on improving the primary outcome. Why is that? Let me repeat. So, when they restricted the analysis to those patients who were transferred from one hospital to an endovascularly-capable center, they did not find the same significant positive impact on endovascular outcomes in the direct to angio approach. I think the way we can explain this from a pathophysiological standpoint is that transferred patients are more likely to be slow progressors and, therefore, less likely to be impacted by delays in the workflow process as compared to the fast progressors.

Dr. Negar Asdaghi:         Take-home message: We've got to be fast in the fast progressors, and it's safe to assume that those who are within the first six hours after presentation are more likely to be fast progressors, and these workflow modifications are, therefore, much more robust and much more impactful in patients who present early on after their symptoms onset. And finally, in terms of safety outcomes, there were no significant differences in the rate of symptomatic intracerebral hemorrhage rate or the 90-day mortality rates either for the whole study population or when the analysis was restricted to those treated in the early time window.

Dr. Negar Asdaghi:         So, in summary, what we learned from this large meta-analysis is that as compared to the current conventional imaging model, the direct transfer to angio model is not only plausible and unlikely to overwhelm the interventional teams, as only less than 30% of patients in a direct method were not eligible for endovascular thrombectomy, but also this method is safe and results in significant improvements in workflow time metrics and functional outcomes. So, as the saying goes, select faster, select less, and treat more will likely be the future of endovascular therapy, particularly in the early time window.

Dr. Negar Asdaghi:         We know that oral anticoagulants reduce the risk of ischemic events in patients with atrial fibrillation. Nonvitamin K antagonist oral anticoagulants, or NOACs, also known as direct oral anticoagulants, or DOACs, are currently the standard of care for treatment of patients with non-valvular atrial fibrillation. Now, we have to keep in mind that although NOACs reduce the risk of ischemic stroke and systemic embolism in atrial fibrillation, they don't completely abolish the risk. So, they're not curative treatments for AFib, and patients can still experience embolic events despite appropriate treatment with these agents. In a meta-analysis of randomized trials, the residual risk of ischemic events in patients treated with NOACs was estimated at 1.4% per year, but this number is a lot lower than what is reported by real-life observational studies.

Dr. Negar Asdaghi:         In the large multicenter RENO study, which was published in this journal in 2019, we learned that in the setting of atrial fibrillation treated with a NOAC, a number of factors, including atrial enlargement, dyslipidemia, scoring high on the CHA2DS2-VASc score, and the use of low dose of NOACs, especially off-label low dose use of these medications, are significantly associated with increased risk of recurrent ischemic events despite treatment. But there's still a number of important questions that we routinely encounter in practice, most important of which is how to manage these patients with these so-called breakthrough ischemic events moving forward? Do we switch them to a different NOAC or go back to a vitamin K antagonist? Should we add an antiplatelet treatment to the regimen? And importantly, how do we counsel these patients and their families on their future risk of recurrent ischemic or hemorrhagic events?

Dr. Negar Asdaghi:         So, in the current issue of the journal, the RENO investigators, led by Dr. Maurizio Paciaroni and Valeria Caso, set out to answer some of these important questions as part of the RENO-EXTEND study, which basically followed the patients in the RENO cohort for at least 12 months, evaluating them for either recurrent ischemic or hemorrhagic events, whether occurring intra or extracranially. So, a bit about this cohort. The RENO study was a multicenter observational cohort across 43 centers in Europe and the United States, including consecutive patients with atrial fibrillation who presented to the hospital with an acute ischemic stroke despite being on a NOAC therapy. Patients were enrolled in the study only if they were compliant with their NOAC treatment and they had not missed their treatment for any reasons for greater than 24 hours prior to their index event.

Dr. Negar Asdaghi:         The patients were followed in the cohort and the choice of whether or not to start and timing, very importantly, for resumption of anticoagulation therapies were left to the discretion of the treating physicians. For the current paper, they analyzed 1240 patients. After the index event, 39.5%, so close to 40%, had their NOACs changed to another NOAC, mostly to a different class of NOAC. 42.5% continued with the same NOAC at the same dose. 6.7% continued with the same NOAC, but the dose was increased, and a small percentage were shifted to warfarin, that was only 4.7% of the patients. And 6.6% were shifted to low molecular weight heparin or were never prescribed oral anticoagulations after that index event for a variety of reasons, such as earlier ischemic recurrence, early hemorrhagic transformation, or early death or severe index stroke. And the overall median follow up in the study was 15 months.

Dr. Negar Asdaghi:         So, with that, here are the main study findings. The annual rate of the primary outcome of recurrent ischemic or hemorrhagic events, again, a reminder that these could have been intra or extracranial events, was 13.4%. The majority of these events were ischemic stroke, followed by major extracranial bleeding, then intracranial bleeding and systemic embolism. We have to note that this overall primary outcome rate is a lot higher than what was observed as part of the randomized trials of NOACs, as we noted earlier, which is an important finding of these real-life studies. Now, with regards to the factors predicting the primary outcome, having a higher CHA2DS2-VASc score and persistent hypertension were both predictive of recurrent ischemic events, whether ischemic stroke or systemic embolism. Next, the predictive factors for hemorrhagic events, either intracranial or major extracranial bleeding, included age, for each year increase in age, the odds increased by 1.1; history of major bleeding in the past; and, very importantly, a scenario that not uncommonly happens in routine practice, which is the addition of antiplatelet to a NOAC after the so-called NOAC failure.

Dr. Negar Asdaghi:         And finally, it turns out that changing that failed NOAC to a different agent didn't really seem to make a difference at all. As we mentioned earlier, close to 40% of patients were changed from one NOAC to another agent after the index ischemic event, and when they looked at the primary outcome, there was no difference in the rate of combined ischemic and hemorrhagic events, or the ischemic events alone, or bleeding outcomes alone, amongst patients who changed their NOAC to a different agent as compared to those who did not. The authors performed a number of subanalyses to see whether a particular strategy, for example, a switch from a particular class of NOACs to another class, or change in dosage, or NOAC to warfarin change, may be more or less beneficial in reducing the primary outcome, and there was really no difference between any of these strategies with the exception of one group.

Dr. Negar Asdaghi:         It turns out that the cumulative risk of ischemic and hemorrhagic events were a lot higher in those 6.6% of patients in whom NOAC treatment was changed to low molecular weight heparin injection. But I think one should consider this observation as hypothesis generating. First off, it was just a very small percentage of patients in this study that actually did go through this switch. And also we should note that in practice, we reserve a switch to low molecular weight heparin injection in only special cases. Some examples would be patients in whom there's a consideration of a hypercoagulable state, whether cancer related or not. But regardless, I think what we learned from this finding is that the patients in whom low molecular weight heparin injection is considered after a NOAC or an anticoagulant failure are likely very high risk patients for recurrent thromboembolic and hemorrhagic events.

Dr. Negar Asdaghi:         So, in summary, we learned a number of important lessons from RENO-EXTEND study. Number one, patients with atrial fibrillation presenting with a breakthrough ischemic stroke, despite treatment with NOAC, represent a high-risk group of patients who continue to be at a substantial risk for recurrent events, mostly ischemic, but also hemorrhagic. And this substantial risk was actually over 10% in the current study. Number two, we also learned that various strategies of changing the dose or class of anticoagulants don't seem to have much, if any, benefit in reducing the recurrent event outcomes. And finally, the addition of antiplatelet to oral anticoagulant therapies in this situation is not a good idea. This strategy gets us more in trouble and can increase the risk of bleeding and confers practically no benefits. Finally, these are the types of patients in whom we may have to consider other treatment options, such as left atrial appendage closure, and I'm sure we'll hear more on this in the future.

Dr. Negar Asdaghi:         Having an abnormal lipid profile has long been recognized as a risk factor for development of vascular disorders, particularly leading to atherosclerosis, but this association varies for the different components of the lipid panel and is most robust for elevated low density lipoprotein cholesterol levels, or LDL, causing various vascular disorders. Amongst patients with ischemic stroke and TIA, randomized trials have also shown that lowering LDL can reduce the risk of major cardiovascular events, including the risk of ischemic stroke, but the connection between elevated triglyceride levels and the risk of recurrent ischemic stroke is less clear. Moving from lipids to sugar, the presence of uncontrolled diabetes increases the risk of stroke by two to five folds, depending on the patient population studied and coexistence of other risk factors. In contrast, impaired glucose tolerance, which is an intermediate metabolic state between normal glucose tolerance and diabetes, has also been found to be associated with an increased risk of stroke in patients with coronary artery disease, but this association is less clear amongst patients with ischemic stroke.

Dr. Negar Asdaghi:         In clinical practice, fasting blood glucose and lipid profiles are routinely measured post-stroke, but we put a greater emphasis on the elevated LDL and hemoglobin A1C levels, and, in general, pay less attention, if any, to other metabolic derangements, including the impaired glucose tolerance state or even abnormal triglyceride levels. So, the question is, what is the impact of these metabolic derangements on the risk of stroke recurrence amongst patients presenting with ischemic stroke? In the current issue of the journal, in the study titled "A Combined Oral Triglyceride and Glucose Tolerance Test After Acute Ischemic Stroke to Predict Recurrent Vascular Events: The Berlin 'Cream&Sugar' Study," we learn about these important associations. Joining me now is the first author of this paper, Dr. Alexander Nave. Dr. Nave is a neurologist and clinician scientist at Charité University Hospital in Berlin. He leads a junior research group as part of the Center of Stroke Research in Berlin and has a special interest in stroke rehabilitation and cardioembolic risk factors of stroke. Good morning, Alex, from Miami. Good afternoon to you in Berlin. Thank you for joining us. Welcome to our podcast.

Dr. Alexander Nave:       Hi, thank you very much. I'm very happy to be with you.

Dr. Negar Asdaghi:         All right. Let's go over the background of what we knew on the association between elevated triglyceride levels and the risk of recurrent stroke.

Dr. Alexander Nave:       Sure. So, as you pointed out earlier, diabetes and hypercholesterolemia are well established risk factors for first and recurrent ischemic stroke. However, for triglyceride levels, this association is less well understood and somewhat inconclusive. So, prior large epidemiological studies of the healthy population from the U.S. and from Denmark have shown an independent association of triglyceride levels in the risk of vascular events, including ischemic stroke. This association was actually stronger for non-fasting triglycerides levels compared to fasting triglycerides levels. In the ischemic stroke population, however, there were only a few investigations with conflicting results. So, the SPARCL trial, for example, which was a large secondary prevention stroke trial with more than 3000 stroke patients, showed that triglyceride levels were associated with major cardiovascular events, but not with recurrent ischemic stroke. So, therefore, we designed the Berlin “Cream&Sugar” study to investigate the association of postprandial triglyceride levels following an oral triglyceride tolerance test with recurrent vascular risk.

Dr. Negar Asdaghi:         So, let me just summarize. From SPARCL, actually, we knew that an increased level of triglycerides were associated with increased risk of development of cardiovascular events, so things such as coronary artery events and so on, but not an increased risk of stroke. And that's where you come in with the new study, the Berlin “Cream&Sugar” study. Now, before we talk about the study, can you tell us a little bit about the tests that were done, the oral triglyceride and glucose tolerance tests?

Dr. Alexander Nave:       Absolutely. So, both tests eventually help us to evaluate the glucose and lipid metabolism of a patient. So, the OGTT, the oral glucose tolerance test, as most of the listeners probably know, is a test that helps us to assess the ability of the patient to metabolize glucose after receiving a drink with a standard dose of 75 grams of glucose. The blood glucose levels after one hour and two hours then help us to diagnose diabetes or pre-diabetic state of the patient. So, we're not only evaluating the fasting state, but we can also quantify the body's response to a glucose challenge. And as an equivalent, the OTTT, the oral triglyceride tolerance test, will test the ability of a patient to metabolize triglycerides after oral ingestion of a lipid challenge, which is usually a certain amount of fat. However, this test is less well studied and without any standardized diagnostic criteria so far. And in contrast to the OGTT, the OTTT has not been tested in the stroke population so far.

Dr. Negar Asdaghi:         So, we're not just looking at those metrics of fasting sugar or fasting lipids and triglycerides specifically, we're looking at the patient's ability to metabolize glucose or triglyceride levels. So, now, with that understanding, can you tell us a little bit about the methodology of the study?

Dr. Alexander Nave:       Yes, of course. So the Berlin “Cream&Sugar” study was a prospective observational study recruiting acute stroke patients between 2009 and 2017 at the Charité University Hospital in Berlin. And we included first-ever ischemic stroke patients within three days to seven days after onset of stroke, and all patients received a sequential OTTT OGTT. So, all recruited patients received fasting blood sampling in the morning before taking the OTTT with 250 cc of cream, which corresponds to 30% of fat intake. So, all patients without known diabetes mellitus additionally had the OGTT with 75 grams of glucose starting three hours after the OTTT.

Dr. Alexander Nave:       And all patients received consecutive blood tests at three hours, four hours, and five hours after start of the OTTT to determine the course of glucose and triglyceride levels in the blood. And after one year, we performed follow up of all patients. The primary outcome was recurrent fatal or non-fatal ischemic stroke, and secondary outcome was a composite endpoint of recurrent vascular events, including ischemic stroke, TIA, myocardial infarction, and coronary revascularization, as well as cardiovascular death. And we compared patients with high versus low fasting and nonfasting triglyceride and glucose levels, respectively, using Cox regression analysis.

Dr. Negar Asdaghi:         Okay. 250 cc of cream and 75 grams of sugar right after a stroke. Was it challenging to recruit patients?

Dr. Alexander Nave:       Yes, that was a task. And we did experience some difficulties during the course of the study. It was not easy to ask a patient to drink a glass of cream during the first week after suffering from a stroke, obviously. In fact, a substantial number of patients eventually did not participate or did not complete the OTTT. However, in our study, we showed that performing a sequential OGTT OTTT within seven days after stroke was feasible. Approximately 10% of patients reported only minor adverse events such as nausea, diarrhea, and bloating. But with regards to the study population, overall, we enrolled 755 patients, 523 have completed the challenge and entered follow up. So, considering the fact that we had some difficulties in recruitment, was not surprising that we predominantly ended up with minor ischemic stroke patients, considering that we did not include patients with dysphagia or patients that were not able to give informed consent in the early phase after stroke. The median NIHSS was one with an interquartile range of zero to three. And, as I mentioned previously, this was because patients with impaired swallowing could not be included into the study.

Dr. Negar Asdaghi:         Okay. So, 750 patients within a week after their stroke, majority of them, as you mentioned, had mild ischemic events, were enrolled, and then they underwent sequential OTTT and OGTT tests. And then they were followed for a year for the primary outcomes. Now I think we're ready to hear the primary results.

Dr. Alexander Nave:       Sure. So, overall, 54 patients, 10% of the total population, reached a study endpoint within one year follow up. 31 patients experienced recurrent ischemic stroke within one year. So, when we compared the highest quartiles of triglyceride levels to the lowest quartiles, neither fasting nor postprandial triglyceride levels were associated with recurrent stroke. Similarly, fasting triglyceride levels were not associated with major cardiovascular events one year after stroke. Surprisingly though, higher postprandial triglycerides, measured at five hours after OTTT, were significantly associated with a lower risk for recurrent vascular events. The hazard ratio was 0.42, and the confidence interval 0.18 to 0.95. So, regarding glucose levels, on the other hand, we found no associations between glucose levels and recurrent vascular risk at all.

Dr. Negar Asdaghi:         Interesting. So, before I ask you what your takeaway is from all of this, the first question is the 10% rate of primary outcome. Were you at all surprised by this? This seems quite high for the recurrent rate of vascular events after the first year after ischemic stroke and TIA.

Dr. Alexander Nave:       Well, actually, when the “Cream&Sugar” study was designed, we expected the recurrent event rate to be even higher, approximately 10% of recurrent stroke events within one year and not 10% recurrent vascular events as a composite outcome. But as we know from previous registries, such as the TIA registry, the recurrent risk of vascular events after TIA and minor stroke is much lower now. So, I think with the reported 7% of recurrent stroke events, we're actually quite in line with the reports of the TIA registry, considering the fact also that we had no TIA patients enrolled in our study and had quite a high proportion of patients with large artery atherosclerosis as well as atrial fibrillation.

Dr. Negar Asdaghi:         So, thank you. This is a grim reminder that ischemic stroke patients remain at high risk of having recurrent vascular events. Alex, what should be our top two takeaway messages from your study?

Dr. Alexander Nave:       So, first, I think a sequential OTTT OGTT probably does not contribute a lot to future vascular risk stratification in ischemic stroke patients. So, I think all patients and carers can be relieved. There's no need to implement an OTTT into routine clinical care. However, based on our results, I think further studies are necessary and needed to better understand the importance of glucose and lipid metabolism in patients after acute ischemic stroke. And eventually we might figure out some nice information how we can improve risk prediction.

Dr. Negar Asdaghi:         So, it's good to know that we don't have to ask patients to drink a lot of cream after stroke. Can you tell us a little bit about the future of the Berlin “Cream&Sugar” study group? What are the next steps for the authors and the study group?

Dr. Alexander Nave:       Absolutely. Well, since there's no urgent need to start another large study soon, I think it would be reasonable to get our data and merge it with datas from other groups who also investigated the role of an OTTT in cardiovascular risk cohorts, also to increase power and detect some other signals. And we want to have a more detailed look at the variability of triglycerides and glucose levels following sequential OTTT OGTT. So, not only go into the absolute levels that you can measure at certain time points, but also how much these parameters fluctuate over time.

Dr. Negar Asdaghi:         To Alexander Nave, it's been a pleasure interviewing you on the podcast today. We look forward to covering more of your work in the future.

Dr. Alexander Nave:       Thank you very much. It was a pleasure to talk to you.

Dr. Negar Asdaghi:         And this concludes our podcast for the August 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including three topical reviews, from “Strategies for Maintaining Brain Health: The Role of Stroke Risk Factors Unique to Elderly Women” to “Ethical Considerations in Surgical Decompression for Stroke.” These articles summarize a large body of evidence, which I encourage you to review. And before we end our August podcast, I'd like to take a moment to recognize the incredible dedication and hard work of our medical students and fellows, especially the young doctors who are just starting their training this year.

Dr. Negar Asdaghi:         And if you happen to be one of those young doctors who is listening to our podcast in one of those sleepless on-call nights, I want to recount the story of Dr. Carl David Anderson, who won the Nobel Prize in physics for his discovery of the first particle of antimatter known as positron on August 2, 1932. A positron is actually the identical twin of the well-known negative electron, and its discovery in the 1930s truly changed our understanding of the origin of the universe, and it's practically impacted all aspects of science, not to mention it's impacted medicine and medical imaging. But the moral of the story lies in the fact that on August 2, when Anderson announced his discovery, he was a post-doctoral fellow himself, hadn't even graduated yet. So, if you are such a trainee, I hope you know that your hard work, combined with that incredible scientific inquisition, has the potential to change our understanding of the universe. And what better way to do this? You guessed it, than staying alert with Stroke Alert.

Dr. Negar Asdaghi:         This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 18 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the July 2022 issue of Stroke: “Impact of Shunting Practice Patterns During Carotid Endarterectomy for Symptomatic Carotid Stenosis” and “Socioeconomic Inequalities in Reperfusion Therapy for Acute Ischemic Stroke.” She also interviews Dr. Magdy Selim about his article “Effect of Deferoxamine on Trajectory of Recovery After Intracerebral Hemorrhage: A Post Hoc Analysis of the i-DEF Trial.”

Dr. Negar Asdaghi:         Let's start with some questions.

1) Is deferoxamine mesylate yet another failed agent for treatment of patients with intracerebral hemorrhage, or is deferoxamine getting us closer than ever to an approved therapy for this deadly form of stroke?

2) Are different strokes happening to different folks due to their disadvantaged socioeconomic status?

3) And finally, how does a surgeon's personal practice preference to either routinely or selectively use carotid shunting during carotid endarterectomy impact the recurrent risk of stroke or death in patients with symptomatic carotid disease?

We'll tackle these questions and a lot more in today's podcast as we continue to cover the cerebrovascular world's latest and greatest because, without a doubt, this is the best in Stroke.

Dr. Negar Asdaghi:         Welcome back to the July issue of the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The July 2022 issue of Stroke contains a range of really interesting papers that I'd like to highlight here. As part of our Cochrane Corner articles, giving us short summaries of the long systematic review of a given topic, we have two short articles, one on the issue of local versus general anesthesia for carotid endarterectomy, where we learn that based on the current evidence, there's no convincing difference between local versus general anesthesia in the risk of stroke and death within 30 days after the procedure. In the second Cochrane Corner article, titled "Information Provision for Stroke Survivors and Their Carers," we learn that stroke survivors and their caregivers routinely report dissatisfaction with information provided to them by their clinicians about their condition and how active approaches to information provision is superior to its passive forms in improving patients' involvement in their care, their satisfaction, and, ultimately and not surprisingly, their stroke outcome.

Dr. Negar Asdaghi:         As part of our original contributions in this issue of the journal, we have an important paper titled "The Risk of Early Versus Later Rebleeding From Dural AV Fistulas With Cortical Venous Drainage." We are reminded in this paper that cranial dural arteriovenous fistulas are classified based on their venous drainage into those with or those without cortical venous drainage, or CVD. Dural AV fistulas without CVD rarely cause intracranial bleeding, while those with CVD may cause hemorrhage. In this study, the authors show that the risk of rebleeding of dural AV fistulas with CVD presenting with hemorrhage is increased in the first two weeks after ICH, emphasizing the importance of early detection of these malformations by vascular imaging and early treatment of AV fistulas with cortical drainage. This paper is another analysis from the CONDOR registry. Our devoted Stroke Alert listeners recall that we covered this registry in more detail when we interviewed Dr. Amin-Hanjani last October on the outcomes of intracerebral hemorrhage patients found to have dural AV fistulas. I encourage you to review these articles in addition to listening to our podcast today.

Dr. Negar Asdaghi:         Later in the podcast, I have the distinct honor of interviewing Dr. Magdy Selim from Harvard Medical School on a critical analysis from i-DEF trial to examine the long-term outcome of patients with ICH who were randomized to receive deferoxamine versus placebo. As an expert in the field of intracerebral hemorrhage and a member of the recently published American Heart Association Guidelines Committee, Dr. Selim was not fazed at all about the neutral results of the trial. "The future of ICH is bright," he says, and in the interview, he tells us why. But first, with these two articles.

Dr. Negar Asdaghi:         Since its first reported successful surgery in 1953, carotid endarterectomy, or CEA, has become a common surgical procedure to prevent ischemic stroke in patients with carotid disease. CEA requires a temporary clamping of the carotid artery that is being worked on. During this time, the ipsilateral hemisphere is, of course, dependent on collateral flow from the posterior circulation or from the contralateral anterior circulation to maintain its perfusion pressure. Intraoperatively, various methods are used to monitor cerebral perfusion, and the risk of clamping-induced hypoperfusion is obviously variable for each patient depending on the patient's specific anatomy, their collateral status, and other risk factors. One way to protect the brain against possible clamp-induced ischemia is to do carotid shunting. The problem is that carotid shunting also comes with its own set of risks and problems. There's the risk of causing carotid dissection, embolization of pieces of the plaque during shunt insertion, or the risk of causing air embolism.

Dr. Negar Asdaghi:         There are also other shunt-related local complications that should be noted, such as possibility of causing injuries to the cranial nerves or development of neck hematoma related to the more extensive surgical exposure required for shunting. So, it's not surprising that the practice patterns with regards to shunting is quite variable amongst different surgeons. There are surgeons that are considered routine shunters, and those who are considered selective shunters, meaning that the shunt is inserted only in cases with a particular indication. The question is whether the surgeon's preference for shunting can impact the CEA outcomes. In the current issue of the journal, we have an interesting study led by Dr. Randall DeMartino from the Division of Vascular and Endovascular Surgery at Mayo Clinic, Rochester, where the authors look at the impact of shunting practice patterns during carotid endarterectomy on the following post-CEA outcomes: number one, in-hospital stroke and in-hospital death rates, and number two, combined stroke and death in patients with a recent symptomatic carotid disease, that is, carotid stenosis associated with a history of either ipsilateral stroke or TIA within the past 14 days of endarterectomy.

Dr. Negar Asdaghi:         So, the data for the study came from the ongoing Vascular Quality Initiative database, which comprises a network of more than 600 North American academic and community hospitals, and collects data on 12 different vascular procedures, one of which is CEA. The study included over 13,000 carotid endarterectomies performed from 2010 to 2019 for symptomatic carotid patients. This number came after they applied their exclusion criteria to all CEAs performed in the database during this timeframe, importantly excluding any asymptomatic carotid surgeries or those in whom surgery was performed after the two-week mark post qualifying TIA or stroke. Now, before we go over the results, let's go over some definitions used in the study. They had to classify surgeons to be able to do the study into two categories of routine versus selective shunters. So, what they did was to analyze all consecutive CEAs, whether they were done on symptomatic or asymptomatic carotids, in this database, aggregated at the surgeon level. Surgeons routinely shunting in over 95% of their procedures were gauged as routine shunters. Otherwise, they were classified as selective shunters.

Dr. Negar Asdaghi:         Now, coming to each case included in this study, each surgical case was, in turn, classified into four categories based on whether or not a shunt was actually used for that particular case: category one, no shunt used; category two, shunt used as a routine procedure; number three, shunt used for a preoperative, mostly anatomical indication; number four, shunt was used for an intraoperative indication, which, as we mentioned before, these are mostly intraoperative hemodynamic compromised situations. And here are the results: In total, 3,186 of surgeries, that is 24% of surgeries, were performed by routine shunters versus 76% by selective shunters. So, most surgeons were selective shunters in this study. The demographic of patients operated by the routine versus selective shunters were more or less similar with regards to the age of the patients, most of their vascular risk factors, and the degree of ipsilateral or contralateral carotid stenosis or occlusion, with a few notable exceptions, in that patients undergoing surgery by routine shunters were more likely White, more likely to have had a prior CABG, more likely to undergo the operation while taking a P2Y12 inhibitor antiplatelet agent, and these patients were more likely to have had a TIA rather than a stroke as their qualifying event, which probably explains why they were more likely to be operated on within 48 hours of symptom onset as well. So, the authors accounted for these differences when they did their multivariate analysis.

Dr. Negar Asdaghi:         The other thing to note was that overall, routine shunters used a shunt in 98.1% of their cases, whereas selective shunters used them in 46% of their cases. Now, in terms of their study outcomes, the shunting practice pattern did not impact the primary outcomes of in-hospital stroke or death, or a combination of these two outcomes, or even the odds of development of cranial nerve injuries or hemorrhage in the adjusted model, which is really good news here. But interestingly, in the final adjusted model, whether or not an actual shunt was placed during surgery did significantly increase the risk of postoperative stroke, with the odds ratio of 1.29, an effect that was entirely driven by the use of shunt by a surgeon classified as a selective shunter in this study.

Dr. Negar Asdaghi:         So, in simple terms, if a shunt was placed during CEA, it did increase the risk of stroke only if that surgeon was a selective shunter. Another interesting association was that amongst selective shunters, placing a shunt for a patient with a very recent ischemic event, that is, TIA or stroke within the past 48 hours prior to surgery, and placing a shunt for an intraoperative indication, meaning shunt placement was not pre-surgically planned, also significantly increased the risk of postoperative stroke. So, what we learned from the study is that, though a surgeon's shunting practice pattern did not have an impact on the overall postoperative risk of stroke or death, the placement of a shunt did indeed increase the risk of postoperative stroke only if it was placed by a surgeon who is a selective shunter, especially for an intraoperative indication in a patient with a recent ischemic event.

Dr. Negar Asdaghi:         So, shunts can be tricky, especially if they're done by a surgeon who doesn't place them routinely. So, my take-home message is that ultimately, like every other procedure in medicine, clinical outcomes are as much operator dependent as they are patient dependent, and for every procedure, it's fair to say that practice makes perfect.

Dr. Negar Asdaghi:         It is now more than 25 years since intravenous thrombolytic therapy has been approved for treatment of patients with acute ischemic stroke and more than seven years since randomized control trials demonstrated the efficacy of mechanical thrombectomy to improve clinical outcome in ischemic stroke patients with large vessel occlusions. To date, reperfusion therapies are the only available acute treatments for select patients with ischemic stroke. What do we mean by "select"? "Select" meaning that not all patients will benefit from these therapies, making it absolutely necessary for clinicians to be up to date with various indications and contraindications to use these therapies. Needless to say that the criteria for reperfusion therapies do not and should not consider the socioeconomic status of patients, but sadly, socioeconomic inequalities seem to impact the use of reperfusion therapies.

Dr. Negar Asdaghi:         In this issue of the journal, in the study titled "Socioeconomic Inequalities in Reperfusion Therapy for Acute Ischemic Stroke," Dr. Øgendahl Buus from Aarhus University Hospital in Denmark and colleagues studied the impact of the socioeconomic status of stroke patients on the odds of receiving reperfusion therapies in the large nationwide Danish Stroke Registry, or DSR. Now a bit about the registry: DSR contains prospectively collected nationwide data on all stroke patients admitted to Danish hospitals. It's interesting to note that in Denmark, stroke patients are exclusively admitted to public hospitals, and all departments treating stroke patients are obligated to report data to DSR. Now, for this study, they included over 63,000 stroke patients from 2013 to 2018. After excluding hemorrhagic stroke, TIAs, and other exclusion criteria of the study, they arrived at their sample size of 37,187 patients that were included in this study.

Dr. Negar Asdaghi:         Now, a few definitions. The socioeconomic status of each patient was determined based on three parameters. Parameter number one, their educational level. It was categorized into three levels of low, medium, or high levels of education. Category number two, income level. This was calculated based on the average family equivalent disposable income, or FED income, during five years prior to stroke onset, again classified into three categories of high, medium, or low income. And the third factor was the employment status of the patient during the calendar year prior to the stroke onset, also categorized into three categories of employed, unemployed, and retired. And, of course, the authors used various definitions to be able to fit special situations into these categories. For instance, a person who is temporarily unemployed due to illness or other special situation was still categorized under the employed category. So, that gave them, in total, nine groups to analyze across these three categories.

Dr. Negar Asdaghi:         And here are their findings. The median age of total stroke patients in the cohort was 73.2 years, 44.1% were women, 41% categorized under low educational level, 68% retired, and 33.3% had low income levels. Not surprisingly, patients and hospital characteristics varied tremendously across these nine groups of education, employment, and income, and a univariate analysis in general, low socioeconomic status was associated with more severe strokes, living alone, living at an assisted living residency, having had prior stroke, high comorbidity index score, hypertension, and late hospital arrival. So, they accounted for these differences in their multivariate analysis.

Dr. Negar Asdaghi:         Now, overall, the treatment rates of IV thrombolysis was 17.6%, which is actually considered a very high percentage as compared to other registry-based studies, but the percentage of IV thrombolytic use dramatically varied based on the different socioeconomic designation. So, let's look at this. In the univariate analysis, for education, intravenous thrombolysis rates were 19.3% among patients with high educational level compared to 16.2% among patients with low educational level. Let's look at income. For income, IV thrombolytic treatment rates reach 20.7% for high-income patients compared to 14.8% for low-income patients. For employment status, thrombolytic rates were 23.7% among employed patients compared to 15.7% for unemployed patients. In their fully adjusted models, unemployed patients were less likely to receive IV lytics as compared to their employed counterparts.

Dr. Negar Asdaghi:         Now, for thrombectomy, socioeconomic gradients were also noted for these three categories. For education, thrombectomy rates were 4.5% among patients with high education level compared to 3.6% among patients with low educational level. For income, treatment rates were 3.2% among low-income patients compared to 4.7% among high-income patients. But arguably, the most robust differences were noted again across the category of employment. Employed patients were nearly twice more likely to receive thrombectomy as compared to unemployed patients, rates being 5.1% versus 2.8%, respectively. Now, when they adjusted their analysis to only those patients presenting within the reperfusion time windows in the fully adjusted models, unemployment and low income remain significant negative predictors of receiving both of these reperfusion therapies. So, what we learned from this study is that stroke patients who were unemployed, earned a relatively low income, or had fewer years of formal education were less likely to receive life-saving reperfusion therapies despite potentially being eligible for these treatments.

Dr. Negar Asdaghi:         Now, let's take a moment to really understand that data presented here are in the context of a tax-funded, universal healthcare offered across Denmark, where we can at least make the assumption that financial constraints potentially preventing access to therapies are likely minimized. There are many countries around the globe where patients or family members have to pay for these therapies before even receiving them. So, these findings from the current study from Denmark are alarming in that they point to possibly more robust inequalities across the globe in other healthcare systems.

Dr. Negar Asdaghi:         Intracerebral hemorrhage, or ICH, is an aggressive form of stroke, typically carrying a higher morbidity and mortality than its ischemic counterpart. Yet much of the research in the field of intracerebral hemorrhage has followed the ischemic stroke footsteps, including defining the optimal primary outcome for the randomized trials of ICH. For ischemic stroke, the 90-day functional outcome, as measured by the modified Rankin Scale, is commonly used as a primary outcome in clinical trials. There are many reasons for this selection, including the ease of use and the fact that the majority of functional recovery post-ischemic stroke occurs during the first 90-day time period. But time to maximum recovery and, importantly, the trajectory of recovery may be different in hemorrhagic as compared to ischemic stroke. Defining the long-term outcomes and longitudinal trajectory of recovery in ICH is, therefore, important to better understand its prognosis and, of course, selecting the appropriate primary outcome measure for future randomized trials of ICH.

Dr. Negar Asdaghi:         In the recent years, the safety and efficacy of various agents to improve ICH outcomes have been tested. Deferoxamine mesylate, an iron-chelating agent, is one such agent that was recently studied as part of the i-DEF multicenter randomized trial, and the main results of the study were published in Lancet Neurology in 2019. In the current issue of the journal, in the study titled "Effect of Deferoxamine on Trajectory of Recovery After Intracerebral Hemorrhage," we learn about the results of a post hoc analysis of i-DEF that looks at the trajectory of functional outcome in patients enrolled in the trial with a special attention on their continued recovery after the 90-day post-ICH mark.

Dr. Negar Asdaghi:         Joining me now is the senior author of this paper, Dr. Magdy Selim, who's also one of the primary investigators of i-DEF trial. Dr. Selim is a Professor of Neurology at Harvard Medical School and Chief of Stroke Division at Beth Israel Deaconess Medical Center in Boston. He's a world renowned researcher in the field of cerebrovascular disorders with special focus on treatment of patients with intracerebral hemorrhage. Dr. Selim has led and currently leads multiple National Institutes of Health-funded clinical trials of intracerebral hemorrhage, including the ongoing SATURN trial. I'm delighted to welcome him to our podcast today. Good afternoon, Magdy. Thank you for joining us today.

Dr. Magdy Selim:             Thank you, Dr. Asdaghi. It's really my pleasure to be here with you, and I'm certainly honored to do this today.

Dr. Negar Asdaghi:         That's great. Thank you. So, let's start with some background on deferoxamine and the literature supporting the use of deferoxamine before i-DEF.

Dr. Magdy Selim:             So, as you mentioned, deferoxamine is an iron chelator; it binds to iron and removes excess iron from the body. The unique thing about it is that it has other neuroprotective properties, which are good for hemorrhagic stroke and ischemic stroke. It also has anti-inflammatory and anti-apoptotic effects. It even lowers the blood pressure, which we know sometimes is helpful in intracerebral hemorrhage. The rationale behind this or why this would be effective really comes from animal studies. After you have a hemorrhage, there is hemolysis of the red blood cells, there is a release of hemoglobin degradation products, in particular, iron, and the accumulation of iron in the hematoma and the surrounding tissue triggers a cascade of molecular and cellular events that lead to what we call secondary injury, characterized by inflammation, hydroxyl radical formation, and cell death. And many animal studies, animal models of intracerebral hemorrhage, whether in pigs or in rats, young or aged rats, have shown that treatment with deferoxamine can reduce iron in the brain after intracerebral hemorrhage and also results in improved performance on behavioral tests. And that was the reason why we moved into clinical testing.

Dr. Negar Asdaghi:         So, a lot of encouraging data before the trial. Can we hear a little bit about the trial, its design, and inclusion criteria, please?

Dr. Magdy Selim:             Sure. So i-DEF was a phase 2 study, and actually it started as Hi-DEF, which was high dose deferoxamine, and then became i-DEF, which intermediate dose deferoxamine. So, it's a randomized, double blind, placebo control trial. We used something called futility design, which is actually sort of new in the stroke field. And we had 294 patients who had supratentorial hemorrhage that were randomized within 24 hours to either get placebo or deferoxamine. And deferoxamine initially was given at 62 mg per day for three days, but then we ran into some safety issues with this high dose, and that's why we lowered it to 32, and that became the intermediate dose, or the i-DEF. So, the only kind of thing unique about inclusion/exclusion criteria was that there was an age cutoff, patients had to be 80 or younger. They needed to have some deficit on the exam, so their NIH Stroke Scale had to be 6 or greater, and their GCS had to be greater than 6, and their modified Rankin before the onset of the hemorrhage had to be less than 1.

Dr. Negar Asdaghi:         And so, what were the primary and secondary outcomes in i-DEF?

Dr. Magdy Selim:             The primary outcome was twofold actually. One of them was safety. One of the issues we ran into with the high dose is that the drug is associated with increased risk for adult respiratory distress syndrome, ARDS. So, we wanted to make sure that this lower dose was safe, and it does not increase the instance of ARDS. The second thing was, as I said, we used something called the futility design, and we wanted to compare the outcome of patients treated with deferoxamine versus placebo to determine whether it's futile to move to a large phase 3 trial or not. And what we were looking at is a difference in outcome and modified Rankin 0 to 2 at 90 days, and the difference would be at least 12% in favor of deferoxamine in order for us to move forward. You asked about the secondary outcomes as well?

Dr. Negar Asdaghi:         Yes.

Dr. Magdy Selim:             So, actually, the secondary outcomes, they're relevant because they're relevant to the study that we just published. So, the secondary outcomes was also to look at modified Rankin 0 to 3, instead of 0 to 2, at 90 days and the difference between the two treatment groups. We wanted to look at the ordinal distribution of the Rankin at the same time point. And we also wanted to look at all the outcomes at six months, 180 days. And that came a little bit later in the course of the study because there was some evidence emerging at that time that maybe assessment of outcome later in intracerebral hemorrhage would be more accurate than assessing it early on.

Dr. Negar Asdaghi:         So, I want to come back to the secondary outcome, of course, that's sort of the topic of your current paper in this issue of the journal, but can you just briefly tell us, please, the primary outcome and the sort of results of what was published in 2019 with i-DEF before we move on to the current paper?

Dr. Magdy Selim:             Yeah. So, as I said, the primary outcome was the difference in the proportion of patients that achieved modified Rankin 0 to 2 at 90 days, and what we wanted to see is a difference of around 12%. Unfortunately, the primary outcome was neutral, we did not see that. But what we saw actually, almost all the secondary outcomes were positive, except for the primary outcome. So, when we looked at the secondary outcome using modified Rankin 0 to 3, instead of 0 to 2, the difference was 12.1%. When we looked at the difference in the modified Rankin 0 to 2 at six months, the difference was 15.6% in favor of deferoxamine, but these were secondary outcomes and not the primary outcomes.

Dr. Negar Asdaghi:         So, the trial is almost positive. It just depends on how you define the primary outcome, which is really a nice segue to your current study. In the current study, you looked at this secondary outcome in a longitudinal way and looked at the mRS of 0 to 2 at six months from ICH. Can you please tell us about this current paper?

Dr. Magdy Selim:             Yeah. So, one of the things that we did with i-DEF is that we were checking the modified Rankin at different time points for all the patients. So, we had it after one week, after one month, after two months, after three months, and after six months. And what we wanted really was a couple of things, just in patients with intracerebral hemorrhage without any treatment, what's the natural course of recovery? And the interesting thing we found out is that patients actually continue to improve over time, and that's what you expect, but what we didn't expect is that they even continue to improve after 90 days.

Dr. Magdy Selim:             We always used to think that maximum recovery is around 90 days from ischemic stroke literature, but we saw a lot of patients getting better after 90 days. And this turns out to be also the case with deferoxamine, but the interesting thing is that the percentage of patients that had a good outcome, modified Rankin 0 to 2, was higher with deferoxamine at day seven, at day 30, at day 60, not at 90 days, but again at six months. So, actually, it was higher at all time points except our primary endpoint.

Dr. Negar Asdaghi:         So, Magdy, you've already answered my next question, which is exactly what you alluded to, deferoxamine seemed to have improved the outcomes at all of those time points, except for the 90 day, which was the primary outcome of your trial. Why do you think the magic was lost at 90 days?

Dr. Magdy Selim:             This is really the million-dollar question. I think we obviously struggled over this. And we went back, we thought maybe there was misrating of the modified Rankin in some of the patients. We tried to correct for this. The difference was bigger, but still not significant. So, we don't really have a good reason to tell you why, at this particular time point, we didn't see the difference except bad luck, I think. But I mean, there are reasons, I think, the question that people actually ask me is the opposite, is why do you think a drug that you give for three days early on is going to make a difference after six months? And I think there are biological reasons to explain this.

Dr. Magdy Selim:             So, what happened is that those hemorrhage patients have a lot of other problems. They have increased ICP, they have hydrocephalus, they have intraventricular hemorrhage, and actually iron has been implicated in the development of hydrocephalus in chronic white matter injury. So, my explanation is that you start early on with the treatment, it does help, but it takes a while for it to kick in and for this kind of medical complication to resolve until actually you see the true effect of the drug. And maybe that's why you see the unmasking at the end between the two groups.

Dr. Negar Asdaghi:         Yeah, I think I want to recap this for our listeners. Very important to, again, think about those things that some of the acute therapies that we offer the patients may not have a measurable improvement outcome difference early on, certainly with intravenous thrombolysis, we saw that, whereas we saw measurable outcome difference at 90 days, or maybe in this case at six months, but not quite early on. So, it doesn't mean that they don't work. We just are unable to measure that difference and improvement early on. So, what do you think the future holds for deferoxamine? Are we going to see another trial?

Dr. Magdy Selim:             Well, I certainly hope so. We're working on some few ideas for that. A lot of people think that maybe we should just do the same thing, but look at six months as the primary outcome. But I think we're actually, that's probably not our primary thinking at this point in time. So, we have published other papers, other analysis, to show that the effect of deferoxamine actually relates to the volume of the hemorrhage. So, if the hemorrhage is very small, there is very minimal benefit. If the hemorrhage is very large, also there is very minimal benefit. And that's really to get kind of the big bang for your buck. You really want people who have mild-to-moderate size hemorrhages. So, we're thinking of a couple of ways to go about deferoxamine with this, whether alone or in combination with other interventions. So, hopefully, we'll have some stuff to share with you in the coming few years, two or three.

Dr. Negar Asdaghi:         We'll definitely look forward to reading about those or being involved in the trials as a site, but there's a great way of just actually talking about my next question. It's just completely different than the current paper. I wanted to digress a bit and talk about the recently published intracerebral hemorrhage guidelines, which just published a few months ago. You were part of the guidelines committee. Can you give us a little bit of your point of view of what are the top two most important updates from the guidelines in ICH treatment?

Dr. Magdy Selim:             Actually, the guidelines, for the first time this year, in the first page, they have the top 10 take-home messages or top 10 new ones. So, in my opinion, the most important ones, we usually tell you what to do, but here we tell you what not to do because we think it's not good for the patients. So, for example, using steroids just as a prophylactic therapy is actually not recommended. The same thing, we see a lot of people put patients with hemorrhage on hypertonic saline, hyperosmolar therapy, just prophylactically. I don't think there's any benefit that this helps as well, and the same thing for antiepileptic drugs. So, that was one important point. The second one was blood pressure lowering, and there is emphasis now that whatever you use to lower the blood pressure, you want to make sure that the blood pressure variability is very minimal and that there is a smooth kind of control over blood pressure that has been shown to be actually important in terms of help. I'm going to make them three, not two, because I think the third one is important.

Dr. Negar Asdaghi:         Okay. I'll give you one more then.

Dr. Magdy Selim:             Which is the first time we include this in the guideline, and with emphasis on the role of the home caregiver for hemorrhage patients and the psychological support, the education that they need, and the training that they need to actually care for these patients and how to improve their quality of life. So, I think that's an important aspect that we didn't touch upon before, and obviously very important.

Dr. Negar Asdaghi:         Very important points. Let me just review them again for our listeners. So, don't do steroids, hypertonics, and preemptive antiepileptic therapies. They don't work. The second point that you raise is reduction of blood pressure, important to keep that in mind, but paying attention to blood pressure variability. And the third one, the importance of social aspect of care of patients with intracerebral hemorrhage. That's great for us. Let me just end with one last question. Magdy, thank you so much for all of this wonderful take-home messages from the current study from i-DEF and also the guidelines. There's been a lot of excitement in the field of ischemic stroke with the success of reperfusion therapies, and yet not much for intracerebral hemorrhage. What is your hope in terms of future therapies for ICH?

Dr. Magdy Selim:             So, I happen to be one of the people who is very optimistic about the future of ICH. I think it's just a matter of time. But I think we need to make some changes. We need to really treat ICH as an emergency, so time is really important. And I think right now, you see a hemorrhage patient, they just put them on the side because they think that there's nothing to do. But the way I see the future evolving, and probably the breaking point to be, is that we can diagnose ICH in the field. You immediately lower the blood pressure, reverse coagulopathy if you can, and even kind of use hemostatic agents, if the FASTEST trial shows evidence to support that, and then you take them to the hospital where there might be some role for hematoma reduction using minimally invasive therapy and some other treatments like deferoxamine, or there are a lot of other agents to target the secondary injury at the same time. So, I think it's going to be a combination of things, and they need to happen in tandem and continuously, but we need to start quickly on these patients.

Dr. Negar Asdaghi:         Dr. Magdy Selim, it's been a pleasure interviewing you on the podcast. We look forward to having you back and covering more of your work. Thank you for joining us.

Dr. Magdy Selim:             Thank you very much for having me.

Dr. Negar Asdaghi:         And this concludes our podcast for the July 2022 issue of Stroke. Please be sure to check out this month's table of contents for a full list of publications, including a series of Focus Updates on the very topic of, you guessed it, intracerebral hemorrhage. These updates are great complements to the newly published American Heart Association guidelines for the management of patients with spontaneous intracerebral hemorrhage in May 2022.

Dr. Negar Asdaghi:         And with this, we end our July podcast and draw inspiration from one particular July story, which unfolded on July 20. In 1969, on this day, Commander Neil Armstrong and lunar module pilot Buzz Aldrin landed on the moon, and Armstrong became the first person to walk on the moon. The crew of Apollo 11 changed the course of history, landing humanity on another celestial body for the first time and later safely returning everyone back to earth. Armstrong, an experienced naval aviator, a test pilot, a decorated veteran, astronaut, and university professor, passed away in 2012 from complications of coronary artery disease, reminding us that every step we take in understanding, diagnosing, and treating vascular disorders is truly part of that giant leap to save the mankind. And what better way to do this than to stay alert with Stroke Alert.

Dr. Negar Asdaghi:         This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 18 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the July 2022 issue of Stroke: “Impact of Shunting Practice Patterns During Carotid Endarterectomy for Symptomatic Carotid Stenosis” and “Socioeconomic Inequalities in Reperfusion Therapy for Acute Ischemic Stroke.” She also interviews Dr. Magdy Selim about his article “Effect of Deferoxamine on Trajectory of Recovery After Intracerebral Hemorrhage: A Post Hoc Analysis of the i-DEF Trial.”

Dr. Negar Asdaghi:         Let's start with some questions.

1) Is deferoxamine mesylate yet another failed agent for treatment of patients with intracerebral hemorrhage, or is deferoxamine getting us closer than ever to an approved therapy for this deadly form of stroke?

2) Are different strokes happening to different folks due to their disadvantaged socioeconomic status?

3) And finally, how does a surgeon's personal practice preference to either routinely or selectively use carotid shunting during carotid endarterectomy impact the recurrent risk of stroke or death in patients with symptomatic carotid disease?

We'll tackle these questions and a lot more in today's podcast as we continue to cover the cerebrovascular world's latest and greatest because, without a doubt, this is the best in Stroke.

Dr. Negar Asdaghi:         Welcome back to the July issue of the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The July 2022 issue of Stroke contains a range of really interesting papers that I'd like to highlight here. As part of our Cochrane Corner articles, giving us short summaries of the long systematic review of a given topic, we have two short articles, one on the issue of local versus general anesthesia for carotid endarterectomy, where we learn that based on the current evidence, there's no convincing difference between local versus general anesthesia in the risk of stroke and death within 30 days after the procedure. In the second Cochrane Corner article, titled "Information Provision for Stroke Survivors and Their Carers," we learn that stroke survivors and their caregivers routinely report dissatisfaction with information provided to them by their clinicians about their condition and how active approaches to information provision is superior to its passive forms in improving patients' involvement in their care, their satisfaction, and, ultimately and not surprisingly, their stroke outcome.

Dr. Negar Asdaghi:         As part of our original contributions in this issue of the journal, we have an important paper titled "The Risk of Early Versus Later Rebleeding From Dural AV Fistulas With Cortical Venous Drainage." We are reminded in this paper that cranial dural arteriovenous fistulas are classified based on their venous drainage into those with or those without cortical venous drainage, or CVD. Dural AV fistulas without CVD rarely cause intracranial bleeding, while those with CVD may cause hemorrhage. In this study, the authors show that the risk of rebleeding of dural AV fistulas with CVD presenting with hemorrhage is increased in the first two weeks after ICH, emphasizing the importance of early detection of these malformations by vascular imaging and early treatment of AV fistulas with cortical drainage. This paper is another analysis from the CONDOR registry. Our devoted Stroke Alert listeners recall that we covered this registry in more detail when we interviewed Dr. Amin-Hanjani last October on the outcomes of intracerebral hemorrhage patients found to have dural AV fistulas. I encourage you to review these articles in addition to listening to our podcast today.

Dr. Negar Asdaghi:         Later in the podcast, I have the distinct honor of interviewing Dr. Magdy Selim from Harvard Medical School on a critical analysis from i-DEF trial to examine the long-term outcome of patients with ICH who were randomized to receive deferoxamine versus placebo. As an expert in the field of intracerebral hemorrhage and a member of the recently published American Heart Association Guidelines Committee, Dr. Selim was not fazed at all about the neutral results of the trial. "The future of ICH is bright," he says, and in the interview, he tells us why. But first, with these two articles.

Dr. Negar Asdaghi:         Since its first reported successful surgery in 1953, carotid endarterectomy, or CEA, has become a common surgical procedure to prevent ischemic stroke in patients with carotid disease. CEA requires a temporary clamping of the carotid artery that is being worked on. During this time, the ipsilateral hemisphere is, of course, dependent on collateral flow from the posterior circulation or from the contralateral anterior circulation to maintain its perfusion pressure. Intraoperatively, various methods are used to monitor cerebral perfusion, and the risk of clamping-induced hypoperfusion is obviously variable for each patient depending on the patient's specific anatomy, their collateral status, and other risk factors. One way to protect the brain against possible clamp-induced ischemia is to do carotid shunting. The problem is that carotid shunting also comes with its own set of risks and problems. There's the risk of causing carotid dissection, embolization of pieces of the plaque during shunt insertion, or the risk of causing air embolism.

Dr. Negar Asdaghi:         There are also other shunt-related local complications that should be noted, such as possibility of causing injuries to the cranial nerves or development of neck hematoma related to the more extensive surgical exposure required for shunting. So, it's not surprising that the practice patterns with regards to shunting is quite variable amongst different surgeons. There are surgeons that are considered routine shunters, and those who are considered selective shunters, meaning that the shunt is inserted only in cases with a particular indication. The question is whether the surgeon's preference for shunting can impact the CEA outcomes. In the current issue of the journal, we have an interesting study led by Dr. Randall DeMartino from the Division of Vascular and Endovascular Surgery at Mayo Clinic, Rochester, where the authors look at the impact of shunting practice patterns during carotid endarterectomy on the following post-CEA outcomes: number one, in-hospital stroke and in-hospital death rates, and number two, combined stroke and death in patients with a recent symptomatic carotid disease, that is, carotid stenosis associated with a history of either ipsilateral stroke or TIA within the past 14 days of endarterectomy.

Dr. Negar Asdaghi:         So, the data for the study came from the ongoing Vascular Quality Initiative database, which comprises a network of more than 600 North American academic and community hospitals, and collects data on 12 different vascular procedures, one of which is CEA. The study included over 13,000 carotid endarterectomies performed from 2010 to 2019 for symptomatic carotid patients. This number came after they applied their exclusion criteria to all CEAs performed in the database during this timeframe, importantly excluding any asymptomatic carotid surgeries or those in whom surgery was performed after the two-week mark post qualifying TIA or stroke. Now, before we go over the results, let's go over some definitions used in the study. They had to classify surgeons to be able to do the study into two categories of routine versus selective shunters. So, what they did was to analyze all consecutive CEAs, whether they were done on symptomatic or asymptomatic carotids, in this database, aggregated at the surgeon level. Surgeons routinely shunting in over 95% of their procedures were gauged as routine shunters. Otherwise, they were classified as selective shunters.

Dr. Negar Asdaghi:         Now, coming to each case included in this study, each surgical case was, in turn, classified into four categories based on whether or not a shunt was actually used for that particular case: category one, no shunt used; category two, shunt used as a routine procedure; number three, shunt used for a preoperative, mostly anatomical indication; number four, shunt was used for an intraoperative indication, which, as we mentioned before, these are mostly intraoperative hemodynamic compromised situations. And here are the results: In total, 3,186 of surgeries, that is 24% of surgeries, were performed by routine shunters versus 76% by selective shunters. So, most surgeons were selective shunters in this study. The demographic of patients operated by the routine versus selective shunters were more or less similar with regards to the age of the patients, most of their vascular risk factors, and the degree of ipsilateral or contralateral carotid stenosis or occlusion, with a few notable exceptions, in that patients undergoing surgery by routine shunters were more likely White, more likely to have had a prior CABG, more likely to undergo the operation while taking a P2Y12 inhibitor antiplatelet agent, and these patients were more likely to have had a TIA rather than a stroke as their qualifying event, which probably explains why they were more likely to be operated on within 48 hours of symptom onset as well. So, the authors accounted for these differences when they did their multivariate analysis.

Dr. Negar Asdaghi:         The other thing to note was that overall, routine shunters used a shunt in 98.1% of their cases, whereas selective shunters used them in 46% of their cases. Now, in terms of their study outcomes, the shunting practice pattern did not impact the primary outcomes of in-hospital stroke or death, or a combination of these two outcomes, or even the odds of development of cranial nerve injuries or hemorrhage in the adjusted model, which is really good news here. But interestingly, in the final adjusted model, whether or not an actual shunt was placed during surgery did significantly increase the risk of postoperative stroke, with the odds ratio of 1.29, an effect that was entirely driven by the use of shunt by a surgeon classified as a selective shunter in this study.

Dr. Negar Asdaghi:         So, in simple terms, if a shunt was placed during CEA, it did increase the risk of stroke only if that surgeon was a selective shunter. Another interesting association was that amongst selective shunters, placing a shunt for a patient with a very recent ischemic event, that is, TIA or stroke within the past 48 hours prior to surgery, and placing a shunt for an intraoperative indication, meaning shunt placement was not pre-surgically planned, also significantly increased the risk of postoperative stroke. So, what we learned from the study is that, though a surgeon's shunting practice pattern did not have an impact on the overall postoperative risk of stroke or death, the placement of a shunt did indeed increase the risk of postoperative stroke only if it was placed by a surgeon who is a selective shunter, especially for an intraoperative indication in a patient with a recent ischemic event.

Dr. Negar Asdaghi:         So, shunts can be tricky, especially if they're done by a surgeon who doesn't place them routinely. So, my take-home message is that ultimately, like every other procedure in medicine, clinical outcomes are as much operator dependent as they are patient dependent, and for every procedure, it's fair to say that practice makes perfect.

Dr. Negar Asdaghi:         It is now more than 25 years since intravenous thrombolytic therapy has been approved for treatment of patients with acute ischemic stroke and more than seven years since randomized control trials demonstrated the efficacy of mechanical thrombectomy to improve clinical outcome in ischemic stroke patients with large vessel occlusions. To date, reperfusion therapies are the only available acute treatments for select patients with ischemic stroke. What do we mean by "select"? "Select" meaning that not all patients will benefit from these therapies, making it absolutely necessary for clinicians to be up to date with various indications and contraindications to use these therapies. Needless to say that the criteria for reperfusion therapies do not and should not consider the socioeconomic status of patients, but sadly, socioeconomic inequalities seem to impact the use of reperfusion therapies.

Dr. Negar Asdaghi:         In this issue of the journal, in the study titled "Socioeconomic Inequalities in Reperfusion Therapy for Acute Ischemic Stroke," Dr. Øgendahl Buus from Aarhus University Hospital in Denmark and colleagues studied the impact of the socioeconomic status of stroke patients on the odds of receiving reperfusion therapies in the large nationwide Danish Stroke Registry, or DSR. Now a bit about the registry: DSR contains prospectively collected nationwide data on all stroke patients admitted to Danish hospitals. It's interesting to note that in Denmark, stroke patients are exclusively admitted to public hospitals, and all departments treating stroke patients are obligated to report data to DSR. Now, for this study, they included over 63,000 stroke patients from 2013 to 2018. After excluding hemorrhagic stroke, TIAs, and other exclusion criteria of the study, they arrived at their sample size of 37,187 patients that were included in this study.

Dr. Negar Asdaghi:         Now, a few definitions. The socioeconomic status of each patient was determined based on three parameters. Parameter number one, their educational level. It was categorized into three levels of low, medium, or high levels of education. Category number two, income level. This was calculated based on the average family equivalent disposable income, or FED income, during five years prior to stroke onset, again classified into three categories of high, medium, or low income. And the third factor was the employment status of the patient during the calendar year prior to the stroke onset, also categorized into three categories of employed, unemployed, and retired. And, of course, the authors used various definitions to be able to fit special situations into these categories. For instance, a person who is temporarily unemployed due to illness or other special situation was still categorized under the employed category. So, that gave them, in total, nine groups to analyze across these three categories.

Dr. Negar Asdaghi:         And here are their findings. The median age of total stroke patients in the cohort was 73.2 years, 44.1% were women, 41% categorized under low educational level, 68% retired, and 33.3% had low income levels. Not surprisingly, patients and hospital characteristics varied tremendously across these nine groups of education, employment, and income, and a univariate analysis in general, low socioeconomic status was associated with more severe strokes, living alone, living at an assisted living residency, having had prior stroke, high comorbidity index score, hypertension, and late hospital arrival. So, they accounted for these differences in their multivariate analysis.

Dr. Negar Asdaghi:         Now, overall, the treatment rates of IV thrombolysis was 17.6%, which is actually considered a very high percentage as compared to other registry-based studies, but the percentage of IV thrombolytic use dramatically varied based on the different socioeconomic designation. So, let's look at this. In the univariate analysis, for education, intravenous thrombolysis rates were 19.3% among patients with high educational level compared to 16.2% among patients with low educational level. Let's look at income. For income, IV thrombolytic treatment rates reach 20.7% for high-income patients compared to 14.8% for low-income patients. For employment status, thrombolytic rates were 23.7% among employed patients compared to 15.7% for unemployed patients. In their fully adjusted models, unemployed patients were less likely to receive IV lytics as compared to their employed counterparts.

Dr. Negar Asdaghi:         Now, for thrombectomy, socioeconomic gradients were also noted for these three categories. For education, thrombectomy rates were 4.5% among patients with high education level compared to 3.6% among patients with low educational level. For income, treatment rates were 3.2% among low-income patients compared to 4.7% among high-income patients. But arguably, the most robust differences were noted again across the category of employment. Employed patients were nearly twice more likely to receive thrombectomy as compared to unemployed patients, rates being 5.1% versus 2.8%, respectively. Now, when they adjusted their analysis to only those patients presenting within the reperfusion time windows in the fully adjusted models, unemployment and low income remain significant negative predictors of receiving both of these reperfusion therapies. So, what we learned from this study is that stroke patients who were unemployed, earned a relatively low income, or had fewer years of formal education were less likely to receive life-saving reperfusion therapies despite potentially being eligible for these treatments.

Dr. Negar Asdaghi:         Now, let's take a moment to really understand that data presented here are in the context of a tax-funded, universal healthcare offered across Denmark, where we can at least make the assumption that financial constraints potentially preventing access to therapies are likely minimized. There are many countries around the globe where patients or family members have to pay for these therapies before even receiving them. So, these findings from the current study from Denmark are alarming in that they point to possibly more robust inequalities across the globe in other healthcare systems.

Dr. Negar Asdaghi:         Intracerebral hemorrhage, or ICH, is an aggressive form of stroke, typically carrying a higher morbidity and mortality than its ischemic counterpart. Yet much of the research in the field of intracerebral hemorrhage has followed the ischemic stroke footsteps, including defining the optimal primary outcome for the randomized trials of ICH. For ischemic stroke, the 90-day functional outcome, as measured by the modified Rankin Scale, is commonly used as a primary outcome in clinical trials. There are many reasons for this selection, including the ease of use and the fact that the majority of functional recovery post-ischemic stroke occurs during the first 90-day time period. But time to maximum recovery and, importantly, the trajectory of recovery may be different in hemorrhagic as compared to ischemic stroke. Defining the long-term outcomes and longitudinal trajectory of recovery in ICH is, therefore, important to better understand its prognosis and, of course, selecting the appropriate primary outcome measure for future randomized trials of ICH.

Dr. Negar Asdaghi:         In the recent years, the safety and efficacy of various agents to improve ICH outcomes have been tested. Deferoxamine mesylate, an iron-chelating agent, is one such agent that was recently studied as part of the i-DEF multicenter randomized trial, and the main results of the study were published in Lancet Neurology in 2019. In the current issue of the journal, in the study titled "Effect of Deferoxamine on Trajectory of Recovery After Intracerebral Hemorrhage," we learn about the results of a post hoc analysis of i-DEF that looks at the trajectory of functional outcome in patients enrolled in the trial with a special attention on their continued recovery after the 90-day post-ICH mark.

Dr. Negar Asdaghi:         Joining me now is the senior author of this paper, Dr. Magdy Selim, who's also one of the primary investigators of i-DEF trial. Dr. Selim is a Professor of Neurology at Harvard Medical School and Chief of Stroke Division at Beth Israel Deaconess Medical Center in Boston. He's a world renowned researcher in the field of cerebrovascular disorders with special focus on treatment of patients with intracerebral hemorrhage. Dr. Selim has led and currently leads multiple National Institutes of Health-funded clinical trials of intracerebral hemorrhage, including the ongoing SATURN trial. I'm delighted to welcome him to our podcast today. Good afternoon, Magdy. Thank you for joining us today.

Dr. Magdy Selim:             Thank you, Dr. Asdaghi. It's really my pleasure to be here with you, and I'm certainly honored to do this today.

Dr. Negar Asdaghi:         That's great. Thank you. So, let's start with some background on deferoxamine and the literature supporting the use of deferoxamine before i-DEF.

Dr. Magdy Selim:             So, as you mentioned, deferoxamine is an iron chelator; it binds to iron and removes excess iron from the body. The unique thing about it is that it has other neuroprotective properties, which are good for hemorrhagic stroke and ischemic stroke. It also has anti-inflammatory and anti-apoptotic effects. It even lowers the blood pressure, which we know sometimes is helpful in intracerebral hemorrhage. The rationale behind this or why this would be effective really comes from animal studies. After you have a hemorrhage, there is hemolysis of the red blood cells, there is a release of hemoglobin degradation products, in particular, iron, and the accumulation of iron in the hematoma and the surrounding tissue triggers a cascade of molecular and cellular events that lead to what we call secondary injury, characterized by inflammation, hydroxyl radical formation, and cell death. And many animal studies, animal models of intracerebral hemorrhage, whether in pigs or in rats, young or aged rats, have shown that treatment with deferoxamine can reduce iron in the brain after intracerebral hemorrhage and also results in improved performance on behavioral tests. And that was the reason why we moved into clinical testing.

Dr. Negar Asdaghi:         So, a lot of encouraging data before the trial. Can we hear a little bit about the trial, its design, and inclusion criteria, please?

Dr. Magdy Selim:             Sure. So i-DEF was a phase 2 study, and actually it started as Hi-DEF, which was high dose deferoxamine, and then became i-DEF, which intermediate dose deferoxamine. So, it's a randomized, double blind, placebo control trial. We used something called futility design, which is actually sort of new in the stroke field. And we had 294 patients who had supratentorial hemorrhage that were randomized within 24 hours to either get placebo or deferoxamine. And deferoxamine initially was given at 62 mg per day for three days, but then we ran into some safety issues with this high dose, and that's why we lowered it to 32, and that became the intermediate dose, or the i-DEF. So, the only kind of thing unique about inclusion/exclusion criteria was that there was an age cutoff, patients had to be 80 or younger. They needed to have some deficit on the exam, so their NIH Stroke Scale had to be 6 or greater, and their GCS had to be greater than 6, and their modified Rankin before the onset of the hemorrhage had to be less than 1.

Dr. Negar Asdaghi:         And so, what were the primary and secondary outcomes in i-DEF?

Dr. Magdy Selim:             The primary outcome was twofold actually. One of them was safety. One of the issues we ran into with the high dose is that the drug is associated with increased risk for adult respiratory distress syndrome, ARDS. So, we wanted to make sure that this lower dose was safe, and it does not increase the instance of ARDS. The second thing was, as I said, we used something called the futility design, and we wanted to compare the outcome of patients treated with deferoxamine versus placebo to determine whether it's futile to move to a large phase 3 trial or not. And what we were looking at is a difference in outcome and modified Rankin 0 to 2 at 90 days, and the difference would be at least 12% in favor of deferoxamine in order for us to move forward. You asked about the secondary outcomes as well?

Dr. Negar Asdaghi:         Yes.

Dr. Magdy Selim:             So, actually, the secondary outcomes, they're relevant because they're relevant to the study that we just published. So, the secondary outcomes was also to look at modified Rankin 0 to 3, instead of 0 to 2, at 90 days and the difference between the two treatment groups. We wanted to look at the ordinal distribution of the Rankin at the same time point. And we also wanted to look at all the outcomes at six months, 180 days. And that came a little bit later in the course of the study because there was some evidence emerging at that time that maybe assessment of outcome later in intracerebral hemorrhage would be more accurate than assessing it early on.

Dr. Negar Asdaghi:         So, I want to come back to the secondary outcome, of course, that's sort of the topic of your current paper in this issue of the journal, but can you just briefly tell us, please, the primary outcome and the sort of results of what was published in 2019 with i-DEF before we move on to the current paper?

Dr. Magdy Selim:             Yeah. So, as I said, the primary outcome was the difference in the proportion of patients that achieved modified Rankin 0 to 2 at 90 days, and what we wanted to see is a difference of around 12%. Unfortunately, the primary outcome was neutral, we did not see that. But what we saw actually, almost all the secondary outcomes were positive, except for the primary outcome. So, when we looked at the secondary outcome using modified Rankin 0 to 3, instead of 0 to 2, the difference was 12.1%. When we looked at the difference in the modified Rankin 0 to 2 at six months, the difference was 15.6% in favor of deferoxamine, but these were secondary outcomes and not the primary outcomes.

Dr. Negar Asdaghi:         So, the trial is almost positive. It just depends on how you define the primary outcome, which is really a nice segue to your current study. In the current study, you looked at this secondary outcome in a longitudinal way and looked at the mRS of 0 to 2 at six months from ICH. Can you please tell us about this current paper?

Dr. Magdy Selim:             Yeah. So, one of the things that we did with i-DEF is that we were checking the modified Rankin at different time points for all the patients. So, we had it after one week, after one month, after two months, after three months, and after six months. And what we wanted really was a couple of things, just in patients with intracerebral hemorrhage without any treatment, what's the natural course of recovery? And the interesting thing we found out is that patients actually continue to improve over time, and that's what you expect, but what we didn't expect is that they even continue to improve after 90 days.

Dr. Magdy Selim:             We always used to think that maximum recovery is around 90 days from ischemic stroke literature, but we saw a lot of patients getting better after 90 days. And this turns out to be also the case with deferoxamine, but the interesting thing is that the percentage of patients that had a good outcome, modified Rankin 0 to 2, was higher with deferoxamine at day seven, at day 30, at day 60, not at 90 days, but again at six months. So, actually, it was higher at all time points except our primary endpoint.

Dr. Negar Asdaghi:         So, Magdy, you've already answered my next question, which is exactly what you alluded to, deferoxamine seemed to have improved the outcomes at all of those time points, except for the 90 day, which was the primary outcome of your trial. Why do you think the magic was lost at 90 days?

Dr. Magdy Selim:             This is really the million-dollar question. I think we obviously struggled over this. And we went back, we thought maybe there was misrating of the modified Rankin in some of the patients. We tried to correct for this. The difference was bigger, but still not significant. So, we don't really have a good reason to tell you why, at this particular time point, we didn't see the difference except bad luck, I think. But I mean, there are reasons, I think, the question that people actually ask me is the opposite, is why do you think a drug that you give for three days early on is going to make a difference after six months? And I think there are biological reasons to explain this.

Dr. Magdy Selim:             So, what happened is that those hemorrhage patients have a lot of other problems. They have increased ICP, they have hydrocephalus, they have intraventricular hemorrhage, and actually iron has been implicated in the development of hydrocephalus in chronic white matter injury. So, my explanation is that you start early on with the treatment, it does help, but it takes a while for it to kick in and for this kind of medical complication to resolve until actually you see the true effect of the drug. And maybe that's why you see the unmasking at the end between the two groups.

Dr. Negar Asdaghi:         Yeah, I think I want to recap this for our listeners. Very important to, again, think about those things that some of the acute therapies that we offer the patients may not have a measurable improvement outcome difference early on, certainly with intravenous thrombolysis, we saw that, whereas we saw measurable outcome difference at 90 days, or maybe in this case at six months, but not quite early on. So, it doesn't mean that they don't work. We just are unable to measure that difference and improvement early on. So, what do you think the future holds for deferoxamine? Are we going to see another trial?

Dr. Magdy Selim:             Well, I certainly hope so. We're working on some few ideas for that. A lot of people think that maybe we should just do the same thing, but look at six months as the primary outcome. But I think we're actually, that's probably not our primary thinking at this point in time. So, we have published other papers, other analysis, to show that the effect of deferoxamine actually relates to the volume of the hemorrhage. So, if the hemorrhage is very small, there is very minimal benefit. If the hemorrhage is very large, also there is very minimal benefit. And that's really to get kind of the big bang for your buck. You really want people who have mild-to-moderate size hemorrhages. So, we're thinking of a couple of ways to go about deferoxamine with this, whether alone or in combination with other interventions. So, hopefully, we'll have some stuff to share with you in the coming few years, two or three.

Dr. Negar Asdaghi:         We'll definitely look forward to reading about those or being involved in the trials as a site, but there's a great way of just actually talking about my next question. It's just completely different than the current paper. I wanted to digress a bit and talk about the recently published intracerebral hemorrhage guidelines, which just published a few months ago. You were part of the guidelines committee. Can you give us a little bit of your point of view of what are the top two most important updates from the guidelines in ICH treatment?

Dr. Magdy Selim:             Actually, the guidelines, for the first time this year, in the first page, they have the top 10 take-home messages or top 10 new ones. So, in my opinion, the most important ones, we usually tell you what to do, but here we tell you what not to do because we think it's not good for the patients. So, for example, using steroids just as a prophylactic therapy is actually not recommended. The same thing, we see a lot of people put patients with hemorrhage on hypertonic saline, hyperosmolar therapy, just prophylactically. I don't think there's any benefit that this helps as well, and the same thing for antiepileptic drugs. So, that was one important point. The second one was blood pressure lowering, and there is emphasis now that whatever you use to lower the blood pressure, you want to make sure that the blood pressure variability is very minimal and that there is a smooth kind of control over blood pressure that has been shown to be actually important in terms of help. I'm going to make them three, not two, because I think the third one is important.

Dr. Negar Asdaghi:         Okay. I'll give you one more then.

Dr. Magdy Selim:             Which is the first time we include this in the guideline, and with emphasis on the role of the home caregiver for hemorrhage patients and the psychological support, the education that they need, and the training that they need to actually care for these patients and how to improve their quality of life. So, I think that's an important aspect that we didn't touch upon before, and obviously very important.

Dr. Negar Asdaghi:         Very important points. Let me just review them again for our listeners. So, don't do steroids, hypertonics, and preemptive antiepileptic therapies. They don't work. The second point that you raise is reduction of blood pressure, important to keep that in mind, but paying attention to blood pressure variability. And the third one, the importance of social aspect of care of patients with intracerebral hemorrhage. That's great for us. Let me just end with one last question. Magdy, thank you so much for all of this wonderful take-home messages from the current study from i-DEF and also the guidelines. There's been a lot of excitement in the field of ischemic stroke with the success of reperfusion therapies, and yet not much for intracerebral hemorrhage. What is your hope in terms of future therapies for ICH?

Dr. Magdy Selim:             So, I happen to be one of the people who is very optimistic about the future of ICH. I think it's just a matter of time. But I think we need to make some changes. We need to really treat ICH as an emergency, so time is really important. And I think right now, you see a hemorrhage patient, they just put them on the side because they think that there's nothing to do. But the way I see the future evolving, and probably the breaking point to be, is that we can diagnose ICH in the field. You immediately lower the blood pressure, reverse coagulopathy if you can, and even kind of use hemostatic agents, if the FASTEST trial shows evidence to support that, and then you take them to the hospital where there might be some role for hematoma reduction using minimally invasive therapy and some other treatments like deferoxamine, or there are a lot of other agents to target the secondary injury at the same time. So, I think it's going to be a combination of things, and they need to happen in tandem and continuously, but we need to start quickly on these patients.

Dr. Negar Asdaghi:         Dr. Magdy Selim, it's been a pleasure interviewing you on the podcast. We look forward to having you back and covering more of your work. Thank you for joining us.

Dr. Magdy Selim:             Thank you very much for having me.

Dr. Negar Asdaghi:         And this concludes our podcast for the July 2022 issue of Stroke. Please be sure to check out this month's table of contents for a full list of publications, including a series of Focus Updates on the very topic of, you guessed it, intracerebral hemorrhage. These updates are great complements to the newly published American Heart Association guidelines for the management of patients with spontaneous intracerebral hemorrhage in May 2022.

Dr. Negar Asdaghi:         And with this, we end our July podcast and draw inspiration from one particular July story, which unfolded on July 20. In 1969, on this day, Commander Neil Armstrong and lunar module pilot Buzz Aldrin landed on the moon, and Armstrong became the first person to walk on the moon. The crew of Apollo 11 changed the course of history, landing humanity on another celestial body for the first time and later safely returning everyone back to earth. Armstrong, an experienced naval aviator, a test pilot, a decorated veteran, astronaut, and university professor, passed away in 2012 from complications of coronary artery disease, reminding us that every step we take in understanding, diagnosing, and treating vascular disorders is truly part of that giant leap to save the mankind. And what better way to do this than to stay alert with Stroke Alert.

Dr. Negar Asdaghi:         This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 17 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the June 2022 issue of Stroke: “Vitamin D Enhances Hematoma Clearance and Neurologic Recovery in Intracerebral Hemorrhage” and “Acute Ischemic Stroke, Depressed Left Ventricular Ejection Fraction, and Sinus Rhythm: Prevalence and Practice Patterns.” She also interviews Dr. Bruce Campbell on his article “Role of Intravenous Thrombolytics Prior to Endovascular Thrombectomy.”

Dr. Negar Asdaghi:         Let's start with some questions.

1) Is vitamin D that golden key to recovery from intracerebral hemorrhage?

2) Endovascular therapies seem to have prevailed where thrombolytics have failed. In the era of fast and furious thrombectomy, what is the role of pre-thrombectomy thrombolysis?

3) And finally, 20 years of clinical research has failed to demonstrate the superiority of anticoagulation over antiplatelet therapies for treatment of patients in sinus rhythm with low left ventricular ejection fraction, and yet, our practice patterns have not changed. Why do we remain resolute in prescribing anticoagulation despite the lack of evidence?

We're back here to tackle the toughest questions with our Stroke Alert Podcast because this is the latest in Stroke. Stay with us.

Dr. Negar Asdaghi:         Welcome back to another extremely motivating Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The June 2022 issue of Stroke contains a number of interesting articles. As part of our Advances in Stroke, we have two articles, one on the topic of cost-effectiveness of stroke care to inform health policy and the second on the current state and the future of emerging stroke therapies. As part of our Original Contributions category, we have an interesting study by Dr. [Ben] Assayag and colleagues from the Department of Neurology at Tel Aviv Sourasky Medical Center, where we learned that just over 10% of patients with TIA and stroke developed post-traumatic stress disorder, or PTSD. Higher presenting stroke severity, preexisting white matter disease, and having anxious coping styles are risk factors for development of post-stroke PTSD.

Dr. Negar Asdaghi:         In another Original Contribution, by Dr. Daehoon Kim and colleagues from Yonsei University College of Medicine in Seoul, South Korea, we read with interest on the topic of whether or not we should be anticoagulating frail patients with atrial fibrillation. In this large population-based cohort, which included patients with atrial fibrillation older than 65 years of age with frailty as defined by a score of equal or greater than five on Hospital Frailty Risk Score, we learned that despite their frailty, patients with atrial fibrillation still significantly benefit from oral anticoagulation therapy. In this study, those treated with anticoagulation had lower net adverse clinical events as compared to those untreated. We also learned that direct oral anticoagulants provided lower incidence of stroke, bleeding, and mortality over Coumadin. This paper really provided practical information on treatment of frail patients with atrial fibrillation. So, I encourage you to review these papers in addition to listening to our podcast today. Later in the podcast, I have the great pleasure of interviewing Dr. Bruce Campbell from University of Melbourne in Australia on an especially timely topic, that is the role of intravenous thrombolytics prior to endovascular therapy. Dr. Campbell is a leading authority on the topic, and his interview does not disappoint. But first, with these two articles.

Dr. Negar Asdaghi:         In the setting of intracerebral hemorrhage, or ICH, aside from the primary brain insult that occurs at the time of hemorrhage, secondary brain injuries continue for days and sometimes to months mostly due to the pathological response of the brain to byproducts of hematoma lysis or RBC degradation products. Today, the majority of spontaneous ICH cases are not surgically evacuated, so we rely on the body's own ability to clear blood for hematoma clearance, and obviously the faster the clearance, the better the outcome. Erythrophagocytosis by monocyte-derived macrophages contributes to hematoma clearance and ultimately to the functional recovery from ICH. So, it's conceivable that therapeutic approaches to enhance the endogenous erythrophagocytosis can potentially improve ICH outcomes. Vitamin D has been known to have variety of functions within the central nervous system, and it turns out that it may also be one such therapeutic option to improve the much needed erythrophagocytosis in intracerebral hemorrhage.

Dr. Negar Asdaghi:         In the current issue of the journal, in the study titled "Vitamin D Enhances Hematoma Clearance and Neurologic Recovery in Intracerebral Hemorrhage," a group of researchers led by Dr. Jiaxin Liu from the Department of Surgery at Queen Mary Hospital at the University of Hong Kong studied the effects of oral vitamin D administered two hours after the induction of hematoma in a rodent model of ICH using direct collagenase injection into the striatum of the mouse. Eighty-nine young mice and 78 middle-aged mice were included in the study and randomly divided into three groups. Group one were sham-operated mice; group two, ICH mice treated with vehicle, which was corn oil; and group three, vitamin D-treated ICH mice. In the third group, 1000 international unit per kg of vitamin D diluted in corn oil was administered orally using a pipette two hours after the induction of ICH to mice, and then daily afterwards. And here are their top three findings of this study.

Dr. Negar Asdaghi:         Number one, vitamin D-treated mice did better than vehicle on two neurobehavioral tests that were completed in the study. On the cylinder test, treatment with vitamin D significantly alleviated the asymmetric usage of four limbs at day seven, and vitamin D elongated the duration that the mice could run on the accelerated rod at day 10 on the rotarod test.

Dr. Negar Asdaghi:         Number two, in terms of hematoma resolution and perihematoma edema, it's an issue that we deal with, with ICH, they used MRI imaging for edema measurement on T2-weighted images, and then sacrificed the mice and used digital quantification of hematoma volume with fresh brain specimens. And they found that treatment with vitamin D significantly alleviated both the ICH-associated brain swelling on MR and resulted in significant reduction in hematoma volume on the fresh brain specimens when compared with the vehicle-treated group at day three and day five.

Dr. Negar Asdaghi:         And finally, their third main finding is in terms of erythrophagocytosis. So, the pathway that is mediated by the monocyte-derived macrophages is an endogenous pathway, that is, PPAR-γ (which stands for peroxisome proliferator-activated receptor γ) and its downstream scavenger receptor CD36 mediated. This pathway is essential for directing the endogenous erythrophagocytosis. Using flow cytometry, they found that vitamin D-treated mice had more mature macrophages expressing the scavenger receptor CD36, which was not expressed by the undifferentiated monocytes.

Dr. Negar Asdaghi:         Western blot analysis confirmed that vitamin D treatment increased the tissue levels of CD36 and the upstream PPAR-γ levels in the brain at day five after collagenase model. Locally, vitamin D-enriched phagocytes that were positive for PPAR-γ and CD36 in the perihematoma regions. So, in summary, vitamin D increased the number of mature macrophages rather than undifferentiated monocytes in the perihematoma region and accelerated the differentiation of reparative macrophages from bone marrow-derived monocytes. So, bottom line is that in vitamin D, we have a simple, accessible, and well-tolerated agent to improve both the ICH outcomes and enhance hematoma resolution, but this we all observed in rodents. So, we stay tuned with interest to find out whether the same success will be seen in humans treated with vitamin D after intracerebral hemorrhage.

Dr. Negar Asdaghi:         Patients with depressed left ventricular ejection fraction, or low EF, are at risk of development of ischemic stroke even if they remain in sinus rhythm. The optimal antithrombotic treatment for these patients is still unknown. Over the past two decades, we have a number of randomized trials studying the efficacy of oral anticoagulation, predominantly Coumadin, over aspirin therapy in prevention of all forms of stroke, that is ischemic and hemorrhagic, and death in patients with a low EF in sinus rhythm.

Dr. Negar Asdaghi:         The meta-analysis of WASH, HELAS, WATCH, and WARCEF trials showed that treatment of low ejection fraction patients in sinus rhythm with Coumadin does reduce the subsequent risk of stroke, but it comes at the cost of a higher major bleeding risk in this population. The COMMANDER HF clinical trial published in New England Journal of Medicine in October 2018 studied whether low-dose rivaroxaban at 2.5 milligram BID was superior to placebo in patients with recent worsening of chronic heart failure, reduced ejection fraction, coronary artery disease, but no atrial fibrillation, and very similar to its prior counterparts, it did not show that rivaroxaban was associated with a lower rate of combined death, myocardial infarction, or stroke as compared to placebo. But very similar to prior studies, it also showed that rivaroxaban-treated patients had a lower risk of subsequent ischemic stroke. This poses a conundrum for stroke neurologists treating patients with this condition, especially after they present with an embolic-appearing stroke. So, the question is, how often do we encounter this situation, and what do we do in routine practice? We know that when there is equipoise, there's practice variation.

Dr. Negar Asdaghi: In the current issue of the journal, in the study titled "Acute Ischemic Stroke, Depressed Left Ventricular Ejection Fraction, and Sinus Rhythm," Dr. Richa Sharma from the Department of Neurology at Yale School of Medicine and colleagues examined the prevalence of heart failure with sinus rhythm among hospitalized patients with acute ischemic stroke and the physician's practice patterns with regard to the choice of antithrombotics in this population.

Dr. Negar Asdaghi:         So, let's look at their study. The study was comprised of five separate study cohorts of hospitalized acute ischemic stroke patients in the Greater Cincinnati Northern Kentucky Stroke Study for the year 2005, 2010, and 2015, and then four additional academic hospital-based cohorts in the United States during different timeframes. These were the Massachusetts General Hospital from 2002 to 2016, Rhode Island Hospital from 2016 to 2018, Yale-New Haven Hospital 2015 to 2017, and Cornell Acute Stroke Academic Registry from 2011 to 2018. All of these cohorts combined contributed to the 19,155 total number of patients in this study, which included over 14,000 patients that had documented left ventricular ejection fraction. Amongst those, 1,426 had a depressed EF and were included in this study. The investigator obviously excluded those with documented atrial fibrillation and flutter. And so the sample size for this analysis was 805 patients. And here are their main results.

Dr. Negar Asdaghi:         The overall prevalence of this condition, that is low ejection fraction and sinus rhythm, among hospitalized acute ischemic stroke patients was 5%. It varied slightly between the different cohorts in this study from 4 to 6%. In terms of the antithrombotic treatment patterns, this information was available in close to 500 patients in the cohort. Overall, 59% of patients were discharged on an antiplatelet treatment alone, and 41% on anticoagulation. But these percentages significantly varied between the different institutions and was as low as 22% in one of the cohorts and as high as 45% in another cohort.

Dr. Negar Asdaghi:         So, what were the factors that were associated with the use of anticoagulation at discharge? They found that the absolute percentage of left ventricular ejection fraction and the presenting NIH Stroke Scales were associated with anticoagulation use. That is, the lower the percentage of EF and the higher the presenting NIH Stroke Scale, the more likely physicians were to discharge the patients on an anticoagulation in univariate analysis, but in multivariate analysis, only the study site and presenting NIH Stroke Scale over eight were independently associated with anticoagulation use.

Dr. Negar Asdaghi:         Now, interestingly, 2002 to 2018, which was their overall study period, was a time during which some of the largest and neutral randomized trials on the topic of anticoagulation versus antiplatelet were published, including the WATCH and the WARCEF trial. But the authors found no temporal variation in anticoagulation practice patterns before and after the publication of the results of these trials. So, it appears that we didn't change our minds. So, overall, we have some important takeaway messages from this study. We learned that 5% of hospitalized acute ischemic stroke patients have low left ventricular ejection fraction and remain in sinus rhythm without atrial fibrillation. Today, over 40% of patients with this condition are anticoagulated at discharge despite the results of the randomized trials, but the practice is widely variable among different institutions, and a higher presenting NIH Stroke Scale is a significant predictor of anticoagulation use at discharge in this population.

Dr. Negar Asdaghi:         Almost 20 years after the approval of intravenous thrombolysis for treatment of patients with acute ischemic stroke, endovascular therapy was approved for treatment of select ischemic stroke patients with a large vessel occlusion. The two treatments are, therefore, entangled, as one was the standard of care while the second one was being tested. Therefore, all endovascularly treated patients enrolled in randomized trials would've received intravenous thrombolysis if eligible. Now, with the overwhelming success of endovascular therapy in achieving reperfusion in areas where IV thrombolysis has drastically failed, there're still critical questions regarding the added value of IV thrombolysis to endovascularly treated patients. The critical question remains as to whether eligible ischemic stroke patients who have immediate access to endovascular thrombectomy should receive prior IV thrombolysis, or should we skip the thrombolysis step altogether and just move to the angio suite as fast as possible. And there are, of course, arguments for and against each approach.

Dr. Negar Asdaghi:         In this issue of the journal, in an invited topical review titled "The Role of Intravenous Thrombolytics Prior to Endovascular Thrombectomy," we learn about these arguments as the authors go through a comprehensive review of the current literature on this issue. I'm joined today by the first author of this review, Dr. Bruce Campbell, to discuss this paper. Dr. Campbell absolutely needs no introduction to our Stroke listeners. He's a professor of neurology and head of neurology and stroke at Royal Melbourne Hospital, University of Melbourne, in Australia. He's a pioneer in the field of acute stroke therapies and acute neuroimaging. He has served as the lead investigator of multiple landmark randomized trials, including EXTEND-IA and EXTEND-IA TNK, and holds multiple leadership roles. He's the clinical director of the Stroke Foundation and co-chairs the Australian Stroke Guidelines Working Party and the coordinator of the National Brain School Training Program for Neurologists in Training. And, of course, last but not least, he's my friend. So, I'm delighted to welcome him to our podcast today. Top of the morning to you, Bruce, 6:00 a.m. in Melbourne. That's quite some dedication. Thank you for being here.

Dr. Bruce Campbell:       It's great to be with you. Thanks for the invitation.

Dr. Negar Asdaghi:         Congrats on the paper, really exciting topic. So, let's just start with this question as part of a case. We have a patient with an M1 occlusion, a large clinical syndrome presenting two hours out from their symptom onset, and we are at a hospital where the angio suite is ready. What are some of the benefits of basically spending time in giving IV thrombolytics first rather than quickly going to the angio suite?

Dr. Bruce Campbell:       I think a key element of this case is that the patient has presented directly to a hospital with immediate access to thrombectomy. Thrombolytic used in drip-and-ship transfer patients really isn't controversial, and the recent randomized trials excluded them. So, the debate's all about this context of bridging thrombolytics in patients presenting directly to a comprehensive stroke center. And you mentioned spending time giving lytics, but in fact, if you do things in parallel, that shouldn't be the case. It shouldn't delay thrombectomy if you go and give thrombolysis.

Dr. Bruce Campbell:       So, the general principle is that getting the artery open faster by any means is better, and IV thrombolytic certainly has the potential to open the artery before thrombectomy in a proportion of patients, perhaps not that many, but it may also facilitate the thrombectomy. So, in the randomized trials, reperfusion after the thrombectomy was significantly better when patients had had bridging thrombolytic despite a low rate of pre-endovascular reperfusion. Other reasons for giving the lytics are the potential safety net it provides if the thrombectomy procedure is unexpectedly delayed or fails to get the artery open, and there's also this potential for lytics to dissolve distal embolic fragments and perhaps improve microvascular reperfusion.

Dr. Negar Asdaghi:         So, great. So, let me summarize for our listeners what you mentioned. First off, so these are arguments in favor of giving lytics. As you mentioned, we're not really wasting time. These processes occur in parallel, so it's not like we're wasting time in giving a therapy that is potentially not as efficacious as thrombectomy is. And number two, we have improved the possibility of early reperfusion, perhaps, with the lytics. And if there are some fragments or distal clots that thrombectomy wouldn't have reached, then the lytics would. And then also there is also the chance that the thrombectomy might have failed in difficult access, and so on and so forth, and at least the patient has some chance of revascularization with the lytics. So, if these are the arguments for giving lytics, what are the arguments against giving lytics in this scenario?

Dr. Bruce Campbell:       The main argument is the potential to reduce both the intracerebral and systemic hemorrhagic complications. There's also potential cost saving by skipping thrombolytics. That's probably more relevant in low-resource settings, particularly when relatives may have to pay for the thrombolytic before treatment is initiated, and that can be burdensome and also potentially delay the thrombectomy. There's a theoretical concern about thrombus fragmentation with lytics and potential migration of the clot out of reach of the thrombectomy or to new territories. But final reperfusion, as I mentioned, was, on average, better with the patient having a lytic on board in the randomized trials.

Dr. Negar Asdaghi:         Perfect. And I want to highlight this issue of thrombus fragmentation because I think our readers will read more and more about this idea of, as you mentioned, fragmentation will potentially make an accessible clot for thrombectomy inaccessible. But I see that later in our questions, we're going to address that as part of the findings of randomized trials as well. So, these are some of the arguments for and against. And before we go to the randomized trials, I'd like to get an overview of what we knew as part of observational studies and non-randomized studies prior to more recent randomized trials on this topic.

Dr. Bruce Campbell:       There've been a couple of nice systematic reviews and meta-analyses of the observational data, and notably in most of these studies, the direct thrombectomy patients had contraindications to lytics, and that introduces confounding factors that are difficult to adjust for. For what that's worth, the functional independence, mortality outcomes were better in the bridging patients. Hemorrhage rates weren't always higher with the lytic, and one study by Jonathan Coutinho in JAMA Neurology for the SWIFT and STAR studies showed the opposite despite them having really careful adjustment for all the confounders they could think of. And the meta-analysis by Eva Mistry in Stroke did not detect a difference in symptomatic ICH between the direct and bridging strategies. One thing that should be less affected by the patient characteristics would be the technical efficacy outcomes, and it was interesting that in the observational data, the patients who'd had bridging lytic had higher mTICI 2b-3 rates and also fewer device passes.

Dr. Negar Asdaghi:         Okay. And now we do have further information with all of these new randomized trials. So, why don't we start with some of the earlier studies, the three, SKIP, DEVT, and DIRECT-MT, and start with those studies first before we move to some more recent European trials.

Dr. Bruce Campbell:       SKIP was performed in Japan, and it used the lower 0.6 milligram per kilogram dose of alteplase that's standard there, and DEVT and DIRECT-MT were performed in China. All three of them showed numerically similar functional outcomes with slight trends favoring direct thrombectomy. SKIP had a smaller sample size and did not meet its non-inferiority criteria, and the other two trials did meet their specified non-inferiority margin, but it could be argued those margins were overly generous. If you think about non-inferiority trials, we generally try to set a margin for non-inferiority such as lower 95% confidence interval for the trial intervention would sacrifice up to 50% of the reference treatment effect. And it's difficult to estimate the effect of alteplase in this specific population. But if you think of the Emberson meta-analysis of alteplase, overall zero to three hours alteplase versus placebo has a 10% effect size and mRS 0-1, three to four and a half hours of 5% effect size. And we regard that as clinically important. So, half of 5%, 2.5%, is a lot tighter margin than any of the direct randomized trials employed.

Dr. Negar Asdaghi:         So, Bruce, let me recap what you just mentioned. Two out of the three earlier trials seem to suggest that perhaps skipping IV therapy is the way to go rather than bridging as these two trials met the non-inferiority criteria if we believe that non-inferiority margins you mentioned. And now we have a couple of more trials, more recent trials. Can you tell us about these trials please?

Dr. Bruce Campbell:       MR CLEAN-NO IV in a European population did not demonstrate non-inferiority, and the point estimate slightly favored bridging. Interestingly, in that trial, the symptomatic intracerebral hemorrhage risk, which was one of the main drivers for trying this strategy, was 5.9% in the direct and 5.3 in the bridging group. So, there's no hint of benefit from dropping the lytic on that metric. SWIFT-DIRECT was more selective in only enrolling internal carotid and M1 occlusions, which had a lower chance of early recanalization with lytic. But the protocol also specified giving the full dose of lytic. In the other trials, it seems the alteplase infusion was often stopped once the patient was in the angio suite, so the full dose may not have been delivered. And despite very low pre-endovascular recanalization in that selected group in SWIFT-DIRECT, the end of procedure reperfusion was significantly better in the bridging group, which is a consistent finding across the trials and suggests that the lytic may improve the thrombectomy outcome.

Dr. Bruce Campbell:       DIRECT-SAFE, the final of those trials, was interesting in that the patients were enrolled roughly 50:50 from Australia, New Zealand, versus Asia. And in contrast to the original three randomized trials in Asian patients, DIRECT-SAFE found a significant benefit of bridging lytic in Asian patients. So, it'd be very interesting to see the results of the IRIS individual patient data meta-analysis, but we may not find a difference in Asian versus Caucasian patients despite those initial trials and despite substantial differences in the prevalence of intracranial atherosclerosis, which has often been proposed as something that would increase the risk of having bridging thrombolytic on board.

Dr. Bruce Campbell:       The original study level estimate of symptomatic hemorrhage had a borderline significant 1.8% absolute reduction in the direct group. Whether those data were not all core lab adjudicated and the final analysis may show a smaller difference than that. Notably, given that trend with symptomatic intracerebral hemorrhage, mortality did not differ significantly, and, in fact, the trend favored bridging patients. So, the symptomatic hemorrhage slight trend into increase did not translate into any hint of increased mortality.

Dr. Negar Asdaghi:         So, Bruce, a lot of information, and I need a recap for me. So, let me try to recap some of the things you said, and please jump in. So, so far, the newer data really basically don't show us any convincing evidence that skipping is the way to go, and direct endovascular we really don't have data in favor of going directly to the angio suite. And the jury is still out regarding an increase in the symptomatic intracerebral hemorrhage rate amongst those that actually are pre-treated with IV therapy. Is that correct?

Dr. Bruce Campbell:       That's correct. So, none of the three recent trials met their non-inferiority margins. And again, we had this issue of relatively generous non-inferiority margins, and the symptomatic hemorrhage, it would make sense that there's a small difference, but it's not really been borne out in the data to be statistically significant at this stage. And again, this individual patient data meta-analysis is keenly awaited to get the most accurate estimate on that.

Dr. Negar Asdaghi:         So, while we wait that, I'm going to digress a little bit and ask you a question that's not addressed in the paper that you have in this issue of the journal, and that's the CHOICE trial. So, by now, we have the results of CHOICE trial. Do you mind first give us a brief overview of what CHOICE was and how you feel that the results of CHOICE would affect this field of direct versus bridging in general?

Dr. Bruce Campbell:       CHOICE is a very interesting study in that it tested giving the intra-arterial lytic at the end of a thrombectomy procedure that had achieved an mTICI 2b or better, which is what we traditionally regarded as angiographic success. The idea was to improve microvascular flow, and that may be the case. The trial was terminated early due to logistic reasons and showed a very large effect size that requires replication. The subgroup analyses are interesting in that the benefits seem to mostly accrue in patients who'd not already had intravenous lytic.

Dr. Bruce Campbell:       So, perhaps giving the IV lytic before thrombectomy can still benefit patients after the thrombectomy, as well as achieving early recanalization in a proportion of patients and perhaps facilitating the thrombectomy. The other issue to address with the DIRECT trials is that with the exception of a few patients in DIRECT-SAFE, the comparator was alteplase and not tenecteplase. And we have data from EXTEND-IA TNK that tenecteplase bridging is not just non-inferior, but superior to alteplase bridging. There's an ongoing Brazilian trial of exactly that, tenecteplase versus the direct approach, which will be very interesting.

Dr. Negar Asdaghi:         So, great, Bruce. I just want to repeat this segment again for our listeners. So, CHOICE is a very interesting study, looked at giving intraarterial alteplase to patients after endovascular therapy was completed and after they'd already achieved the complete and successful revascularization, and the trial was terminated early because of logistic reasons. So, we have to keep in mind, this was a smaller study, early termination, but the effect size was pretty large in favor of giving lytics.

Dr. Negar Asdaghi:         So, what you mentioned is interesting, and I think that it's really worth paying attention to, that the majority of the benefits seem to have occurred from intraarterial thrombolytics in patients that have not been given intravenous lytics prior to endovascular therapy. So, in other words, you need some sort of lytics either before or after the endovascular thrombectomy to achieve that ultimate improved outcome. So, moving forward now from the randomized trials that we have on bridging versus direct thrombectomy, you have mentioned in the paper some interesting subgroups that may benefit or not benefit as much from bridging versus direct thrombectomy. Do you want to elaborate a little more about those subgroup analyses?

Dr. Bruce Campbell:       The idea of precision selection or individualized treatment is being talked about a lot given there didn't seem to be much overall difference between strategies in the randomized trials, but it's important to note that the randomized trial actually disadvantages the bridging group by delaying lytic until the patient was firstly confirmed eligible for thrombectomy and then consented and randomized. Putting that aside, if we could identify a subgroup who clearly benefit from skipping lytic and, importantly, identify them without delaying lytic for those who likely benefit, that's clearly attractive.

Dr. Bruce Campbell:       Currently, I'd say we have not identified that kind of subgroup, and the planned IRIS individual patient data meta-analysis will be critical for that. Patients with a large ischemic core are one potential group where there's a high risk of bleeding hypothesized. To date, there is no definitive data to indicate the risk is lower with the direct approach. Patients who need stents certainly may benefit from not having a lytic on board because they often need adjuvant antithrombotics that could increase the bleeding risk. But the question there is whether we can confidently identify those patients before the procedure, and I think that's unclear at this stage. Patients with really large clot burdens and proximal occlusions have sometimes been said not to benefit from IV lytic based on the low rates of pre-endovascular reperfusion, but the randomized trials really hinted other benefits like this potential facilitative thrombectomy. So, that hypothesis may be insecure as well.

Dr. Negar Asdaghi:         And how about age? Have you come across and has there been any signal towards an impact or interaction between age and benefit from pre-endovascular thrombectomy and thrombolytics?

Dr. Bruce Campbell:       It's an interesting question because age has not generally been a treatment effect modifier in previous stroke studies with thrombolytics and thrombectomy, and the individual direct thrombectomy trials that have reported subgroups haven't shown any convincing heterogeneity by age. There's certainly no indication that older patients are at risk from bridging in what I've seen so far.

Dr. Negar Asdaghi:         So, this question comes up in clinical practice all the time, that a person's older, perhaps more atrophy, more vascular risk factors and white matter disease, and they're more prone, so to speak, of having a symptomatic intracerebral hemorrhage. So, what you're saying is, from the data we have, there's really no signal in favor of withholding pre-thrombectomy lytics in this population. So, it's important to know this. Bruce, what should be our final takeaway message from this study?

Dr. Bruce Campbell:       I tend to agree with the recent European Stroke Organization and ESMINT guideline that for now, patients should receive lytic as early as possible and in parallel with the decision to perform thrombectomy such that neither treatment delays the other. I think if we can identify a subgroup that benefits from direct thrombectomy, and that's confirmed in the individual patient data and meta-analysis, and we can identify them without disadvantaging the majority of patients, and also that the ongoing improvements in IV lytic strategies don't render the existing trial data obsolete, then we may, in future, skip lytic for some patients, but we are not there yet.

Dr. Negar Asdaghi:         So, that's amazing, Bruce. We look forward to reviewing the paper and individual data meta-analysis and interviewing you, hopefully at a better hour your time, on that. Thank you very much for joining us on the podcast today.

Dr. Bruce Campbell:       Thanks again for the invitation. It's been great talking to you.

Dr. Negar Asdaghi:         Thank you.

Dr. Negar Asdaghi:         And this concludes our podcast for the June 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including three very interesting images that are presented as part of a new article type, Stroke Images, and a special report in Comments and Opinions section on "Bias in Stroke Evaluation: Rethinking the Cookie Theft Picture." June is the month of Pride, and in spirit of equality, we hope to do our part to reduce all biases in stroke processes of care, diagnosis, and outcomes as we continue to stay alert with Stroke Alert.

Dr. Negar Asdaghi:         This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 17 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the June 2022 issue of Stroke: “Vitamin D Enhances Hematoma Clearance and Neurologic Recovery in Intracerebral Hemorrhage” and “Acute Ischemic Stroke, Depressed Left Ventricular Ejection Fraction, and Sinus Rhythm: Prevalence and Practice Patterns.” She also interviews Dr. Bruce Campbell on his article “Role of Intravenous Thrombolytics Prior to Endovascular Thrombectomy.”

Dr. Negar Asdaghi:         Let's start with some questions.

1) Is vitamin D that golden key to recovery from intracerebral hemorrhage?

2) Endovascular therapies seem to have prevailed where thrombolytics have failed. In the era of fast and furious thrombectomy, what is the role of pre-thrombectomy thrombolysis?

3) And finally, 20 years of clinical research has failed to demonstrate the superiority of anticoagulation over antiplatelet therapies for treatment of patients in sinus rhythm with low left ventricular ejection fraction, and yet, our practice patterns have not changed. Why do we remain resolute in prescribing anticoagulation despite the lack of evidence?

We're back here to tackle the toughest questions with our Stroke Alert Podcast because this is the latest in Stroke. Stay with us.

Dr. Negar Asdaghi:         Welcome back to another extremely motivating Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The June 2022 issue of Stroke contains a number of interesting articles. As part of our Advances in Stroke, we have two articles, one on the topic of cost-effectiveness of stroke care to inform health policy and the second on the current state and the future of emerging stroke therapies. As part of our Original Contributions category, we have an interesting study by Dr. [Ben] Assayag and colleagues from the Department of Neurology at Tel Aviv Sourasky Medical Center, where we learned that just over 10% of patients with TIA and stroke developed post-traumatic stress disorder, or PTSD. Higher presenting stroke severity, preexisting white matter disease, and having anxious coping styles are risk factors for development of post-stroke PTSD.

Dr. Negar Asdaghi:         In another Original Contribution, by Dr. Daehoon Kim and colleagues from Yonsei University College of Medicine in Seoul, South Korea, we read with interest on the topic of whether or not we should be anticoagulating frail patients with atrial fibrillation. In this large population-based cohort, which included patients with atrial fibrillation older than 65 years of age with frailty as defined by a score of equal or greater than five on Hospital Frailty Risk Score, we learned that despite their frailty, patients with atrial fibrillation still significantly benefit from oral anticoagulation therapy. In this study, those treated with anticoagulation had lower net adverse clinical events as compared to those untreated. We also learned that direct oral anticoagulants provided lower incidence of stroke, bleeding, and mortality over Coumadin. This paper really provided practical information on treatment of frail patients with atrial fibrillation. So, I encourage you to review these papers in addition to listening to our podcast today. Later in the podcast, I have the great pleasure of interviewing Dr. Bruce Campbell from University of Melbourne in Australia on an especially timely topic, that is the role of intravenous thrombolytics prior to endovascular therapy. Dr. Campbell is a leading authority on the topic, and his interview does not disappoint. But first, with these two articles.

Dr. Negar Asdaghi:         In the setting of intracerebral hemorrhage, or ICH, aside from the primary brain insult that occurs at the time of hemorrhage, secondary brain injuries continue for days and sometimes to months mostly due to the pathological response of the brain to byproducts of hematoma lysis or RBC degradation products. Today, the majority of spontaneous ICH cases are not surgically evacuated, so we rely on the body's own ability to clear blood for hematoma clearance, and obviously the faster the clearance, the better the outcome. Erythrophagocytosis by monocyte-derived macrophages contributes to hematoma clearance and ultimately to the functional recovery from ICH. So, it's conceivable that therapeutic approaches to enhance the endogenous erythrophagocytosis can potentially improve ICH outcomes. Vitamin D has been known to have variety of functions within the central nervous system, and it turns out that it may also be one such therapeutic option to improve the much needed erythrophagocytosis in intracerebral hemorrhage.

Dr. Negar Asdaghi:         In the current issue of the journal, in the study titled "Vitamin D Enhances Hematoma Clearance and Neurologic Recovery in Intracerebral Hemorrhage," a group of researchers led by Dr. Jiaxin Liu from the Department of Surgery at Queen Mary Hospital at the University of Hong Kong studied the effects of oral vitamin D administered two hours after the induction of hematoma in a rodent model of ICH using direct collagenase injection into the striatum of the mouse. Eighty-nine young mice and 78 middle-aged mice were included in the study and randomly divided into three groups. Group one were sham-operated mice; group two, ICH mice treated with vehicle, which was corn oil; and group three, vitamin D-treated ICH mice. In the third group, 1000 international unit per kg of vitamin D diluted in corn oil was administered orally using a pipette two hours after the induction of ICH to mice, and then daily afterwards. And here are their top three findings of this study.

Dr. Negar Asdaghi:         Number one, vitamin D-treated mice did better than vehicle on two neurobehavioral tests that were completed in the study. On the cylinder test, treatment with vitamin D significantly alleviated the asymmetric usage of four limbs at day seven, and vitamin D elongated the duration that the mice could run on the accelerated rod at day 10 on the rotarod test.

Dr. Negar Asdaghi:         Number two, in terms of hematoma resolution and perihematoma edema, it's an issue that we deal with, with ICH, they used MRI imaging for edema measurement on T2-weighted images, and then sacrificed the mice and used digital quantification of hematoma volume with fresh brain specimens. And they found that treatment with vitamin D significantly alleviated both the ICH-associated brain swelling on MR and resulted in significant reduction in hematoma volume on the fresh brain specimens when compared with the vehicle-treated group at day three and day five.

Dr. Negar Asdaghi:         And finally, their third main finding is in terms of erythrophagocytosis. So, the pathway that is mediated by the monocyte-derived macrophages is an endogenous pathway, that is, PPAR-γ (which stands for peroxisome proliferator-activated receptor γ) and its downstream scavenger receptor CD36 mediated. This pathway is essential for directing the endogenous erythrophagocytosis. Using flow cytometry, they found that vitamin D-treated mice had more mature macrophages expressing the scavenger receptor CD36, which was not expressed by the undifferentiated monocytes.

Dr. Negar Asdaghi:         Western blot analysis confirmed that vitamin D treatment increased the tissue levels of CD36 and the upstream PPAR-γ levels in the brain at day five after collagenase model. Locally, vitamin D-enriched phagocytes that were positive for PPAR-γ and CD36 in the perihematoma regions. So, in summary, vitamin D increased the number of mature macrophages rather than undifferentiated monocytes in the perihematoma region and accelerated the differentiation of reparative macrophages from bone marrow-derived monocytes. So, bottom line is that in vitamin D, we have a simple, accessible, and well-tolerated agent to improve both the ICH outcomes and enhance hematoma resolution, but this we all observed in rodents. So, we stay tuned with interest to find out whether the same success will be seen in humans treated with vitamin D after intracerebral hemorrhage.

Dr. Negar Asdaghi:         Patients with depressed left ventricular ejection fraction, or low EF, are at risk of development of ischemic stroke even if they remain in sinus rhythm. The optimal antithrombotic treatment for these patients is still unknown. Over the past two decades, we have a number of randomized trials studying the efficacy of oral anticoagulation, predominantly Coumadin, over aspirin therapy in prevention of all forms of stroke, that is ischemic and hemorrhagic, and death in patients with a low EF in sinus rhythm.

Dr. Negar Asdaghi:         The meta-analysis of WASH, HELAS, WATCH, and WARCEF trials showed that treatment of low ejection fraction patients in sinus rhythm with Coumadin does reduce the subsequent risk of stroke, but it comes at the cost of a higher major bleeding risk in this population. The COMMANDER HF clinical trial published in New England Journal of Medicine in October 2018 studied whether low-dose rivaroxaban at 2.5 milligram BID was superior to placebo in patients with recent worsening of chronic heart failure, reduced ejection fraction, coronary artery disease, but no atrial fibrillation, and very similar to its prior counterparts, it did not show that rivaroxaban was associated with a lower rate of combined death, myocardial infarction, or stroke as compared to placebo. But very similar to prior studies, it also showed that rivaroxaban-treated patients had a lower risk of subsequent ischemic stroke. This poses a conundrum for stroke neurologists treating patients with this condition, especially after they present with an embolic-appearing stroke. So, the question is, how often do we encounter this situation, and what do we do in routine practice? We know that when there is equipoise, there's practice variation.

Dr. Negar Asdaghi: In the current issue of the journal, in the study titled "Acute Ischemic Stroke, Depressed Left Ventricular Ejection Fraction, and Sinus Rhythm," Dr. Richa Sharma from the Department of Neurology at Yale School of Medicine and colleagues examined the prevalence of heart failure with sinus rhythm among hospitalized patients with acute ischemic stroke and the physician's practice patterns with regard to the choice of antithrombotics in this population.

Dr. Negar Asdaghi:         So, let's look at their study. The study was comprised of five separate study cohorts of hospitalized acute ischemic stroke patients in the Greater Cincinnati Northern Kentucky Stroke Study for the year 2005, 2010, and 2015, and then four additional academic hospital-based cohorts in the United States during different timeframes. These were the Massachusetts General Hospital from 2002 to 2016, Rhode Island Hospital from 2016 to 2018, Yale-New Haven Hospital 2015 to 2017, and Cornell Acute Stroke Academic Registry from 2011 to 2018. All of these cohorts combined contributed to the 19,155 total number of patients in this study, which included over 14,000 patients that had documented left ventricular ejection fraction. Amongst those, 1,426 had a depressed EF and were included in this study. The investigator obviously excluded those with documented atrial fibrillation and flutter. And so the sample size for this analysis was 805 patients. And here are their main results.

Dr. Negar Asdaghi:         The overall prevalence of this condition, that is low ejection fraction and sinus rhythm, among hospitalized acute ischemic stroke patients was 5%. It varied slightly between the different cohorts in this study from 4 to 6%. In terms of the antithrombotic treatment patterns, this information was available in close to 500 patients in the cohort. Overall, 59% of patients were discharged on an antiplatelet treatment alone, and 41% on anticoagulation. But these percentages significantly varied between the different institutions and was as low as 22% in one of the cohorts and as high as 45% in another cohort.

Dr. Negar Asdaghi:         So, what were the factors that were associated with the use of anticoagulation at discharge? They found that the absolute percentage of left ventricular ejection fraction and the presenting NIH Stroke Scales were associated with anticoagulation use. That is, the lower the percentage of EF and the higher the presenting NIH Stroke Scale, the more likely physicians were to discharge the patients on an anticoagulation in univariate analysis, but in multivariate analysis, only the study site and presenting NIH Stroke Scale over eight were independently associated with anticoagulation use.

Dr. Negar Asdaghi:         Now, interestingly, 2002 to 2018, which was their overall study period, was a time during which some of the largest and neutral randomized trials on the topic of anticoagulation versus antiplatelet were published, including the WATCH and the WARCEF trial. But the authors found no temporal variation in anticoagulation practice patterns before and after the publication of the results of these trials. So, it appears that we didn't change our minds. So, overall, we have some important takeaway messages from this study. We learned that 5% of hospitalized acute ischemic stroke patients have low left ventricular ejection fraction and remain in sinus rhythm without atrial fibrillation. Today, over 40% of patients with this condition are anticoagulated at discharge despite the results of the randomized trials, but the practice is widely variable among different institutions, and a higher presenting NIH Stroke Scale is a significant predictor of anticoagulation use at discharge in this population.

Dr. Negar Asdaghi:         Almost 20 years after the approval of intravenous thrombolysis for treatment of patients with acute ischemic stroke, endovascular therapy was approved for treatment of select ischemic stroke patients with a large vessel occlusion. The two treatments are, therefore, entangled, as one was the standard of care while the second one was being tested. Therefore, all endovascularly treated patients enrolled in randomized trials would've received intravenous thrombolysis if eligible. Now, with the overwhelming success of endovascular therapy in achieving reperfusion in areas where IV thrombolysis has drastically failed, there're still critical questions regarding the added value of IV thrombolysis to endovascularly treated patients. The critical question remains as to whether eligible ischemic stroke patients who have immediate access to endovascular thrombectomy should receive prior IV thrombolysis, or should we skip the thrombolysis step altogether and just move to the angio suite as fast as possible. And there are, of course, arguments for and against each approach.

Dr. Negar Asdaghi:         In this issue of the journal, in an invited topical review titled "The Role of Intravenous Thrombolytics Prior to Endovascular Thrombectomy," we learn about these arguments as the authors go through a comprehensive review of the current literature on this issue. I'm joined today by the first author of this review, Dr. Bruce Campbell, to discuss this paper. Dr. Campbell absolutely needs no introduction to our Stroke listeners. He's a professor of neurology and head of neurology and stroke at Royal Melbourne Hospital, University of Melbourne, in Australia. He's a pioneer in the field of acute stroke therapies and acute neuroimaging. He has served as the lead investigator of multiple landmark randomized trials, including EXTEND-IA and EXTEND-IA TNK, and holds multiple leadership roles. He's the clinical director of the Stroke Foundation and co-chairs the Australian Stroke Guidelines Working Party and the coordinator of the National Brain School Training Program for Neurologists in Training. And, of course, last but not least, he's my friend. So, I'm delighted to welcome him to our podcast today. Top of the morning to you, Bruce, 6:00 a.m. in Melbourne. That's quite some dedication. Thank you for being here.

Dr. Bruce Campbell:       It's great to be with you. Thanks for the invitation.

Dr. Negar Asdaghi:         Congrats on the paper, really exciting topic. So, let's just start with this question as part of a case. We have a patient with an M1 occlusion, a large clinical syndrome presenting two hours out from their symptom onset, and we are at a hospital where the angio suite is ready. What are some of the benefits of basically spending time in giving IV thrombolytics first rather than quickly going to the angio suite?

Dr. Bruce Campbell:       I think a key element of this case is that the patient has presented directly to a hospital with immediate access to thrombectomy. Thrombolytic used in drip-and-ship transfer patients really isn't controversial, and the recent randomized trials excluded them. So, the debate's all about this context of bridging thrombolytics in patients presenting directly to a comprehensive stroke center. And you mentioned spending time giving lytics, but in fact, if you do things in parallel, that shouldn't be the case. It shouldn't delay thrombectomy if you go and give thrombolysis.

Dr. Bruce Campbell:       So, the general principle is that getting the artery open faster by any means is better, and IV thrombolytic certainly has the potential to open the artery before thrombectomy in a proportion of patients, perhaps not that many, but it may also facilitate the thrombectomy. So, in the randomized trials, reperfusion after the thrombectomy was significantly better when patients had had bridging thrombolytic despite a low rate of pre-endovascular reperfusion. Other reasons for giving the lytics are the potential safety net it provides if the thrombectomy procedure is unexpectedly delayed or fails to get the artery open, and there's also this potential for lytics to dissolve distal embolic fragments and perhaps improve microvascular reperfusion.

Dr. Negar Asdaghi:         So, great. So, let me summarize for our listeners what you mentioned. First off, so these are arguments in favor of giving lytics. As you mentioned, we're not really wasting time. These processes occur in parallel, so it's not like we're wasting time in giving a therapy that is potentially not as efficacious as thrombectomy is. And number two, we have improved the possibility of early reperfusion, perhaps, with the lytics. And if there are some fragments or distal clots that thrombectomy wouldn't have reached, then the lytics would. And then also there is also the chance that the thrombectomy might have failed in difficult access, and so on and so forth, and at least the patient has some chance of revascularization with the lytics. So, if these are the arguments for giving lytics, what are the arguments against giving lytics in this scenario?

Dr. Bruce Campbell:       The main argument is the potential to reduce both the intracerebral and systemic hemorrhagic complications. There's also potential cost saving by skipping thrombolytics. That's probably more relevant in low-resource settings, particularly when relatives may have to pay for the thrombolytic before treatment is initiated, and that can be burdensome and also potentially delay the thrombectomy. There's a theoretical concern about thrombus fragmentation with lytics and potential migration of the clot out of reach of the thrombectomy or to new territories. But final reperfusion, as I mentioned, was, on average, better with the patient having a lytic on board in the randomized trials.

Dr. Negar Asdaghi:         Perfect. And I want to highlight this issue of thrombus fragmentation because I think our readers will read more and more about this idea of, as you mentioned, fragmentation will potentially make an accessible clot for thrombectomy inaccessible. But I see that later in our questions, we're going to address that as part of the findings of randomized trials as well. So, these are some of the arguments for and against. And before we go to the randomized trials, I'd like to get an overview of what we knew as part of observational studies and non-randomized studies prior to more recent randomized trials on this topic.

Dr. Bruce Campbell:       There've been a couple of nice systematic reviews and meta-analyses of the observational data, and notably in most of these studies, the direct thrombectomy patients had contraindications to lytics, and that introduces confounding factors that are difficult to adjust for. For what that's worth, the functional independence, mortality outcomes were better in the bridging patients. Hemorrhage rates weren't always higher with the lytic, and one study by Jonathan Coutinho in JAMA Neurology for the SWIFT and STAR studies showed the opposite despite them having really careful adjustment for all the confounders they could think of. And the meta-analysis by Eva Mistry in Stroke did not detect a difference in symptomatic ICH between the direct and bridging strategies. One thing that should be less affected by the patient characteristics would be the technical efficacy outcomes, and it was interesting that in the observational data, the patients who'd had bridging lytic had higher mTICI 2b-3 rates and also fewer device passes.

Dr. Negar Asdaghi:         Okay. And now we do have further information with all of these new randomized trials. So, why don't we start with some of the earlier studies, the three, SKIP, DEVT, and DIRECT-MT, and start with those studies first before we move to some more recent European trials.

Dr. Bruce Campbell:       SKIP was performed in Japan, and it used the lower 0.6 milligram per kilogram dose of alteplase that's standard there, and DEVT and DIRECT-MT were performed in China. All three of them showed numerically similar functional outcomes with slight trends favoring direct thrombectomy. SKIP had a smaller sample size and did not meet its non-inferiority criteria, and the other two trials did meet their specified non-inferiority margin, but it could be argued those margins were overly generous. If you think about non-inferiority trials, we generally try to set a margin for non-inferiority such as lower 95% confidence interval for the trial intervention would sacrifice up to 50% of the reference treatment effect. And it's difficult to estimate the effect of alteplase in this specific population. But if you think of the Emberson meta-analysis of alteplase, overall zero to three hours alteplase versus placebo has a 10% effect size and mRS 0-1, three to four and a half hours of 5% effect size. And we regard that as clinically important. So, half of 5%, 2.5%, is a lot tighter margin than any of the direct randomized trials employed.

Dr. Negar Asdaghi:         So, Bruce, let me recap what you just mentioned. Two out of the three earlier trials seem to suggest that perhaps skipping IV therapy is the way to go rather than bridging as these two trials met the non-inferiority criteria if we believe that non-inferiority margins you mentioned. And now we have a couple of more trials, more recent trials. Can you tell us about these trials please?

Dr. Bruce Campbell:       MR CLEAN-NO IV in a European population did not demonstrate non-inferiority, and the point estimate slightly favored bridging. Interestingly, in that trial, the symptomatic intracerebral hemorrhage risk, which was one of the main drivers for trying this strategy, was 5.9% in the direct and 5.3 in the bridging group. So, there's no hint of benefit from dropping the lytic on that metric. SWIFT-DIRECT was more selective in only enrolling internal carotid and M1 occlusions, which had a lower chance of early recanalization with lytic. But the protocol also specified giving the full dose of lytic. In the other trials, it seems the alteplase infusion was often stopped once the patient was in the angio suite, so the full dose may not have been delivered. And despite very low pre-endovascular recanalization in that selected group in SWIFT-DIRECT, the end of procedure reperfusion was significantly better in the bridging group, which is a consistent finding across the trials and suggests that the lytic may improve the thrombectomy outcome.

Dr. Bruce Campbell:       DIRECT-SAFE, the final of those trials, was interesting in that the patients were enrolled roughly 50:50 from Australia, New Zealand, versus Asia. And in contrast to the original three randomized trials in Asian patients, DIRECT-SAFE found a significant benefit of bridging lytic in Asian patients. So, it'd be very interesting to see the results of the IRIS individual patient data meta-analysis, but we may not find a difference in Asian versus Caucasian patients despite those initial trials and despite substantial differences in the prevalence of intracranial atherosclerosis, which has often been proposed as something that would increase the risk of having bridging thrombolytic on board.

Dr. Bruce Campbell:       The original study level estimate of symptomatic hemorrhage had a borderline significant 1.8% absolute reduction in the direct group. Whether those data were not all core lab adjudicated and the final analysis may show a smaller difference than that. Notably, given that trend with symptomatic intracerebral hemorrhage, mortality did not differ significantly, and, in fact, the trend favored bridging patients. So, the symptomatic hemorrhage slight trend into increase did not translate into any hint of increased mortality.

Dr. Negar Asdaghi:         So, Bruce, a lot of information, and I need a recap for me. So, let me try to recap some of the things you said, and please jump in. So, so far, the newer data really basically don't show us any convincing evidence that skipping is the way to go, and direct endovascular we really don't have data in favor of going directly to the angio suite. And the jury is still out regarding an increase in the symptomatic intracerebral hemorrhage rate amongst those that actually are pre-treated with IV therapy. Is that correct?

Dr. Bruce Campbell:       That's correct. So, none of the three recent trials met their non-inferiority margins. And again, we had this issue of relatively generous non-inferiority margins, and the symptomatic hemorrhage, it would make sense that there's a small difference, but it's not really been borne out in the data to be statistically significant at this stage. And again, this individual patient data meta-analysis is keenly awaited to get the most accurate estimate on that.

Dr. Negar Asdaghi:         So, while we wait that, I'm going to digress a little bit and ask you a question that's not addressed in the paper that you have in this issue of the journal, and that's the CHOICE trial. So, by now, we have the results of CHOICE trial. Do you mind first give us a brief overview of what CHOICE was and how you feel that the results of CHOICE would affect this field of direct versus bridging in general?

Dr. Bruce Campbell:       CHOICE is a very interesting study in that it tested giving the intra-arterial lytic at the end of a thrombectomy procedure that had achieved an mTICI 2b or better, which is what we traditionally regarded as angiographic success. The idea was to improve microvascular flow, and that may be the case. The trial was terminated early due to logistic reasons and showed a very large effect size that requires replication. The subgroup analyses are interesting in that the benefits seem to mostly accrue in patients who'd not already had intravenous lytic.

Dr. Bruce Campbell:       So, perhaps giving the IV lytic before thrombectomy can still benefit patients after the thrombectomy, as well as achieving early recanalization in a proportion of patients and perhaps facilitating the thrombectomy. The other issue to address with the DIRECT trials is that with the exception of a few patients in DIRECT-SAFE, the comparator was alteplase and not tenecteplase. And we have data from EXTEND-IA TNK that tenecteplase bridging is not just non-inferior, but superior to alteplase bridging. There's an ongoing Brazilian trial of exactly that, tenecteplase versus the direct approach, which will be very interesting.

Dr. Negar Asdaghi:         So, great, Bruce. I just want to repeat this segment again for our listeners. So, CHOICE is a very interesting study, looked at giving intraarterial alteplase to patients after endovascular therapy was completed and after they'd already achieved the complete and successful revascularization, and the trial was terminated early because of logistic reasons. So, we have to keep in mind, this was a smaller study, early termination, but the effect size was pretty large in favor of giving lytics.

Dr. Negar Asdaghi:         So, what you mentioned is interesting, and I think that it's really worth paying attention to, that the majority of the benefits seem to have occurred from intraarterial thrombolytics in patients that have not been given intravenous lytics prior to endovascular therapy. So, in other words, you need some sort of lytics either before or after the endovascular thrombectomy to achieve that ultimate improved outcome. So, moving forward now from the randomized trials that we have on bridging versus direct thrombectomy, you have mentioned in the paper some interesting subgroups that may benefit or not benefit as much from bridging versus direct thrombectomy. Do you want to elaborate a little more about those subgroup analyses?

Dr. Bruce Campbell:       The idea of precision selection or individualized treatment is being talked about a lot given there didn't seem to be much overall difference between strategies in the randomized trials, but it's important to note that the randomized trial actually disadvantages the bridging group by delaying lytic until the patient was firstly confirmed eligible for thrombectomy and then consented and randomized. Putting that aside, if we could identify a subgroup who clearly benefit from skipping lytic and, importantly, identify them without delaying lytic for those who likely benefit, that's clearly attractive.

Dr. Bruce Campbell:       Currently, I'd say we have not identified that kind of subgroup, and the planned IRIS individual patient data meta-analysis will be critical for that. Patients with a large ischemic core are one potential group where there's a high risk of bleeding hypothesized. To date, there is no definitive data to indicate the risk is lower with the direct approach. Patients who need stents certainly may benefit from not having a lytic on board because they often need adjuvant antithrombotics that could increase the bleeding risk. But the question there is whether we can confidently identify those patients before the procedure, and I think that's unclear at this stage. Patients with really large clot burdens and proximal occlusions have sometimes been said not to benefit from IV lytic based on the low rates of pre-endovascular reperfusion, but the randomized trials really hinted other benefits like this potential facilitative thrombectomy. So, that hypothesis may be insecure as well.

Dr. Negar Asdaghi:         And how about age? Have you come across and has there been any signal towards an impact or interaction between age and benefit from pre-endovascular thrombectomy and thrombolytics?

Dr. Bruce Campbell:       It's an interesting question because age has not generally been a treatment effect modifier in previous stroke studies with thrombolytics and thrombectomy, and the individual direct thrombectomy trials that have reported subgroups haven't shown any convincing heterogeneity by age. There's certainly no indication that older patients are at risk from bridging in what I've seen so far.

Dr. Negar Asdaghi:         So, this question comes up in clinical practice all the time, that a person's older, perhaps more atrophy, more vascular risk factors and white matter disease, and they're more prone, so to speak, of having a symptomatic intracerebral hemorrhage. So, what you're saying is, from the data we have, there's really no signal in favor of withholding pre-thrombectomy lytics in this population. So, it's important to know this. Bruce, what should be our final takeaway message from this study?

Dr. Bruce Campbell:       I tend to agree with the recent European Stroke Organization and ESMINT guideline that for now, patients should receive lytic as early as possible and in parallel with the decision to perform thrombectomy such that neither treatment delays the other. I think if we can identify a subgroup that benefits from direct thrombectomy, and that's confirmed in the individual patient data and meta-analysis, and we can identify them without disadvantaging the majority of patients, and also that the ongoing improvements in IV lytic strategies don't render the existing trial data obsolete, then we may, in future, skip lytic for some patients, but we are not there yet.

Dr. Negar Asdaghi:         So, that's amazing, Bruce. We look forward to reviewing the paper and individual data meta-analysis and interviewing you, hopefully at a better hour your time, on that. Thank you very much for joining us on the podcast today.

Dr. Bruce Campbell:       Thanks again for the invitation. It's been great talking to you.

Dr. Negar Asdaghi:         Thank you.

Dr. Negar Asdaghi:         And this concludes our podcast for the June 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including three very interesting images that are presented as part of a new article type, Stroke Images, and a special report in Comments and Opinions section on "Bias in Stroke Evaluation: Rethinking the Cookie Theft Picture." June is the month of Pride, and in spirit of equality, we hope to do our part to reduce all biases in stroke processes of care, diagnosis, and outcomes as we continue to stay alert with Stroke Alert.

Dr. Negar Asdaghi:         This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 16 of the Stroke Alert Podcast, Dr. Negar Asdaghi highlights two articles from the May issue of Stroke: “Number of Affected Relatives, Age, Smoking, and Hypertension Prediction Score for Intracranial Aneurysms in Persons With a Family History for Subarachnoid Hemorrhage” and “Endovascular Treatment for Acute Ischemic Stroke With or Without General Anesthesia.” She also interviews Dr. Patrick Lyden on “The Stroke Preclinical Assessment Network: Rationale, Design, Feasibility, and Stage 1 Results.”

Dr. Negar Asdaghi:         Let's start with some questions.

1) How is it that stroke can be cured in rodents but not in humans?

2) Are we wasting time or gaining time with general anesthesia before endovascular thrombectomy?

3) My father had an aneurysmal subarachnoid hemorrhage, Doctor. What is my risk of having an aneurysm, and how often should we check for one?

We're back here with the Stroke Alert Podcast to tackle the toughest questions in the field because this is the best in Stroke. Stay with us.

Dr. Negar Asdaghi:         Welcome back to the May 2022 issue of the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. For the May 2022 issue of Stroke, we have a number of papers that I'd like to highlight. We have seven articles as part of our Focused Update on the topic of neuroimmunology and stroke, organized by our own Stroke editors, Drs. Johannes Boltze and Miguel Perez-Pinzon. We also have an interesting study by Dr. David Saadoun and colleagues from Sorbonne University in Paris, where we learn that in patients with Takayasu disease, how the delay in diagnosis, as defined by the time from symptom onset to the diagnosis being over one year, was significantly associated with development of ischemic cerebrovascular events. In the Comments and Opinions section, we have an interesting study by Dr. Goldenberg and colleagues from University of Toronto on the benefits of GLP-1 receptor agonists for stroke reduction in type 2 diabetes and why should stroke neurologists be familiar with this new class of diabetic medication.

Dr. Negar Asdaghi:         Later, in the interview section of the podcast, I have the great honor of interviewing Dr. Patrick Lyden, one of the founding fathers of thrombolytic therapy in stroke, as he walks us through the Stroke Preclinical Assessment Network and what his hopes are for the future of stroke therapy. I also ask him for some advice, and he did tell us about the view from the top, as he truly stands on the shoulder of giants. But first with these two articles.

Dr. Negar Asdaghi:         In a landmark population-based study out of Sweden that was published in Brain in 2008, we learned that the odds of development of aneurysmal subarachnoid hemorrhage for individuals with one first-degree relative with a prior history of aneurysmal subarachnoid hemorrhage was 2.15. For individuals with two affected first-degree relatives, the odds ratio was 51. So, it's not surprising that a great deal of anxiety is caused within a family when a relative has an aneurysmal subarachnoid hemorrhage, especially if that family member was young or another member of the family had the same condition before. This scenario is commonly followed by a number of inevitable questions: Should all family members of the affected individual be screened for presence of an intracranial aneurysm? If yes, how often should vascular imaging be performed, and should other aneurysmal risk factors, such as age, sex, smoking, and hypertension, be also considered in the screening decision-making? In this issue of the journal, as part of a derivation-validation study, a group of investigators, led by Dr. Charlotte Zuurbier from University Medical Center at Utrecht Brain Center in the Netherlands, studied the ability of a simple scoring system that was developed in their derivation cohort to predict the presence of an intracranial aneurysm on vascular imaging.

Dr. Negar Asdaghi:         They then tested the scoring model in their validation cohort. So, for their development cohort, they used data on 660 persons who were screened at the University Medical Center for presence of an intracranial aneurysm because they had two or more affected first-degree relatives with a prior history of aneurysmal subarachnoid hemorrhage. The median age of participants at the time of first screening was 40, and 59% were female.

Dr. Negar Asdaghi:         So, in this cohort, the investigators simply looked at factors that were independently associated with finding an aneurysm on vascular screening by their multivariate analysis. And they identified the following factors; the first factor was the number of affected relatives. Now, a reminder that all of these people in the cohort had at least two first-degree relatives with an aneurysmal subarachnoid hemorrhage. And they found that amongst these people, those that had three or more family members with aneurysmal subarachnoid hemorrhage were significantly more likely to have a positive screening test for intracranial aneurysm. The next factor was older age — the older that relative, the more likely their screening imaging was positive for an aneurysm — and the other independent factors were smoking and hypertension. So they created the NASH acronym; N for number of relatives, A for age, S for smoking, and H for hypertension. When assigning points for each of these factors, the NASH scoring system had a C statistics of 0.68 in predicting whether or not someone would have a positive test, which is an intracranial aneurysm.

Dr. Negar Asdaghi:         And now a reminder for our listeners that C statistics gives us the probability that a person with a certain condition, in this case, a certain NASH score, will have the outcome of interest, in this case, an aneurysm found by vascular imaging. In general, for C statistics, the closer we get to 1, the more robust is our predictive model. Values over 0.7 indicate that we have a good model, but values over 0.8 indicate a very strong model. So the NASH score, at 0.68, has a reasonably good capability in predicting who will or will not have an intracranial aneurysm if we complete the vascular imaging. But it's not a very strong model, and this should be kept in mind. Let's look at some of their numbers. In their development cohort, the probability of finding an intracranial aneurysm for a person who scored low on NASH, that is a young person who never smoked and is not hypertensive, was only 5%, whereas the probability of finding an intracranial aneurysm in a person who scored high on NASH, that is an older person in their 60s or 70s, with three or more affected relatives, who is hypertensive and a smoker, was 36%.

Dr. Negar Asdaghi:         So, then they tested this NASH score in their external validation cohort and found that the likelihood of identifying an aneurysm increased as expected along the range of predicted probabilities of NASH. That is, the higher the score, the more likely to find an aneurysm on screening with vascular imaging. And the C statistics in the validation cohort was slightly lower than the C statistics in the derivation cohort. So, the important lesson we learned from this study is that the risk of having an intracranial aneurysm in a person who has a first-degree family member with a prior history of aneurysmal subarachnoid hemorrhage is substantially different depending on their NASH score, and this should be taken into consideration when deciding on screening and counseling various family members of the affected patient or prioritizing who should be screened first in routine practice.

Dr. Negar Asdaghi:         The ideal anesthetic management during endovascular therapy is still unknown. A number of studies have compared the different anesthetic options available during thrombectomy, which include general anesthesia, or GA, conscious sedation, use of local anesthesia, and no sedation at all. The main argument for doing endovascular therapy under general anesthesia is that although this procedure will take some precious pre-thrombectomy time, it does result in strict immobility. And that is really ideal in the sense that it improves catheter navigation and interpretation of angiography, in addition to obviously providing a secure airway and, of course, avoiding the need to have to do an emergency intubation in case of procedural complications. The argument against general anesthesia is not only the issue of time but also the risk of hypotension and hemodynamic compromise, especially during induction, and the loss of very valuable neurological examination in a completely sedated patient during the procedure.

Dr. Negar Asdaghi:         The question is, does general anesthesia improve or worsen neurological and functional outcomes post-thrombectomy? Several smaller randomized trials have looked at this very question, mainly comparing GA to all other forms of sedation during thrombectomy, but they have yielded inconsistent findings regarding the three-month functional outcome.

Dr. Negar Asdaghi:         Some of them showed that patients under GA ended up doing better. Some showed no difference in the overall outcomes. But overall, their pooled analysis suggested that GA might be superior to the competing counterpart, which is the conscious sedation, and associated with better functional outcome. But these centers had highly specialized anesthesia teams, and it's possible that their findings may not be generalizable to routine practice. So, in this issue of the journal, using the Swiss Stroke Registry, Dr. Benjamin Wagner from the Department of Neurology at the University Hospital in Basel and colleagues report on the outcomes of endovascularly treated patients in the Swiss Stroke Registry receiving thrombectomy for an anterior circulation stroke with or without general anesthesia. The primary outcome was disability on the modified Rankin Scale after three months. For this study, they excluded one out of the nine centers in the registry that had lots of missing data on their three-month follow-up.

Dr. Negar Asdaghi:         And so, from 2014 to 2017, 1,284 patients across eight stroke centers in the registry were included in this study. Sixty-six percent received thrombectomy under general anesthesia. On baseline comparison, the patients in the GA group were older, had a higher NIH Stroke Scale on admission, had worse preclinical functional status, and more likely to have presented with multi-territorial ischemic stroke. So, many reasons as to why people who underwent general anesthesia would have a worse clinical outcome in this study. So, now let's look at their primary outcome. In the unadjusted model, the three-month modified Rankin Scale was significantly worse in the GA group as compared to the non-GA group, which is obviously expected given the differences in their baseline characteristics.

Dr. Negar Asdaghi:         But what was surprising was that the odds of having a higher mRS score was significantly greater still in the adjusted models. They also did propensity score matching analysis, and they found that the NIH Stroke Scale after 24 hours, and the odds of dependency and death and mortality were all higher in the adjusted model in the GA group. They also looked at a number of secondary outcomes and found that door-to-puncture time was longer in the GA group.

Dr. Negar Asdaghi:         And also these patients were more likely to be transferred to ICU after treatment as compared to the non-GA treated counterparts. The authors point out that these real-world data are in keeping with the findings from the HERMES meta-analysis, which included over 1,700 endovascularly treated patients, and two previously published large registry data, one from Italy, which included over 4,000 endovascularly treated patients, and one from Germany, including 5,808 patients, all of them showing a worse functional outcome in endovascular therapy if the treatment was performed under general anesthesia, as compared to all other forms of sedation or no sedation at all. Again, these findings are in contrast with the reassuring results of the randomized trials on this topic, specifically in contrast to the AnStroke, SIESTA, and GOLIATH randomized trials, which compare GA to conscious sedation, showing either neutral or positive results in favor of general anesthesia pre-thrombectomy.

Dr. Negar Asdaghi:         So, in summary, what we learned from this real-world, observational study is that general anesthesia was associated with worse functional outcome post-endovascular thrombectomy, independent of other confounders, which means that the jury is still out on the ideal form of anesthesia for an individual patient prior to endovascular therapy, and we definitely need larger, multicenter studies on this topic.

Dr. Negar Asdaghi:         There are over a thousand experimental treatments that have shown benefit in prevention of neurological disability in animal models of ischemic stroke but have failed to show the same efficacy in human randomized trials. In fact, to date, reperfusion therapies, either in the form of intravenous lytic therapies or endovascular treatments, are the only successful treatments available to improve clinical outcomes in patients who suffer from ischemic stroke, and stroke remains a leading cause of death and disability worldwide. How come stroke can be cured in rodents but not in humans? Are neuroprotective therapies, or as more correctly referred to, the cerebroprotective therapies, the epitome of bench-to-bedside translational research failure? And if this is true, what are the key contributors to the scientific conundrum, and how can this be averted in the future? This is the question that a remarkable group of neuroscientists, led by Dr. Patrick Lyden from University of Southern California, are hoping to answer.

Dr. Negar Asdaghi:         In this issue of the journal, these investigators describe the rationale, design, feasibility, and stage 1 results of their multicenter SPAN collaboration, which stands for the Stroke Preclinical Assessment Network. I'm joined today by Professor Lyden himself to discuss this collaboration. Now, Professor Lyden absolutely needs no introduction to our stroke community, but as always, introductions are nice. So, here we go. Dr. Lyden is a Professor of Physiology, Neuroscience, and Neurology at Zilkha Neurogenetic Institute, Keck School of Medicine, at USC. He has truly been a leader in the field of preclinical and clinical vascular research with over 30 years of experience in conducting studies and randomized trials, including conducting the pivotal NINDS clinical trial that led to the approval of the first treatment for acute ischemic stroke in 1996. Throughout his exemplary career, he has accumulated many accolades and is the recipient of multiple awards and honors, including the prestigious 2019 American Stroke Association William Feinberg Award for Excellence in Clinical Stroke. Good morning, Pat, it's truly an honor to welcome you to our podcast today.

Dr. Patrick Lyden:            Thanks, I'm glad to be here.

Dr. Negar Asdaghi:         Well, in the era of successful reperfusion therapies, it seems that the new generation of stroke neurologists and interventionalists have their eyes, so to speak, on the clock and are interested in opening the blood vessels and opening them fast. In the age of reperfusion treatments, why do we still need to talk about the role of cerebroprotective treatments?

Dr. Patrick Lyden:            Well, not to sound too glib about it, but not everybody gets better after a thrombectomy. So, thrombectomy is good, it's more effective than anything else that we've tried before, but there are a remaining number of patients with a residual disability. Not only that, and from a more scientific standpoint, thrombectomy offers us the opportunity now to combine cerebroprotective therapy with known reperfusion. Remember, before, we didn't know when the artery had opened, but now we do an embolectomy, we know there's reperfusion. It gives us the opportunity to know that we're combining our treatment with reperfusion.

Dr. Negar Asdaghi:         So, in the paper, you discussed how hundreds of treatments have been studied and shown efficacy in reducing neurological disability in animal models of stroke, and yet failed in human studies. In your opinion, what were the top two most disappointing studies in terms of clinical failure despite pre-clinical encouraging data?

Dr. Patrick Lyden:            Well, the first one I mentioned was personal because it was the first one that I led, and it was a molecule called clomethiazole that I had helped establish the rationale for in my very first grant. So, it was the first trial I led, it was multinational, and, of course, I firmly believed we were going to hit a home run, and we failed. But to the field, the real watershed moment in neuroprotective therapy was the so-called SAINT II Trial. SAINT II was a study of a drug called NXY-059, and it was the first drug that purportedly had satisfied all of the so-called STAIR criteria. The STAIR criteria came out of a roundtable between academics and industry on how to best qualify drugs preclinically before going to human trials. And the idea was, if you were a 10 out of 10 on the STAIR criteria, then you should win when you come to human clinical trials. And the SAINT II Trial, which I was a co-leader, a co-investigator, on, also failed.

Dr. Patrick Lyden:            And so many, many, many drugs had failed by that point. Tens of millions, if not a hundred million dollars, had been spent by industry, and SAINT II really caused the field to stop. Industry stopped investing in stroke; academic investment in stroke dried up. NIH funding became more difficult to get after SAINT II, and that really was sort of the really historical low moment in the development of treatment for stroke.

Dr. Negar Asdaghi:         I was a resident when SAINT II came out, and I remember that somber feeling.

Dr. Patrick Lyden:            It was a sad day.

Dr. Negar Asdaghi:         Yeah. So, in the paper, you outline a number of potential causes as to why this translational failure may have occurred. But you highlighted the absence of preclinical scientific rigor as the most responsible source. And you already alluded to this a little bit. Can you please tell us a bit more?

Dr. Patrick Lyden:            Absolutely. And first, of course, we have to say that the ideal clinical trial design is not available. We really don't know the absolute best way to test the drugs in human clinical trials. But leave that for another day.

Dr. Patrick Lyden:            On the preclinical side, what can we say we're doing wrong? We're not sure, but one thing that has been highlighted over and over is that we don't approach preclinical characterization with as much rigor as we should. What do I mean by that? Animal models recapitulate for us some of the biology of a stroke, but not all. For example, many, many times we test a drug in a young model, an animal that's quite young, corresponding to a late teenager in human terms. Well, that's ridiculous. Stroke occurs in elderly people, and so on. So, the NIH called in a landmark conference for additional rigor, enhanced rigor. And I should mention the STAIR criteria were a first attempt at this. STAIR put out guidelines that said animals should be elderly, the animals should be randomized, et cetera, et cetera. And so that didn't happen. Although the STAIR criteria were out there, very few laboratories really committed to full rigor. And so the NIH funded the Stroke Preclinical Assessment Network, SPAN, to implement every aspect that we could think of that would add the best possible scientific design, the utmost rigor. So, we implemented true blinded assessment, true randomization, complete case ascertainment where we follow every single subject in the study and account for dropouts and subjects that don't complete the treatment, and, most importantly, a proper statistical design with adequate power and very large numbers. And the hypothesis that we're testing is that additional rigor in SPAN will lead to a better positive predictive value when we think about drugs that should go forward for testing in human stroke trials.

Dr. Negar Asdaghi:         So, I think you already answered my next question, which was basically, why do you think SPAN is going to achieve what all others have failed to achieve? But I wanted to simplify and repeat what you mentioned. So, in simple terms, what SPAN is trying to do is to bring all preclinical research to a level of scientific rigor that was not necessarily present and make it a multicenter effort. And can you a little bit tell us about the different stages, again, of SPAN?

Dr. Patrick Lyden:            Well, I'm not arguing that all preclinical research needs to be done following a SPAN type of model. Where SPAN fits in is at the end of a development project. So, if you want to characterize the cellular and molecular mechanisms, you don't need to do all of this rigor that we're doing. Just study the drug in the lab and do the mechanistic studies that need to be done. If you want to do dose finding, it doesn't need to be done this way. But at the end of that, OK, first we establish the mechanism, that's the first stage. Then we establish the toxicity. Then we establish target engagement. At the end, we are looking for some evidence that the drug will have a beneficial effect on outcomes. And in previous animal models, the only outcome, generally, the most common outcome that was studied, was size of the stroke. But in humans, the FDA does not recognize stroke size as a valid outcome.

Dr. Patrick Lyden:            We look at function, most often measured with the Rankin score and the NIH Stroke Scale. So, we had to create a functional outcome, and then we had to study it at multiple laboratories to make sure we could replicate the effect across multiple sites. And we chose what's called a multi-arm, multi-stage (MAMS) statistical design. All the drugs start out in the experiment at the end of the first interim analysis, which is 25% of the sample size. We cull any compounds or treatments that appear futile are removed. Any that appear effective move on. At the end of the second stage, there's more culling. There's a total of four stages, and we're about to enter stage four, by the way. That's starting next week. And in stage four, there will be, at most, two, maybe only one treatment that has appeared non-futile and possibly effective for final characterization.

Dr. Negar Asdaghi:         So, really interesting. I just want to highlight two important comments that you mentioned for our listeners again. So this is multi-layer, as you mentioned, multi-arm, multi-stages. It's sort of filter by filter, just ensuring that what we're seeing, the efficacy we're seeing in preclinical studies, will potentially be replicated in clinical studies. And what you mentioned that's very important is outcomes that classically is measured in animal models are infarct volume that are obviously very important but not necessarily may translate to exactly what we look at in clinical studies, which is functional outcomes, modified Rankin score and NIH Stroke Scale. So, with that, I want to then come back to the treatments that are actually being studied as part of SPAN. You have six very different agents as part of SPAN, from tocilizumab to uric acid. Why do you think these therapies will work?

Dr. Patrick Lyden:            Well, my job as the PI of the coordinating center is to remain completely agnostic to the treatments. So, everybody's equal, and they all come in on an equal playing field. We actually have a mechanical treatment called remote ischemic conditioning, as well, and then five drugs. And these were selected through a peer review process at NIH. And then we were informed at the coordinating center what drugs we would be studying. Five drugs and one treatment. And then, of course, the challenge to us was to somehow create a blinded, randomized situation. Now, this turned out to be a fascinating, it's more mechanical, but how do you blind when some of the drugs are given orally, some are given intraperitoneally, some are given intravenously, some are given once, some are given multiple times? So, we had to work with the manufacturers and inventors of these drugs and figure out a way to package them, and in the paper, actually, there's a photograph in the appendix that shows we had to find these bottles that were amber-colored and how to load them and lyophilize the drug.

Dr. Patrick Lyden:            And it's actually pretty fascinating how we were able to get all of these different, wildly different therapies, as you say, into a paradigm where they could be tested one against another in a truly blinded, truly randomized way.

Dr. Negar Asdaghi:         Do you think you can go on record and say which one is your favorite?

Dr. Patrick Lyden:            My favorite drug's not even in SPAN. I am truly agnostic because where my heart is, is with a drug that I've been studying in my laboratory completely separately and not part of SPAN.

Dr. Negar Asdaghi:         All right, so we don't have a favorite. So, in a recent review article in Stroke, you commented on treatments used by ancient Persians, Greeks, and Romans to remedy the brain affected by stroke and how the future generation of physicians will look back at our current practices of stroke with the same, how you said, awe and bemusement we hold for Galen, Aristotle, and Avicenna. How do you think stroke will be treated in the year 2222?

Dr. Patrick Lyden:            Well, first of all, and to be serious for just one moment, 200 years from now, I worry more about the climate than about medicine. And I really believe our biggest efforts need to be spent on saving the planet. But assuming we make it that long, obviously diagnostic methods will be completely different. Using ionizing radiation to scan the body will be laughed at by physicians in the future. There'll be detection technologies that aren't even on our radar yet today. And then treatments will be cellular focused and regionally focused. We give a drug through a vein and it circulates throughout the entire body, and I'm sure physicians in the future will find a way to somehow get treatment into the part of the body that's injured, not the whole body. And then, who knows? All we can say is they will laugh at us in the same way that we laugh at Theodoric the Barber of York.

Dr. Negar Asdaghi:         Let's move on from the future to the past. You're arguably one of the founding fathers of reperfusion therapies. You were instrumental in getting intravenous lytic therapy approved in 1996. It literally took the field 20 years for the next treatment to be approved, that's endovascular treatment. If you could go back in time and give your young self an advice on the subject of research, of course, design and execution, what advice would you give yourself?

Dr. Patrick Lyden:            Don't listen to old guys. We got a lot of advice from gray-bearded folks back when we were putting together the tPA trial, and fortunately we ignored some very bad advice and did what we imagined was the right thing to do as young, headstrong up-and-comers do. The other thing is, we really believed that by publishing our science very objectively, without editorial comment, we would be listened to. And that was dead wrong. So, the data was printed in the New England Journal in a very neutral tone, and we felt people would read that data and they would start using tPA the day after the publication. And, as you say, it took 20 years for tPA to really gain widespread acceptance, thrombolytic therapy. Today, people view it as standard, but it wasn't that way at the beginning. And I would say to myself and my colleagues at that time, "Don't be afraid to promote a positive result." Yes, it has to be done with the utmost rigor, but once you have a positive result, there will be plenty of people around pretending they know more than you and telling the world why you are wrong. And it's very important to stand up for your science and stand up for your results and say, no, no, no, no, that interpretation is wrong. The data says what we said it says, and this is an effective treatment and should be used, as an example.

Dr. Negar Asdaghi:         What a great advice. Just be bold and say it loud and stand up for your science. Pat, it's been a pleasure interviewing you and having you on the podcast. We really look forward to watching your research. Bring, let me say it again, 2222 closer to now.

Dr. Patrick Lyden:            Thank you. Glad to be here.

Dr. Negar Asdaghi:         Thank you.

Dr. Negar Asdaghi:         And this concludes our podcast for the May 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including two articles on quality improvement in stroke and neurohospitalist—inpatient teleneurology, which comes as part of our Advances in Stroke series prepared by our section editors. And as we close our podcast today, let's take a moment and ask ourselves the same question that I asked Dr. Lyden earlier. What is the next frontier in stroke treatment? Past reperfusion therapies, we have to find ways to preserve the neurons and not just the neurons, all components of the brain. So, is the future of stroke therapy cerebroprotection? Ever since the dawn of history, humanity has lived alongside of death with the conscious apprehension that as we age, we lose the very gift of life. But unlike our ancestors, the search for immortality isn't the quest to find a fountain of youth anymore. We learned that death is inevitable, but with medicine, we can reduce illness and suffering to prolong a life worth living, one with a healthy brain. And today we're closer than ever to this modern immortality with cerebroprotection in stroke, as we stay alert with Stroke Alert.

Dr. Negar Asdaghi:         This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 16 of the Stroke Alert Podcast, Dr. Negar Asdaghi highlights two articles from the May issue of Stroke: “Number of Affected Relatives, Age, Smoking, and Hypertension Prediction Score for Intracranial Aneurysms in Persons With a Family History for Subarachnoid Hemorrhage” and “Endovascular Treatment for Acute Ischemic Stroke With or Without General Anesthesia.” She also interviews Dr. Patrick Lyden on “The Stroke Preclinical Assessment Network: Rationale, Design, Feasibility, and Stage 1 Results.”

Dr. Negar Asdaghi:         Let's start with some questions.

1) How is it that stroke can be cured in rodents but not in humans?

2) Are we wasting time or gaining time with general anesthesia before endovascular thrombectomy?

3) My father had an aneurysmal subarachnoid hemorrhage, Doctor. What is my risk of having an aneurysm, and how often should we check for one?

We're back here with the Stroke Alert Podcast to tackle the toughest questions in the field because this is the best in Stroke. Stay with us.

Dr. Negar Asdaghi:         Welcome back to the May 2022 issue of the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. For the May 2022 issue of Stroke, we have a number of papers that I'd like to highlight. We have seven articles as part of our Focused Update on the topic of neuroimmunology and stroke, organized by our own Stroke editors, Drs. Johannes Boltze and Miguel Perez-Pinzon. We also have an interesting study by Dr. David Saadoun and colleagues from Sorbonne University in Paris, where we learn that in patients with Takayasu disease, how the delay in diagnosis, as defined by the time from symptom onset to the diagnosis being over one year, was significantly associated with development of ischemic cerebrovascular events. In the Comments and Opinions section, we have an interesting study by Dr. Goldenberg and colleagues from University of Toronto on the benefits of GLP-1 receptor agonists for stroke reduction in type 2 diabetes and why should stroke neurologists be familiar with this new class of diabetic medication.

Dr. Negar Asdaghi:         Later, in the interview section of the podcast, I have the great honor of interviewing Dr. Patrick Lyden, one of the founding fathers of thrombolytic therapy in stroke, as he walks us through the Stroke Preclinical Assessment Network and what his hopes are for the future of stroke therapy. I also ask him for some advice, and he did tell us about the view from the top, as he truly stands on the shoulder of giants. But first with these two articles.

Dr. Negar Asdaghi:         In a landmark population-based study out of Sweden that was published in Brain in 2008, we learned that the odds of development of aneurysmal subarachnoid hemorrhage for individuals with one first-degree relative with a prior history of aneurysmal subarachnoid hemorrhage was 2.15. For individuals with two affected first-degree relatives, the odds ratio was 51. So, it's not surprising that a great deal of anxiety is caused within a family when a relative has an aneurysmal subarachnoid hemorrhage, especially if that family member was young or another member of the family had the same condition before. This scenario is commonly followed by a number of inevitable questions: Should all family members of the affected individual be screened for presence of an intracranial aneurysm? If yes, how often should vascular imaging be performed, and should other aneurysmal risk factors, such as age, sex, smoking, and hypertension, be also considered in the screening decision-making? In this issue of the journal, as part of a derivation-validation study, a group of investigators, led by Dr. Charlotte Zuurbier from University Medical Center at Utrecht Brain Center in the Netherlands, studied the ability of a simple scoring system that was developed in their derivation cohort to predict the presence of an intracranial aneurysm on vascular imaging.

Dr. Negar Asdaghi:         They then tested the scoring model in their validation cohort. So, for their development cohort, they used data on 660 persons who were screened at the University Medical Center for presence of an intracranial aneurysm because they had two or more affected first-degree relatives with a prior history of aneurysmal subarachnoid hemorrhage. The median age of participants at the time of first screening was 40, and 59% were female.

Dr. Negar Asdaghi:         So, in this cohort, the investigators simply looked at factors that were independently associated with finding an aneurysm on vascular screening by their multivariate analysis. And they identified the following factors; the first factor was the number of affected relatives. Now, a reminder that all of these people in the cohort had at least two first-degree relatives with an aneurysmal subarachnoid hemorrhage. And they found that amongst these people, those that had three or more family members with aneurysmal subarachnoid hemorrhage were significantly more likely to have a positive screening test for intracranial aneurysm. The next factor was older age — the older that relative, the more likely their screening imaging was positive for an aneurysm — and the other independent factors were smoking and hypertension. So they created the NASH acronym; N for number of relatives, A for age, S for smoking, and H for hypertension. When assigning points for each of these factors, the NASH scoring system had a C statistics of 0.68 in predicting whether or not someone would have a positive test, which is an intracranial aneurysm.

Dr. Negar Asdaghi:         And now a reminder for our listeners that C statistics gives us the probability that a person with a certain condition, in this case, a certain NASH score, will have the outcome of interest, in this case, an aneurysm found by vascular imaging. In general, for C statistics, the closer we get to 1, the more robust is our predictive model. Values over 0.7 indicate that we have a good model, but values over 0.8 indicate a very strong model. So the NASH score, at 0.68, has a reasonably good capability in predicting who will or will not have an intracranial aneurysm if we complete the vascular imaging. But it's not a very strong model, and this should be kept in mind. Let's look at some of their numbers. In their development cohort, the probability of finding an intracranial aneurysm for a person who scored low on NASH, that is a young person who never smoked and is not hypertensive, was only 5%, whereas the probability of finding an intracranial aneurysm in a person who scored high on NASH, that is an older person in their 60s or 70s, with three or more affected relatives, who is hypertensive and a smoker, was 36%.

Dr. Negar Asdaghi:         So, then they tested this NASH score in their external validation cohort and found that the likelihood of identifying an aneurysm increased as expected along the range of predicted probabilities of NASH. That is, the higher the score, the more likely to find an aneurysm on screening with vascular imaging. And the C statistics in the validation cohort was slightly lower than the C statistics in the derivation cohort. So, the important lesson we learned from this study is that the risk of having an intracranial aneurysm in a person who has a first-degree family member with a prior history of aneurysmal subarachnoid hemorrhage is substantially different depending on their NASH score, and this should be taken into consideration when deciding on screening and counseling various family members of the affected patient or prioritizing who should be screened first in routine practice.

Dr. Negar Asdaghi:         The ideal anesthetic management during endovascular therapy is still unknown. A number of studies have compared the different anesthetic options available during thrombectomy, which include general anesthesia, or GA, conscious sedation, use of local anesthesia, and no sedation at all. The main argument for doing endovascular therapy under general anesthesia is that although this procedure will take some precious pre-thrombectomy time, it does result in strict immobility. And that is really ideal in the sense that it improves catheter navigation and interpretation of angiography, in addition to obviously providing a secure airway and, of course, avoiding the need to have to do an emergency intubation in case of procedural complications. The argument against general anesthesia is not only the issue of time but also the risk of hypotension and hemodynamic compromise, especially during induction, and the loss of very valuable neurological examination in a completely sedated patient during the procedure.

Dr. Negar Asdaghi:         The question is, does general anesthesia improve or worsen neurological and functional outcomes post-thrombectomy? Several smaller randomized trials have looked at this very question, mainly comparing GA to all other forms of sedation during thrombectomy, but they have yielded inconsistent findings regarding the three-month functional outcome.

Dr. Negar Asdaghi:         Some of them showed that patients under GA ended up doing better. Some showed no difference in the overall outcomes. But overall, their pooled analysis suggested that GA might be superior to the competing counterpart, which is the conscious sedation, and associated with better functional outcome. But these centers had highly specialized anesthesia teams, and it's possible that their findings may not be generalizable to routine practice. So, in this issue of the journal, using the Swiss Stroke Registry, Dr. Benjamin Wagner from the Department of Neurology at the University Hospital in Basel and colleagues report on the outcomes of endovascularly treated patients in the Swiss Stroke Registry receiving thrombectomy for an anterior circulation stroke with or without general anesthesia. The primary outcome was disability on the modified Rankin Scale after three months. For this study, they excluded one out of the nine centers in the registry that had lots of missing data on their three-month follow-up.

Dr. Negar Asdaghi:         And so, from 2014 to 2017, 1,284 patients across eight stroke centers in the registry were included in this study. Sixty-six percent received thrombectomy under general anesthesia. On baseline comparison, the patients in the GA group were older, had a higher NIH Stroke Scale on admission, had worse preclinical functional status, and more likely to have presented with multi-territorial ischemic stroke. So, many reasons as to why people who underwent general anesthesia would have a worse clinical outcome in this study. So, now let's look at their primary outcome. In the unadjusted model, the three-month modified Rankin Scale was significantly worse in the GA group as compared to the non-GA group, which is obviously expected given the differences in their baseline characteristics.

Dr. Negar Asdaghi:         But what was surprising was that the odds of having a higher mRS score was significantly greater still in the adjusted models. They also did propensity score matching analysis, and they found that the NIH Stroke Scale after 24 hours, and the odds of dependency and death and mortality were all higher in the adjusted model in the GA group. They also looked at a number of secondary outcomes and found that door-to-puncture time was longer in the GA group.

Dr. Negar Asdaghi:         And also these patients were more likely to be transferred to ICU after treatment as compared to the non-GA treated counterparts. The authors point out that these real-world data are in keeping with the findings from the HERMES meta-analysis, which included over 1,700 endovascularly treated patients, and two previously published large registry data, one from Italy, which included over 4,000 endovascularly treated patients, and one from Germany, including 5,808 patients, all of them showing a worse functional outcome in endovascular therapy if the treatment was performed under general anesthesia, as compared to all other forms of sedation or no sedation at all. Again, these findings are in contrast with the reassuring results of the randomized trials on this topic, specifically in contrast to the AnStroke, SIESTA, and GOLIATH randomized trials, which compare GA to conscious sedation, showing either neutral or positive results in favor of general anesthesia pre-thrombectomy.

Dr. Negar Asdaghi:         So, in summary, what we learned from this real-world, observational study is that general anesthesia was associated with worse functional outcome post-endovascular thrombectomy, independent of other confounders, which means that the jury is still out on the ideal form of anesthesia for an individual patient prior to endovascular therapy, and we definitely need larger, multicenter studies on this topic.

Dr. Negar Asdaghi:         There are over a thousand experimental treatments that have shown benefit in prevention of neurological disability in animal models of ischemic stroke but have failed to show the same efficacy in human randomized trials. In fact, to date, reperfusion therapies, either in the form of intravenous lytic therapies or endovascular treatments, are the only successful treatments available to improve clinical outcomes in patients who suffer from ischemic stroke, and stroke remains a leading cause of death and disability worldwide. How come stroke can be cured in rodents but not in humans? Are neuroprotective therapies, or as more correctly referred to, the cerebroprotective therapies, the epitome of bench-to-bedside translational research failure? And if this is true, what are the key contributors to the scientific conundrum, and how can this be averted in the future? This is the question that a remarkable group of neuroscientists, led by Dr. Patrick Lyden from University of Southern California, are hoping to answer.

Dr. Negar Asdaghi:         In this issue of the journal, these investigators describe the rationale, design, feasibility, and stage 1 results of their multicenter SPAN collaboration, which stands for the Stroke Preclinical Assessment Network. I'm joined today by Professor Lyden himself to discuss this collaboration. Now, Professor Lyden absolutely needs no introduction to our stroke community, but as always, introductions are nice. So, here we go. Dr. Lyden is a Professor of Physiology, Neuroscience, and Neurology at Zilkha Neurogenetic Institute, Keck School of Medicine, at USC. He has truly been a leader in the field of preclinical and clinical vascular research with over 30 years of experience in conducting studies and randomized trials, including conducting the pivotal NINDS clinical trial that led to the approval of the first treatment for acute ischemic stroke in 1996. Throughout his exemplary career, he has accumulated many accolades and is the recipient of multiple awards and honors, including the prestigious 2019 American Stroke Association William Feinberg Award for Excellence in Clinical Stroke. Good morning, Pat, it's truly an honor to welcome you to our podcast today.

Dr. Patrick Lyden:            Thanks, I'm glad to be here.

Dr. Negar Asdaghi:         Well, in the era of successful reperfusion therapies, it seems that the new generation of stroke neurologists and interventionalists have their eyes, so to speak, on the clock and are interested in opening the blood vessels and opening them fast. In the age of reperfusion treatments, why do we still need to talk about the role of cerebroprotective treatments?

Dr. Patrick Lyden:            Well, not to sound too glib about it, but not everybody gets better after a thrombectomy. So, thrombectomy is good, it's more effective than anything else that we've tried before, but there are a remaining number of patients with a residual disability. Not only that, and from a more scientific standpoint, thrombectomy offers us the opportunity now to combine cerebroprotective therapy with known reperfusion. Remember, before, we didn't know when the artery had opened, but now we do an embolectomy, we know there's reperfusion. It gives us the opportunity to know that we're combining our treatment with reperfusion.

Dr. Negar Asdaghi:         So, in the paper, you discussed how hundreds of treatments have been studied and shown efficacy in reducing neurological disability in animal models of stroke, and yet failed in human studies. In your opinion, what were the top two most disappointing studies in terms of clinical failure despite pre-clinical encouraging data?

Dr. Patrick Lyden:            Well, the first one I mentioned was personal because it was the first one that I led, and it was a molecule called clomethiazole that I had helped establish the rationale for in my very first grant. So, it was the first trial I led, it was multinational, and, of course, I firmly believed we were going to hit a home run, and we failed. But to the field, the real watershed moment in neuroprotective therapy was the so-called SAINT II Trial. SAINT II was a study of a drug called NXY-059, and it was the first drug that purportedly had satisfied all of the so-called STAIR criteria. The STAIR criteria came out of a roundtable between academics and industry on how to best qualify drugs preclinically before going to human trials. And the idea was, if you were a 10 out of 10 on the STAIR criteria, then you should win when you come to human clinical trials. And the SAINT II Trial, which I was a co-leader, a co-investigator, on, also failed.

Dr. Patrick Lyden:            And so many, many, many drugs had failed by that point. Tens of millions, if not a hundred million dollars, had been spent by industry, and SAINT II really caused the field to stop. Industry stopped investing in stroke; academic investment in stroke dried up. NIH funding became more difficult to get after SAINT II, and that really was sort of the really historical low moment in the development of treatment for stroke.

Dr. Negar Asdaghi:         I was a resident when SAINT II came out, and I remember that somber feeling.

Dr. Patrick Lyden:            It was a sad day.

Dr. Negar Asdaghi:         Yeah. So, in the paper, you outline a number of potential causes as to why this translational failure may have occurred. But you highlighted the absence of preclinical scientific rigor as the most responsible source. And you already alluded to this a little bit. Can you please tell us a bit more?

Dr. Patrick Lyden:            Absolutely. And first, of course, we have to say that the ideal clinical trial design is not available. We really don't know the absolute best way to test the drugs in human clinical trials. But leave that for another day.

Dr. Patrick Lyden:            On the preclinical side, what can we say we're doing wrong? We're not sure, but one thing that has been highlighted over and over is that we don't approach preclinical characterization with as much rigor as we should. What do I mean by that? Animal models recapitulate for us some of the biology of a stroke, but not all. For example, many, many times we test a drug in a young model, an animal that's quite young, corresponding to a late teenager in human terms. Well, that's ridiculous. Stroke occurs in elderly people, and so on. So, the NIH called in a landmark conference for additional rigor, enhanced rigor. And I should mention the STAIR criteria were a first attempt at this. STAIR put out guidelines that said animals should be elderly, the animals should be randomized, et cetera, et cetera. And so that didn't happen. Although the STAIR criteria were out there, very few laboratories really committed to full rigor. And so the NIH funded the Stroke Preclinical Assessment Network, SPAN, to implement every aspect that we could think of that would add the best possible scientific design, the utmost rigor. So, we implemented true blinded assessment, true randomization, complete case ascertainment where we follow every single subject in the study and account for dropouts and subjects that don't complete the treatment, and, most importantly, a proper statistical design with adequate power and very large numbers. And the hypothesis that we're testing is that additional rigor in SPAN will lead to a better positive predictive value when we think about drugs that should go forward for testing in human stroke trials.

Dr. Negar Asdaghi:         So, I think you already answered my next question, which was basically, why do you think SPAN is going to achieve what all others have failed to achieve? But I wanted to simplify and repeat what you mentioned. So, in simple terms, what SPAN is trying to do is to bring all preclinical research to a level of scientific rigor that was not necessarily present and make it a multicenter effort. And can you a little bit tell us about the different stages, again, of SPAN?

Dr. Patrick Lyden:            Well, I'm not arguing that all preclinical research needs to be done following a SPAN type of model. Where SPAN fits in is at the end of a development project. So, if you want to characterize the cellular and molecular mechanisms, you don't need to do all of this rigor that we're doing. Just study the drug in the lab and do the mechanistic studies that need to be done. If you want to do dose finding, it doesn't need to be done this way. But at the end of that, OK, first we establish the mechanism, that's the first stage. Then we establish the toxicity. Then we establish target engagement. At the end, we are looking for some evidence that the drug will have a beneficial effect on outcomes. And in previous animal models, the only outcome, generally, the most common outcome that was studied, was size of the stroke. But in humans, the FDA does not recognize stroke size as a valid outcome.

Dr. Patrick Lyden:            We look at function, most often measured with the Rankin score and the NIH Stroke Scale. So, we had to create a functional outcome, and then we had to study it at multiple laboratories to make sure we could replicate the effect across multiple sites. And we chose what's called a multi-arm, multi-stage (MAMS) statistical design. All the drugs start out in the experiment at the end of the first interim analysis, which is 25% of the sample size. We cull any compounds or treatments that appear futile are removed. Any that appear effective move on. At the end of the second stage, there's more culling. There's a total of four stages, and we're about to enter stage four, by the way. That's starting next week. And in stage four, there will be, at most, two, maybe only one treatment that has appeared non-futile and possibly effective for final characterization.

Dr. Negar Asdaghi:         So, really interesting. I just want to highlight two important comments that you mentioned for our listeners again. So this is multi-layer, as you mentioned, multi-arm, multi-stages. It's sort of filter by filter, just ensuring that what we're seeing, the efficacy we're seeing in preclinical studies, will potentially be replicated in clinical studies. And what you mentioned that's very important is outcomes that classically is measured in animal models are infarct volume that are obviously very important but not necessarily may translate to exactly what we look at in clinical studies, which is functional outcomes, modified Rankin score and NIH Stroke Scale. So, with that, I want to then come back to the treatments that are actually being studied as part of SPAN. You have six very different agents as part of SPAN, from tocilizumab to uric acid. Why do you think these therapies will work?

Dr. Patrick Lyden:            Well, my job as the PI of the coordinating center is to remain completely agnostic to the treatments. So, everybody's equal, and they all come in on an equal playing field. We actually have a mechanical treatment called remote ischemic conditioning, as well, and then five drugs. And these were selected through a peer review process at NIH. And then we were informed at the coordinating center what drugs we would be studying. Five drugs and one treatment. And then, of course, the challenge to us was to somehow create a blinded, randomized situation. Now, this turned out to be a fascinating, it's more mechanical, but how do you blind when some of the drugs are given orally, some are given intraperitoneally, some are given intravenously, some are given once, some are given multiple times? So, we had to work with the manufacturers and inventors of these drugs and figure out a way to package them, and in the paper, actually, there's a photograph in the appendix that shows we had to find these bottles that were amber-colored and how to load them and lyophilize the drug.

Dr. Patrick Lyden:            And it's actually pretty fascinating how we were able to get all of these different, wildly different therapies, as you say, into a paradigm where they could be tested one against another in a truly blinded, truly randomized way.

Dr. Negar Asdaghi:         Do you think you can go on record and say which one is your favorite?

Dr. Patrick Lyden:            My favorite drug's not even in SPAN. I am truly agnostic because where my heart is, is with a drug that I've been studying in my laboratory completely separately and not part of SPAN.

Dr. Negar Asdaghi:         All right, so we don't have a favorite. So, in a recent review article in Stroke, you commented on treatments used by ancient Persians, Greeks, and Romans to remedy the brain affected by stroke and how the future generation of physicians will look back at our current practices of stroke with the same, how you said, awe and bemusement we hold for Galen, Aristotle, and Avicenna. How do you think stroke will be treated in the year 2222?

Dr. Patrick Lyden:            Well, first of all, and to be serious for just one moment, 200 years from now, I worry more about the climate than about medicine. And I really believe our biggest efforts need to be spent on saving the planet. But assuming we make it that long, obviously diagnostic methods will be completely different. Using ionizing radiation to scan the body will be laughed at by physicians in the future. There'll be detection technologies that aren't even on our radar yet today. And then treatments will be cellular focused and regionally focused. We give a drug through a vein and it circulates throughout the entire body, and I'm sure physicians in the future will find a way to somehow get treatment into the part of the body that's injured, not the whole body. And then, who knows? All we can say is they will laugh at us in the same way that we laugh at Theodoric the Barber of York.

Dr. Negar Asdaghi:         Let's move on from the future to the past. You're arguably one of the founding fathers of reperfusion therapies. You were instrumental in getting intravenous lytic therapy approved in 1996. It literally took the field 20 years for the next treatment to be approved, that's endovascular treatment. If you could go back in time and give your young self an advice on the subject of research, of course, design and execution, what advice would you give yourself?

Dr. Patrick Lyden:            Don't listen to old guys. We got a lot of advice from gray-bearded folks back when we were putting together the tPA trial, and fortunately we ignored some very bad advice and did what we imagined was the right thing to do as young, headstrong up-and-comers do. The other thing is, we really believed that by publishing our science very objectively, without editorial comment, we would be listened to. And that was dead wrong. So, the data was printed in the New England Journal in a very neutral tone, and we felt people would read that data and they would start using tPA the day after the publication. And, as you say, it took 20 years for tPA to really gain widespread acceptance, thrombolytic therapy. Today, people view it as standard, but it wasn't that way at the beginning. And I would say to myself and my colleagues at that time, "Don't be afraid to promote a positive result." Yes, it has to be done with the utmost rigor, but once you have a positive result, there will be plenty of people around pretending they know more than you and telling the world why you are wrong. And it's very important to stand up for your science and stand up for your results and say, no, no, no, no, that interpretation is wrong. The data says what we said it says, and this is an effective treatment and should be used, as an example.

Dr. Negar Asdaghi:         What a great advice. Just be bold and say it loud and stand up for your science. Pat, it's been a pleasure interviewing you and having you on the podcast. We really look forward to watching your research. Bring, let me say it again, 2222 closer to now.

Dr. Patrick Lyden:            Thank you. Glad to be here.

Dr. Negar Asdaghi:         Thank you.

Dr. Negar Asdaghi:         And this concludes our podcast for the May 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including two articles on quality improvement in stroke and neurohospitalist—inpatient teleneurology, which comes as part of our Advances in Stroke series prepared by our section editors. And as we close our podcast today, let's take a moment and ask ourselves the same question that I asked Dr. Lyden earlier. What is the next frontier in stroke treatment? Past reperfusion therapies, we have to find ways to preserve the neurons and not just the neurons, all components of the brain. So, is the future of stroke therapy cerebroprotection? Ever since the dawn of history, humanity has lived alongside of death with the conscious apprehension that as we age, we lose the very gift of life. But unlike our ancestors, the search for immortality isn't the quest to find a fountain of youth anymore. We learned that death is inevitable, but with medicine, we can reduce illness and suffering to prolong a life worth living, one with a healthy brain. And today we're closer than ever to this modern immortality with cerebroprotection in stroke, as we stay alert with Stroke Alert.

Dr. Negar Asdaghi:         This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 15 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the April 2022 issue of Stroke: “Kawasaki Disease May Increase the Risk of Subsequent Cerebrovascular Disease” and “Effect of Moderate and Severe Persistent Hyperglycemia on Outcomes in Patients With Intracerebral Hemorrhage.” She also interviews Dr. François Gros-Louis about his article “Moyamoya Disease Susceptibility Gene RNF213 Regulates Endothelial Barrier Function.”

Dr. Negar Asdaghi:                       

1) How would you counsel the parent of a child who has just recovered from Kawasaki disease on their child's future risk of having a stroke?

2) Should we or should we not treat stress hyperglycemia in the setting of acute intracerebral hemorrhage?

3) What is the CRISPR-Cas9 gene editing technology? And why, if you haven't heard of it already, you most definitely should be listening to this podcast?

We're back here with the April issue of the Stroke Alert Podcast, and this is the latest in Stroke. Stay with us.

Dr. Negar Asdaghi:                        Welcome back to another extremely informative Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine, and your host for the monthly Stroke Alert Podcast. The April 2022 issue of Stroke contains a range of really exciting papers and topics. In the paper titled "Vascular Response to Spreading Depolarization Predicts Stroke Outcome," we have a really interesting in vivo mouse model of ischemic stroke, looking at the spreading patterns of cortical depolarization and the subsequent vascular response to this by way of hyperemia. The researchers from Zurich University, led by Dr. Binder and colleagues, walk us through how the patterns of hyperemia can actually predict the severity of subsequent ischemic injury.

Dr. Negar Asdaghi:                        In a separate paper in this issue of the journal, we're reminded of how the classic NIH Stroke Scale can underestimate the severity of neurological symptoms and outcomes in patients with posterior circulation infarcts. In the paper led by Dr. Alemseged and colleagues, the investigators from the Royal Melbourne Hospital in Australia evaluate the prognostic accuracy of the Posterior NIH Stroke Scale, which is the modified version of the classic NIH Stroke Scale, in predicting the outcomes of patients with posterior circulation infarcts.

Dr. Negar Asdaghi:                        I encourage you to review these papers in addition to listening to our podcast today. Later in the podcast, I have the great pleasure of interviewing Dr. François Gros-Louis from Laval University in Quebec to discuss the latest in gene editing technology and how this technology has helped his team unravel the biological function of RNF213 susceptibility gene in Moyamoya disease. But first with these two articles.

Dr. Negar Asdaghi:                        Kawasaki disease, which was first described in 1976, is an acute febrile illness predominantly affecting children younger than five years of age. In addition to fever, other clinical signs of the disease include rash, bilateral conjunctival injection, cervical lymphadenopathy, swelling of the hands and feet, and irritation and inflammation of the mouth, lips, and throat. Now, for those of us like me who are adult neurologists, here is a quick review of the pathophysiology of Kawasaki disease.

Dr. Negar Asdaghi:                        This is a medium vessel vasculopathy, most significantly affecting the coronary arteries, a vasculopathy that is characterized by three linked pathological processes, necrotizing arteritis, subacute to chronic vasculitis, and luminal myofibroblastic proliferation. So, simply put, these processes can lead to stenotic lesions in various vascular beds, which are affected by this disease.

Dr. Negar Asdaghi:                        And as we mentioned earlier, the most recognized vascular blood vessels affected by Kawasaki disease are the coronary arteries, which can lead to myocardial ischemia, infarction, and sudden death in these cases. However, involvement of other vascular beds, including cerebral vessels, are also increasingly reported as part of Kawasaki disease.

Dr. Negar Asdaghi:                        So, in the current issue of the journal, Dr. Chien-Heng Lin from the Division of Pediatric Pulmonology at China Medical University Children's Hospital in Taiwan and colleagues studied the subsequent risk of cerebrovascular events in patients with Kawasaki disease. Using the National Health Insurance Research Database of Taiwan, they collected data on 8467 children with Kawasaki disease from 2000 to 2012. And for each child with Kawasaki, data was also collected on four randomly selected non-Kawasaki disease children who were matched with the Kawasaki cohort for sex, urbanization level of residence, and parental occupation.

Dr. Negar Asdaghi:                        So, that gave them a sample size of over 33,000 children for their non-Kawasaki cohort. And then they compared the risk of subsequent stroke in children between the two cohorts. The study period for any given patient would end when the said patient was either diagnosed with a cerebrovascular disease or withdrew from the research database.

Dr. Negar Asdaghi:                        So, in terms of their demographics, 61% of patients in the Kawasaki group were boys; 88% of the Kawasaki cohort were younger than five years of age. So, here are the findings. Number one, the incident rate of subsequent cerebrovascular disease was 14.7 per hundred thousand person years in the Kawasaki cohort versus only 4.6 per hundred thousand person years in the non-Kawasaki cohort. That's greater than a threefold higher incidence rate of cerebrovascular disorders for children who had Kawasaki disease before.

Dr. Negar Asdaghi:                        This finding was independent of other potential confounders, which they adjusted for in their multivariate analysis. Now, the length of follow up was a median of 9.8 years for the entire cohort. And on the issue of time, they found two important associations. The first finding was that when the follow-up time was stratified by five-year periods, Kawasaki disease cohort patients showed a significantly higher risk of developing a stroke within the first five years after being diagnosed.

Dr. Negar Asdaghi:                        And the second important association was that when they looked at the age at the time of diagnosis of Kawasaki, children who were younger than five years at the time of diagnosis were at a significantly higher risk of having a future stroke as compared to those who were older than five at the time of diagnosis.

Dr. Negar Asdaghi:                        So, simply put, the risk of subsequent stroke was higher in children who acquired the disease at a younger age, and that risk was higher in the first few years after the diagnosis of Kawasaki disease. The authors discuss a number of putative mechanisms to link Kawasaki with stroke. The most important being a cardiac source of embolism that we already alluded to, but other etiologies, including medium vessel cerebral vasculitis, or hypercoagulability in the setting of increased systemic inflammation, and even Kawasaki disease-associated aneurysmal rupture to cause hemorrhagic forms of stroke, are discussed in the paper and should be considered in the correct setting in children with a prior history of this disease.

Dr. Negar Asdaghi:                        So, what we learned from this large population-based pediatric study is that Kawasaki disease does indeed increase the risk of subsequent cerebrovascular disorders, and its influence is stronger in children who are diagnosed with this condition under the age of five, and the time period during which the risk of stroke is the highest is within the first five years after the diagnosis.

Dr. Negar Asdaghi:                        In the setting of spontaneous intracerebral hemorrhage, or ICH, much research has focused on the association between hypertension and blood pressure-lowering therapies and hematoma expansion and functional outcomes, but a lot less attention relatively has been given to the impact of hyperglycemia and ICH-related outcomes.

Dr. Negar Asdaghi:                        The current guidelines state that serum glucose should be monitored and both hypo- and hyperglycemia should be avoided in the setting of ICH. The older studies have given us inconsistent results as to whether or not hyperglycemia can increase the risk of ICH-related mortality. More recent studies have suggested that perhaps persistent hyperglycemia is indeed a predictor of poor neurological outcomes in ICH, but these results come from smaller single-center studies, which require further confirmation. And this confirmation is exactly what Dr. Adnan Qureshi from Zeenat Qureshi Stroke Institute and the Department of Neurology at University of Missouri and colleagues aim to give us in their study titled "Effect of Moderate and Severe Persistent Hyperglycemia on Outcomes in Patients With Intracerebral Hemorrhage."

Dr. Negar Asdaghi:                        So, they use data from the ATACH-2 study, and a quick reminder that ATACH-2 was a multicenter randomized control trial of a thousand patients with acute spontaneous intracerebral hemorrhage enrolled within four and a half hours from symptom onset, and patients were randomized to either the intensive blood pressure control treatment arm to maintain their systolic blood pressure goal of 110 to 139 millimeter of mercury versus standard treatment arm, which was keeping their systolic blood pressure above 140, between 140 to 179 millimeter of mercury, in the first 24 hours after randomization.

Dr. Negar Asdaghi:                        You will recall that enrollment of ATACH-2 was stopped early because of futility after pre-specified interim analysis. The main results of the trial was published in 2016 in New England Journal of Medicine, and the primary results did not show a lower rate of death or disability in patients assigned to the intensive treatment group.

Dr. Negar Asdaghi:                        So, in the current paper, in this current issue of the journal, the authors looked at the glycemic status of the patients enrolled in the trial. As part of the trial, patients had a complete chemistry panel at baseline, 24, 48, and 72 hours from onset. So, they used the glucose measurement from this panel and defined moderate hyperglycemia as serum glucose level of over 140 and under 180 and severe hyperglycemia as serum glucose levels of equal or greater than 180.

Dr. Negar Asdaghi:                        Now, persistent hyperglycemia was if two consecutive serum glucose levels were in the moderate or severe categories. And, very simply, they looked at the effects of hyperglycemia on ICH outcomes. And importantly, they evaluated whether hyperglycemia modified the effects of intensive blood pressure reduction on outcomes of ICH. So, of the thousand participants in ATACH-2, 11% had persistent moderate hyperglycemia, and 17% had severe persistent hyperglycemia. Those in the hyperglycemic group were more likely to be diabetic, not surprisingly, more likely to have a history of hypertension and dyslipidemia as compared to the normal glycemic patients.

Dr. Negar Asdaghi:                        And here are the results. Number one, serious adverse events were higher in the hyperglycemic groups, whether we're talking about the moderate or the severe hyperglycemic groups. This is despite the fact that the rate of hematoma expansion and perihematomal edema was not different based on the hyperglycemic status. However, the hyperglycemic patients were more likely to have serious adverse events, which were operationally defined as complications that were not expected to have occurred from the study intervention, in this case, the intensive hypertensive therapy, and resulted in either death or prolonged hospitalization or persistent or significant disabilities. Now, serious renal adverse events, which are, of course, expected as a complication for aggressive blood pressure therapy, were also significantly higher in the hyperglycemic category.

Dr. Negar Asdaghi:                        Now, their next important finding was that overall, both moderate and severe hyperglycemia was associated with higher odds of 90 days disability or death post-ICH adjusting for typical variables that could predict these outcomes, such as GCS score, hematoma volume, presence or absence of intraventricular hemorrhage, amongst other factors that they accounted for.

Dr. Negar Asdaghi:                        Now, number three, this is perhaps the most important finding of the study. Among patients without a preexisting history of diabetes, both moderate and severe hyperglycemia increased the risk of death and disability at 90 days after adjusting for all the potential confounders, but hyperglycemia was not associated with these poor outcomes in those with a prior history of diabetes. I'm going to pause here to let this information sink in. Let's go over them again, stress hyperglycemia in non-diabetics was associated with poor ICH outcomes, but high sugars in diabetics did not predict the same poor outcomes. And finally, they looked at the possible interactions between the glycemic status and the ATACH-2 intervention, which as we alluded to earlier, which was intensive versus standard blood pressure therapy, and it turns out that the intensive systolic blood pressure reduction was indeed associated with a lower rate of hematoma expansion only in patients with normal glycemia, but not in those with moderate or severe hyperglycemia.

Dr. Negar Asdaghi:                        So, this is again food for thought. Simply put, if the sugars are not well controlled, it appears that intensive blood pressure control would not lower the rate of hematoma expansion. Blood pressure lowering works when the sugar levels are controlled. So, overall, here are the two simple messages of this study. Number one, hyperglycemia in the acute setting of intracerebral hemorrhage is associated with poor outcomes or death only in those with stress hyperglycemia, meaning in those who have high sugar levels, but are not diabetic.

Dr. Negar Asdaghi:                        Number two, there seems to be an important interaction between the acute glycemic status of the patients and how intensive blood pressure control can prevent hematoma expansion, in that intensive BP control is only effective in prevention of hematoma expansion if the sugar levels are normal. So, a lot of thought-provoking and hypothesis-generating findings, and definitely more to come on this topic.

Dr. Negar Asdaghi:                        Moyamoya disease, or MMD, is an idiopathic disorder characterized by progressive stenosis of the supraclinoid internal carotid artery and its main branches in subsequent formation of a network of abnormal lenticulostriate collaterals. First described in Japan, the term "Moyamoya" is a Japanese expression for the puff of smoke and describes the characteristic appearance of the tangled and abnormal collateral vessels that are seen in angiography in various stages of the Moyamoya disease.

Dr. Negar Asdaghi:                        Epidemiological studies have revealed several risk factors associated with Moyamoya disease, including Asian ethnicity, female gender, and a family history of the disorder. Given that 15% of MMD patients have a family history of this disease, it's not surprising that genetic factors are suspected to underlie its pathogenesis. Now, a polymorphism in the ring finger protein 213, or RNF213, gene on chromosome 17 has been identified as the strongest genetic susceptibility factor for Moyamoya disease specifically in the East Asian population.

Dr. Negar Asdaghi:                        But despite the many advances in understanding the pathophysiology of MMD, as well as advances in animal models and genetic studies, to date, none of the animal models of RNF213 have quite replicated the vascular abnormalities that are typically seen in human Moyamoya disease.

Dr. Negar Asdaghi:                        The scientists feel that this is related to how little is known about the exact biological function of RNF213 gene and the protein it encodes. So, in the current issue of the journal, in the study titled "Moyamoya Disease Susceptibility Gene RNF213 Regulates Endothelial Barrier Function," Dr. François Gros-Louis from CHU de Québec Research Center at Laval University in Québec and colleagues aim to study the biological functions of RNF213 using a novel genome editing technology by the name of CRISPR-Cas9 technology.

Dr. Negar Asdaghi:                        Joining me now is Dr. Gros-Louis himself to discuss the findings of this paper. Dr. Gros-Louis is a Professor of Neurosciences at the Department of Surgery at Laval University. He holds the Canada Research Chair in Brain Disease Modeling and is the Director of the Induced Pluripotent Stem Cell Platform research in Québec.

Dr. Negar Asdaghi:                        Good morning, François. Welcome to our podcast. And thank you so much for joining us.

Dr. François Gros-Louis:               My pleasure.

Dr. Negar Asdaghi:                        François, you have to promise to hold my clinician's hand through this interview as obviously these are some foreign subjects for us, but very excited to learn from your study and learn from you on the association between RNF213 and the pathophysiology of what happens in Moyamoya disease. Now, before we talk about your paper, can you please talk to us about some basic concepts? What is the RNF213 protein?

Dr. François Gros-Louis:               Yes. The RNF213 gene is thought to be involved in mediating protein, protein interactions. The protein also contains a domain which is associated with an ATPase activity. This gene is a susceptibility gene for Moyamoya disease, as you mentioned in the introduction, vascular disorder of intracranial arteries. It's encoded in ubiquitously expressed protein. The protein is found to be expressed throughout the cytocell with the partial association in the intracellular membrane and cytoskeleton. Its expression varies according to the tested tissue type or location or cellular types.

Dr. François Gros-Louis:               Although the function of RNF213 protein is unknown, studies suggest that it plays a role in the proper development of blood vessels, cell proliferation, and inflammation. Recently, RNF213 has been reported to be associated with angiogenesis. However, little is known about its endogenous function or its pathogenic role in Moyamoya disease. Our results are in line with these results and indicate that RNF213 could also be a key regulator of cerebral endothelial integrity, whose disruption could be an early pathological mechanism leading to Moyamoya disease.

Dr. Negar Asdaghi:                        So, just to continue on this, there's quite a bit of research already done on association of the RNF213 gene, that's located, as we noted earlier, on chromosome 17, and basically susceptibility of development of Moyamoya disease. Can you give our listeners a brief overview of this genetic connections and what was known from past research?

Dr. François Gros-Louis:               Yeah, there is a couple polymorphism describing this gene, the most frequent, the most prevalent genetic study have identified the variant R4810K, meaning for arginine is replaced by another amino acid at the position of 4810 within the protein. It's a large protein and a large gene and a susceptible gene and a risk factor for developing Moyamoya disease.

Dr. François Gros-Louis:               So, people bearing this variant have a higher chance to develop the disease. This is a loss of function variant, also called inactivating mutation, meaning that the mutated gene product have less or no function. So, this variant is found in heterozygous, meaning one copy, or two copy homozygous in Moyamoya disease patients. While patient bearing homozygous mutation develop a more severe disease with earlier age of onset and worse prognosis, patients bearing heterozygous mutation can also develop the disease.

Dr. François Gros-Louis:               So, strong evidence suggests that the carrying rate of RNF213 R4810K mutant is closely related and give a higher chance to develop the disease. Interestingly, also with colleagues, we found that there are other variants within this genes leading to what we think is a gain of function mutation have been associated also with other cerebrovascular disease, such as intracranial aneurysms.

Dr. Negar Asdaghi:                        So, François, this is very interesting. Let me recap what you mentioned so I know that I understood it. So, this is an interesting gene, this RNF213, and basically evidence shows that mutations in the RNF213, whether it's loss of function or gain of function, both can result in variety of cerebrovascular disorders. And interestingly, the phenotype of the disease when it comes to loss of function of this gene is actually correlated with whether a person is a carrier, homozygous carrier of this gene, loss of function, or heterozygous carrier of the gene.

Dr. Negar Asdaghi:                        So, very interesting information for clinicians who treat patients with Moyamoya disease, specifically those who have a family history of Moyamoya disease, so perhaps a higher chance of carrying a genetic susceptibility gene. Now, we want to get to the paper that you published in this issue of the journal, but I think before we talk about your paper, we also have to have a basic understanding of this CRISPR-Cas9 technology, which is the new genome editing technology that you use in your experiments. Can you please give us a little bit of an overview of this technology?

Dr. François Gros-Louis:               Yes. CRISPR-Cas9 gene editing is genetic engineering technique in molecular biology by which the genomes of living organisms may be modified. This technology allows genetic material to be added, removed, or altered at particular location in the genome. Several approaches to genome editing have been developed. Recent one is known as CRISPR-Cas9. So, the CRISPR-Cas9 system has generated a lot of excitement in the scientific community because it is faster, cheaper, and more accurate, and also more efficient than other existing genome editing methods. It's clearly revolutionizing the field in research.

Dr. Negar Asdaghi:                        So, it's very exciting. It's truly a new chapter in gene targeting research and editing research. So, now we're ready to hear about your study. And I guess the first part of the study was just to look at how various cells in vitro that you used had expressed RNF213. Can you please tell us about the first part of your experiments?

Dr. François Gros-Louis:               Yeah. We first wanted to know where the protein is expressed or where the protein is more highly expressed. So, we found by doing immunofluorescence analysis that the RNF213, so we confirmed that it's ubiquitously expressed in the cytoplasm of different cellular types. So, we found that significant difference also in the expression of RNF213 protein levels in several endothelial cells, where we found it's been highly expressed when compared to other endothelial cells isolated from different other body location, meaning outside of the CNS. So, it's highly expressed also when compared to smooth muscle cells or fibroblasts.

Dr. Negar Asdaghi:                        Okay. So, just again, to recap for our listeners, this is, this RNF213 protein, is ubiquitously expressed in many different cell types, but you did find a significantly higher expression rates in endothelial cells, specifically those endothelial cells that were derived from cerebrovasculature. So, that's the first exciting part of the experiments that you showed in the study. Now, using the CRISPR-Cas9 technology, you and your team were able to successfully create an in vitro RNF213 knockout model. Can you please tell us about these models and also the main findings of your study?

Dr. François Gros-Louis:               Yeah, so taken together, the results we presented in the article indicate that RNF213 could be a key regulator of cerebral, endothelial and tight junctions integrity whose disruption could be an early pathological mechanisms leading to Moyamoya disease. So, we established for the first time an easily reproducible and stable in vitro 3D model generated using the CRISPR-Cas9 gene editing technology.

Dr. François Gros-Louis:               This advanced 3D culture approach has emerged as an excellent system to recapitulate histopathological feature reminiscent to disease pathogenesis. So, 3D cell culture approach is different from standard 2D culture, where cells are cultured, monolayered into a Petri dish. And we have results showing that the 3D cell culture system better mimic the in vivo conditions in terms of cell to cell and cell to matrix interaction and lead to histopathological phenotypic feature can be observed in cell culture, in a 3D fashion. Quite interestingly, alongside of providing the first evidence for the role of RNF213, the maintenance of endothelial barrier and the potential implication of this gene in the expression of maturation of tight junctions. So, we define a novel role for PECAM-1 as well in barrier impairment as a part of the disease pathogenic mechanisms.

Dr. Negar Asdaghi:                        Okay. And now this is really interesting. So, I wanted to, again, recap some of the important points that you raised here. First of all, your in vitro models are different than the classic in vitro models, where 2D cells were basically grown in a Petri dish. You are trying to, more and more, replicating what happens, for instance, in blood vessels, where you have endothelial cells overlying mesenchymal cells underneath them, so tunica intima and then tunica media, and so you have 3D cells, where various types of cells are overlying each other in a more in vivo representation of what happens in blood vessels, which is truly interesting.

Dr. Negar Asdaghi:                        And what you found was, in sort of summary, was that these knockout endothelial cells ended up having abnormal tight junctions and abnormal connectivity, which basically would lead in an in vivo model to abnormal leaky blood brain barrier, if this were truly in the in vivo model. Does that summarize the findings of the paper?

Dr. François Gros-Louis:               Yes, perfectly.

Dr. Negar Asdaghi:                        Perfect. And so I want to also give us a chance to talk about the important pro-inflammatory aspects of these knockout cells. You did find that a number of cytokines were expressed in excess in those RNF213 deficient cells. Can you please elaborate on those findings?

Dr. François Gros-Louis:               So, to further investigate whether inflammation plays an important role in RNF213-associated Moyamoya disease development, we indeed performed experiments to study pro-inflammatory cytokines and analyze the immune secretome profiles of cerebral RNF213 deficient endothelial cells. So, then the cells can secrete different cytokines or different other proteins. So, by analyzing the secretome, we found an end secretion of a few pro-inflammatory cytokines indicating that inflammation may also play a central role in the initiation of the immune response in the pathogenesis of the disease.

Dr. Negar Asdaghi:                        So, this is exciting, François. For years, we thought about the pathophysiology of Moyamoya disease as a disorder involving large vessels. And perhaps the initial thought was that it starts with excessive proliferation of smooth muscles within the middle layer of the cerebral blood vessels, in tunica media, and then perhaps subsequently there will be other abnormalities, including the intimal hyperplasia that is classically seen in Moyamoya.

Dr. Negar Asdaghi:                        Your study seems to propose a shift in that pathophysiological paradigm, where the problem seems to start from endothelial cells, so inside of the blood vessels and the tunica intima, and then gradually would go out to the middle layers, and, of course, proposes the hyperinflammatory state in the Moyamoya disease as well. So truly interesting. Do you think that that is the new or rather a paradigm shift for pathophysiology of MMD?

Dr. François Gros-Louis:               That's a great question. Our results certainly demonstrated that endothelial cells are involving in the disease pathogenesis in Moyamoya disease, but it doesn't exclude the possibility that other cell types might also be involved in the disease pathogenesis. We know, like you mentioned, that a blood vessel is formed by two different cell layers, tunica intima, media, and adventitia, containing, respectively, endothelial cells, smooth muscle cells, and fibroblasts. So which cells are to be blamed in Moyamoya disease is a question of many ongoing results studies over the years.

Dr. François Gros-Louis:               So, using tissue-engineered approach to reconstruct small caliber blood vessels, as we developed in my lab, in combination with patient-derived stem cells, in which adult cells isolated from a patient of any individuals can be reprogrammed into stem cells and re-differentiated into different cell types in occurrence, smooth muscle, fibroblasts, or endothelial cells. We would like to generate blood vessels in which each of the different cellular layers will harbor or not, or a combination with RNF213 mutants. So, this will hopefully help us to elucidate this question.

Dr. Negar Asdaghi:                        That's perfect. So, François, before we end the interview, I wanted to ask two more questions. So, what should be our top two takeaway messages from your study?

Dr. François Gros-Louis:               We believe that the innovative transdisciplinary approach to generate, for the first time, as we describe in the article, an in vitro 3D model recapitulating important diseases features. So, this model could become a unique tool in precision medicine to study Moyamoya disease or other RNF213-associated pathologies. So, our study provides, for the first time, role of RNF213 in the maintenance of blood-brain barrier and the potential implication of RNF213 in the expression and maturation of tight junctions. Taken together, our data define a novel role for PECAM-1 in the blood-brain barrier impairment in Moyamoya disease.

Dr. François Gros-Louis:               So, better characterization of each, also this regulated inflammatory molecules, we found taken separately could reveal a crucial information and help elaborate a more precise approach. Hence, this pro-inflammatory signature could be used as a circulatory biomarker for the follow-up of Moyamoya disease patients and to manage an appropriate treatment, according to the pathology progression.

Dr. Negar Asdaghi:                        François, this is great. And last, I want to digress a little bit and ask you about the future of gene editing. I think it's important to end our interview with a little bit of a discussion regarding the future of CRISPR-Cas9 technology. In subatomic quantum physics, people talk about the God particles. And I feel that the CRISPR-Cas9 technology is, in a way, like playing God, if you agree. What do you think is the future for gene editing, and how do you see that helping us in terms of treatment of genetic causes of cerebrovascular disorders?

Dr. François Gros-Louis:               Yes, gene editing is, like I said, revolutionizing, of course, experimental therapies for genetic disorder and generated excitement for new and improved gene therapies. We can think that it will be possible to correct any gene mutations associated with a disease to reestablish the normal or natural gene function and help treating the targeted diseases. But also, to me, the future of genome editing also resides in optimizing next generation disease models. The use of genome editing, in particular, the CRISPR-Cas9 technology, has extended to potential in generating new personalized model for a number of disorder, not only including Moyamoya disease or other cerebrovascular diseases, but also diseases like Alzheimer's, ALS, or Parkinson's disease, for which obtaining patient sample is difficult.

Dr. François Gros-Louis:               No one wants to give up a bit of his brain. So modeling it, this disease, in vitro will be really helpful in combination also gene editing with the stem cells, induced pluripotent stem cells technology, will allow the generation of better model to mimic human disease and reflects the genetic drivers that govern specific pathology. So, the synergy between IPS cell-based model system and gene editing will play a pivotal role in the root of precision medicine and clinical translation in the future.

Dr. Negar Asdaghi:                        Dr. François Gros-Louis, it was a pleasure learning from you. And we look forward to the endless possibilities brought by the future of genome editing technology.

Dr. François Gros-Louis:               It was a pleasure discussing with you.

Dr. Negar Asdaghi:                        Thank you for joining us.

Dr. Negar Asdaghi:                        And this concludes our podcast for the April 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including a series of Focused Updates on the topic of blood pressure management in stroke, organized by Dr. Else Sandset. I would also like to draw your attention to two scientific statements from the American Heart Association, which appear in print in the April issue. The first one is titled "Identifying Best Practices to Improve Evaluation and Management of In-Hospital Stroke," and the second one is on the effect of marijuana use on brain health.

Dr. Negar Asdaghi:                        And now, to end our podcast, last month, in honor of the 2022 Olympic Games, and to celebrate those with determination to survive and push despite the most difficult of circumstances, we ended our podcast with the story of a refugee Olympic athlete.

Dr. Negar Asdaghi:                        Sadly, since our last podcast, the world has seen even darker days of war, mass immigration, displacement, and human suffering. At times like this, we're reminded that although not all of us can help everyone, but at least each of us can do something to help someone, and the comfort in knowing that what we do in the field of medicine, from daily patient care to the scientific work leading to the next medical breakthrough, every action is a step forward in reducing the suffering of another person. And what better way to do this than staying alert with Stroke Alert.

Dr. Negar Asdaghi:         This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 14 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the March 2022 issue of Stroke: “Natural Course of Cerebral Cavernous Malformations in Children” and “Direct Oral Anticoagulants Versus Warfarin in Cerebral Venous Thrombosis (ACTION-CVT).” She also interviews Dr. Mohammad Anadani about his article “Magnitude of Blood Pressure Change After Endovascular Therapy and Outcomes.”

Dr. Negar Asdaghi:                       

1) Are direct oral anticoagulants a reasonable alternative to warfarin for treatments of patients with cerebral venous thrombosis?

2) What are the predictors of first and recurrent intracerebral hemorrhage in patients with cerebral cavernous malformation?

3) Is there an optimal blood pressure target after successful endovascular thrombectomy?

We have the answers and much more in today's podcast. This is the latest in Stroke. Stay with us.

Dr. Negar Asdaghi:                        Welcome to another incredibly informing Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The March 2022 issue of Stroke includes a number of papers published in conjunction with their oral presentation at the International Stroke Conference in New Orleans, from contemporary trends in the nationwide incidence of primary intracerebral hemorrhage, to disparities in Internet use among U.S. stroke survivors' implication for telerehabilitation during COVID-19 and beyond. I encourage you to review these timely topics in addition to listening to our podcast today. Later, in our interview section, I discussed the optimal blood pressure goal after endovascular therapy and the results of a subgroup analysis of the BP-TARGET randomized trials with Dr. Mohammad Anadani from the Department of Neurology at Washington University in St. Louis. But first with these two articles.

Dr. Negar Asdaghi:                        Cerebral cavernous malformations, also referred to as cavernous angiomas, cavernomas, cav mals, or CCMs, are angiographically occult, low flow, vascular lesions with no large arterial inflow or venous outflow vessels. These are clusters of dilated sinusoidal vascular channels that are aligned by a single layer of endothelium without the normal surrounding vascular smooth muscles, and they lack the normal tight junctions between their endothelial cells. Cavernomas can be found in both children and adults. So, the question is, how do these lesions present, especially in children, and what is their natural course? Now, before we answer these questions, let's review a few important points about cavernomas and what is known about these lesions in the literature. Number one, cavernomas are acquired lesions. Although initially thought to be congenital, they're now known to be acquired as comparing by many reports of patients with normal MRI findings, who later developed a CCM. Number two, they're not always benign. While most of them can have a benign course, cerebral cavernomas can be a cause for headaches, seizure disorders and intracerebral hemorrhage, which is, of course, their most feared complication.

Dr. Negar Asdaghi:                        Number three, though CCMs are rare vascular disorders with a prevalence of 0.6% in children and young adults, about a quarter of patients with a confirmed diagnosis of cerebral cavernous malformation are under the age of 18. And number four and finally, data seem to suggest that the risk of hemorrhage is potentially higher in the pediatric population than their adult counterparts. So, determining the natural course of CCMs and predictors of intracerebral hemorrhage is important for all patients, but especially important in the pediatric population. Now, in the current issue of the journal, in the paper titled "Natural Course of Cerebral Cavernous Malformations in Children: A Five-Year Follow-Up Study," a German group of investigators led by Dr. Alejandro Santos from the Department of Neurosurgery and Spine Surgery at University Hospital in Essen and colleagues studied the clinical presentation and predictors of intracerebral hemorrhage in their pediatric population over a 17-year study period.

Dr. Negar Asdaghi:                        So, they identified 129 patients with a diagnosis of cerebral cavernous malformation that had baseline MRI imaging completed and at least one or more follow-ups during the study period. Now, some of these patients were treated surgically and some conservatively in the study. The mean age of their study was 10, and over 50% of their study population was male. Developmental venous anomalies, or DVAs, were detected in 15% of their study population, and 20% had brain stem cavernoma localization. Now, importantly, half of these kids, so that's 55.8% of their study population, presented with an intracerebral hemorrhage, and that's how their cavernomas were diagnosed. So, what were their top three findings?

Dr. Negar Asdaghi:                        Number one, on the comparison of conservatively treated patients to those treated surgically, which was 37% of their cohort, they found that overall these two groups had comparable clinical characteristics and demographics with regards to sex, age, multiplicity of cavernomas, brain stem location, and family history of their lesions. But not surprisingly, those who were surgically treated were more likely to have presented with an intracerebral hemorrhage and less likely to be asymptomatic, meaning that their cavernoma was not an incidental finding as compared to those who were conservatively treated.

Dr. Negar Asdaghi:                        Number two, when they looked at predictors of presentation with intracerebral hemorrhage, they found that family history of cavernomas and brain stem cavernomas were significant predictors of presenting intracerebral hemorrhage. Number three, when they excluded those who underwent surgery, the annual risk of hemorrhage for the overall untreated participants was 4.1%. However, we should note that this rate significantly varied based on certain characteristics of the patients. The risk of hemorrhage, or rather the risk of re-hemorrhage, was double this baseline, that is 8.1%, for those cavernomas that presented with a bleed at presentation. The annual rate of hemorrhage was equally high at 7.1% for brain stem cavernomas, and then this rate gradually declined for familial form cavernomas at 6.2% annual risk of hemorrhage and multiple cavernomas at 4.8%. And it went all the way down to 0.4% annual risk of hemorrhage for asymptomatic incidentally found cerebral cavernomas. So, in the multivariate analysis, presentation with an ICH remained an independent predictor of re-hemorrhage and cavernomas with a high hazard ratio of 14. That is 14-fold higher risk of hemorrhage in cavernomas that present with a bleed as compared to those that did not.

Dr. Negar Asdaghi:                        Now, finally, on the association between DVAs and risk of hemorrhage, this study showed a possible reduced risk of hemorrhage in cavernomas that had associated DVAs, but this was not a statistically significant association. It is important to note that this finding is in keeping with the published studies in the adult population, but in contrast to the previously published data in the pediatric population. So, this association between presence of a developmental venous anomaly and cavernomas and the risk of subsequent hemorrhage needs to be furthered studied. So, what did we learn from this study? Pediatric patients with brain stem cavernomas and familial cavernomas have a higher risk of intracerebral hemorrhage as mode of presentation. The risk of re-hemorrhage is 14 times higher in cavernomas that present with an ICH as compared to cavernomas that did not bleed. And the probability of bleed tends to increase over time.

Dr. Negar Asdaghi:                        Cerebral venous sinus thrombosis, or CVST, refers to thrombosis in the dural venous sinuses, cortical veins, deep cerebral veins, or a combination of these venous structures. CVST is an uncommon cause of stroke accounting for overall 1% of all strokes and can cause venous ischemic infarcts or intracerebral hemorrhage and importantly has a high morbidity and mortality if unrecognized and left untreated. Anticoagulation is generally the mainstay of therapy for CVST, which needs to be initiated as soon as possible, even in the presence of hemorrhage in the brain. The data regarding the choice of anticoagulation in CVST is generally extrapolated from randomized studies completed in patients with systemic venous thromboembolism, so conditions such as pulmonary emboli or deep venous thrombosis, and indicate that direct oral anticoagulants, or DOACs, are viable alternatives to traditional warfarin therapy in this patient population. This question was specifically studied in the RESPECT-CVT trial, which was a small European randomized trial that included 120 patients with cerebral vein thrombosis, randomized to either receiving dose adjusted warfarin or dabigatran at 150 milligram BID.

Dr. Negar Asdaghi:                        The results of the study was published in JAMA Neurology in 2019 and showed that CVST patients treated with either dabigatran or warfarin were at low risk of recurrent venous thromboembolism, and they also showed a comparable safety profile in terms of risk of hemorrhage or mortality in patients treated with DOAC as compared to warfarin. But how do DOACs perform as compared to warfarin in routine practice is unknown. So, in this issue of the journal, in the study titled, "Direct Oral Anticoagulants Versus Warfarin in Cerebral Venous Thrombosis (ACTION-CVT): A Multicenter International Study," the ACTION-CVT investigators, led by Dr. Shadi Yaghi from the Department of Neurology at Brown University, aimed to compare the safety profile of DOACs to that of warfarin, in a multicenter international study that included 1025 imaging-confirmed CVST patients from multiple centers in the United States, Italy, Switzerland, and New Zealand.

Dr. Negar Asdaghi:                        They had a number of exclusion criteria for this study, excluding patients with active cancer, those with a confirmed history of antiphospholipid antibody syndrome and those who were not treated with an oral anticoagulant. And after excluding these patients, it gave them their study sample of 845 CVST patients. So, what were their main findings? Number one, in keeping with a prior literature on CVST, these patients were young, their mean age was 44, and majority of them were women, so that was 67% of their cohort. And they found that a third of these patients were actually treated with a DOAC, and, in addition, another 15% received a DOAC at some times during their treatment course. Finding number two, the most common DOAC used in this population was apixaban, that was 66% of cases treated with a direct oral anticoagulant, followed by rivaroxaban in 18% of cases, and then dabigatran used in 13.5% of DOAC-treated cases.

Dr. Negar Asdaghi:                        Important finding number three. A total of 27 patients had recurrent CVST, which also included patients with progression of their cerebral vein thrombosis on follow-up vascular imaging, and 17 patients had recurrent venous thromboembolism, and two had both. So, during their mean follow-up of 345 days, they had the rate of 5.68 recurrent venous thrombosis per 100 patient years. These rates were not different for DOAC-treated versus warfarin-treated patients in both unadjusted and adjusted models. Now, very important finding number four. When they looked at the rate of recanalization on follow-up imaging, for those in whom this information was available, partial or complete recanalization occurred in 86% of DOAC-treated patients versus 84% of warfarin-treated patients. This was not a statistically significant difference in the unadjusted or the adjusted models. Recanalization is, of course, an important determinant of outcomes in CVST and should be noted that recanalization is, of course, an important determinant of outcomes in CVST since persistent thrombosis through chronic raised ICP can potentially lead to a variety of neurological morbidities, such as chronic headache, chronic papilledema and increased risk of development of dural AV fistulas.

Dr. Negar Asdaghi:                        Now, finally, in terms of safety profile, they had 31 hemorrhages, 23 intracranial, majority were symptomatic and 9 extracranial hemorrhages. The hazard ratio for hemorrhage or death was similar for DOAC- and warfarin-treated patients, again in the unadjusted and adjusted models. So, bottom line, in this large international cohort of patients with CVST treated with an oral anticoagulant in routine practice, patients treated with DOACs had similar clinical and radiographic outcomes and had a similar favorable safety profile when compared to those treated with warfarin. So, we stay tuned for the results of the ongoing randomized trials on this subject.

Dr. Negar Asdaghi:                        What is the optimal blood pressure target after endovascular therapy? This is a commonly encountered question in routine clinical practice with a not-so-straightforward and easy answer. After a successful endovascular treatment, high systolic blood pressure targets are thought to be associated with increased risk of reperfusion injury and development of intraparenchymal hemorrhage, leading to worsening of clinical outcomes. Conversely, low blood pressure targets may worsen the ischemic penumbra, especially in the setting of incomplete perfusion. The current stroke guidelines recommendations regarding blood pressure control after endovascular treatment are mostly extrapolated from the post-thrombolysis studies. The BP-TARGET trial was a recently completed randomized study in France that aimed to assess the safety and efficacy of intensive blood pressure lowering, that is systolic blood pressure of less than 130, as compared to standard of care, that is systolic blood pressure between 130 to 185, after successful endovascular therapy in acute ischemic stroke.

Dr. Negar Asdaghi:                        This was a neutral study, and the main results of the trial was published in early 2021 in Lancet Neurology. And if you missed it, well, as always, we're here with the Stroke Alert Podcast to fill in the gaps. So, we'll review the trial results with our podcast guest today, Dr. Mohammad Anadani, from the Department of Neurology at Washington University in St. Louis, who's also the first author of a paper in the current issue of the journal titled "Magnitude of Blood Pressure Change After Endovascular Therapy and Outcomes: Insight From the Blood Pressure-TARGET Trial." This was a post hoc analysis of the BP-TARGET trial, looking at the extent of blood pressure reduction and its implications of clinical outcomes. Welcome, Mohammad, thank you for joining us on the podcast today.

Dr. Mohammad Anadani:            Thank you for having me. It's a pleasure to be here with you today.

Dr. Negar Asdaghi:                        Thank you. So, blood pressure control is a really simple and yet extremely complicated topic when it comes to the collateral support before reperfusion therapies, and then, of course, the possibility of reperfusion injury post-thrombectomy in the setting of an ischemic stroke related to a large vessel occlusion. Can you please give our listeners an overview of the topic of blood pressure control in this setting?

Dr. Mohammad Anadani:            Yes, absolutely. I totally agree. The topic of blood pressure control after, in patients with large vessel occlusion, is very complicated. And when we talk about blood pressure control, I think we should differentiate between pre-recanalization and post-recanalization. In the pre-recanalization period, the main focus should be to maintain adequate perfusion to ischemic penumbra to prevent infarct expansion. So, there is consensus that hypotension should be avoided at all costs pre-recanalization. When it comes to the post-reperfusion, here it gets a little bit more complicated. We do have a large body of evidence, as you mentioned, for the association between high blood pressure in the post-reperfusion period and the risk of poor outcome. What we don't know yet is if active reduction of blood pressure after reperfusion is beneficial. And that's why, as you mention, the American Heart Association guidelines just recommend a systolic blood pressure less than 180, just because of the lack of data to support the benefit of blood pressure reduction.

Dr. Negar Asdaghi:                        Perfect. So, this was definitely the topic that the BP-TARGET trial set out to investigate. What is the optimal blood pressure target after successful revascularization therapy? Can you please tell us a little bit about the trial, the design and the inclusion criteria?

Dr. Mohammad Anadani:            The Blood Pressure-TARGET trial, or BP-TARGET trial, aimed to assess the safety and efficacy of intensive blood pressure lowering treatment. The trial enrolled patients with anterior circulation large vessel occlusion, that is M1 or ICA occlusion, or tandem occlusion, which is both M1 and ICA occlusion. The patients who were treated with endovascular therapy and achieved successful reperfusion, and they defined successful reperfusion as modified treatment cerebral ischemia 2b to 3. And then after enrollment, the patients were randomized in one-to-one ratio into intensive blood pressure control, which is systolic blood pressure less than 130, and standard blood pressure control, which is systolic blood pressure less than 185. Now, these two cutoffs came in from some evidence that systolic blood pressure less than 130 is beneficial in these patients or this is the optimal cutoff for patients with successful reperfusion. For the standard group, the design of the trial, at the time of the design of the trial, that was the standard or recommended European guidelines, blood pressure group. And the study was conducted in France between June 2017 and September 2019.

Dr. Negar Asdaghi:                        Thank you, Mohammad. So, I want to recap for our listeners, we're looking at a French study that was conducted in four centers, in France. And it's a very recent study, recently completed. The whole thing was completed over the past five years. So, very interesting because it's applicable to our current treatment models. And these were patients with a large vessel occlusion in the anterior circulation that had undergone thrombectomy. All have achieved a successful revascularization, as you defined, TICI 2b or C or TICI 3, and then they were randomized to either standard of care in terms of post-thrombectomy blood pressure control or the intensive group, which was under systolic blood pressure of 130. Did I recap that correctly?

Dr. Mohammad Anadani:            Correct.

Dr. Negar Asdaghi:                        Perfect. So, now we're ready for the primary outcome. So, what was the primary outcome of the trial?

Dr. Mohammad Anadani:            The primary outcome was any radiographic intraparenchymal hemorrhage that was seen on CT within 24 hours to 36 hours after successful reperfusion.

Dr. Negar Asdaghi:                        This is interesting, Mohammad, this is a different primary outcome than we're used to in a usual randomized trial that commonly uses a modified Rankin scale of usually at 90 days. Do you have any insight as to why a radiographic outcome was chosen for this particular study, and obviously what would be fine as part of the trial?

Dr. Mohammad Anadani:            Yes. So, the main reason why the study investigator chose this as a primary outcome was because really the benefit of, or at least what is thought to be the benefit from systolic blood pressure reduction, is to lower intraparenchymal hemorrhage or the risk of intraparenchymal hemorrhage. So, to assist the efficacy of this intensive blood pressure lowering, the first thing we expect to see is lower intraparenchymal hemorrhage. So, when you have your target as intraparenchymal hemorrhage, it truly requires much smaller sample size than having functional outcome as the primary outcome.

Dr. Negar Asdaghi:                        Okay, perfect. And I think we're ready to hear the results for the main BP-TARGET trial.

Dr. Mohammad Anadani:            The results of the trial were disappointing for people who were interested in this topic. The primary outcome, which, again, was an intraparenchymal hemorrhage, occurred in 42% of patient intensive arm and 43% of patient the standard arm. And there was no difference in the risk of intraparenchymal hemorrhage between the two groups.

Dr. Negar Asdaghi:                        Well, I think you can phrase it as disappointing, or more room to understand the pathophysiology and also onto bigger and better trials. And so I want to now move on the current paper in this issue of the journal, which is a post hoc analysis of the trial. Can you tell us a little more about your study?

Dr. Mohammad Anadani:            In our study, we wanted to study the blood pressure as dynamic target. So, we wanted to see if there is any association between blood pressure change from baseline with the functional and safety outcome after endovascular therapy. And also we wanted to understand the shape of the association. In other words, to see, is there a point after which the blood pressure reduction becomes helpful? So, to do that, we did this post hoc analysis of the BP-TARGET trial, and we only enrolled patients who had more than 50% of planned blood pressure measurements. And then we defined systolic blood pressure change as the difference in the mean achieved blood pressure in three different time points: zero to one hour, one to six hours, and six to 24 hours minus the baseline systolic blood pressure. And here we considered the end-of-procedure blood pressure as the baseline systolic blood pressure.

Dr. Negar Asdaghi:                        All right. So, I want to recap what you mentioned before we hear what you found in the study. So, really, blood pressure, as you noted, is a dynamic factor. It's not just a target, but other words, is how fast you're reducing it, in what timeframe after endovascular thrombectomy, and also how much. So, as an example, as we were discussing this earlier, before we did the podcast recording, is if you started a systolic blood pressure at 190 and then reduced that patient quickly to 130, is that the same as if starting blood pressure was 150, and then you reduce it to, again, 130? So, delta, or the magnitude of change in blood pressure, and also time intervals, that how long after thrombectomy you were able to reduce that blood pressure, are all important factors in terms of determining the outcome. That's a nice summary of what this current study aimed to do. Perfect. So, with that, we're ready to hear the results of your study.

Dr. Mohammad Anadani:            We included 267 patients, 137 in the intensive arm and 130 patients in the standard arm. And then, when we compared patients who had poor outcome at 90 days to patients who had good outcome at 90 days, we found that the patient who had poor outcome had less systolic pressure reduction, meaning these patients had less systolic pressure reduction compared to the baseline than the patient who had good outcome. And then, when we controlled for other confounders, their association remained significant, especially for the one- to six-hour period and six- to 24-hour period. And the same results were when we had our outcome as intraparenchymal hemorrhage, we found the same results. The patient who had intraparenchymal hemorrhage had less systolic blood pressure reduction than patients who did not have intraparenchymal hemorrhage. And, again, the association remained significant even after we adjusted for possible confounders, like age, the degree of recanalization, and the stroke severity.

Dr. Mohammad Anadani:            And then we wanted to see, if we looked at the blood pressure change as categorical variable, meaning we want to see if there is a difference between large systolic blood pressure reduction compared to minimum or no systolic blood pressure reduction. So, we divided the systolic blood pressure reduction into three categories: the minimal, which was just zero to 10 systolic blood pressure reduction; the moderate, which was 10 to 20; and large, which was more than 20 millimeter mercury systolic blood pressure reduction. And when we looked at that, a patient who had more than 20 millimeter mercury systolic blood pressure reduction had significantly lower risk of poor outcome than patients who had no systolic blood pressure reduction or just minimal systolic blood pressure reduction. And the difference was striking. There were the patients who had more than 20 systolic blood pressure reduction, they had almost 62% lower risk or lower odds of having poor outcome than a patient who did not have significant systolic blood pressure reduction.

Dr. Negar Asdaghi:                        These are some very interesting findings. Let me try and to summarize this for our listeners and make sure that I understood the study results correctly. So, in other words, if we had a patient that at the end of a successful revascularization treatment, say, had a systolic blood pressure of 150, and that was reduced to 140, so there's a 10 millimeter mercury difference, that patient, in this particular study, had a higher risk for development of intracerebral hemorrhage than the person that finished at 180, so finished endovascular therapy at 180 millimeter of mercury. But then with rapid reduction, we dropped the blood pressure to, say, for example, 140, so that 40 millimeter of mercury of reduction carried a higher weight or higher impact on reduction of intracerebral hemorrhage than the absolute target of blood pressure, because your results did not look at which category were these patients under, were they under intensive category or standard, but they looked at just the magnitude of that drop, which showed a bigger implication on effective blood pressure reduction on outcomes.

Dr. Mohammad Anadani:            Yeah, that is correct. Now, the primary outcome for our study and really what we want to look at here is the functional outcome, more than the intraparenchymal hemorrhage. And, like you said, if we have, let's say, patients who started with 160 and they dropped to 120 or started with 180 and they dropped to 150, these patients had better functional outcome than patients who started, let's say, with 160 and remained 160 or even their blood pressure increased after reperfusion. We did not look at absolute numbers, but we did look at if the patients were presented, let's say, above 180 or patient presented less than 180, and both of these patients had the same, or both of these groups had the same results, meaning systolic blood pressure seems to be beneficial for both of these patients. And also we looked at the patients who were in the standard arm or in the patients who were in the intensive arm, also both of them have the same results. The systolic blood pressure reduction remained associated with poor outcome.

Dr. Negar Asdaghi:                        Mohammad, the current American Heart Association guidelines and also the European stroke guidelines both recommend a target systolic blood pressure of under 180 or 185 after successful recanalization. What do you think the optimal target blood pressure should be based on BP-TARGET trial and based on your post hoc analysis?

Dr. Mohammad Anadani:            Yeah, that's a difficult question. We learn from the BP-TARGET trial, that's lowering systolic blood pressure is safe. And our study added to that, that significant reduction, especially in the first hour after reperfusion therapy, may be beneficial because patient had lower risk of poor outcome. However, I don't think we will have a one number that we will be able to say, this is the optimal blood pressure that fits all patients. I think the optimal blood pressure needs to be tailored to individual patient based on their admission blood pressure, based on their comorbidities, and also based on the degree of reperfusion. I don't think patients who have TICI 2b, for example, should be treated exactly the same as patients who had TICI 3.

Dr. Negar Asdaghi:                        So, a lot still to come on this topic, and we are still learning. So, on that topic, can you tell us a little bit about the currently ongoing randomized trials on the topic of blood pressure controlled post-thrombectomy?

Dr. Mohammad Anadani:            Yes. I think there are three main trials that are ongoing now and trying to assess the safety and efficacy also of intensive blood pressure reduction. The first trial is the Second Enhanced Control of Hypertension and Thrombectomy Stroke Study, or ENCHANTED2 study. And this study is being conducted now in China. And it's comparing systolic blood pressure less than 120 target to systolic blood pressure less than 180. And the study has the primary outcome here, is the shift in mRS score at 90 days. The study is estimated to be completed in 2023, so, hopefully next year, we will have some results. The second study is the Outcome in Patients Treated With Intraarterial Thrombectomy - optiMAL Blood Pressure Control, or OPTIMAL-BP. And this study is being conducted in South Korea, and it's comparing systolic blood pressure target of less than 140 to systolic blood pressure target of less than 180.

Dr. Mohammad Anadani:            And the primary outcomes of this study are mRS zero to two at 90 days and symptomatic intracerebral hemorrhage. The study here is estimated to be completed in 2024. And the last trial is the Blood Pressure After Endovascular Stroke Therapy-II, or the BEST-II trial. And this is being conducted here in the U.S. and comparing three different blood pressure cohorts: less than 160 and less than 140 as the experimental group to less than 180 as the standard group. And the primary outcome of this study is final infarct volume. And also the co-primary outcome is utility-weighted mRS at 90 days. And this study is estimated to be completed next year, in 2023.

Dr. Negar Asdaghi:                        So, a diverse group of randomized trials from Korea, China, and the United States. Hopefully, we'll have a lot more answers in the next two years then on this topic. So, just the last few minutes of our recording here. Mohammad, can you please summarize for our listeners, what should be our top two takeaway messages from your study and what we know from collectively in the field on the topic of blood pressure control post-thrombectomy?

Dr. Mohammad Anadani:            I think the main home message that one, we found a leaner association between blood pressure change after endovascular therapy and poor functional outcome, and two, effective and significant systolic blood pressure reduction, which we defined in our study as a more than 20 millimeter mercury in the first hour after endovascular therapy, is potentially beneficial, and these patients had significantly lower risk of poor outcome than the patient who did not have significant blood pressure reduction.

Dr. Negar Asdaghi:                        Thank you so much, Dr. Mohammad Anadani. Thank you for joining on the podcast today, and we look forward to having you back and covering more of your work in the future.

Dr. Mohammad Anadani:            Thank you for having me, and I look forward to learning more about the Stroke studies from your podcast.

Dr. Negar Asdaghi:                        Thank you.

Dr. Negar Asdaghi:                        And this concludes our podcast for the March 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including a series of Focused Updates on the topic of health equity and reduction of disparities in stroke, organized by Dr. Bruce Ovbiagele. It's hard to believe that we're already in March, and coming off the heels of one of our largest cerebrovascular annual meetings, the International Stroke Conference, which coincidentally concurrently happened with one of the biggest sports events of the year, the 2022 Winter Olympics in Beijing. Now, what do these two very different events have in common? Well, I think they both represent the extraordinary stories of talent and grit on the world stage. So, let's end our Stroke podcast with an inspirational story of the Olympian swimmer Yusra Mardini.

Dr. Negar Asdaghi:                        In August 2015, after her family home was invaded and destroyed in the Syrian civil war, the 17-year-old Yusra and her sister, Sarah, fled Syria to Beirut, Istanbul, and finally İzmir, in Turkey, where they managed to squeeze onto a dingey crossing the Mediterranean to the Greek island of Lesbos. Carrying 20 people, rather than just six or seven, they found their boat sinking less than 30 minutes into their journey. Yusra, Sara, and another woman were the only ones on board who knew how to swim. Fighting for their life and that of the other refugees on board, they would swim the cold open water of the heavy seas for three and a half hours before reaching the shore. Less than a year later, Yusra became one of the top 10 athletes worldwide to qualify and compete in the 2016 Summer Olympics, as part of the first refugee Olympic athletes team. She won the opening heat of women 100-meter butterfly race, but did not make it to the podium in the Olympic Games. And that is, of course, only part of her story.

Dr. Negar Asdaghi:                        Very much like the story of many scientists, doctors, engineers, and staff who make the international stroke meeting possible. Many stories are not celebrated on a podium, but nevertheless are the essence of the success of our stroke community. So, wherever you are in the field of neurosciences, whatever the challenge, and however cold the waters, know that while we don't share the same border, the same flag, or even a common language, together we push the field of cerebrovascular disorders forward. And, as always, we stay alert with Stroke Alert.

Dr. Negar Asdaghi:         This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 13 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the February 2022 issue of Stroke: “Cannabis Use and Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage” and “Infertility, Miscarriage, Stillbirth, and the Risk of Stroke Among Women: A Systematic Review and Meta-Analysis.” She also interviews Dr. Pierre Amarenco about his article “Intracranial Hemorrhage in the TST Trial.”

Dr. Negar Asdaghi:

1) Can marijuana use increase the risk of ischemic stroke in patients with aneurysmal subarachnoid hemorrhage?

2) Is there an association between infertility or miscarriage and development of stroke later in life?

3) Does lowering the bad cholesterol increase the risk of intracerebral hemorrhage?

We will cover these and much more in today's podcast. This is the latest in Stroke. Stay with us.

Dr. Negar Asdaghi:         Welcome to another exciting Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast.

Dr. Negar Asdaghi:         The February 2022 issue is the second installment of Stroke's annual Go Red for Women issue. This is to highlight the journal's continuous effort to bring to attention the research which focuses on reduction of sex disparities and enhancing inclusivity in stroke care. This issue of the journal features a number of articles from sex disparities in enrollment in randomized trials of stroke, to sex-related differences in ischemic stroke presentation, outcome of endovascular therapy, plaque composition of carotid stenosis, and the sex-dependent rupture rate of cerebral aneurysms and the risk of subarachnoid hemorrhage, which I encourage you to review in addition to listening to today's podcast.

Dr. Negar Asdaghi:         Later in the podcast, I have the distinct honor of interviewing one the leaders in the field of secondary stroke prevention, Dr. Pierre Amarenco from Bichat University in Paris, to discuss the latest analysis of the association between LDL cholesterol levels and intracerebral hemorrhage risk in a sub-analysis of the Treat Stroke to Target trial, and what is next to come on cholesterol-lowering therapies post-ischemic stroke. But first with these two articles.

Dr. Negar Asdaghi:         It should come at no surprise to our listeners that the use of marijuana in its variety of forms is increasing not only in the United States, but also across the globe, both for recreational purposes and also for treatment of a range of medical conditions. There's also a growing body of evidence to link marijuana use to cerebrovascular disorders, including ischemic and hemorrhagic strokes. In fact, national surveys in the United States show that over two million Americans with established cardiovascular disorders currently use or report having used marijuana in the past.

Dr. Negar Asdaghi:         Aneurysmal subarachnoid hemorrhage is a hemorrhagic stroke subtype that is frequently complicated by cerebral vasospasm and delayed cerebral ischemia, or DCI. Now, we know that development of DCI can significantly increase the neurological morbidity and mortality related to the disease. So, the question is, can marijuana use increase the risk of DCI in subarachnoid hemorrhage? And what is the difference between cannabis and marijuana? And how are they even related to the brain and vascular disorders? Now, to answer these questions, we first have to do a quick review of three key points.

Dr. Negar Asdaghi:         Key point number one: The word "cannabis" refers to all products derived from the plant cannabis sativa. This plant contains about 540 chemical substances. The word "marijuana" refers to parts of or products from the plant with substantial amounts of tetrahydrocannabinol, or THC. THC is the active ingredient of marijuana responsible for mediating its psychoactive effects through activation of G protein-coupled cannabinoid receptors, which are easier to remember as CB1 and CB2 receptors.

Dr. Negar Asdaghi:         Key point number two: CB1 and CB2 receptors are diffusely expressed throughout the brain, but interestingly, CB1 receptors are also richly expressed across various vascular beds, including the cardiac and cerebral vessels. So, there we have it, a connection between marijuana and the blood vessels.

Dr. Negar Asdaghi:         Key point number three: The differential activation of CB1 receptors in cerebral vessels may lead to vasoconstriction or vasodilation, potentially linking marijuana to vasospasm seen in aneurysmal subarachnoid hemorrhage, which then leads to DCI. But it should be noted that THC can also lead to ischemia through other mechanisms, such as altering the brain's oxidative capacity, impairing mitochondrial respiratory chain complexes, and increasing reactive oxygen species in free radicals. So, causing brain ischemia through mechanisms other than vasospasm.

Dr. Negar Asdaghi:         So, with these three points in mind, in the current issue of the journal, in the study titled "Cannabis Use and Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage," Dr. Joshua Catapano from the Department of Neurosurgery at the Barrow Neurological Institute and colleagues report on the outcomes of 1,014 aneurysmal subarachnoid hemorrhage patients treated over a 12-year period at their institution from August 2007 to July 2019.

Dr. Negar Asdaghi:         The primary exposure was cannabis use, which was detected by routine urine toxicology at the time of hospital presentation with subarachnoid hemorrhage. Patients were also screened for the use of other vasoactive substances, including cocaine, amphetamines, and also tobacco use. The primary outcome was DCI defined as cerebral infarction detected either by CT or MRI or proven on autopsy after exclusion of procedure-related infarctions.

Dr. Negar Asdaghi:         And here's what they found. Number one: Overall, 36.2% of their patient population with aneurysmal subarachnoid hemorrhage developed DCI. 50.2% of their total population had poor functional outcome defined as modified Rankin Scale of over two by the time of discharge, and 13.5% died. These are important reminders that aneurysmal subarachnoid hemorrhage remains a deadly form of stroke, despite modern neurosurgical and neurocritical care advances in treatments.

Dr. Negar Asdaghi:         Number two: 4.5% of their patient population tested positive for cannabis. And here's the alarming finding of their study. The rate of DCI was significantly higher in those who were positive for cannabis, that was 52%, versus only 35% in those negative for cannabis. This association was not seen with other vasoactive agents such as cocaine and methamphetamine. Now, radiographic vasospasm was also significantly more common in cannabis users, the rate of which was 88% in cannabis users than in non-users, which was 70%.

Dr. Negar Asdaghi:         Now, number three: When they adjusted for baseline patient characteristics, presenting Hunt and Hess classification, and other vasoactive substances and active smoking, cannabis use was independently associated with an increased likelihood of development of DCI. So, what did we learn from this study? Active cannabis users were 2.7 times more likely to develop ischemic stroke post-aneurysmal subarachnoid hemorrhage as compared to their non-user counterparts. This is one of the largest studies to potentially link marijuana to development of cerebral ischemia in this population.

Dr. Negar Asdaghi:         There is now ample scientific evidence to connect some pregnancy-related complications, such as gestational hypertension, gestational diabetes, preeclampsia, and some pregnancy outcomes, such as preterm birth or having small-for-gestational-age infants, to an increased long-term risk of cerebrovascular events in the mother. Infertility, miscarriage and stillbirth are also common abnormalities in the process of conceiving and being pregnant, but whether there is an association between these abnormalities and development of future vascular disorders in women is not clear.

Dr. Negar Asdaghi:         In the current issue of the journal, in the study titled "Infertility, Miscarriage, Stillbirth, and the Risk of Stroke Among Women," Dr. Chen Liang from the School of Public Health at the University of Queensland in Brisbane and colleagues report on the results of a systematic review and meta-analysis on this topic. So, let's dive into it.

Dr. Negar Asdaghi:         First, a brief look at their methodology. After a comprehensive literature search, a total of 18 studies were included in this meta-analysis, including over 7,800,000 women between the ages of 23 to 63 with a mean follow-up of 3.8 to 19 years. So, a big study. Five studies evaluated the association between infertility and stroke. Infertility was defined in broad terms as either a formal diagnosis or receiving fertility treatment or testing through databanks or medical records. And the other 13 studies explored the association between a history of either miscarriage and/or stillbirth and the main outcome of the study, which was stroke.

Dr. Negar Asdaghi:         In 11 studies, the outcomes of ischemic and hemorrhagic strokes were specified, four studies only reported on the ischemic stroke, and the rest did not identify the stroke subtype. So, what did they find? Well, their first finding was on the association between infertility and stroke. Overall, the five studies included over 4,600,000 women, and this association was inconsistent due to heterogeneity of the results between the different studies. But, when excluding the one study from Asia, which created most of the heterogeneity in results, infertility was indeed found to be associated with a 17% increase in the risk of stroke in the mother. In terms of possible causes, well, they looked at common infertility etiologies and vascular risk factors, and not surprisingly, they found many connecting points.

Dr. Negar Asdaghi:         For example, polycystic ovarian syndrome is a common cause of infertility and is frequently associated with insulin resistance and type 2 diabetes. Endometriosis, another cause of infertility, is commonly associated with hyperlipidemia and hypertension as a result of chronic systemic inflammation. Another example is premature ovarian insufficiency that could increase the risk of stroke through elevated follicle-stimulating hormone, a lower level of estrogen, and a relatively elevated level of androgen.

Dr. Negar Asdaghi:         So, their next finding was on the association between miscarriage and stillbirth in stroke. As you know, both of these conditions, so miscarriage and stillbirth, describe pregnancy loss at various stages. A stillbirth is the loss of fetus after the 20th week of development while a miscarriage refers to a loss of pregnancy before the 20th week of gestation. Women with a history of miscarriage had a 7% increased risk, and those with a history of stillbirth had a 38% increase in the risk of stroke later in life. Now, since having a miscarriage is a very common occurrence, it's important to pay attention to their dose response sub-analysis. When data was available on the number of miscarriages or number of stillbirths, increased risk of stroke was apparent among women with three or more miscarriages, but not two or less. For stillbirths, similarly, a history of repeated stillbirths was associated with increased risk of stroke, but evidence on association for a single stillbirth with stroke was insufficient.

Dr. Negar Asdaghi:         These are important findings to keep in mind when reviewing these results, and importantly, when counseling patients in routine practice. Now, in terms of causes, the authors discuss a variety of associated mechanisms, such as persistent endothelial dysfunction, a common cause for both pregnancy loss and vascular disease, elevated level of homocystine, autoimmune disorders, including presence of antiphospholipid antibodies and a cause for both pregnancy loss and development of arterial stenosis, noting that especially for the autoimmune conditions, specifically in the case of the APS syndrome, pregnancy loss is likely to be repeated, which is consistent with the findings of their subgroup analysis and dose response analysis in the paper, showing that repeated miscarriages and stillbirths are more likely associated with a higher risk of stroke rather than a single event.

Dr. Negar Asdaghi:         So, bottom line, what my takeaway from this study is, that many factors that can cause infertility, miscarriage and stillbirth can also cause vascular disorders, and these associations should be kept in mind when treating women at a younger age for fertility and pregnancy-related complications.

Dr. Negar Asdaghi:         Intensive therapy to lower serum lipid levels with the use of statins is recommended after transient ischemic attack or ischemic stroke of atherosclerotic origin. Treatment with statins has been shown to reduce the risk of major vascular events in the stroke population, but there remains a concern regarding an increased risk of development of intracranial hemorrhage with this therapy. Whether this increased risk of ICH is a class effect related to treatment with statins, or is associated with a certain low target levels of LDL cholesterol, is uncertain.

Dr. Negar Asdaghi:         The Treat Stroke to Target randomized trial tested the hypothesis that a target level of LDL cholesterol of less than 70 milligram per deciliter would be superior to a target range of 90 milligrams to a hundred milligram per deciliter in reducing the overall cardiovascular events after an ischemic stroke or TIA in patients with evidence of atherosclerosis. The primary results of the trial was published in New England Journal of Medicine in early 2020.

Dr. Negar Asdaghi:         In the current issue of the journal, in the study titled "Intracranial Hemorrhage in the Treat Stroke to Target Trial," the trial investigators report the results of a pre-specified analysis of the TST trial to evaluate the baseline and on-treatment predictors of incident ICH. I'm joined now by Dr. Pierre Amarenco, who's the first author of the study and one of the primary investigators of the TST trial, to discuss this paper. Dr. Amarenco is an internationally renowned neurologist who absolutely needs no introduction to the Stroke readership, but as always, an introduction is nice.

Dr. Negar Asdaghi:         He's a Professor of Neurology and the founder of the Department of Neurology and Stroke Center, as well as the SOS-TIA Clinic, at Bichat University Hospital in Paris. He's a leader in the field of secondary prevention of stroke with special interests in treatment of patients with TIA and mild stroke. He has served as the primary investigator of multiple randomized trials of antithrombotic therapies, lipid modifying agents, and acute revascularization treatments. Dr. Amarenco leads the international TIA registry involving centers from 21 countries around the globe. Welcome to our podcast, Pierre. Thank you so much for joining us all the way from Paris.

Dr. Pierre Amarenco:     Good afternoon, Negar. Thank you for asking me.

Dr. Negar Asdaghi:         Well, thank you for being here. Let's start with the Treat Stroke to Target trial. It addresses an important gap in the secondary prevention of ischemic stroke literature. Can you please start us off with an overview of the trial?

Dr. Pierre Amarenco:     Yes. The objective of Treat Stroke to Target trial was to evaluate in 2,860 patients with ischemic stroke of atherosclerotic origin randomized into a target LDL cholesterol less than 70 milligram or a target LDL cholesterol 90 to 110 milligram per deciliter to see the benefit in the lower target group as compared to the higher target group. That was the purpose of the TST trial.

Dr. Negar Asdaghi:         And the trial, Pierre, was terminated early. Do you mind commenting for our listeners as to why this happened?

Dr. Pierre Amarenco:     Yes. The TST trial had a very long duration. It was an academic trial with low funding, funded by the French government, which is not quite the same as the NIH-funding trials. To give you an example, patient cost was $1,500 for the whole duration of the trial per patient. Around $1,500 per patient. So, it was a very low funding, and because of that, after nine years, we had to stop. But we had recruited all patients, and we had a three-year follow-up, so we could have a meaningful result.

Dr. Negar Asdaghi:         So, perfect. So, just to recap for our listeners: Over eight-year period of time, despite the early termination, you had 2,860 patients enrolled, and so the termination of the trial was administrative reasons alone, as you mentioned. And so what were the primary outcomes of the trial?

Dr. Pierre Amarenco:     The primary outcome of the trial was a reduction of 22% in this primary outcome, which was the composite of ischemic stroke and non-stroke, microinfarction, vascular death, and urgent revascularization for coronary or carotid ischemic event.

Dr. Negar Asdaghi:         Okay, so the primary outcome was reduction of vascular events, truly, whether cardiac or in the brain. But now coming to the issue that is going to be addressed in your current paper, there remains a concern in the secondary prevention literature regarding an increased risk of intracerebral hemorrhage with statin therapy. Before we talk about the paper again, I want to give us a little bit of a background regarding the roots of this concern. Where does this all stem from?

Dr. Pierre Amarenco:     In fact, when you do a meta-analysis of all statin trials, there is no increase of hemorrhagic stroke, particularly trials in primary prevention of stroke. However, in trials in secondary prevention, which include mostly HPS trial with simvastatin and SPARCL trial with atorvastatin, there was a 60% increase in hemorrhagic stroke. That did not outweigh the benefit observed in this trial, but there was a concern about statin in secondary prevention, particularly high dose statin.

Dr. Pierre Amarenco:     So, in SPARCL, we did a post-stroke analysis looking at predictors of hemorrhagic stroke, and we found that, as usual, age and male sex increase risk of hemorrhagic stroke, but the most important was uncontrolled hypertension and atorvastatin. Atorvastatin stayed into the model. We know that atorvastatin reduce LDL cholesterol, that low LDL cholesterol in SPARCL was not associated with hemorrhagic stroke. So, there was a paradox because atorvastatin stayed into the model and we know that atorvastatin lower LDL cholesterol importantly. It is possible that something goes wrong between statin and vascular disease in the brain. In SPARCL, we looked at stroke subtypes at the baseline, and we found that atherosclerotic stroke, TIA and cryptogenic stroke were not associated with hemorrhagic stroke. But we found also that patients randomized with brain hemorrhage, 2% of the sample, and patient randomized with lacunar stroke were at increased risk of hemorrhagic stroke.

Dr. Pierre Amarenco:     So, altogether, we can say that small vessel disease of ischemic type or hemorrhagic type were associated with hemorrhagic stroke, and we know that small vessel disease is associated with high blood pressure. So, the fact that we found uncontrolled hypertension as a predictor of hemorrhagic stroke in SPARCL was logical since also we found that small vessel disease was a predictor.

Dr. Negar Asdaghi:         So, very important points that you mentioned, and I, again, want to repeat them for our listeners. And I think it's one of my questions later on to ask about independent predictors of hemorrhage, but based on the cumulative literature for what we knew before the current study, you had mentioned uncontrolled hypertension, small vessel disease, which is sort of a marker of both ischemic and hemorrhagic events in the brain, were all independent predictors of development of ICH. Whether statin therapy or low target level of LDL adds to that fueling, that fire, or not was something that you wanted to really decipher in the TST trial. I think we're ready to hear about the methodology of your current paper, if you could tell us, please.

Dr. Pierre Amarenco:     So, in TST, of course, because of this background, we pre-specified an analysis of incident hemorrhagic stroke. So, we looked at patients with incident hemorrhagic stroke versus those without, and we did a multivariable analysis to look at predictors, and that was the methodology of the paper we use for this specific paper.

Dr. Negar Asdaghi:         And what were the primary results?

Dr. Pierre Amarenco:     So, the primary result was that after a median of three years follow-up, we found 31 hemorrhagic stroke in the lower target group and 28 hemorrhagic stroke in the higher target group, and the difference was not significant. In the paper, we show a graph with a distribution of hemorrhagic stroke according to the level of LDL cholesterol three months before the hemorrhagic stroke, and it is striking to see that half of the events occurred for an LDL cholesterol above 100 milligram per deciliter and half of the events occurred for an LDL cholesterol below 100 milligram per deciliter. So, clearly, in TST trial, like in SPARCL trial, we did not find a relationship between low LDL cholesterol and incident hemorrhagic stroke.

Dr. Negar Asdaghi:         So, very important information for all practicing neurologists and stroke neurologists out there. I want to recap, again, very important numbers that you mentioned. Achieving low LDL cholesterol target, even very low numbers, as you mentioned, was not a predictor of development of intracerebral hemorrhage in the trial. And, as you mentioned, half of them, actually it occurred even before achieving the target LDL for the trial. But you did find some other significant predictors of ICH in the study. Can you please elaborate on those?

Dr. Pierre Amarenco:     Yes, we found predictors, and the only predictors we found, in fact, were uncontrolled hypertension, exactly what we found in SPARCL. So, uncontrolled hypertension is really something important, and anticoagulant treatment, which was not found in SPARCL. So they were the only predictors, uncontrolled hypertension and anticoagulant treatment with of use therapeutic implications. When you put patients on a low level of LDL cholesterol, when you target the low level, you have to tightly control blood pressure, which is always a case in secondary prevention of stroke, but particularly when you target the low LDL cholesterol, and then anticoagulant treatment, of course, you have to monitor closely blood pressure and also the level of anticoagulation.

Dr. Negar Asdaghi:         So, it's, again, I want to repeat what you mentioned, because it seems like we've been blaming the wrong person all along, concentrating on this issue of statins or low LDL levels being associated or the causative reason for development of intracerebral hemorrhage, and forgetting about the obvious, which is uncontrolled hypertension and now the new finding of being on oral anticoagulants, which is not unexpected. Pierre, my next question was on SPARCL trial, but you've already alluded to the SPARCL study. I'm going to repeat and ask the question regarding SPARCL, because for years and years as practicing neurologists, we've referred to the results of SPARCL, and you already alluded to some of the similarities between the two trials, but is there something else as you compared TST with SPARCL that you want to mention in terms of patient population included in both studies or the differences in the results?

Dr. Pierre Amarenco:     The most important difference was that in SPARCL, there was a placebo group, which was not the case in TST since we compared two levels of LDL cholesterol. So, literally all patients were on statins in TST trial, which was not the case in SPARCL since half of the patients were on statins. So, that was the main difference, but the concept of TST clearly came from SPARCL sub-analysis. In SPARCL sub-analysis, we found that achieving an LDL cholesterol less than 70 milligram was associated with a benefit compared to patients with an achieved LDL cholesterol of 100 milligram per deciliter. But that was a post-stroke analysis in SPARCL, and so we had to confirm this, which is why we did the TST trial, which was clearly a follow-up of the SPARCL trial. And then we confirmed what we found in SPARCL, that is low LDL cholesterol was not associated with incident hemorrhagic stroke while there was a benefit of achieving a low LDL cholesterol target compared to a higher target.

Dr. Negar Asdaghi:         All right, so just the follow-up question on the LDL levels. Statins are, of course, not the only agent to use to achieve a lower level of LDL cholesterol. There's a growing literature with the PCSK9 inhibitors, especially in patients with acute coronary syndrome, to lower the LDL levels. How are the findings from those studies of PCSK9 inhibitors on the risk of ICH compared to your study?

Dr. Pierre Amarenco:     The findings of four-year trial with evolocumab and ODYSSEY OUTCOMES trial with alirocumab was that going to less than 40 milligram per deciliter or even 30 milligram in mean per deciliter in four-year trial was not associated with an increased risk of hemorrhagic stroke. For example, in four year, the risk of hemorrhagic stroke was 0.21% in the evolocumab group versus 0.18% in the placebo group. And in ODYSSEY OUTCOMES trial, it was 0.2% in both groups. So, clearly, going to a very, very low level of LDL cholesterol was not associated with an increased risk of hemorrhagic stroke. To give a comparison, in TST, in the lower target group, we had a 1.25% risk of incident hemorrhagic stroke versus 0.9% in the higher target group. There was a slight increase, but that was not reaching statistical significance, and it was not associated with low LDL cholesterol.

Dr. Negar Asdaghi:         Perfect. So, quite reassuring, these results from various trials, again, showing and reassuring that the risk of intracerebral hemorrhage seems to not be significantly associated with lower target levels of LDL cholesterol. Now, we do have time, Pierre, I want to digress a little bit from your current study and ask a question that comes up rather frequently in routine practice. And that is the association between statin therapy, lower levels of LDL and incident ICH in the setting of microbleeds that are found typically incidentally on an MRI study. Do you think there is any possible interaction between the two, or are there plans to look at this as part of TST?

Dr. Pierre Amarenco:     Yes. I would like first to say that I don't like the term "microbleeds" or "microbleeding" because it is scary for the patients. I have plenty of patients coming to my outpatient clinic because they are afraid of what they have read on the radiologist report, "microbleeds." "Doctor, my brain is full of microbleeds." I prefer to use the term "microdeposit of hemosiderin," which is descriptive, which is associated with small vessel disease.

Dr. Pierre Amarenco:     So, regarding the relationship between microdeposit of hemosiderin and incidence of intracranial hemorrhage on statin, in fact, we don't know the relationship, but we can't say that in SPARCL, there was an association between small vessel disease of hemorrhagic or ischemic type with incident hemorrhage on atorvastatin 80 milligram per day. So, these patients with microdeposits of hemosiderin have small vessel disease, and then they may be at risk of more hemorrhagic stroke. So, in these patients, I would be cautious, and on high dosage of statin. I prefer to use low dosage associated with ezetimibe or with PCSK9 inhibitor to go low for LDL cholesterol, but not with statins. So, this is the way I'm used to do when there is a lot of microdeposit of hemosiderin in my patient, but it has not been tested in clinical trials.

Dr. Negar Asdaghi:         So, very important, again, to repeat and recap what you mentioned. First of all, love the term "microdeposit of hemosiderin," and I'm going to use that with my patients. I totally agree with you that telling someone, "Oh, there's tons of blood in your brain," is not quite a good start. But definitely, again, as you mentioned, these are markers of small vessel disease, both for ischemic stroke and hemorrhagic. So, it's important to, again, address the causes of small vessel developments and etiologies very aggressively. And, as you mentioned, the jury's still out whether the statin class affect an association with incident ICH or an association between low target levels of LDL cholesterol, and more to come on that in the future. Pierre, just to end our podcast, what would be your top two takeaway messages for our listeners on the topic of target LDL and incident ICH?

Dr. Pierre Amarenco:     Well, the message is simple. Targeting an LDL cholesterol of less than 70 milligram per deciliter in atherosclerotic ischemic stroke non-significantly increases the risk of subsequent intracranial hemorrhage. Incident intracranial hemorrhage were not associated with low LDL cholesterol level. And we found two predictors of incident intracranial hemorrhage, which were uncontrolled hypertension and anticoagulant therapy, which has important clinical implication for our patients.

Dr. Negar Asdaghi:         Dr. Pierre Amarenco, it's been a pleasure interviewing you on the podcast today, and we look forward to having you back with more on this topic.

Dr. Negar Asdaghi:         And this concludes our podcast for the February 2022 issue of Stroke. Please don't forget to check out this month's table of contents for the full list of publications, including a series of Focused Updates on vascular brain health organized by Dr. Steve Greenberg.

Dr. Negar Asdaghi:         February is also a special month for our stroke community, with our annual International Stroke Conference, which this year is held as a hybrid event, both face-to-face in New Orleans and simultaneously as a virtual event for those who cannot attend it in person, as the fight against the COVID-19 pandemic continues. Reminding us all that with every challenge, there comes new ways to live, to cope, and to rise above it all. And we're here to do just that with staying alert with Stroke Alert.

Dr. Negar Asdaghi:         This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 12 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the January 2022 issue of Stroke: “Efficacy of Intravenous Mesenchymal Stem Cells for Motor Recovery After Ischemic Stroke: A Neuroimaging Study” and “Cumulative Concussion and Odds of Stroke in Former National Football League Players.” She also interviews Dr. Mike Sharma about his article “Frequency and Patterns of Brain Infarction in Patients With Embolic Stroke of Undetermined Source: NAVIGATE ESUS Trial.”

Dr. Negar Asdaghi:

1) Can repeated concussions increase the risk of stroke in professional athletes?

2) Does stem cell therapy enhance the recovery from ischemic stroke?

3) ESUS stands for “embolic stroke of unknown source.” Is ESUS just a fancy new term, or is there more to it than meets the eye?

These are some of the topics that we will discuss in today's podcast. We're covering the best in Stroke. Stay with us.

Dr. Negar Asdaghi:         Welcome to a new year of Stroke podcasts. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The January 2022 issue of Stroke covers a host of topics, from molecular biomarkers and drug targets in brain arteriovenous malformation to examining the role of calcium in atherosclerotic carotid disease, which I encourage you to review in addition to listening to today's podcast. Later in the podcast, I have the honor of interviewing Dr. Mike Sharma from McMaster University in Hamilton, Ontario, on his work with embolic stroke of unknown source and some of the therapies to soon be studied in this population, including the new Factor XI inhibitors. But first with these two articles.

Dr. Negar Asdaghi:         Stem cells are truly the new kids on the block of therapies to potentially enhance stroke recovery. There's now four decades worth of experience with preclinical research and studies with animal models to evaluate the safety and efficacy of stem cell therapies and stroke. Now, this is a complex topic, and I will try to simplify it as much as possible. So, what are the things that we need to know about stem cell therapy and ischemic stroke? Well, first, in humans, the bone marrow has emerged as the widely used source of stem cells, primarily because of its long track record of safety profile. In fact, bone marrow derived cell populations, some examples being mesenchymal stem cells, mononuclear cells, endothelial progenitor cells, are the leading candidates for stem cell therapies in ischemic stroke. Number two, stem cells can be practically delivered to the brain through a variety of pathways. Intravenous and intra-arterial treatments have been and are currently being studied, but stem cells can also be delivered intranasally and, of course, surgically transplanted in the brain.

Dr. Negar Asdaghi:         So, with these in mind, there are two recently concluded clinical trials of mesenchymal stem cells in adult stroke patients. The STARTING-2 trial, which stands for the Stem Cell Application Researches and Trials in Neurology-2, was one of those two trials. This trial evaluated the safety and efficacy of intravenous autologous, meaning from the same individual, mesenchymal stem cells in patients with moderate to severe neurological deficit originating from the middle cerebral artery territory infarct within 90 days of symptom onset. The primary results of the trial was published in Neurology very recently in February of 2021, and if you missed it, well, luckily, you are listening to the podcast today. So, here's a quick recap of the trial. Fifty-four patients were enrolled in the trial with mean stroke onset to randomization of 20 days. Patients were randomized 2:1 to either receive intravenous mesenchymal stem cell treatment or placebo.

Dr. Negar Asdaghi:         Well, in terms of the primary outcome, stem cell therapy did not improve the primary outcome, which was improvement of modified Rankin Scale at 90 days after treatment. So, disappointing, but secondary analysis showed a significant improvement in lower extremity motor function in the stem cell group as compared to the control group. So, in the current issue of the journal, in the study titled "Efficacy of Intravenous Mesenchymal Stem Cells For Motor Recovery After Ischemic Stroke: A Neuroimaging Study," the STARTING-2 collaborators, led by Dr. Jungsoo Lee from the Department of Physical and Rehabilitation Medicine from Sungkyunkwan University School of Medicine in Seoul, South Korea, aimed to look at this improved motor recovery in more detail using advanced neuroimaging. So, of the original 54 patients in the trial, 44 were eligible for the current neuroimaging study. Participants underwent a variety of testings, including diffusion tensor imaging and resting-state functional MRI studies, at the time of enrollment and then 90 days afterwards.

Dr. Negar Asdaghi:         So, not surprisingly, at baseline, patients in both the stem cell and control group had comparable demographics, clinical characteristics and infarct volumes, as well as similar motor function, which was measured by the Fugl-Meyer, or the FMA, score. So here's a look at their main findings. So, number one, the FMA scores that were comparable at baseline were significantly higher at follow-up in the stem cell-treated group. Number two is the interesting results; they looked at the motor pathways using diffusion tensor imaging. So, they looked at fractional anisotropy values of the corticospinal pathways and the posterior limb of the internal capsule. Now, just a quick review of a somewhat complex concept of the fractional anisotropy for our listeners. In general, FA is one of the calculated parameters in DTI with a value between zero to one, and what it does is that it defines the degree of diffusion directionality.

Dr. Negar Asdaghi:         A value of zero means that the diffusion is isotropic, meaning it is unrestricted or equally restricted in all directions. A value of one means that diffusion occurs only along one axis and is fully restricted along all the other directions. So, it's easy to understand in terms of axons creating white matter tracts. When the tracts are intact, then the FA values would be high because the diffusion is occurring only in one direction as the tract is intending it to do so, whereas if the white matter tracts are damaged, then the uni-directionality of the tract would be disrupted and the molecules would diffuse freely in various directions and the FA values for that white matter tract is then, as expected, reduced. So, in the stroke model, for example, if a neuron in the motor cortex is damaged, the white matter tract related to that region will, over time, degenerate, a process which we know as Wallerian degeneration and, as such, the FA values of that tract is expected to decrease as we go from the acute to the chronic stages of stroke.

Dr. Negar Asdaghi:         So, back to the current study. At time zero, FA values for the corticospinal tract and the posterior limb of internal capsule were fairly similar between the two groups, but interestingly, at 90-day follow-up, those in the control group had a significant and expected drop in their FA values, whereas those who had received stem cell therapy did not show a significant drop, meaning that intravenous administration of mesenchymal stem cells did modulate and perhaps prevented degeneration of the motor tracts after stroke. The third and final interesting finding of the study was the findings of the resting-state functional MRI. They used RS, or resting-state, fMRI as a measure of functional motor connectivity and found that stem cell treatment increased the strength of ipsilesional connectivity in the motor network and prevented a drop in the strength of intrahemispheric connectivity, whereas these findings were not seen in the control group.

Dr. Negar Asdaghi:         So, what does this all mean? We now have some detailed neuroimaging evidence that indeed stem cell treatment can facilitate motor recovery possibly by reducing degeneration, which is what their DTI data showed, and potentially by leading to positive motor network organization or reorganization, which is what the resting-state fMRI findings showed. So, obviously, lots still to come in this topic and a reminder to our listeners that there are ongoing clinical trials on this topic. So, we will stay tuned as the neuroprotection and regeneration paradigm is truly changing for ischemic stroke with stem cell therapy.

Dr. Negar Asdaghi:         Sports-related concussive symptoms typically resolve within a few weeks of the injury, but there is now ample scientific evidence to suggest that repeated concussion can cause long-term neurological disorders extending way beyond the short-term post-concussive period. How can traumatic brain injury, or TBI, be a cause for stroke? Well, in the more severe forms of TBI, it can actually cause damage to the large vessels and cause dissection, but there is more and more research showing that even milder trauma can lead to microvascular disruptions and even alterations in coagulation pathway, which will then increase the risk of stroke. So, how about repeated mild trauma or repeated concussion in professional athletes? Is concussion a risk factor for stroke in this population?

Dr. Negar Asdaghi:         Well, in the current issue of the journal, in the study titled "Cumulative Concussion and Odds of Stroke in Former NFL Players," Dr. Benjamin Brett and Zachary Kerr from Department of Neurosurgery, Medical College of Wisconsin, and Department of Exercise and Sports Science, University of North Carolina at Chapel Hill, and colleagues report on a cross-sectional study that included professional football players who had at least played for one year in the National Football League and were over the age of 50 at the time of the study.

Dr. Negar Asdaghi:         Now, before we go over the results, there are a few important definitions from this study to note. Number one, concussion was defined as a blow to the head followed by a variety of neurological symptoms, such as headache, dizziness, loss of balance, etc. Getting knocked out or being unconscious was not necessary to define concussion. For our listeners, this is an important shift from the original definition of concussion that required some alteration of level of consciousness. Number two, the participants were asked as part of the study survey about a history of stroke, which was defined as any health provider giving the participant the diagnosis of stroke at some point in their life. So, there were no mandates of any neuroimaging or particular testings to confirm this diagnosis as part of the study. So, with these in mind, 979 participants met the study inclusion criteria and were included in the study. The mean age was 65 years ranging from 50 to 99, self-reported lifetime concussion history was recorded, and the participants were then divided into five categories of zero, meaning never had experienced concussion, to those with over 10 concussions.

Dr. Negar Asdaghi:         So, the first important finding was that over a quarter of their study population actually were in the over 10 concussions category. The second finding was the overall prevalence of stroke was 3.4% amongst the pro-NFL players, which was significantly lower than that expected from age-matched normative population, meaning the prevalence of stroke amongst U.S. men over age of 50. So, in simple words, being athletic is a good thing and not surprisingly is associated with a lower risk of vascular disease. But what they found was that NFL players with a history of 10 or more prior concussions had five times the odds of stroke as compared to those with no prior concussions in the adjusted models. So, what we learned from this study is that traumatic brain injury, specifically repeated TBI, however mild, seems to be an independent risk factor for stroke. Microvascular disruptions and potentially alterations in coagulation pathways have been proposed as potential mechanisms for this association.

Dr. Negar Asdaghi:         About a quarter of patients with ischemic stroke do not have a clear cause for the stroke and fall under the cryptogenic or unknown category. In 2014, an international panel of experts developed a criteria to define a group of patients with cryptogenic stroke that are likely to have an embolic, but yet undefined source for their ischemic event and called them ESUS, which stands for "embolic stroke of unknown source." These were operationally defined as non-lacunar brain infarcts without significant proximal arterial stenosis or known cardioembolic sources of infarct. Now, the idea behind the development of this new term, ESUS, was to identify a more homogenous subgroup of cryptogenic stroke patients that would perhaps benefit from preemptive anticoagulation therapy over the standard antiplatelet treatment for secondary prevention of stroke.

Dr. Negar Asdaghi:         Indeed, since 2014, ESUS has become a rather commonly used terminology in the stroke literature with multiple ongoing and a few already completed randomized trials examining the efficacy and safety of the newer oral anticoagulants in patients with ESUS over antiplatelet therapy. Similarly, much has been done to further study the clinical and radiographic characteristics of patients with ESUS. In this issue of the journal, in the study titled "Frequency and Patterns of Brain Infarction in Patients With Embolic Stroke of Undetermined Source," the NAVIGATE ESUS randomized control trial investigators set out to examine the radiographic characteristics and infarct patterns of ESUS patients enrolled in the NAVIGATE ESUS randomized trial.

Dr. Negar Asdaghi:         Joining me now is the first author of the paper, Dr. Mike Sharma, to discuss the findings of this paper. I always say that my guest needs no introduction, and today's guest is, of course, no exception to that. Dr. Sharma is well known to our Stroke readership. He is a stroke neurologist and a scientist at the Population Health Research Institute at McMaster University in Ontario, Canada. He is truly a leader in the field of clinical epidemiology in secondary stroke prevention with an interest in randomized trials, covert stroke, and economics of stroke care. He holds the Michael G. DeGroote Chair in Stroke Prevention and is the immediate past chair of the Canadian Stroke Consortium and also leads the Hamilton McMaster Stroke Program. Good morning, Mike. It's so good to connect with you after so many years. Thanks for being with us.

Dr. Mike Sharma:            Good morning, Negar. It's a pleasure to talk to you again, and thank you for that kind introduction.

Dr. Negar Asdaghi:         Well, thank you so much. Can you please start us off with a brief summary of what the NAVIGATE ESUS trial set out to do, and what were the main findings of the trial?

Dr. Mike Sharma:            So, in NAVIGATE, we really wanted to advance the care of patients with cryptogenic stroke. Cryptogenic has been a somewhat nebulous term for decades, and care really hasn't advanced beyond using aspirin. The problem with that term is, there is no agreed upon criteria to define cryptogenic stroke. Sometimes it means that the workup is incomplete, where there are multiple competing causes or indeed there is a disagreement as to what the cause is. So, in NAVIGATE, we took a different approach, which was to look for markers which would identify patients who had strokes which were embolic. Our feeling was that they might respond better to anticoagulation than antiplatelet therapy. So that was the main goal in NAVIGATE, was to use this construct of ESUS to test the hypothesis that anticoagulation will be more effective in preventing stroke recurrence than antiplatelet therapy.

Dr. Negar Asdaghi:         And what did the trial find?

Dr. Mike Sharma:            So, NAVIGATE randomized over 7,000 patients with ESUS, and it was stopped, unfortunately, at the time of the second interim analysis after about 67% of primary events had occurred. At that point in time, our mean follow-up was only about 11 months. It was stopped because there was a difference in the risk of bleeding between the rivaroxaban arm and the aspirin arm and, at that point in time, no evidence of benefit. So, the DMC reasonably halted the trial. So, at that point, we saw an excess of hemorrhage with rivaroxaban without an offsetting benefit in preventing recurrent ischemia.

Dr. Negar Asdaghi:         Okay, so to recap for our listeners, NAVIGATE is an early terminated randomized trial that basically looked at the safety and efficacy of rivaroxaban over aspirin in secondary prevention of stroke in ESUS. Now, the dose of rivaroxaban used in NAVIGATE ESUS was slightly lower than the current standard of care for treatment of embolic stroke patients with known atrial fibrillation. So, you used 15 milligrams per day rivaroxaban, whereas the standard is 20 milligrams per day. Was there a reason why a slightly lower dose of rivaroxaban was chosen for the trial?

Dr. Mike Sharma:            That's a great question. So, 20 milligrams a day in atrial fibrillation is approved in the U.S. I must say that many guidelines, including the AHA guidelines, suggest 15 milligrams for patients with renal impairment and creatinine clearance that is less than 50. Now, in other countries, as the label is slightly different recommending the lower dose. So, in planning this very large international trial, we had a variability in dosing and the complexity of possibly having to change the dose during the course of the trial if a patient's renal function changed. When we looked at the drug exposure between the 15 and 20 milligrams, it turns out that they were very similar. So, taking 15 milligrams, you get very close to the drug exposure with 20 milligrams. The lower dose, we felt, would eliminate the need for dose adjustments during the course of the trial and make running the trial simpler and possibly have a slightly lower risk of hemorrhage than the 20 milligram dose. So, for all those reasons, 15 milligrams was chosen.

Dr. Negar Asdaghi:         Mike, I love these interviews mainly because of these valuable background information we get on trials that is otherwise impossible to easily access. Now, coming back to your current paper, the current paper in the January issue actually is an MRI sub-study of the NAVIGATE ESUS trial. Can you please walk us through the details of the current study?

Dr. Mike Sharma:            Sure. You know, in NAVIGATE, in the parent trial, we included people who had embolic strokes of uncertain source, and those were operationally defined as either visible on imaging, the majority were, or having symptoms that lasted greater than 24 hours. You couldn't have atrial fibrillation, and we required at least 20 hours of monitoring. Now, 20 hours sounds like a funny time period to request. Originally, we asked for 24 hours, but it turns out that when you put a monitor on for 24 hours, it's never exactly 24 hours. It's often just slightly less. So, we had to make a practical decision as to how much was enough, and in addition, you had to have less than 50% extracranial stenosis. We didn't require imaging of the intracranial vasculature; however, if it was imaged, the stenosis had to be less than 50% to the affected area.

Dr. Mike Sharma:            You needed an echocardiogram. We didn't specify a transesophageal echo. Most were transthoracic, which excluded left ventricular thrombus or left atrial appendage thrombus. People who had prosthetic mitral valves were excluded as well. So, from that population of about 7,000, our aim was to select 1,000 patients who met those criteria, but in addition had no contraindication to MRI, and the plan in the MRI sub-study was to look at what happened to covert infarcts, infarcts we didn't identify clinically during the course of the trial, if there was a treatment effect on those and also with MRI, a very sensitive, I would say, exquisite measure of hemorrhage that occurs in the brain. Because the trial was closed early, we ended up at baseline having 918 usable images and participants from 87 sites across the world, less than our original target. You know, our goal really was to see what would happen to these MRI lesions and if treatment affected them.

Dr. Negar Asdaghi:         Okay. So we are talking about baseline MRIs of a subpopulation of the patients who were enrolled in NAVIGATE ESUS, and I think we are ready now to hear about your main results.

Dr. Mike Sharma:            Thanks very much. I'm bursting to talk about them. You know, in spite of the fact that this was a subset of the whole ESUS population, 918 out of 7,000, roughly 13%, the characteristics of these patients was very similar to the main trial. So, I think that with the usual caveats of the subgroup, I think it's reasonable to think that what we found is representative of the ESUS population in general. The most exciting finding for us was that, so we set out to define clinically a group that would be embolic. The majority of the MRIs that we had first off had visible infarcts, and secondly, 70% of these were multiple infarcts often in multiple vascular territories. So, the clinical construct, I would say, worked. We did identify a group of patients who have embolic lesions and often proximal sources, as we see with these multiple vascular territories affected.

Dr. Mike Sharma:            So, this clinical construct works really very well in identifying them. The second thing we found, which shouldn't have been overly surprising but really stood out, were the number of lesions that these people had. The ones with multiple lesions, on average, had four infarcts visible on their MRI, and these were present even in patients who did not have a previous history of TIA or stroke. So, this was their first symptomatic event, and I think that tells us a lot about what's happening in this condition. It's an embolic disease with multiple events, which seems to be very active over time, even when these lesions aren't identified symptomatically.

Dr. Negar Asdaghi:         So, Mike, you've already alluded to what I was going to ask you in this question, but I want to recap and repeat for our listeners again, some very pretty impressive findings you have in the study, 93% of ESUS patients with evidence of infarcts, 70% in multiple vascular territories. What I find very interesting is that two-thirds of your patients without even a history of TIA or stroke had multiple infarcts on their neuroimaging. Does that represent to you this clinical radiographic dissociation in the ESUS population?

Dr. Mike Sharma:            You know, I think that's a really great question. So, it certainly does. What we know in the number of other covert studies and some other work that colleagues have done epidemiologically is the proportion of covert infarcts. These are infarcts without clinical symptoms that have been identified as stroke, is roughly 5 to 10 times symptomatic events. And we are seeing this recapitulated in this population.

Dr. Mike Sharma:            In looking across literature, I suspect that some of these and perhaps a majority had symptoms which were transient, which they didn't appreciate the significance of, or were not identified as stroke at the time. So, this is similar to what's been seen in other populations, just more striking, I think, because of the embolic nature of this condition. You know, I think this really points to the significance of identifying these patients. We expect them to continue to have these covert infarcts, and I prefer the term "covert" to "silent." Silent means it's not really having any manifestation, whereas covert indicates a hidden and nefarious purpose. So, these things do detract from cognition, from motor function, they correlate with disability and recurrent stroke. So, this condition seems to us to be very dynamic and really needs to be addressed.

Dr. Negar Asdaghi:         So, striking indeed and definitely concerning findings, Mike, as you pointed out. I think it goes along with all the continuous efforts of increasing public awareness about mild or transient neurological symptomatology along the lines of what you were mentioning. For our listeners, what should be the top two takeaway messages from your study?

Dr. Mike Sharma:            So, you know, I think from this study, the really important things are when you identify one of these patients where there is an infarct that you cannot comfortably identify the etiology of, please know that it is likely to be embolic often from a proximal source, but not exclusively, and that patient has an ongoing risk of recurrent infarcts, which may not present symptomatically. So, I think that what this underscores is the need to pay a very serious attention to these patients, look carefully for underlying causes, and we really do need a better treatment.

Dr. Negar Asdaghi:         Fair enough. Now I want to end by something that I derived from your study, and I wanted your opinion on that. ESUS is truly proving to encompass a more heterogeneous group of ischemic stroke patients than I think previously recognized. Can you please tell us what's the future for the ESUS trials? Are you going to more elaborate on the etiology of ESUS, again truly cardioembolic versus others, and can you please share with our listeners some of the work that you are currently doing in this field?

Dr. Mike Sharma:            Very exciting future, I think, for this. If you consider where we are with this condition, it's similar to where we were with mechanical thrombectomy with the early trials, which were negative but taught us a lot, and so has this one. Our approach with mechanical thrombectomy, we did two things. First, we honed in on the patient population that was likely to respond, and secondly, we improved the treatments, and I think our approach to ESUS, and this goes along with what we are doing currently, is along the same lines. So, in terms of honing down on the population likely to respond, there is now a number of interesting trials being done. One of these is ARCADIA, and I would encourage everybody to refer patients for this trial. In a post hoc analysis of NAVIGATE, we found that patients with markers of atrial myopathy, particularly a large left atrial diameter, seemed to respond to anticoagulation.

Dr. Mike Sharma:            So, in ARCADIA, which is being run from Columbia University through NIH StrokeNet, is looking for patients with ESUS who have markers of atrial myopathy, randomizing to anticoagulation or aspirin. So, really honing in on a population likely to respond. The other thing that we are working on are better treatments. So, at the same time NAVIGATE was being done at our institute, we were doing COMPASS. Now, COMPASS used low dose rivaroxaban 2.5 milligrams BID with aspirin, and one of the startling findings in COMPASS was a 50% reduction in ischemic stroke occurrence in that trial. And if you think about it, emboli can be fibrin rich or platelet rich or some combination and we really don't know. So, if there is a safe dose to combine aspirin with an anticoagulant, that is a promising approach. So, currently what we are doing is a trial using Factor XI inhibitors.

Dr. Mike Sharma:            Now, you know, if you think broadly across stroke prevention, we have made advances using dual antiplatelet therapy, but they seem to be hitting a ceiling in terms of efficacy with some risk of hemorrhage, and it certainly seems to be the case from NAVIGATE and also RE-SPECT ESUS, which used dabigatran, that anticoagulation by itself won't work. So, from COMPASS, we have this dual pathway approach combining anticoagulation and antiplatelet agents. The novelty here that we are pursuing is using anticoagulants, which have a much lower risk of hemorrhage. So, Factor XI, unlike Factor X, which is affected by rivaroxaban, is not involved in hemostasis, but rather amplifies thrombi, and we know that Factor XI-deficient patients have a low rate of stroke, lower than matched controls, and really no significant spontaneous hemorrhage.

Dr. Mike Sharma:            So, there's a number of trials currently in DVT. We are running really the first trial ever done in stroke at phase two to develop an appropriate dose of anticoagulation for these patients. So, I think the future is going to be combining anticoagulants with antiplatelet agents to reduce these patterns of embolic stroke. Holds a lot of promise after what we saw in COMPASS, and indeed we did a similar MRI study in COMPASS, which taught us a lot about how to do these trials. So, currently, we are working on those, and the first results from two trials using Factor XI inhibition. This approach should be available to us next year.

Dr. Negar Asdaghi:         So, wow, a lot of information, and we look forward to reading about all of this and perhaps collaborating with you on this. Now, Mike, one question that came up along the lines of what you were mentioning is that, what about the duration of therapy? Do you think that much like CHANCE and POINT, where dual antiplatelet therapy is beneficial for shorter period of time and not for long period of time, that you might choose that as well for ESUS patients, that a short period of anticoagulation or combined anticoagulation and antiplatelet therapy might be beneficial and then not continuing them indefinitely for this population?

Dr. Mike Sharma:            You know, it's an entirely reasonable approach to consider. The problem really is what we found in the MRI study, which is that infarcts continue to occur over the long period. We have data now for about a year. But, in other trials and COMPASS, we saw it over many, many years. So, I think that if we focus on the short term, we will have success in reducing the recurrence rate, and the payoff might be a lower risk of hemorrhage, but at the cost of leaving patients vulnerable to recurrences over the long term, you know, and NAVIGATE, we saw recurrence rate of about 5% per year. So quite a significant recurrence rate of symptomatic stroke, and we won't have touched the occurrence of covert infarcts and all that means for the brain.

Dr. Negar Asdaghi:         Dr. Mike Sharma, thank you so much for joining us on the podcast this morning. We look forward to covering more of your work in the future.

Dr. Mike Sharma:            It's a pleasure, Negar, very nice to talk to you.

Dr. Negar Asdaghi:         And this concludes our podcast for the January 2022 issue of Stroke. Please be sure to check out this month's table of contents for a full list of publications, including an organizational update from the European Stroke Conference, which highlights some of the top science presented as part of the plenary sessions at this year's meeting to give us that extra motivation to start the year. Now, speaking of motivation, starting the year, in my view, is much like running a long distance race. Anyone who has done it would tell you that this is as much about mental fitness as it is about physical fitness. So, I think it's only fitting to end the beginning of this year's podcast remembering one of America's inspirational distance runners, Steve Prefontaine.

Dr. Negar Asdaghi:         As a kid, he was told that he's too short and perhaps too slow to be played in any of his school's sport teams. Later, when he became a runner, people would say that they had never seen anyone run like him, a runner who never slowed down nor paced himself. And he famously said "to give anything less than your best is to sacrifice a gift." All of 2022 is now ahead of us. Let's not sacrifice the gift. There is no time to pace ourselves, and what better way to do this than staying alert with Stroke Alert?

Dr. Negar Asdaghi:         This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org

On Episode 11 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the December 2021 issue of Stroke: “Baseline Cognitive Impairment in Patients With Asymptomatic Carotid Stenosis in the CREST-2 Trial” and “Serious Adverse Events and Their Impact on Functional Outcome in Acute Ischemic Stroke in the WAKE-UP Trial.” She also interviews Dr. Mark Parsons about his article “Stroke Patients With Faster Core Growth Have Greater Benefit From Endovascular Therapy.”

Dr. Negar Asdaghi:        

1) Can the presence of a high-grade asymptomatic carotid stenosis result in development of early dementia?

2) Have you ever wondered if a random poststroke urinary tract infection or hospital-acquired pneumonia can impact the 90-day poststroke outcome?

3) When it comes to the beneficial effect of endovascular thrombectomy, what is the concept of late window paradox, and why do we need to know about this and its relation with the speed of infarct growth?

These are the questions that we will tackle in our December podcast. We're covering the best in Stroke. Stay with us.

Dr. Negar Asdaghi:         Welcome back to the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. For the December 2021 issue of Stroke, we have a large selection of topics, from whether adjusting antiplatelet therapies after stenting for intercranial aneurysms can potentially reduce ischemic events, to studying the outcomes of patients with reversible cerebral vasoconstriction syndrome and analysis from a nationwide study in the United States, which I encourage you to review in addition to listening to our podcast today. Later in the podcast, I have the pleasure of interviewing Dr. Mark Parsons, from the University of New South Wales in Sydney, Australia, on his work suggesting that the beneficial effect of endovascular thrombectomy may be modified based on the speed of infarct growth, from the time of symptom onset to the time when the patient is being considered for reperfusion therapies. But first with these two articles.

Dr. Negar Asdaghi:         It has been suggested that the presence of chronic high-grade carotid stenosis can result in early cognitive decline, even in the absence of ischemic stroke secondary to the carotid disease. Multiple mechanisms for this decline have been proposed, including an alteration of cerebrovascular reactivity and ipsilateral hemispheric hypoperfusion. Now, if this is true, then asymptomatic patients harboring a high-grade carotid stenosis would have a lower cognitive status than their age and risk factor in matched counterparts. And this is the exact topic that Dr. Ronald Lazar from the Department of Neurology at the University of Alabama and colleagues studied in this issue of the journal, in their article titled “Baseline Cognitive Impairment in Patients With Asymptomatic Carotid Stenosis in the CREST-2 Trial.”

Dr. Negar Asdaghi:         Now, a very quick recap of the CREST-2 Trial. You will recall that CREST-2 is an ongoing randomized trial of patients over 35 years of age with asymptomatic carotid disease of equal or greater than 70%. Asymptomatic is defined as absence of ipsilateral stroke or TIA symptoms within 180 days prior to randomization. Also, a reminder, that to be able to be enrolled in the CREST-2 Trial, patients had to be independent, with no diagnosis of dementia, and they were then randomized to either intensive medical management versus carotid artery stenting, or intensive medical management alone versus carotid endarterectomy. It's important to keep in mind that a secondary outcome of CREST-2 is to see whether carotid intervention over intensive medical management is better in reducing cognitive decline over time in this patient population.

Dr. Negar Asdaghi:         Obviously, we'll have these results after the completion of the CREST-2 trial and its follow-up completion, but in the current study, the authors were interested to compare the baseline cognitive function of the CREST-2 candidates, and they were able to compare this baseline cognitive status to participants of the REGARDS population-based study. Now, the acronym for REGARDS stands for "Reasons for Geographic and Racial Differences in Stroke." This was a population-based study in the United States that included over 30,000 community-dwelling White and Black adults over the age of 45. So, think about the REGARDS cohort as the stroke-free participants without the high-grade carotid stenosis.

Dr. Negar Asdaghi:         So, to match the two populations, the authors included only CREST-2 participants that were older than 45 years of age and did not have any prior strokes. So, that gave them a sample size of 786 patients for the current analysis with a complete neurocognitive battery of four tests administered over the phone, in the same order in both studies. So, let's go over these cognitive tests. The test included the Word List Learning Sum, assessing the cognitive domain of learning; the Word List Recall, which is a test of memory; and the two tests for executive function, Word Fluency for animal names and fluency for the single letter 'F'; and a brief screen for depression.

Dr. Negar Asdaghi:         So, simply put, we have four cognitive tests assessing the three cognitive domains of learning, memory, and executive function. And depending on how the person did on each test, it gave the investigators Z scores for each participant in each category and then they compiled the Z scores in a percentile tabulation for the CREST-2 population and compared these percentiles to the normative data obtained for the REGARDS population.

Dr. Negar Asdaghi:         So, what they found was that, well, not surprisingly, the population of CREST-2 had a higher prevalence of cardiovascular risk factors, things like hypertension, elevated lipids, smoking and diabetes. Slightly more than half, exactly 52% of the CREST-2 patients, had a target carotid stenosis vessel on the right side. And then they did some complex statistical models, adjusting for age, race and educational level, and then further adjusting for some vascular risk factors, such as hypertension, diabetes, dyslipidemia, and smoking, for each cognitive test, and they found that the overall Z score for patients in CREST-2 was significantly below expected for higher percentiles and marginally below expected for the 25th percentile for all four cognitive tests, as compared to the normative population.

Dr. Negar Asdaghi:         For example, if they were expecting that 90% of the CREST-2 population would score in the 75th percentile for a particular test, or at 95th percentile on a different test, these percentages were significantly lower in the CREST-2 candidates. The greatest cognitive differences were detected for Word List Delay, which is a test of memory, followed with the Word List Learning, which is a test for learning. And the results really did not change when they adjusted for the vascular risk factors, and importantly, unchanged when they adjusted for right- or left-sided stenosis of the carotid, which is important, as language plays an important role in assessment of memory function.

Dr. Negar Asdaghi:         So, what did we learn from this study? Well, number one, poor cognition is associated with harboring high-grade asymptomatic carotid occlusive disease, an effect that was only modestly attenuated by further adjustment for other risk factors. Number two, patients with high-grade carotid stenosis showed a significantly lower cognitive performance in the learning and memory domains. This profile of cognitive decline is different than what was typically expected to be seen in the case of vascular dementia, where abnormalities are predominately seen in the test of executive function. Number three, though we don't know the precise mechanism for cognitive impairment in the setting of carotid stenosis, cerebral hypoperfusion seemed to be the leading plausible cause as hippocampus and amygdala are known to be susceptible to hypoperfusion, and the findings of the current study show that the predominant impairment seen in patients with carotid disease seemed to be involving memory and learning. So, really important findings, and lots to still learn on this topic.

Dr. Negar Asdaghi:         The occurrence of adverse events during acute treatment and within the first few weeks of acute ischemic stroke are common and can negatively influence the course and clinical outcomes of stroke patients. Serious adverse events, or SAEs, are defined as life-threatening events resulting in death or requiring hospitalization, prolongation of hospitalization, or resulting in significant disability, and they can be either neurological, such as recurrent ischemic events, hemorrhagic complications, seizure disorders, but also can include a myriad of systemic complications, including, but not limited to, occurrence of deep vein thrombosis, pulmonary emboli, cardiac arrhythmias, various infections, GI bleeds, to name a few.

Dr. Negar Asdaghi:         In a setting of a clinical trial, patients are regularly and systematically monitored for SAEs, and from these studies we know that, indeed, both adverse events, or AEs, and SAEs are quite common poststroke and are reported in up to 95% of participants of prior randomized trials. Intravenous thrombolysis increased the risk of symptomatic intracerebral hemorrhage, but in general, the rate of SAEs are similar in thrombolyzed and non-thrombolyzed patients. Which clinical characteristics prone stroke patients to what type of side effects is, of course, an intriguing subject for a stroke neurologist. Similarly, it's important to know how, for example, a seemingly indirect complication of ischemic stroke, such as a hospital-acquired urinary tract infection, can potentially affect the stroke outcomes.

Dr. Negar Asdaghi:         So, in this issue of the journal, Dr. Iris Lettow from University Medical Center in Hamburg, Germany, and colleagues looked at the subject in the paper titled “Serious Adverse Events and Their Impact on Functional Outcome in Acute Ischemic Stroke in the WAKE-UP Trial.” This was a post-hoc analysis of the WAKE-UP Trial, which was a multicenter randomized trial of MR-guided intravenous thrombolysis with alteplase in ischemic stroke patients with unknown time of onset. The WAKE-UP Trial included 503 patients, and they had 199 SAEs reported for 110 patients, meaning that one in five patients had at least one serious adverse event in the trial. Of those patients who did suffer an SAE, 20 patients, which was 10%, had a fatal outcome.

Dr. Negar Asdaghi:         The rate of SAEs were not different between thrombolyzed and non-thrombolyzed patients. But, when they categorized the patients based on who did and who did not experience an SAE, they found that those who experienced an SAE were older, presented with more severe strokes, and were more likely to have a large vessel occlusion. But only higher age and male sex were independent predictors of development of an SAE poststroke. So, let's pause and think about these findings. This was in contrast to the previous studies, where traditionally, the severity of stroke was a predictor of complications, and importantly, the first study to identify male sex as an independent predictor of SAE, whereas, traditionally, female sex had been identified as a risk factor for development of adverse events poststroke.

Dr. Negar Asdaghi:         Perhaps what we're seeing with a paradigm shift in improvement in poststroke quality of care. Now, another important finding of this study was that the presence of any SAE, whether neurological or non-neurological, resulted in reduction of favorable outcome by half and almost quadrupled the odds of poor outcome, defined as modified Rankin Scale of four to six at 90 days, even after accounting for all the known confounders. Now, the authors also looked at some interesting details. The organ most effected by serious adverse events poststroke was indeed the nervous system. Almost 50% of all SAEs were neurological in nature. This was then followed by cardiac events. Some examples would include an acute coronary syndrome, MI, various arrhythmias. And the surgical and medical procedures were the third most common category of serious adverse events in this study.

Dr. Negar Asdaghi:         And what they found was that SAEs by organ of involvement had a significant association with 90-day outcomes, where any neurological serious adverse events significantly affected 90-day functional outcome poststroke. When adjusting and accounting for important variables, such as age, sex, LVO, this still remained true in terms of a predictor of outcome. In contrast, cardiac serious adverse events, infectious serious adverse events, did not have any effect on the 90-day functional outcome.

Dr. Negar Asdaghi:         So, what are the top takeaway messages from this study? Number one, SAEs occur commonly poststroke, and in this particular study, occurred in one in five ischemic stroke patients. Number two, 10% of those who suffer from an SAE had a fatal outcome. Number three, nervous system disorders and cardiac disorders were the most frequent classes of side effects poststroke. And finally, patients suffering from at least one serious adverse event had a lower odds of reaching favorable outcome at 90 days. These findings emphasize the importance of dedicated stroke care, neurointensive care units, and all poststroke efforts to reduce preventable adverse events poststroke.

Dr. Negar Asdaghi:         Time is an exceedingly important concept in treatment of patients with acute ischemic stroke. As an example, in a typical stroke related to a proximal large vessel occlusion, the ischemic brain loses an average of two million neurons per minute. Now, endovascular therapy is the standard reperfusion treatment for patients with acute ischemic stroke secondary to a large vessel occlusion. It is an effective treatment to restore blood flow and reperfusion to the brain and had been shown to improve outcomes in stroke patients.

Dr. Negar Asdaghi:         Therefore, one would naturally anticipate that the benefits of endovascular therapy would be dramatically reduced with treatment so late. If this is true, then why is it that the beneficial treatment effect from endovascular therapy was even larger in patients treated in the late time window trials, and you will recall that these were patients included from 6 to 16 hours, or 6 to 24 hours, from their symptom onset time. This compared to treatment effects noted in patients enrolled in the early time window trials. This concept is known as the "late window paradox" and does not mean that we have to wait to provide reperfusion therapies to patients. It actually refers to those fortunate few that have robust collaterals and, as a result, have slow infarct growth, which will afford them that extra precious time to remain eligible to receive this life-saving treatment.

Dr. Negar Asdaghi:         Joining me now on the podcast is Dr. Mark Parsons from the University of New South Wales in Sydney, Australia, to talk to us about the concept of infarct growth. Dr. Parsons is one of the senior authors of the study published in the current issue of the journal titled “Stroke Patients With Faster Core Growth Have Greater Benefit From Endovascular Therapy,” and will discuss how the beneficial effect of endovascular treatment may be modified by the speed of infarct growth in the early time window after symptom onset. As in every podcast, when I have the pleasure of interviewing a pioneer in the field of stroke, that my guest needs no introduction, but truly Dr. Parsons needs no introduction to our listeners. He's a Professor of Neurology at the University of New South Wales in southwestern Sydney. He's an internationally recognized leader in the field of stroke, stroke clinical trials, and brain imaging whose research has helped improve patient selection for acute stroke reperfusion therapies. It's truly an honor to have him on the podcast today. Welcome, Mark. Thank you so much for joining us all the way in Sydney on a Saturday morning.

Dr. Mark Parsons:           Yes, thank you, Negar. It's OK, I have been up for a little while. So, yes, lovely to chat with you, and we haven't chatted in person for quite a long time, and I think I actually remember the last time was in Hamburg, in Germany, at a big stroke conference. I remember it quite well. We had a very pleasant evening with a group of Canadians and Australians, and I had to present a major tenecteplase study finding the next day, and I was a little bit off my game, some of my friends said, and I think that's probably your fault, Negar.

Dr. Negar Asdaghi:         Mark, you did really great, and we really, truly, look forward to getting back to in-person meetings. So, let's start with the study here. Can you please tell us about the INSPIRE registry?

Dr. Mark Parsons:           So, the INSPIRE registry, that's an acronym. So, it's best to spell out this acronym, so that stands for the "International Stroke Perfusion Imaging Registry." So, that was something we set up quite a while ago when perfusion CT was quite considered advanced or novel. We set that up, I think, in about 2010, and because that was obviously one of my areas of interest, perfusion imaging, we started collecting perfusion CT and CT angiography , and noncontract CT, for that matter, from our stroke patients from a number of centers in several countries. And over time, that built up to over 20 centers around the world, so predominantly Australia and China, because of the close connections that we've got there, but also one site in Canada, actually two sites now. We have so many sites that I sometimes overlook a few.

Dr. Mark Parsons:           So, it is international. And what we do is, we collect prospective data from stroke patients, both clinical and their acute imaging, follow-up imaging, follow-up clinical information, and in the majority of patients, we also get three-month Rankin. So, there's now over 3,000 patients in that database with complete datasets from acute baseline imaging through to three months. And that was the dataset that we used for this current study.

Dr. Negar Asdaghi:         So, Mark, this is truly an impressive registry. It is not easy to do large-scale imaging-based registries, and this is really impressive to have so many centers involved. Can you tell us about the current study population? Who did you include in the current study paper?

Dr. Mark Parsons:           Firstly, we specifically looked at patients that had a large vessel occlusion, or LVO. Of course, the definition of large vessel occlusion varies a bit from place to place, but essentially, that means a clot in a proximal artery to the brain that's potentially retrievable via endovascular thrombectomy. I guess the beauty of the INSPIRE registry is, we started collecting stroke patient data well before endovascular thrombectomy was a routine treatment. We had quite a large number of large vessel occlusion patients in this study who didn't receive endovascular thrombectomy because it simply wasn't available at the time. And then, of course, with all of those big trials that came out in 2015, as you know, and beyond, with thrombectomy becoming routine at all of our INSPIRE sites and many other places around the world, we then had a, I guess, a historical cohort comparison of large vessel occlusion patients that were not given EVT and then, more recently, a cohort of large vessel occlusion patients who were treated with thrombectomy.

Dr. Mark Parsons:           The non-thrombectomy patients, in the vast majority, received intravenous thrombolysis because they were in the 4.5-hour time window. I guess the only other thing, the main other inclusion criteria, was we specified that patients in this particular study needed to have a relatively small infarct core, less than 70 mL, and we can talk more about that later, if you like, and a significant area of tissue that's potentially salvageable with reperfusion, the so-called penumbra.

Dr. Negar Asdaghi:         Thank you. Just to recap for our listeners, so your current study population included patients presenting early on, within 4.5 hours from symptom onset, with a large vessel occlusion, and because, as you mentioned, the study had been ongoing even before endovascular therapy became a standard of care, you have a group of patients in whom endovascular therapy was offered and you have the comparison to this group to those patients who had an LVO, large vessel occlusion, but simply received intravenous thrombolysis only. Can you now tell us about these two groups, basically, IV thrombolysis versus endovascular therapy group. What were the differences between the two groups, and what were the main clinical outcomes in your study?

Dr. Mark Parsons:           Yes. We had about 400 patients in each arm. And though reasonably well matched, I mean, of course, registry, it's not randomized, so you can't have perfectly matched groups, and indeed, in the more recent era where most patients with large vessel occlusion, particularly with this small core, big penumbra on imaging, would go to thrombectomy because they had the so-called ideal target population. So, in the modern era, if patients don't receive EVT, then there's probably a good reason for that. But, essentially, they are around 70 years of age. Their NIH Stroke score was around 15, or the median score, so that's reasonably consistent with large vessel occlusion. And then if you look at the perfusion imaging, so this was all with perfusion CT in our studies, so the core volume was quite small, 15 mL, but there was quite a large range. And the median penumbra volume was actually a bit bigger in the EVT group; it was 80 versus 65 in the penumbral group.

Dr. Mark Parsons:           We probably don't need to go into the details of how those core penumbral volumes are calculated, but that might be a bit over-technical for our audience, but happy to elucidate further if you want.

Dr. Negar Asdaghi:         Actually, I think it's important to, just briefly, talk about how those values were measured.

Dr. Mark Parsons:           Yes, OK. The other thing I should say is that, interestingly enough, we specified the 4.5-hour time window, but in fact, the median time from stroke onset to imaging was just under two hours in both groups, which is quite short.

Dr. Mark Parsons:           And indeed, some of the people that are less enthusiastic about perfusion CT than I am would say, "Well, maybe measures of core are not so reliable in that early time window with perfusion CT." I would probably debate that to some degree. But, if we talked to the technicalities, there's quite a lot of data to suggest that the cerebral blood flow threshold is probably the most robust for identifying core, or at least tissue that's destined to infarct. It may not actually be infarcted at the time we measure it, particularly at two hours, but there's quite a lot of data now showing that with perfusion CT with a cerebral blood flow threshold of 30%, depending on software variations, that's a pretty accurate estimate of the final infarct in people that have rapid reperfusion fairly quickly after the perfusion CT.

Dr. Mark Parsons:           So, all of these figures that we use are based on, for example, the core threshold on perfusion CT relates to, we validate that from patients, particularly that have had thrombectomy, so we know when they've reperfused. And the theory should be that if the CT perfusion core is an accurate measure of the final infarct, that there should not be much change from the baseline CT perfusion core to the follow-up infarct because there's been reperfusion not long after the perfusion scan. Now, with the penumbral volume, we use software that measures a delay time. Other software, particularly in North America, you would use a Tmax, but they're both basically direct measures of collateral flow.

Dr. Mark Parsons:           So, as you know, when you have a large vessel occlusion, say, of a middle cerebral artery and in one segment, the way that blood gets to the cortex, it's typically supplied from the middle cerebral, is via retrograde flow from the anterior cerebral and the posterior cerebral via leptomeningeal collateral, so you actually get blood coming back retrograde bypassing the occlusion. And these measures on perfusion CT delay time in Tmax, actually, give you a measurement in seconds of how long it takes the blood to travel to that part of the brain. And, obviously, the longer the delay in seconds means the poorer the collateral flow. And then, typically, that means the poorer the collaterals, the less time you've got to salvage the penumbra, and the quicker the infarct core will expand.

Dr. Negar Asdaghi:         Right. So, in your study, using these perfusion parameters. First, before even we come to the perfusion parameters, you found that overall, when you adjusted for all confounders, endovascular-treated patients had a better, or higher, odds of achieving good 90-day outcomes. This was not a surprising finding when you compare this population of endovascularly-treated patients to those treated with intravenous thrombolysis alone. But what was interesting was, indeed, those analyses related to infarct growth rate. Can you tell us a little bit about this concept of infarct growth rate, and you already mentioned how you measured infarct growth by perfusion imaging.

Dr. Mark Parsons:           Thanks, Negar. I guess that's the novel part in it. I guess it would have been quite surprising if we didn't show that EVT was superior to IVT in the early time window. So, that certainly wasn't unexpected, that finding. But I guess the novel part of this study is this relatively new concept of infarct core growth rate. I'm not saying we're the first that's described it because, as you know, there are a number of papers in the literature and talking about the concept of slow infarct core growers versus fast infarct core growers. And you mentioned the late time window thrombectomy studies, DAWN and DEFUSE 3, which actually showed a dramatic benefit in the later time window, up to 24 hours after stroke, in patients who had evidence of perfusion core mismatch. And the concept then was suggested that the reason that these people benefited so much in that late time window was that they had very slow infarct core growth because they had great collaterals.

Dr. Mark Parsons:           The treatment effect was bigger in those late time window studies than it was in the early time window thrombectomy studies, which was hypothesized might have included a lot of patients with fast infarct core growth rate, which wasn't really measured in a number of the thrombectomy studies in the early time window. We wanted to look more at, does the rate of infarct core growth have an influence on the effective treatment, with both IV and endovascular treatment?

Dr. Mark Parsons:           So, the way we measured infarct core growth was pretty simple, actually. It's basically, we excluded patients with uncertain time of stroke onset because we had more than double this total number of LVO stroke patients with target mismatch, but we had to exclude the patients with uncertain time of onset, which included wake-up stroke and others. So, in this group, where there was a defined time of onset, basically, the infarct core growth rate was simply measured from the volume of the infarct core measured on perfusion CT divided by the time from stroke onset. So, just simplistically, if you've got a core of 50 mL, and it's two hours after stroke onset, then the infarct core growth rate is 25 mL per hour. That's simple, but that obviously assumes a linear core growth rate. And we based that linear model on previous studies of repeated diffusion MR imaging, which is another measure of core, that showed that the core growth rate was linear.

Dr. Mark Parsons:           Now, of course, you could criticize that because I suspect, in some patients, the core growth rate is not linear. This is an estimate of core growth rate.

Dr. Negar Asdaghi:         Right. So, your study actually found something quite interesting, which I really want you to go over for us and for our listeners, and that's that the beneficial effect of endovascular therapy is superior in those with a fast infarct growth rate, and was not superior, in fact not any different, in those patients who had a slow infarct growth rate. Can you walk us through that, and also tell us how that does not contradict what we've found as part of DAWN and DEFUSE with the slow infarct growers?

Dr. Mark Parsons:           Thanks, Negar. It is slightly complicated, so we'll go one step at a time. So, first of all, the core growth rate varied quite a bit in this population. A number of patients, and this is because you saw that the median core in this group was 15 mL, so there was quite a large population of patients that had a core growth rate of less than 15 mL per hour. So, they're your traditional slow growers, slow core growers, who have really great collateral flow. You probably have a number of hours to save the penumbra. Now, I'm not saying that you should waste time in this group of patients, but it might be particularly relevant, for example, if you're transferring from a primary stroke center to a comprehensive stroke center. You know that you're going to have time to save that penumbra because the infarct core is going to grow slowly.

Dr. Mark Parsons:           In, for example, in Australia, at least half of our thrombectomy patients come from regional or out of metro centers, where there is a significant transfer time from the primary stroke center to the comprehensive center. So, that may be a particularly important finding to look at in the future for longer transfer times from primary to comprehensive stroke centers. So, then, at the other end of the scale, we had a proportion of patients who had what we call a fast core growth rate of more than 25 mL per hour. And then there were people in the middle between 15 and 25 who we called sort of moderate core growth. So greater than 25 mL per hour was a fast core growth.

Dr. Mark Parsons:           We categorized it into those sort of three categories. Again, that's a bit arbitrary, but the reason we did that was that if you look at the IVT group alone, those who had slow core growth rate, less than 15 mL per hour, their rates of good outcome, so a Rankin 0 to 2, so getting back to close to normal function at three months, their rates of a good outcome were almost 60% in the slow core growth rate with IVT. Then, if you go to the other end of the scale with fast core growth with intravenous therapy, the rates of good outcome in that group were only 30%. So, there was a clear decline in terms of three-month good outcomes with intravenous thrombolysis versus core growth rate. So, as the core growth rate increased, the chances of good outcome with intravenous thrombolysis decreased.

Dr. Mark Parsons:           Then, if you looked at the EVT group, it was quite interesting that this core growth rate effect had minimal impact on the outcome of the EVT patients. So, in the EVT patients with slow core growth rate, less than 15 mL, the rates of good outcome at three months were, again, close to 60% and identical to the IV therapy group. But, at the other end of the scale, with fast core growth rate above 25 mL with the EVT group, they had a much higher rate of good outcome compared to the IVT group. Their rates of good outcome were around 45%. So, they are a little bit lower than the slow core growers with EVT, but there wasn't much drop-off with core growth rate, and there was a significant increase in good outcomes in the EVT group who had fast core growth compared to the IVT group.

Dr. Negar Asdaghi:         So, I just want to summarize this so that I understand it and, of course, want to make sure that it's simplified also for our listeners. So, you found that those people, and it should be noted these are all within the first 4.5 hours.

Dr. Mark Parsons:           Yes.

Dr. Negar Asdaghi:         So, we understood in that time frame. Those people who had a fast growth rate, they had the greatest benefit from endovascular therapy in this time frame. And those people who had the slow growth rate, that is defined in your study as less than 15 cc per hour, they actually had a similar benefit from endovascular therapy as they did with intravenous thrombolysis. Did I summarize that?

Dr. Mark Parsons:           Yes. That's correct.

Dr. Negar Asdaghi:         So, Mark, how do you explain this from a pathophysiological standpoint?

Dr. Mark Parsons:           Fortunately, there's a relatively simple explanation. So, because of the way that we set up INSPIRE, we collected follow-up infarct volumes as well. From the time window for follow-up infarct measurement was a little bit variable, but it was around 48 hours after stroke onset. In this group of patients, we actually were able to measure final infarct volume and essentially, in the slow core group, so less than 15 cc growth per hour, in that group, with both IVT and EVT, there was minimal infarct growth by the time we measured it at 48 hours. So, both therapies basically led to minimal infarct growth after the treatment, whereas in the fast core growth group, more than 25 cc per hour, the IVT group had much greater infarct growth by 48 hours, about 40 or 50 mL more, on average, than the EVT group.

Dr. Mark Parsons:           I guess also, to explain that a touch more, if you look at the slow core growth EVT group versus the fast core growth EVT group, there was still more infarct growth in the fast core growth rate. And this is because you measure the core at a certain time on the CT or the MR. And then, even with the very best system, you're not going to get reperfusion with EVT for at least 30 minutes after that because you have got to get into the angio lab, you have to puncture the groin, and you have got to get up there, and you have got to pull the clot. So, even if you get complete perfect circumstances, it's still usually at least a 30- to 60-minute delay between the perfusion CT and when you're fully reperfused.

Dr. Mark Parsons:           But the theory should be, if there's a minimal delay from the perfusion CT to reperfusion, the core at that time should be identical to the follow-up, final infarct volume. And that's what we actually found in the slow core group. It was almost the same. The interesting thing was, it was the same in both IVT and EVT, which basically, we don't know for sure, because we don't know exactly when the IVT group reperfused, but it probably means that because the core growth is so slow in this group, even if you reperfuse later with IV therapy, which we know is the case, often with IV thrombolysis the recanalization is a bit slower than with EVT, so even if you've got delayed reperfusion, if you've got slow core growth rate, you may not get much infarct expansion at all, whereas if you've got fast core growth rate, getting reperfusion as quickly as possible after your CT is crucial to limit subsequent infarct growth before reperfusion. And that's exactly what we found in the fast core growers, that EVT substantially limited that subsequent infarct growth and led to better clinical outcomes as well. Sorry, again, that was a long explanation.

Dr. Negar Asdaghi:         Mark, but these are really important findings, and as you alluded to earlier, I believe that they have major implications in how the systems of care are organized and our transfers are going to be decided upon in the future. We have a few minutes before we end the podcast here, and I want to ask you, do you think it's fair to have a similar concept that's studying the infarct growth rate in the late time window, especially in the sort of past 12 hours time window in the future?

Dr. Mark Parsons:           Yeah, it's a fascinating question, Negar. In fact, we do have a paper somewhere under review. I think Stroke might have knocked it back. Anyway, but it's actually looking exactly at this concept, but the fascinating thing is, in the late time window, you see very few true fast growers because they actually present early. This is what the paper under review is talking about. So, in fact, most people that you see with a favorable imaging pattern in the late time window, such as DAWN and DEFUSE 3, the core is relatively small. In patients with fast core growth, by the time you get to six hours, you've got a massive core and no penumbra, so they are typically not offered endovascular therapy because there's no salvageable tissue and there's already lots of damage, even on the non-con CT.

Dr. Mark Parsons:           So, it would be actually really interesting to look just at the late time window, and I'm sure others are doing that, too, but I suspect what we'll find is that the distribution of core growth is pretty narrow. It's mostly the slower core growers, and it's very clear that most of the really fast, and we're actually looking at this now in people with large infarct core over 70 mL, in fact, they present, the ones that we've got at least, present very early. So, it'll be a fascinating area to look at, for sure.

Dr. Negar Asdaghi:         Mark, it is definitely fascinating. We look forward to covering that paper, hopefully in our future podcast. But I want to leave you, reminding you that I'm a mild stroke person, so I am definitely interested in looking at these slow grow rate infarct patients because there are also, as you know, some studies suggesting that the slow growth infarct actually can happen sub-clinically on only a radiographic basis, and especially important in the mild group patients. But, we are out of time. Professor Mark Parsons, thank you so much for joining us all the way from Sydney, and it's been a pleasure interviewing you.

Dr. Mark Parsons:           Thank you, Negar. Lovely to chat and hope to see you very soon in person.

Dr. Negar Asdaghi:         Thank you.

Dr. Negar Asdaghi:         And with that, we end our podcast for the December 2021 issue and close the first year of the Stroke podcast. A year ago, Dr. Ralph Sacco, the Editor-in-Chief of Stroke, approached me to talk about the importance of starting a podcast for Stroke as an accessible means to highlight the great work published in the journal, and also introduce me to the amazing Stroke editorial staff.

Dr. Negar Asdaghi:         One year, hundreds of reviewed papers, and 11 podcasts later, from missed deadlines to late night emails, early morning texts, and weekend recordings, our podcast has become a bit more than just a quick review of the literature. It has truly become our podcast family. Overcoming the time differences and impossible schedules, you made time to interview with us, listen to us, and work with us as we reached out to researchers across the globe who contributed to this journal and to the podcast. Lots of laughter and a few tears. Like every family, ending the year reminds us of some good times and, of course, the difficult times.

Dr. Negar Asdaghi:         So, I want to end our final podcast of the year with a topic that we haven't really covered in our journal, but I think may sprinkle some magic on your holiday season, and that's the topic of quantum biology. Wrapped in mysticism with a pseudoscientific flavor, physicists, neurologists, anesthesiologists, and philosophers have been hard at work deciphering whether consciousness may have similar properties to quantum particles. From superposition to entanglement and coherence, is it possible that your mind may have something to do with the epigenetics, up and down regulation of genes and presentation treatment and, importantly, outcome of various medical or neurological disorders? Now, even if this was proved to have a low scientific validity, as a stroke scientist, isn't it amazing to be working in the one field that ensures the brain, which is the home of consciousness, remains healthy? So, let's think about the power of consciousness in altering the outcome of medical conditions with our ever-excitement to stay alert with Stroke Alert.

Dr. Negar Asdaghi:         This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 10 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the November 2021 issue of Stroke: “Biomarkers of Coagulation and Inflammation in COVID-19–Associated Ischemic Stroke” and “Treatment-Associated Stroke in Patients Undergoing Endovascular Therapy in the ARUBA Trial.” She also interviews Dr. S. Claiborne Johnston about “Ischemic Benefit and Hemorrhage Risk of Ticagrelor-Aspirin Versus Aspirin in Patients With Acute Ischemic Stroke or Transient Ischemic Attack.”

Dr. Negar Asdaghi:

1) What is the net ischemic benefit derived from combination of ticagrelor and aspirin treatment in patients with mild ischemic stroke or transient ischemic attack?

2) Is the ischemic stroke in patients hospitalized with COVID-19 associated with the rise in biomarkers of inflammation and coagulopathy?

3) What are the characteristics associated with periprocedural stroke in patients treated endovascularly for an unruptured AVM?

We'll discuss these topics and much more at today's podcast. Stay with us.

Dr. Negar Asdaghi:                        Welcome back to the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. For the November 2021 issue of Stroke, we have a large selection of topics, from peanut consumption reducing the risk of ischemic stroke, and the decline in the rate of progression of coronary atherosclerosis in patients on a Mediterranean diet, to how the efficacy of endovascular thrombectomy diminishes in patients with more pervious thrombus composition, which I encourage you to review in addition to our podcast today.

Dr. Negar Asdaghi:                        Later in the podcast, I have the distinct honor of interviewing Dr. Claiborne Johnston from Dell Medical School at UT Austin on his latest work with data from the THALES trial to clarify the net ischemic benefits derived from a combination of ticagrelor and aspirin therapy in comparison with the risks of hemorrhage associated with this treatment in patients with mild and moderate stroke and TIA. But first with these two articles.

Dr. Negar Asdaghi:                        COVID-19–associated ischemic stroke, or CAIS, is a new term that, unfortunately, stroke physicians need to be familiar with. While acute ischemic stroke can occur in parallel from, say, traditional causes of stroke in patients infected with coronavirus, ischemic stroke and other thrombotic events, such as myocardial infarction, pulmonary embolism, deep vein thrombosis, and acute limb thrombosis, can occur in the setting of overt hyperinflammation and subsequent coagulopathy that is observed in patients hospitalized with severe COVID-19 illness.

Dr. Negar Asdaghi:                        Elevated D-dimer, although quite non-specific, has emerged as a marker of COVID-19–associated coagulopathy, but whether an elevated D-dimer in isolation or in combination with various other inflammatory and coagulation markers is associated with development of acute in-hospital ischemic stroke in those hospitalized with COVID is not known.

Dr. Negar Asdaghi:                        So, in the current issue of the journal, in the article titled "Biomarkers of Coagulation and Inflammation in COVID-19–Associated Ischemic Stroke,” Dr. Charles Esenwa from the Department of Neurology at Montefiore Medical Center and colleagues did an interesting analysis of over 5,000 patients with COVID-19 who were admitted to one of the Montefiore Health System hospitals between March 1, 2020 and May 8, 2020. This was a retrospective analysis, so they had to work with the available biomarkers for each patient and use a machine learning cluster analysis of these biomarkers to divide the patients basically based on five biomarkers to four clusters.

Dr. Negar Asdaghi:                        The following five biomarkers were chosen by this machine learning cluster analysis. These included CRP, D-dimer, LDH, white BC, and PTT. So, they had to come up with some arbitrary rules to exclude biomarkers that were either missing in over 30% of their population, and they also excluded those patients that were hospitalized for a long period of time, and they chose a 30-day hospitalization and over. And they also only used the first reading for each biomarker. Again, these were arbitrary rules that were set forth by the authors, and they found some alarming findings. When they clustered patients based on similarities in these biomarkers, they came up with predicted models for combined thrombotic events and acute ischemic stroke.

Dr. Negar Asdaghi:                        For example, in the cluster where the patients had the highest mean values for CRP, D-dimer, LDH, and white BC, and a relatively low PTT, these patients had the highest prevalence of acute ischemic stroke. They had the highest prevalence of in-hospital strokes and severe strokes and highest percentage of total thrombotic events. In contrast, the cluster with the lowest mean of all of these five biomarkers had no cases of in-hospital acute ischemic strokes; they had the lowest prevalence of composite, all thrombotic events, and patients had the least severe complications.

Dr. Negar Asdaghi:                        So, they also tested the effects of biomarkers individually for prediction of acute ischemic stroke. And it turns out that when they used a lone marker, only D-dimer again was associated with acute ischemic stroke. Very interestingly, D-dimer was specifically elevated in those COVID-19 patients in whom the stroke was ultimately classified as cryptogenic.

Dr. Negar Asdaghi:                        So, what does that mean? That means that it's more likely that a stroke had occurred in the setting of severe COVID-19 hyperinflammatory response, and less likely associated with other classical causes of stroke.

Dr. Negar Asdaghi:                        So, what did we learn overall from this study? Well, hospitalized COVID-19 patients with a combination of high CRP, D-dimer, LDH, and white BC, and slight reduction in their PTT, had a 4.5-fold increase in the risk of in-hospital mortality and a fivefold increase in the risk of in-hospital stroke as compared to the COVID-19 patients with the lowest mean values for all the five biomarkers mentioned above. So, important information to keep in mind as we treat hospitalized COVID-19 patients, and we await more prospective data on this topic.

Dr. Negar Asdaghi:                        Arteriovenous malformations, or AVMs, are congenital vascular lesions that are associated with long-term excess mortality and morbidity, essentially almost all related to their risk of intracerebral hemorrhage. Roughly half the patients with brain AVMs present with intracerebral hemorrhage, resulting in a first-ever hemorrhage rate of about 0.5 per 100,000 person years.

Dr. Negar Asdaghi:                        Annual risk of hemorrhage is estimated at 1 to 4% for all comers with AVMs, but varies significantly, and can be as low as 0.9% in patients with unruptured, superficially located brain AVMs with superficial drainage, but may be as high as over 34% in patients with ruptured, deeply seated brain AVMs with deep venous drainage. So, treatment would entirely be dependent on the type of presentations and characteristics of each patient with an AVM.

Dr. Negar Asdaghi:                        Whether unruptured AVMs should be managed clinically or treated either endovascularly or surgically is the subject of the ARUBA trial that is a randomized trial of unruptured brain AVMs. The enrollment of ARUBA was halted by the study's DSMB board, but medical management was found to be superior to treatment arm for the primary outcome of symptomatic stroke and death.

Dr. Negar Asdaghi:                        Since then, there's been a lot of focus in the literature and comparison of outcomes between treated and untreated patients with unruptured AVMs, but less has been published on characteristics of patients who suffered from periprocedural stroke, an important part of the primary outcome of ARUBA. So, in the current issue of the journal, we have the study titled “Treatment-Associated Stroke in Patients Undergoing Endovascular Therapy in the ARUBA Trial.”

Dr. Negar Asdaghi:                        Dr. Joshua Burks and colleagues from the Department of Neurosurgery at the University of Miami and colleagues evaluated 64 patients with unruptured AVMs enrolled in the ARUBA trial who underwent endovascular treatment as part of the trial and looked at the characteristics of those who suffered a perioperative stroke, defined as a stroke recorded at or within 48 hours of intervention, as this would represent a direct procedure-related complication rather than sequelae of, say, treated or partially treated AVM itself.

Dr. Negar Asdaghi:                        All patients who initiated endovascular intervention, including attempted interventions in cases where therapy was aborted secondary to technical or anatomical limitations, were included regardless of randomization or subsequent withdrawal from the study beyond 48 hours following the intervention. So, what they found was that 16% of interventions resulted in stroke, 11% hemorrhagic, and 5% ischemic strokes. And they had no perioperative mortality, which is good news.

Dr. Negar Asdaghi:                        In univariate analysis, they found many factors that were more commonly seen in patients that suffered from perioperative stroke as compared to those who did not have a stroke perioperatively. Those factors included, for instance, female sex. Over half of these patients were female. Close to half were enrolled in France. And over 40% of those who suffered a stroke in the perioperative timeframe had Spetzler-Martin grade two AVMs.

Dr. Negar Asdaghi:                        When they accounted for all confounding variables, they found that endovascularly treated unruptured AVMs that are supplied by the posterior cerebral artery cortical feeders and those with Spetzler-Martin grade two and three had a higher perioperative stroke risk as compared to their counterparts without these characteristics. Interestingly, there are also significant geographical disparities in the risk of stroke in that patients treated in the United States or Germany had a significantly lower stroke risk than patients treated in other countries.

Dr. Negar Asdaghi:                        So, what did we learn from this study? There are patients and lesion characteristics that increase the risk of stroke associated with endovascular treatment of unruptured AVMs. The current study suggests that AVMs with cortical arterial feeders from posterior cerebral artery and those with grade two and three Spetzler-Martin were associated with a higher risk of procedural and periprocedural stroke.

Dr. Negar Asdaghi:                        And very importantly, as with every surgical intervention, the risk of a procedure is operator-dependent, as well as center-dependent. And these are important factors to keep in mind as technology evolves and more treatments become available to decide whether to keep or to refer patients with unruptured AVMs to a more experienced center.

Dr. Negar Asdaghi:                        Patients with mild ischemic stroke and transient ischemic attack are at high risk of having recurrent ischemic events, especially in the immediate aftermath of their symptom onset. Early diagnosis and initiation of secondary preventive measures, such as antiplatelet or anticoagulation therapies, in the appropriate setting considerably reduce this recurrent risk.

Dr. Negar Asdaghi:                        Multiple randomized trials have shown that as compared to treatment with a single antiplatelet agent, dual antiplatelet treatment is more effective in reducing the risk of stroke and other major vascular events in the TIA mild stroke population, a benefit that comes with an expected increase in the risk of hemorrhage.

Dr. Negar Asdaghi:                        THALES trial is one of the latest trials to determine the efficacy of dual, which is combination of ticagrelor and aspirin, versus mono-antiplatelet therapy, that is aspirin alone, in eligible patients with non-cardioembolic acute ischemic stroke and TIA. Now, it's important to keep in mind that the primary outcome of THALES is a composite of stroke or death, which included both ischemic and hemorrhagic events.

Dr. Negar Asdaghi:                        Now, it's important to understand that while in the setting of a clinical trial, combining the risks associated with dual antiplatelet therapy, which is hemorrhage, and the potential treatment benefit, that is reduction of recurrent ischemic events, is appropriate as part of the outcome selection. In routine practice, this type of primary outcome can obscure the actual trade-offs between the benefits of dual antiplatelet treatment and its inherent hemorrhagic risk.

Dr. Negar Asdaghi:                        So, in this issue of the journal, in the study titled "Ischemic Benefit and Hemorrhage Risk of Ticagrelor-Aspirin Versus Aspirin in Patients With Acute Ischemic Stroke or Transient Ischemic Attack," the THALES investigators led by Dr. Claiborne Johnston sought to separate the ischemic benefits of combination of ticagrelor and aspirin therapy from its hemorrhagic risks in patients enrolled in the trial.

Dr. Negar Asdaghi:                        I'm joined today by Professor Johnston to discuss the findings of this paper. Dr. Johnston absolutely needs no introduction to the stroke community and our readership. He's a Professor of Neurology at Dell Medical School at the University of Texas at Austin. He's a leader in the field of cerebrovascular disorders, has served as the primary investigator of multiple randomized trials and large prospective studies to evaluate the preventive treatment outcomes in TIA and mild stroke, and has pioneered the development and validation of predictive models for recurrent stroke in this population. He's authored over 700 peer-reviewed manuscripts, has won several awards for research and teaching, and is recognized for his leadership in the field of medicine and healthcare.

Dr. Negar Asdaghi:                        Good morning, Clay. We're delighted that you could join us on the podcast.

Dr. S. Claiborne Johnston:           Well, thank you. It's wonderful to be here. Thank you for having me.

Dr. Negar Asdaghi:                        Thank you. So, THALES is an exciting new addition to the most recent trials of dual antiplatelet therapy that studied mostly the role of clopidogrel and aspirin combination therapy. Can you please start us off by telling us why did we need a new trial in a very similar patient population?

Dr. S. Claiborne Johnston:           Well, the primary reason was, yes, clopidogrel works in combination with aspirin in the setting, but clopidogrel is actually a prodrug. It requires conversion in the liver to its active form. And polymorphisms in CYP2C19 and Cyt P450 pathways are really common and associated with an inability or limited ability to convert that prodrug into its active form. So, there are a number of people who may not benefit much, if at all, from clopidogrel. So, it's kind of surprising that it works as well as it does.

Dr. S. Claiborne Johnston:           Ticagrelor doesn't have that problem. It's not a prodrug. It acts directly on the P2Y12 inhibitor. And so, the hope was that we would have a more consistent and pronounced effect on risk reduction in patients after TIA and mild to moderate strokes.

Dr. Negar Asdaghi:                        Primary efficacy outcome in THALES was different from the primary efficacy outcome chosen for the POINT trial, that was major ischemic events and death from ischemic vascular events, and that of the CHANCE trial, that was a combination of ischemic and hemorrhagic strokes in 90 days. Can you please tell us about the thought process behind choosing this particular primary efficacy outcome in THALES?

Dr. S. Claiborne Johnston:           Yeah, so this was encouraged by the regulatory authorities. And so the primary efficacy outcome in THALES is all stroke, hemorrhagic and ischemic, and all death, hemorrhagic and ischemic. And we teased apart just the ischemic etiologies in POINT.

Dr. S. Claiborne Johnston:           The rationale was that we were including all the major outcomes that the drug could impact. The problem is that people forget that it includes hemorrhagic events, and then they weigh that efficacy outcome against the safety outcome. And so there's confusion. There's sort of double-counting of safety elements in doing that comparison.

Dr. Negar Asdaghi:                        Okay, great. And now, before we hear about how you disentangled the two safety and efficacy outcomes, can you please remind our listeners about the primary results of THALES, which was published obviously a few months ago?

Dr. S. Claiborne Johnston:           Yeah, sure. So, it showed that the combination of ticagrelor and aspirin works. It reduced the stroke and death by about 17% over the 30-day period of treatment. So robust effect. There were some increased hemorrhages, and looking at severe hemorrhage as defined by the GUSTO definition, there was almost a fourfold increase, but it was tiny in absolute terms of 0.4% increase.

Dr. Negar Asdaghi:                        Okay. So, now it's very important, as you mentioned, this disentangling of recurrent ischemic, again, safety from efficacy outcomes. Your current study that is published in the November issue of Stroke clarified these results. And we're excited to hear about those results.

Dr. S. Claiborne Johnston:           That's right. So, there were two problems with the way people have interpreted the results of the THALES trial. One is this entanglement of safety events and both efficacy outcome and the safety outcome. The other was the use of relative risks as opposed to absolute risks, because a high relative risk for a rare event is less important than a small relative risk for a more difference between more common events. And so we wanted to deal with both of those issues.

Dr. S. Claiborne Johnston:           So, we defined new outcomes that were not entangled. So, we defined major ischemic events, similar to what we had done in POINT, and then we defined major hemorrhage as being basically irreversible hemorrhage, and compared outcomes in the two groups. And what we found was that when we did it that way, for every 1,000 patients treated, we avoided 12 major ischemic events and produced three major hemorrhages. So, about a four-to-one ratio of ischemic benefit to hemorrhage risk. And that was true at various cutpoints for disability.

Dr. S. Claiborne Johnston:           So, if we said, "Okay, yes, you had an event, and are you disabled at last follow-up at 30 days?" Then if we said that, there was also a four-to-one difference in disabling events, ischemic versus hemorrhagic. And if we said a two or greater, so moderate disability or worse, it was the same ratio, four-to-one.

Dr. Negar Asdaghi:                        Okay, so four-to-one ratio of benefit. That's an important number to keep in mind. Also reassuring to see that this net clinical benefit or net clinical impact of the combination of therapy was practically the same across all the pre-specified subgroups in the trial. Were you at all surprised by the subgroup analysis?

Dr. S. Claiborne Johnston:           Well you know if you do enough subgroup analyses, you're going to find differences, right? And thankfully, we have the looking at interaction terms to keep us honest, but even so, you look at 20 and you're going to have some significant interaction terms, as well. But yeah, it was reassuring that the effects were so consistent across groups.

Dr. S. Claiborne Johnston:           I think there's been a tendency to over-interpret results from subgroup analyses. We don't have any evidence to suggest that we should be doing that here. I'm sure we can pick out groups that do better, and we've done that actually. The group with atherosclerosis does particularly well, but is that a chance event or is that real? I think we just have to be super-cautious about subgroup analyses.

Dr. Negar Asdaghi:                        So, absolutely. One of the subgroups that I'm personally very interested in is just the time subgroup. So, all of the patients in THALES were enrolled within the first 24 hours, and the subgroup analysis did not show that there were any differences in terms of the net benefit between those that were enrolled earlier, within the first 12 hours, and those that were enrolled later, between 12 and 24 hours. But in routine clinical practice, we often see patients with TIA and mild stroke actually presented to us later than that timeframe entirely. Should we be giving them dual antiplatelet treatment?

Dr. S. Claiborne Johnston:           That's a great question. So, we did an analysis in POINT where we modeled out, would we still have an important significant net benefit if we had started the trial later? And we didn't start the trial later, right? So, this was just pretending like anybody who had an event early on was not in the study in starting at a later timepoint and modeling that out. And basically what we found was that for out to three days, there was still a benefit. And, in fact, if you look at that data and look at those tables, you could even say, even out to five days.

Dr. S. Claiborne Johnston:           I would say it's not unreasonable to do that given that the risks are so small and they're going to be even later with later treatment. But I would say, too, that even though we're not seeing greater impact within that first 24 hours versus 12 to 24, it just makes sense with event rates being as great as they are early on that if you don't treat with a preventive medication before an event occurs, it doesn't work. So, it just makes sense that as much as possible we ought to treat people as early as possible after their events.

Dr. Negar Asdaghi:                        Very important findings and things to keep in mind. I want to ask you about the top two takeaway messages from the study.

Dr. S. Claiborne Johnston:           One is that there's a favorable benefit-to-risk ratio for ticagrelor/aspirin in mild to moderate actually ischemic stroke and high-risk TIA from THALES. So that would be number one.

Dr. S. Claiborne Johnston:           And then number two is watch your endpoints carefully. Think carefully, too, about whether balancing safety to efficacy events really makes sense and also whether focusing on relative risks really makes sense. I would encourage us, even though our journals tend to push us towards relative risks and we're more familiar with those, I'd encourage us to get more comfortable with using absolute risks in the way we look at data, but also in the way we talk to patients about their impact.

Dr. Negar Asdaghi:                        Fair enough. I remember a few years ago, you visited us here at the University of Miami to deliver the annual Cerebrovascular Scheinberg Lecture. And you had mentioned that the idea of dual antiplatelet therapy treatment of patients with TIA mild stroke had come to you many years back when you were still in training, but it took many years for that idea to turn into reality, into randomized trials, and now translated into clinical practice.

Dr. Negar Asdaghi:                        At the time, if you recall, this was right before you went to Europe to present the primary results of POINT at the European conference. And the trial results were not publicly available, so you were sworn to secrecy. You couldn't tell us about the results. It's been a few years since then. You've already completed yet another trial on this topic. Can I ask what's next for you and your team as it pertains to acute treatment of patients with TIA and mild stroke?

Dr. S. Claiborne Johnston:           Well, there are a few things. So, CHANCE-2 is a really interesting trial. My role in that was peripheral, just really advisory, but it's an exciting trial. So, basically it's looking at people with those CYP2C19 polymorphisms that I mentioned before, people who don't rapidly and readily convert clopidogrel to its active form, and randomizing them to clopidogrel versus ticagrelor.

Dr. S. Claiborne Johnston:           So, it's going to give us some head-to-head data on the two drugs and the people who may benefit the most from ticagrelor. And that is complete, and that will be published in the next few months. So, I that's going to be an important trial in people's thinking about how best to approach these patients.

Dr. S. Claiborne Johnston:           The second is, you know, we're not done. We still have a 5% risk of events, even in those three dual antiplatelet therapy. And so we need more agents. And we need to think about secondary prevention extending to other groups as well, just as you said, longer periods of time, more severe strokes, people after thrombolysis/thrombectomy. Those are big groups of patients at extreme risk for secondary events, and we have no agents and no data right now.

Dr. S. Claiborne Johnston:           I would be concerned about dual antiplatelet therapy in those patients, just given what we've seen about the risks of hemorrhage in the existing groups, which are again manageable and shouldn't change people's decision about treatment. But for the groups I just mentioned, risks of hemorrhage start to get greater. And so one worries about whether dual antiplatelet therapy's the right thing or whether other agents make more sense. So, yeah, we're interested in looking at other agents, some novel, for those other indications as well.

Dr. Negar Asdaghi:                        Professor Johnston, thank you for your time, and we look forward to covering more of your research in the future.

Dr. S. Claiborne Johnston:           Well, thank you. It's been a pleasure.

Dr. Negar Asdaghi:                        Thank you.

Dr. Negar Asdaghi:                        And this concludes our podcast for the November 2021 issue of Stroke. Please be sure to check out the November table of contents for a full list of publications, including two important topical review articles, one on thrombus composition after thrombectomy, and one on pearls and pitfalls of perfusion imaging in acute ischemic stroke, as advanced neuroimaging continues to play a critical role in decision-making for acute stroke therapies.

Dr. Negar Asdaghi:                        Now, speaking of advanced neuroimaging and the immense role that neuroimaging plays in our day-to-day practice, let's take a moment as we end our November podcast to remember how the concept of medical imaging first began over 120 years ago with the discovery of X-ray by German professor of physics Wilhelm Röntgen.

Dr. Negar Asdaghi:                        On Friday, November 8, 1895, while experimenting with electricity, Röntgen accidentally discovered a new kind of rays that he referred to as X-rays. He soon realized that X-rays were capable of passing through most substances, including the soft tissues of the body, but left bones and metals visible.

Dr. Negar Asdaghi:                        One of his earliest photographic plates of his experiments was a film of his wife Bertha's hand with her wedding ring clearly visible. This was the first time that the inside of human body was seen without performing surgery.

Dr. Negar Asdaghi:                        From Röntgen’s first X-ray image to the advanced neuroimaging that we review today on our portable devices, I can't help but wonder, what will your accidental discovery on a Friday fall afternoon in November do to advance the field of science and stroke 100 years from now, as we continue to stay alert with Stroke Alert.

Dr. Negar Asdaghi:                        This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 9 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the October 2021 issue of Stroke: “Endovascular Therapy of Anterior Circulation Tandem Occlusions” and “Automated Perfusion-Diffusion Magnetic Resonance Imaging in Childhood Arterial Ischemic Stroke.” She also interviews Dr. Sepideh Amin-Hanjani about her article “Outcome Following Hemorrhage From Cranial Dural Arteriovenous Fistulae.”

Dr. Negar Asdaghi:

1) Should perfusion imaging be incorporated into routine neuroimaging for stroke-like presentation in the pediatric population?

2) Is performing emergent cervical carotid stenting beneficial in patients undergoing endovascular thrombectomy for a tandem occlusion?

3) What are the outcomes of patients with intracranial hemorrhage secondary to dural AV fistula?

These are the questions that we will answer in our podcast today. Stay with us.

Dr. Negar Asdaghi:                        Welcome back to Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. For the October 2021 issue of Stroke, we have a comprehensive list of publications, from studying the role of C-reactive protein in outcome prediction after subarachnoid hemorrhage to studying the association of over 81 classes of routinely prescribed drugs with the risk of ischemic stroke, which I encourage you to review in addition to our podcast today. Later in the podcast, I have the pleasure of interviewing Dr. Sepideh Amin-Hanjani on her work with outcome prediction in patients with dural AV fistula–related intracranial hemorrhage. But first, with these two articles.

Dr. Negar Asdaghi:                        Between 10-20% of patients with an anterior circulation large vessel occlusion have tandem occlusions. That means that they have a concurrent cervical carotid occlusion or significant stenosis in addition to their target intracranial occlusion. Performing endovascular therapy for a tandem occlusion is often difficult, providing technical and access challenges for the operator.

Dr. Negar Asdaghi:                        In practicality, we have two options for carotid treatment in the acute setting. One option is doing nothing, or do carotid angioplasty predominantly to gain access to that target intercranial occlusion. But the second option is to do an emergent carotid stenting. Currently, we have two ongoing clinical trials to assess the very question of whether emergent cervical carotid stenting is an option in tandem occlusions. One is the ongoing TITAN trial out of France, and the second one is a Canadian trial, Endovascular Acute Stroke Intervention - Tandem OCclusion Trial, or EASI-TOC.

Dr. Negar Asdaghi:                        And while we await the completion of these trials, the treatment option for cervical carotid remains a contentious subject. Though performing emergent cervical ICA stenting is feasible, the opponents of the procedure highlight that emergent stenting is associated with higher rates of intracranial hemorrhage, a high risk of in-stent thrombosis, iatrogenic artery-to-artery embolization, and hemodynamic instability during stent deployment. Not to mention that it will increase time to reperfusion if stenting is done prior to the intracranial recanalization. In contrast, the proponents of emergent cervical ICA stenting argue that leaving the carotid alone can lead to an increased risk of infarct recurrence and infarct progression. Of course, it goes without saying that the current practice pattern is widely variable. So, in the current issue of the journal, Dr. Mohammad Anadani, from the Department of Neurology at Washington University School of Medicine, and a group of international collaborators from the TITAN and ETIS registries compared the outcomes of endovascularly treated patients with tandem occlusions in the anterior circulation who received concurrent carotid stenting to those who did not receive stenting of the carotid.

Dr. Negar Asdaghi:                        It is important to note that the no-stent group included those with either no cervical carotid intervention or angioplasty alone.

So, the authors identified 760 patients with a tandem occlusion that were included in the pooled analysis of TITAN and ETIS registries. TITAN stands for Thrombectomy in Tandem Lesions and endovascular treatment in ischemic stroke. That included EVT-treated patients; these are endovascularly treated patients with tandem occlusions from 18 comprehensive stroke centers across Europe and United States.

And ETIS is an ongoing prospective multicenter registry that enrolls all patients treated with endovascular thrombectomy at six large comprehensive stroke centers in France. In both cohorts, treatment of cervical ICA was left at the discretion of the treating physician. Overall, cervical ICA stenting was performed in 56% of total patients with tandem occlusion. In the adjusted model, they found that the odds of favorable outcome and successful reperfusion were higher in the stent group. In contrast, the risk of any hemorrhage was higher in the stent group, but the rate of symptomatic hemorrhage was not different within the two groups.

Dr. Negar Asdaghi:                        Some very important findings from their subgroup analysis include a stronger benefit from emergent carotid stenting, unfavorable outcome in patients with lower NIH Stroke Scale, and in patients in whom the etiology of carotid stenosis or occlusion was deemed to be related to atherosclerosis rather than dissection.

Dr. Negar Asdaghi:                        So, what are the top three things we learned from this paper? Number one, we learned that emergent carotid stenting overall increased the odds of favorable outcome in patients with tandem occlusion. Number two, emergent cervical ICA stenting came with a cost of increased hemorrhage, perhaps related to the necessity of administering antiplatelet therapies in the angiosuite. Number three, benefit from emergent carotid ICA stenting in the setting of endovascular therapy was confined to patients with carotid occlusion or significant stenosis in whom the etiology was deemed to be related to athero and not dissection. And of course, people seem to benefit from emergent cervical ICA stenting in whom the presenting NIH Stroke Scale was mild. So, many things to keep in mind, and most important of all, that these results are from registry-based data, and we still have to wait for the results of the two ongoing trials to confirm these findings.

Dr. Negar Asdaghi:                        Diagnosis of stroke in children is often delayed beyond the conventional thrombolytic and endovascular time windows. In 2018, randomized trials in adults showed that patients with an ischemic mismatch, that is the presence of a large ischemic penumbra in a setting of a small ischemic core, can significantly benefit from endovascular therapy. Whether these results can be directly applied to the pediatric population from simply the adult population is, of course, unknown. In this issue of Stroke, Dr. Mark Mackay and Melissa Visser, from the Department of Neurology, Royal Children's Hospital of Melbourne, and colleagues present the results of a retrospective, observational cohort study of 29 children who underwent MRI diffusion and dynamic susceptibility contrast perfusion imaging within 72 hours of stroke onset. Perfusion-diffusion mismatch was estimated using the RAPID software with the same criteria used in adults, which was defining ischemic penumbra as regions with a Tmax delay of more than six seconds and core as defined by diffusion positive lesions with corresponding low signal on the apparent diffusion coefficient, or ADC, map with values less than 620.

Dr. Negar Asdaghi:                        Favorable mismatch profile was defined the same way that they are defined in the adult population, that is, core volumes less than 70 mL and mismatch volumes of over 15 mL with a mismatch ratio of over 1.8. Now, the primary goal of this paper was to demonstrate feasibility of assessing automated perfusion-diffusion mismatch in childhood stroke. So, among 187 children with confirmed stroke on MR imaging, 58 underwent perfusion imaging in the study and only 29 fulfilled the inclusion criteria. Most cases had cryptogenic stroke followed by local cerebral arteriopathy as part of their etiology of stroke. Vessel occlusion was confirmed in 12 cases, two of which involve the posterior circulation. So, RAPID detected an ischemic core in 66% of patients only, remembering that the remaining diffusion positive cases were excluded from this finding simply because either the ADC values were not below the 620 value or they had a smaller infarct core, at which point determining the ADC values becomes very difficult.

Dr. Negar Asdaghi:                        Overall, three patients only had favorable mismatch profile as we defined earlier and we use to guide us for thrombectomy in the adult population. Of the three children who met the target mismatch criteria, only one received IV alteplase and none underwent thrombectomy, which makes this difficult to validate the penumbral thresholds that are used in the adults for the pediatric population.

Dr. Negar Asdaghi:                        So, what are the top two points from the study? Number one, in this large cohort of children with confirmed ischemic stroke, only a third had perfusion imaging, and most cases received their neuroimaging more than 72 hours after their symptom onset. Number two, the ischemic mismatch as defined by the adult criteria was present in children even as late as 23 hours from symptom onset. So, in summary, this study and others confirm the feasibility of performing perfusion imaging in the pediatric population, but there remains a necessary reluctance in adoption of perfusion imaging as part of the stroke protocols in pediatric centers.

Dr. Negar Asdaghi:                        There are a number of concerns that we should keep in mind, including contrast-induced nephrogenic systemic fibrosis and gadolinium deposition in the brain, which are major concerns in the pediatric population, especially in those kids with impaired renal function or those requiring multiple scans over time. You have to also consider unfamiliarity with stroke imaging protocols, given that the majority of stroke-like presentations in children are non-ischemic in origin, in which case, perfusion imaging performance is of little or no value. And there should also be technical considerations, including uncertainty regarding the optimal bolus injection dose, rate, and scan duration of kids. Lots to learn, but still, studies like this represent the first step forward to further our understanding of the role of perfusion imaging in pediatric stroke.

Dr. Negar Asdaghi:                        Dural arteriovenous fistulas, or dural AVFs, are intracranial vascular malformations defined by abnormal communications within the dural leaf that's between meningeal arteries and dural venous sinuses and/or cortical veins. Dural AV fistulas represent approximately 10-15% of all intracranial vascular malformations and can remain asymptomatic or have a variety of neurological presentations, the most feared of which is intracranial hemorrhage. It is important to remember that much of the research on the topic is focused on high-risk features of dural AV fistulas associated with the risk of either initial or recurrent hemorrhage, things such as the pattern of venous drainage or location of the fistulas. But less is known about the clinical outcomes of these patients after they present with a bleed.

Dr. Negar Asdaghi:                        The CONsortium for Dural arteriovenous fistula Outcomes Research, or CONDOR, Registry is an international multi-institutional database to study the outcomes of dural AV fistulas. In the current issue of the journal, in the study titled “Outcome Following Hemorrhage After Cranial Dural Arteriovenous Fistulae: Analysis of Multicenter CONDOR Registry,” Dr. Matthew Koch, from the Department of Neurosurgery at the University of Illinois in Chicago, and colleagues used this registry to determine the morbidity and mortality of dural AV fistula–related intracranial hemorrhage. I'm joined today by the senior author of the study, Dr. Sepideh Amin-Hanjani, to discuss this paper.

Dr. Negar Asdaghi:                        Dr. Amin-Hanjani needs no introduction to the Stroke readership. She's a Professor of Neurosurgery and Co-Director of Neurovascular Surgery at the University of Illinois. She's the past Chair of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons Cerebrovascular Section. She serves on multiple national and international cerebrovascular committees, including serving as the Chair of the Neurovascular Intervention Committee for the American Heart Association Stroke Council. Good morning to you, Sepi, and thank you for joining us on the podcast.

Dr. Sepideh Amin-Hanjani:          Good morning, Negar. I really appreciate the opportunity to have time to discuss this paper a little bit with you and the folks listening in today.

Dr. Negar Asdaghi:                        Great, Sepi, let's start off with discussing the prevalence of dural AV fistulas. In the current era of increased availability and accessibility of vascular imaging, how often are these malformations found? And importantly, what are the known predictors of so-called bad neurological behavior or intracranial hemorrhage in these fistulas?

Dr. Sepideh Amin-Hanjani:          So, I would say these are rare lesions, which is, I think, what makes it particularly useful sometimes to pay a little bit more attention to them because they're less frequently encountered, and so there's not as much thought about looking for these lesions when a patient presents with neurological symptoms or hemorrhage. And so I think highlighting it here is important. They are rare. They're probably, as you mentioned, only about 10-15% of all vascular malformations. The crude incidence is probably somewhere around 0.5 per 100,000. So, again, infrequently encountered.

Dr. Sepideh Amin-Hanjani:          Because of the nature of the lesion, they're not as easily, I would say, identified incidentally. Unlike AVMs that will show up on routine MRI or aneurysms that'll show up on routine MRA, fistulas may or may not be apparent because of their nature. They're fed by dural arterial feeders; the fistula itself is within the dural leaflets. They can have venous drainage or ectasia associated with them. So, the secondary phenomenon of the venous congestion may show up on MR, but the actual fistula may be hard to identify. And I think, in some ways, that's why we tend to see them a little bit less incidentally, at least in my own practice, in my own experience, than we do when they present with symptoms, either non-hemorrhagic or hemorrhagic symptoms.

Dr. Sepideh Amin-Hanjani:          There are some features of these fistulas that tend to predict if they're going to be bad actors, so to speak, if they're going to have those more aggressive symptoms of neurological dysfunction from venous congestion. Things like seizures, headaches, even dementia as a prolonged effect of venous congestion, or the most dreaded complications, in some ways, hemorrhage, which relates to if there is evidence of significant cortical venous reflux from the fistula itself.

Dr. Negar Asdaghi:                        Perfect. So this is a great start to get us now to the topic of the registry. What was the overall purpose of the CONDOR Registry? Please tell us a little bit about the patient population, specifically the population of your interest that you included in your study.

Dr. Sepideh Amin-Hanjani:          So, given the rarity of the condition, you find that in the literature, there's lots of kind of relatively smaller case series, and it's hard to make broader assessments of outcomes and treatments, etc., when you're looking at small retrospective series.

So, the idea behind CONDOR, which was really launched by one of my colleagues, neurosurgeon Greg Zipfel at Wash. U. in St. Louis, was the idea of getting together a consortium of centers who have either previously published or have a particular interest in dural AV fistulas to collate our series and get a larger cohort of patients together that could be analyzed for just the kinds of interventions and outcomes that would be of interest in looking at a larger sample size.

Dr. Sepideh Amin-Hanjani:          So, the consortium now is up to, I think, 16 or 17 centers. The data that was collected and analyzed for the purposes of this particular manuscript came from 12 centers and was over a thousand patients. So, really a large cohort that allowed us to do a deeper dive analysis on a number of topics, including looking at folks who had presented with hemorrhage. There's a number of other studies that have come out of this registry, and the collaboration to form the registry has also been published as well. And it's retrospective data, but the hope is that CONDOR will eventually transform into a prospective database that will allow us to get even higher level data for this condition.

Dr. Negar Asdaghi:                        So, perfect. Sepi, I was going to ask this question of whether the registry's ongoing, so thank you for clarifying that, but coming back to your paper. So, you included those patients who have bled. This was data up until 2017. And it's important to look at this number, 25% of patients with dural AV fistulas in the CONDOR Registry up until the time that you looked at the data. That's 1 in 4 patients presented with an intracranial hemorrhage. Is this an overall good estimate of the risk of hemorrhage for this malformation, especially when we're counseling patients on this? Or do you think this number is higher than routine practice and that it's just basically biased because it's a hospital-based registry?

Dr. Sepideh Amin-Hanjani:          I think both things are true in some ways, meaning that because this is a consortium of tertiary care centers, obviously there's a referral bias. Patients who are symptomatic or who have hemorrhage are more likely to be cared for in that setting. So, we are going to tend to see a higher proportion of the patients that are presenting with aggressive symptoms or with hemorrhage within this kind of cohort.

Dr. Sepideh Amin-Hanjani:          But along with that, similarly, if you look at the features of these fistulae, they're the ones that have the cortical venous reflux, the high-risk features. So, in as much as to say, "do 25% of all fistulas hemorrhage?" No, because presumably there's a lot of more benign fistulas, ones that aren't discovered or aren't worked up that are low risk for hemorrhage that don't show up. But within the paradigm of, again, the construct of a consortium where you're looking at centers who are really taking care of patients presumably presenting more actively with neurological symptoms, I think this proportion is fairly representative. And it, again, speaks to the fact that depending on the type of fistula and the features of the fistula, it's going to be more or less likely to present in an aggressive manner, hemorrhage being one of those presentations.

Dr. Negar Asdaghi:                        Perfect. So now let's talk about treatment modalities. A majority of patients in your study had undergone surgical intervention of the fistula. What was the most common intervention in this registry? And can you briefly tell us about the current treatment modalities, whether endovascular or surgical, that are available for dural fistulas?

Dr. Sepideh Amin-Hanjani:          So, I think what we found with this registry, and these were centers both within the U.S. and internationally, that the most common treatment paradigm is endovascular, so embolization of AV fistulas. And I think that very much reflects current practice because of the relative, I think, being not an endovascular person, I probably shouldn't comment on the ease or lack thereof, but the ability to access these fistulae endovascularly and use a number of agents, including glue or other embolization materials to obliterate them. So, we certainly found that in the series, embolization, either alone or in combination with other modalities, was the most prevalent.

Dr. Sepideh Amin-Hanjani:          Having said that, surgical intervention still has a significant role. Sometimes these fistulas can be difficult to access, depending on their supply or drainage endovascularly, and then the surgical option for obliterating them becomes important as well. And then, more rarely, lesions that are not amenable to either of those modalities can be treated with radiosurgery, although the concern there always with a hemorrhagic lesion is that the effect is not immediate, as opposed to embolization or surgery, where your goal is to obliterate the fistula and remove the source of hemorrhage, which is really the cortical venous reflux, immediately to make sure that there's not a risk for recurrence.

Dr. Negar Asdaghi:                        Thank you. This is a great review of AV fistulas. So, coming back to the paper now to recap, you had a highly selected group of AV fistulas that presented with an intercranial hemorrhage, the majority of which underwent embolization in this cohort. So, what were the outcomes? And let's start with just a brief overview of what outcomes are actually collected in your study, and what did you find?

Dr. Sepideh Amin-Hanjani:          Yeah, so we were interested to see, in kind of the current paradigm of management of these fistulae, when they present with hemorrhage. As you said, the great majority were treated. So, this is not a natural history study in the sense that it's not looking at untreated malformations after hemorrhage. It's looking at patients in the real world who pragmatically are going to present into tertiary centers with hemorrhage. What is their overall outcome with the current state of interventions that are available and with whatever primary injury is caused by the hemorrhage itself?

Dr. Sepideh Amin-Hanjani:          That's really what the study is looking at, is what is morbidity and mortality after hemorrhage from a lesion like this, and current management paradigm for these fistulas. And in that context, we were looking to see if there were predictors of worse or better outcome in that situation following the hemorrhage itself, and defining morbidity as Modified Rankin score of 3 or greater, with the idea of looking at independent versus dependent outcome, and also looking at mortality.

Dr. Sepideh Amin-Hanjani:          In other words, how severe are these patients in terms of their neurological outcomes if they do suffer hemorrhage event? We were able to define and look at a variety of potential predictors of outcome. The hemorrhage from dural AV fistulas can be either intraparenchymal intracranial hemorrhage or it can be subarachnoid, or it can be a combination thereof. There can be intraventricular hemorrhage, all depending on the venous congestion pattern related to the fistula. And the idea was, do any of those hemorrhage subtypes matter? Do the comorbidities of the patient matter? Do the specific angio-architecture or location of the fistula matter as relates to the outcome from the hemorrhage?

Dr. Negar Asdaghi:                        Perfect. So, at 13% morbidity and 3.6% mortality associated with AV fistula hemorrhages in your study, tell us please about some of the independent factors associated with this primary outcome.

Dr. Sepideh Amin-Hanjani:          Yeah. So, after we analyzed the features that were available within the database, really age emerged as a predictor of poor outcome. And I think that's not surprising. That's very true for the full range of cerebrovascular conditions. If we thresholded at age 65, folks older than 65 had a twofold risk of a worse outcome.

Dr. Sepideh Amin-Hanjani:          The other things that we found, really a lot of the other features fell out on multivariate analysis, but the couple that remained strongly associated with poor outcome were folks who were on anticoagulants at the time of the hemorrhage. It was a small number within the cohort, but nonetheless, a very robust effect in that those folks did worse following their hemorrhage and certainly recurrent hemorrhage.

Dr. Sepideh Amin-Hanjani:          Now, a lot of these fistulae were treated, but in the instance where recurrent hemorrhage did occur prior to treatment, or if the patient had not undergone treatment, recurrent hemorrhage certainly had a really significant effect on worsening outcome as well. That age effect, as I said, has been seen in other vascular conditions. Anticoagulant use as a predictor of poor outcome at the time of hemorrhage has also been seen as a predictor of worse outcomes and other conditions like aneurysmal hemorrhage, things of that nature, and, similarly recurrent hemorrhage. So we're finding similar features as have been described for other cerebrovascular conditions as relates to hemorrhagic lesions as being important predictors of poor outcome.

Dr. Negar Asdaghi:                        Perfect. Very important features to keep in mind when we are dealing with patients with intracranial hemorrhage that are found to have these fistulas. So, things that you mentioned that I want to repeat just for our listeners were: age; recurrent hemorrhage that occurs if a patient is not treated and presented with a hemorrhage initially and added a recurrent one prior to receiving the appropriate therapy; and obviously, and not surprisingly as you mentioned, being on anticoagulants at the time of presentation with their hemorrhage. So, 1 in 6 patients, in summary, with dural AV fistula–associated hemorrhage in your study is dead or dependent follow-up. How does this morbidity and mortality, Sepi, compare to the outcomes from other vascular malformations, say, for instance, that of AVMs?

Dr. Sepideh Amin-Hanjani:          Yeah, I think that's one of the things we're particularly interested to kind of compare and contrast. Now, one end of the spectrum, you have aneurysmal subarachnoid hemorrhage. I think out of all hemorrhagic vascular lesions, that has the worst outcome. We know morbidity and mortality of that far exceeds 50%. For AVMs, it's been pretty well described even from prospective series that you can have 10-15% mortality and about 30% morbidity related to an AVM hemorrhage.

Dr. Sepideh Amin-Hanjani:          And we were interested to see if that was similar profile for fistulas. I think our results show that it's somewhat better than the AVM hemorrhage. The mortality is lower at about 3-4%, like you noted, and the morbidity is around 13% for survivors. But all in all, if you aggregate that, that is, as you say, a 1 in 6 chance of a very poor outcome. So, it's not trivial by any means and certainly much higher than the hemorrhagic consequences of something like cavernous malformations, where hemorrhages from cavernous malformations are rarely fatal. These dural AV fistula hemorrhages can be fatal and can result in long-term morbidity. I think that has implications in terms of how we think about risk-benefit profile of treatment for a malformation, an AV fistula that's discovered and has predictors that would indicate it's at high risk for hemorrhage.

Dr. Negar Asdaghi:                        Thank you very much, Sepi. I think you've already eloquently summarized all of this, but I want us to leave our listeners with your top two or three takeaway messages on the topic.

Dr. Sepideh Amin-Hanjani:          Thanks, Negar. So, I think the key takeaways that we took from looking at this analysis is that we now at least have some idea about what the morbidity and mortality related to dural AV fistula hemorrhage is. That 1 in 6 number, as you indicated, really benchmarks what morbidity and mortality for the condition is. Now, what's the relevance of that? I think, by inference, we can take this into practice in a couple of different ways.

Dr. Sepideh Amin-Hanjani:          First would be that if a patient presents with a fistula with high-risk features for hemorrhage, that knowing this morbidity and mortality related to hemorrhage certainly informs that discussion about treatment and certainly favors the idea of treating fistulas at high risk for hemorrhage based on cortical venous drainage early to prevent this morbidity and mortality from occurring.

Dr. Sepideh Amin-Hanjani:          Secondly, I think it argues towards making sure that there's a thorough workup done when a dural AV fistula is suspected, even if it's presenting with more benign symptoms like tinnitus, for example, or is discovered incidentally, and that workup really should be thorough enough to determine if there are high-risk features from this fistula. And that workup really entails catheter angiography because that's truly the way to determine if these cortical venous reflux and other features that are most associated with hemorrhage are present or not. So, I think those two key elements should be kept in mind.

Dr. Sepideh Amin-Hanjani:          And finally, given the rarity of the condition and because these are complex and heterogeneous lesions, I think it makes sense upon discovery or suspicion of a dural fistula to really refer these to tertiary centers that manage these conditions frequently enough to be able to determine those risk features and to offer the appropriate type of treatment for it, whether it be, as we discussed, mostly embolization or surgery.

Dr. Negar Asdaghi:                        Dr. Sepideh Amin-Hanjani, congratulations on this work, a huge collaboration and a great addition to the existing literature of vascular malformation–related intracranial hemorrhage. It was a pleasure having you on the podcast today.

Dr. Sepideh Amin-Hanjani:          Thank you so much, Negar, much appreciated.

Dr. Negar Asdaghi:                        And this concludes our podcast for the October 2021 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including two articles published online in September simultaneous with their presentation at the European Stroke Conference, which appear in the October issue of Stroke. The first article is on clinical outcome of thrombolysis with tenecteplase, and the second one discusses the effects of fluoxetine on outcomes after acute stroke, results from EFFECTS randomized controlled trial.

Dr. Negar Asdaghi:                        Now, for a second year in a row, the European Stroke Conference was entirely online, bringing a wealth of knowledge and stroke expertise from all over the world to a completely virtual audience. Now, we hope to soon return to our good old times when we traveled for conferences, but let's take a moment and think about the magnitude of this virtual accomplishment, the incredible role that technology plays in our abilities to do research and provide healthcare. And we owe this to the men and women that pioneered the development and the ever-growing fast-paced progress of computer sciences.

Dr. Negar Asdaghi:                        Ten years ago in October, the world lost one such pioneer. Steve Jobs, the father of mobile technology and digital revolution, is recognized not just for his technical creations but also for his way of life, his incredible mind that led to the seemingly utopian ideas for how things should be. In a powerful commencement speech he delivered at Stanford University a few years before his death, he talked about his life experiences, the power of mind, and the power that lies in doing every part of one's work with absolute perfection and love. So, in honor of his genius and the legacy he left behind, we end our October podcast with his parting words of wisdom to the graduating class of 2005: "Stay hungry, stay foolish." And, as always, stay alert with Stroke Alert.

Dr. Negar Asdaghi:                        This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 8 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the September 2021 issue of Stroke: “Risk of Fractures in Stroke Patients Treated With a Selective Serotonin Reuptake Inhibitor” and “Carotid Plaques From Symptomatic Patients Are Characterized by Local Increase in Xanthine Oxidase Expression.” She also interviews Drs. Jukka Putaala and Markku Kaste about their article “Should Tenecteplase be Given in Clinical Practice for Acute Ischemic Stroke Thrombolysis?”.

Dr. Negar Asdaghi:        

1) Are we ready to say goodbye to our old friend alteplase and replace it with a new one, tenecteplase, for acute stroke thrombolysis?

2) Does treatment of depression with SSRIs increase the risk of fractures in stroke patients?

3) When it comes to carotid intervention, should we continue offering treatment based on the degree of luminal stenosis, or are there better biomarkers in the horizon?

These are some of the questions that we'll tackle in today's podcast. We're covering the best in Stroke. Stay with us.

Dr. Negar Asdaghi:         Welcome back to Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. For the September 2021 podcast, we have an exciting program where we discuss some of the controversies in stroke therapies. The September issue also contains a Focused Update with a set of articles and comprehensive reviews on the topic of genetics and stroke, organized by Professor Martin Dichgans, which I encourage you to review in addition to our podcast today. Later in today's podcast, I have the pleasure of interviewing Drs. Putaala and Kaste, from Helsinki Institute, to help us with a burning question of whether there's enough evidence now to use tenecteplase instead of alteplase for ischemic stroke thrombolysis. But first with these two articles.

Dr. Negar Asdaghi:         Over a third of stroke survivors either have depressive symptoms or a formal diagnosis of depression. Selective serotonin reuptake inhibitors, or SSRIs, are the mainstay of depression treatment and the most common antidepressants prescribed in the U.S. In addition, in 2011, we had the results of the FLAME trial suggesting that early poststroke treatment with fluoxetine, a commonly prescribed SSRI, improves motor recovery and functional independence in stroke patients with motor deficit. Though these results were not replicated in the subsequent larger FOCUS trial, the use of SSRIs poststroke dramatically increased over the past decade. So what are the side effects of using SSRIs poststroke? It's a known fact that adult stroke survivors are more likely to experience bone fracture, and that there's some evidence that SSRIs may increase this risk.

Dr. Negar Asdaghi:         So, in the current issue of the journal, Dr. Graeme Hankey and Joshua Jones, from Faculty of Health and Medical Sciences, University of Western Australia, in Perth, and colleagues aimed to answer this question with a systematic review and meta-analysis of randomized controlled trials that included an SSRI treatment for an adult patient with a previous hemorrhagic or ischemic stroke and included incident fractures, either as a primary or secondary study outcome, amongst other criteria. So they found four randomized controlled trials that fulfilled their research criteria. Three of them looked at the effects of fluoxetine, used at a dose of 20 mg per day for six months duration, on functional recovery and outcomes after stroke. And one trial, which has studied neuroregeneration in vascular protection by citalopram, either at a 10 mg or 20 mg daily dose also for six months duration, in patients with acute ischemic stroke. So three studies included with fluoxetine and one study included citalopram.

Dr. Negar Asdaghi:         So, what they found was that although the risk of falls, seizures and recurrent stroke were not statistically increased with SSRI treatment, it was actually a significant increased risk of fractures with a risk ratio of 2.36 in patients treated with SSRI as compared to the placebo. Now, how the SSRIs will increase the risk of fractures is still unknown. There are multiple postulated mechanisms that are discussed in the paper, such as SSRIs potentially increasing spastic motor activity, causing orthostatic hypotension, dizziness, delayed reaction time or temporary imbalance or sleep disorders. But the most important mechanism to keep in mind is the possibility of SSRIs lowering bone mineral density. It's also important to note that the duration of exposure to SSRIs is an important predictor of factors. It's worth noting that the usual SSRI exposure in patients with the primary diagnosis of depression is a lot longer than the exposure time in these trials.

Dr. Negar Asdaghi:         So, what are the top two takeaway points for stroke physicians? Number one: Fluoxetine and citalopram SSRIs, used for six months poststroke, double the risk of fracture as compared to placebo in this meta-analysis. Number two: While the mechanism of this association is still debated, fracture prevention should be an important discussion point when considering prescribing an SSRI to stroke patients.

Dr. Negar Asdaghi:         We all know that carotid disease is a major cause of ischemic stroke. Now we have to keep in mind that the bulk of the literature in carotid disease are practically concentrated on the association between the degree of luminal stenosis and the risk of recurrent stroke. So, in practice, we constantly counsel and discuss risk of future ischemia in symptomatic and asymptomatic carotid disease based on the degree of stenosis that's less than 50%, or between 50% to 70%, or over 70%.

Dr. Negar Asdaghi:         But what if we learn that some plaques can be active despite causing small or little stenosis? And conversely, some may be active despite being very large. There seems to be a growing literature that much of the recurrent strokes are occurring in destabilized plaques. And it turns out that there are actually biomarkers that could cause this destabilization, and we can actually measure them. Xanthine oxidase, or XO, is one of these biomarkers. XO is a key enzyme involved in degradation of purine into uric acid. Now I'm trying to simplify a complex subject here. Xanthine oxidase oxidizes the conversion of hypoxanthine into xanthine and xanthine into uric acid. Along the way, it also does create a whole bunch of reactive oxygen species such as superoxide and hydrogen peroxide, which can create tissue damage.

Dr. Negar Asdaghi:         Now, how is XO and serum uric acid levels related to carotid disease? Well, it turns out that XO is enhanced in carotid arteries with evidence of atherosclerosis. Better yet, in animal models, inhibition of XO is associated with reduction in progression of atherosclerosis. So, in the current issue of the journal, Drs. Morsaleh Ganji and Valentina Nardi, from Departments of Cardiovascular Medicine and Anatomic Pathology of Mayo Clinic in Rochester, Minnesota, and colleagues set out to investigate whether carotid plaques from symptomatic patients had increased expression of xanthine oxidase than their asymptomatic counterparts. So, what they did was they looked at 88 patients undergoing carotid endarterectomy for symptomatic or asymptomatic carotid disease, part of the routine clinical practice, and then measured the XO expression by immunohistochemical staining in CA obtained specimens.

Dr. Negar Asdaghi:         In addition, they collected a number of serum samples and other demographics and vascular risk factors from the participating patients. They found four major findings in their paper. Number one: XO expression was indeed higher in symptomatic carotid arteries. Number two: Symptomatic patients had a higher serum uric acid levels. Number three: Higher XO expression was inversely associated with the serum levels of HDL. Number four: The symptomatic plaques had higher amount of macrophages expressing XO.

Dr. Negar Asdaghi:         Very interesting, but these findings were irrespective of the actual degree of luminal stenosis. In fact, the asymptomatic carotid plaques patients, as routine practice dictates, had a higher degree of luminal stenosis, but they had lower expression of XO and other associated findings. So what did we learn from this study? Well, there seems to be a strong association between certain biomarkers, in this case xanthine oxidase, and symptomatic state of carotid plaques, suggesting that perhaps in future we'll have other ways of measurements that may help us decide on carotid intervention rather than just the symptomatic state of the artery and the degree of stenosis.

Dr. Negar Asdaghi:         It's been over 25 years since alteplase was approved as the thrombolytic agent of choice for treatment of patients with acute ischemic stroke. But in the past decade, tenecteplase, a genetically modified variant of alteplase with regulatory approval for treatment of ST-segment–elevation, myocardial infarction, has gained interest as an alternative reperfusion therapy for treatment of patients with acute ischemic stroke. Whether tenecteplase is ready to completely replace alteplase in clinical practice is certainly a burning question faced by the stroke community today. This was the subject of a lively debate at the most recent and entirely virtual 2021 International Stroke Conference, where a panel of experts reviewed the current evidence regarding the use of tenecteplase in acute ischemic stroke, examining data from animal models, preclinical studies to dose escalation studies and randomized trials, directly comparing tenecteplase with alteplase, as well as the collective clinical experience to date with this thrombolytic agent.

Dr. Negar Asdaghi:         The proponents of change point out the many advantages of tenecteplase over alteplase, including its ease of use, increased fibrin specificity, longer half-time and its non-inferiority to alteplase in the head-to-head trials. On the other hand, the opponents caution stroke physicians, drawing attention to the inherent issues with the already completed clinical trials of tenecteplase, and argue that more data is needed before tenecteplase is considered as a thrombolytic agent of choice in routine clinical practice. Continuing on this debate in the September issue of the journal as part of the Controversies in Stroke series, Drs. Jeffrey Saver and May Nour provide opposing views to Drs. Dawn Kleindorfer and Mollie McDermott on the present evidence and current guidelines around tenecteplase use in acute ischemic stroke.

Dr. Negar Asdaghi:         Acting as moderators, the senior authors of paper, Dr. Jukka Putaala, Head of Stroke Unit at Neurocenter, Helsinki University Hospital, and Dr. Markku Kaste, Emeritus Professor of Neurology at the University of Helsinki and past chairman of Neurocenter, Helsinki University Hospital, in Finland, provide us with the balancing remarks on the issue. I'm joined today by Professors Putaala and Kaste to give us an overview on the debate of tenecteplase versus alteplase. Is it time to make the switch? Good morning from sunny Florida and good afternoon to you both in Finland. Thank you for joining us on the podcast. I hope the weather is as beautiful in Helsinki today as it is here in Miami.

Dr. Jukka Putaala:           Here it is not as warm as you have, but we have had a really beautiful summer, and at the moment, although it is also autumn, temperature is around 20 Celsius, so it's just great.

Dr. Negar Asdaghi:         It's great to have you both. The paper outlines a generally recognized criteria to support the use of any new pharmacotherapy. Can you please start us off by reviewing the components of this criteria and tell us, please, how many checkmarks does TNK get on this checklist when considered as a reperfusion therapy in acute ischemic stroke?

Dr. Jukka Putaala:           These eight criteria include a well-characterized mechanism of action; strong preclinical data; evidence of benefits and safety in a closely related clinical condition, which here is myocardial infarction; important practical advantages over existing agents; the clinical efficacy in how the patient has demonstrated in randomized trials; and endorsement by national practice guidelines. Also, support from regulatory authorities. And finally, clinical effectiveness, which has demonstrated in routine care. We think that tenecteplase for acute ischemic stroke meets actually all of these eight criteria. But we could also think that a smaller number of criteria will be enough to satisfy or meet, would be sufficient.

Dr. Negar Asdaghi:         Perfect. So definitely many important steps, starting with the basics all the way to post-marketing clinical experience. Markku, now over to you. Can you remind us about the mechanism of action of tenecteplase? And what are some of the similarities and differences in terms of pharmacodynamic and pharmacokinetics with alteplase?

Dr. Markku Kaste:           So alteplase catalyze plasminogen cleavage to plasmin and, in turn, degrades fibrin in thrombi, yielding clot lysis. TNK, compared to alteplase, is 14-fold greater fibrin activity and 80 times higher resistance to plasminogen activator inhibitor-1, which means it has a longer half-life, which is a major advantage. Patients need only one injection. In case you're compared to alteplase, when you had to have third dose injection and then one-hour infusion, which delay the care of patient, if the patient need thrombectomy. So it takes an hour for the infusion before patient can be transferred to thrombectomy, and time matters in brain infarction. So the faster you are, the better it is for patients.

Dr. Negar Asdaghi:         Perfect. So more fibrin specificity, as you mentioned, and longer half-time for TNK. And in addition, TNK is not a new drug. In fact, there is over two decades' worth of experience with this in cardiology. Can you also tell us about this? And also some of the preclinical and animal studies that make TNK a potential candidate as a thrombolytic therapy in stroke?

Dr. Markku Kaste:           In animal studies, both in vitro model of mural platelet deposits under arterial flow and a rabbit model using extracorporeal arterial-venous shunts, TNK was more potent, showing benefits up to three hours versus one hour when alteplase was used. So, it's a major benefit already in animal experiments and in the code team, of course, it will be transferred in clinical practice. So, in myocardial infarctions, in three randomized trials, including our 17,000 patients, TNK showed significant reduction for bleeding rates and similar intracerebral hemorrhage rates and 30-day mortality.

Dr. Markku Kaste:           So, these facts support the use of TNK, also in ischemic stroke, the results from myocardial infarction, some steady encouraging. Although we have to keep in mind that myocardial infarction is very homogeneous disease, it's arterial occlusion, while ischemic stroke can be caused by the local occlusion just like myocardial infarction, but also from artery-to-artery thrombi or from a cardiac emboli. And these three [inaudible 00:17:43] mechanisms generate different kind of thrombi, so we need a better drug than alteplase, which really is effective, whatever is the etiology of the occlusion of brain artery.

Dr. Negar Asdaghi:         Right. Thank you. Jukka, now over to you. Before we review the data from randomized trials of tenecteplase, can you please tell us about some of the practical advantages of tenecteplase over alteplase? We're comfortable with alteplase. Why should we make the switch?

Dr. Jukka Putaala:           The key practical advantages arise from the fact that tenecteplase can be given as one single dose; it takes only one minute. And if you compare that to alteplase, you'll have to give the bolus first, and then following the bolus is 60 minutes infusion. And that also has many advantages in clinical practice, for example, if you have a patient with large vessel occlusion in a remote hospital, which is not thrombectomy-capable, you can give tenecteplase and then put the patient in the ambulance and transfer swiftly the patient to the thrombectomy center. While, when using alteplase, you have to start infusion, which you have to have the nursing staff that is capable of monitoring the infusion and taking care of any complications arising during the infusion and so forth.

Dr. Jukka Putaala:           With tenecteplase, you can immediately transport the patient to a thrombectomy site after the bolus without any infusion-capable paramedics staff. Another practical advantage is that by using tenecteplase, you avoid the potential gap between the bolus and the infusion, which means that there is at least several minutes or longer gap in four out of five patients treated with alteplase. You can also think the other scenarios during this coronavirus era, and you have 15 patients with suspected or very fast coronavirus infection. By using bolus, you don't need to put nurses in the same room with the patients many times with the infusion if you use alteplase. Instead, you can use tenecteplase, it's only one single bolus, and you can go away and you don't have to be exposed to potential coronavirus infection.

Dr. Negar Asdaghi:         So, many important advantages, as you mentioned. It seems very reasonable, then, to use tenecteplase in routine practice if it is indeed non-inferior to alteplase. Jukka, what dose of tenecteplase should be used for treatment of acute ischemic stroke patients? And we're definitely excited to hear about the head-to-head trials with tenecteplase versus alteplase.

Dr. Jukka Putaala:           Well, the trial, the dose is 0.25 mg/kg or 0.4 mg/kg. It depends if you have LVO, if you review the evidence what we have now available, you have to use the lower dose in LVO patients. But you can use the higher dose in non-LVO patients. All of this arises from the evidence we have available right now. So, basically, five randomized trials have been completed, to date, comparing tenecteplase with alteplase in acute ischemic stroke. And shortly, if they pull out these five trials and compare primary outcome, which is modified Rankin Scale 0 to 1 versus prior, which means excellent outcome.

Dr. Jukka Putaala:           So, when pulling out these five trials, 58% percent of patients rates excellent outcome versus 55% of alteplase, and this satisfied the criteria for non-inferiority. Regarding safety and secondary outcomes, major intracranial bleeding, mortality, this meta-analysis according to five trials shows similar results for tenecteplase and alteplase. You have to consider some details of this trial. I think Markku was going to quickly review some of the details of the science and doses used in these trials later on.

Dr. Negar Asdaghi:         So, yes, this sounds great for tenecteplase, but so now over to you, Markku. As Jukka mentioned, do we hear a "not so fast for tenecteplase"? Is the current data enough to say goodbye to alteplase entirely and completely turn over to tenecteplase? What are some of the issues with the already completed trials?

Dr. Markku Kaste:           It's not today, we cannot say goodbye to alteplase. As Jukka referred to those trials, there's no reason to go into these really deep details because the trials are quite small compared to ordinary clinical randomized trials studying stroke care. Like I don't want to give neuroprotection agents, for example. One larger trial was, let's say, reasonably well designed. But as to say that most of these trials are not really double-blind randomized clinical trials. And so the results which can be generated is not as reliable as double-blind trials because, of course, there are reasons, I mean, colleagues randomizing cases may think that, OK, a randomizing case and I'm not totally convinced about TNK. And I think this gentleman or this lady really needs effective thrombolytic agents, so I give alteplase, while if another patient with a mild symptom, same physician may think, OK, this stroke patient will recover no matter what, so let us randomize the patient.

Dr. Markku Kaste:           So, it means these kind of unbalanced randomization provides data which is not really reliable. We had to have lots double-blinded randomized trials before it's time to say goodbye, if this double-blinded randomized trial verified that TNK beats alteplase. And, of course, we need also meta-analysis of those advanced trials, and these things can take time, although many guidelines, like AHA guidelines, European Stroke Organization guidelines, Chinese guidelines, Indian guidelines, they, in a way, how do you say, might recommend use of TNK, but I think we need more reliable scientific evidence before it's time to say goodbye to alteplase.

Dr. Negar Asdaghi:         So, Jukka, Markku already alluded to this. I wanted you to review this for our listeners, the national practice guidelines and drug regulatory authority guidelines around the globe with regards to the issue of tenecteplase versus alteplase.

Dr. Jukka Putaala:           Yeah, actually, already American, European, Chinese, Australian and Indian guidelines are recommending tenecteplase into the guidelines, which were recently published in 2019, between 2019 and 2021. What we can read from the guidelines is that tenecteplase can be considered over alteplase. But we have to remember that the strength of the recommendation will remain weak at present and quality of evidence is by the facts that we discussed of these five completely randomized trials and meta-analysis pulling out the data. Qualitative evidence remains slow, and, therefore, the wording in the guidelines is that it may be reasonable to choose or consider alteplase. Tenecteplase might be considered as an alternative to alteplase in certain conditions.

Dr. Jukka Putaala:           The recommendations are a little bit mixed in the guidelines, but generally, in large vessel occlusions, the guidelines say that you could consider TNK over alteplase or even that you should consider TNK over alteplase in large vessel occlusion before proceeding to thrombectomy. However, in cases without large vessel occlusion, the statements are more mixed and they say tenecteplase might be considered or even that alteplase is preferred over tenecteplase until we have more evidence.

Dr. Negar Asdaghi:         Thank you, Jukka. Markku, what should be our final takeaway message for the practicing stroke physicians at this point considering the use of tenecteplase in routine practice?

Dr. Markku Kaste:           Before your paper has been accepted and published in high-quality journal, it takes weeks, mostly it takes months, even a half a year. While in Stroke Conference, you get the most recent data, which is, let's say, generated last week or even the same day. So, when you want to really provide high-quality care of your patient, keep you updated. And then it's best for you and her, and it's better, of course, for your patient. International Stroke Conference and also European Stroke Conference, they are excellent places to get the most recent, yet unpublished, reliable information.

Dr. Negar Asdaghi:         Professors Jukka Putaala and Markku Kaste, thank you for summarizing a large body of evidence for our listeners. We're definitely excited to learn how tenecteplase will ultimately stand against the old competitor and perhaps learn that both may be reasonable thrombolytic options, depending on the specifics of the clinical setting.

Dr. Negar Asdaghi:         And this concludes our podcast for the September 2021 issue of Stroke. Please be sure to check the September table of contents for the full list of publications, including two special reports on consensus recommendations from the 11th STAIR Consortium, that is, Stroke Treatment Academic Industry Roundtable.

Dr. Negar Asdaghi:         The first report is intended to enhance patient, clinician and policymaker comprehension at modified Rankin Scale findings in clinical trials and quality improvement initiatives. The second report from the STAIR Consortium is on top priorities for cerebroprotective studies, an important manuscript where the roundtable considered and presented a new paradigm for evaluation of putative therapies that may work together with recanalization treatments to improve outcome after ischemic stroke, with special attention to using the correct nomenclature, such as replacing the term "neuroprotection" with "cerebroprotection" when the intention of an investigation is to demonstrate that a new treatment benefits the entire brain, rather than neurons alone. Or replacing the term "time window" with "tissue window" or "target window" when selecting patients for recanalization therapies to enhance the notion that various elements of the neurovascular unit show vulnerability to ischemia evolving over different time scales in different brain regions. An important paradigm shift in ways we think of the brain under ischemic attack. With that, we invite you to continue to stay alert with Stroke Alert.

Dr. Negar Asdaghi:         This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 7 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the August 2021 issue of Stroke: “Stroke Risks in Adult Survivors of Preterm Birth: National Cohort and Cosibling Study” and “Roles of Phytoestrogen in the Pathophysiology of Intracranial Aneurysm.” She also interviews Drs. Nirav Bhatt and Diogo Haussen about their article “Reliability of Field Assessment Stroke Triage for Emergency Destination Scale Use by Paramedics: Mobile Stroke Unit First-Year Experience.”

Dr. Negar Asdaghi:

1) Can preterm birth be associated with increased risk of stroke in adulthood?

2) Can a plant-based diet high in phytoestrogens reduce the risk of aneurysm formation and aneurysmal rupture in postmenopausal women?

3) What is the predictive ability of FAST-ED score in detection of large vessel occlusion?

We will review these questions in today's podcast. You're listening to the Stroke Alert Podcast. Stay with us.

Dr. Negar Asdaghi:         From the Editorial Board of Stroke, welcome to the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The August 2021 issue of Stroke covers a wide range of topics from examining if the presence of spot sign modifies the treatment effect of tranexamic acid in patients with intracerebral hemorrhage to the results of the PRESERVE randomized clinical trial examining whether intensive blood pressure lowering in patients with severe cerebral small vessel disease can be associated with progression of white matter damage as detected by diffusion tensor imaging or MRI studies, which I encourage you to review in addition to our podcast today.

Dr. Negar Asdaghi:         Later in today's podcast, I have the pleasure of interviewing Drs. Diogo Haussen and Nirav Bhatt from Emory University on their work on reliability of FAST-ED scale when used by the paramedics in mobile stroke units and learn about the implementation of mobile stroke units in Atlanta. But first with these two articles.

Dr. Negar Asdaghi:         Preterm birth, defined as birth prior to 37 weeks of gestation, affects approximately 11% of births worldwide. Today, with the advent of modern neonatal and pediatric care, the majority of preterm babies survive into adulthood. Multiple studies have shown that adult survivors of preterm birth are at increased risk of developing vascular risk factors, such as diabetes and hypertension, and have a higher incidence of ischemic heart disease as compared to their age-matched individuals born at term, though the association between preterm birth and risk of stroke is not well studied.

Dr. Negar Asdaghi:         In the current issue of the journal, Dr. Casey Crump from Departments of Family Medicine and Community Health and Population Health Science and Policy at Icahn School of Medicine, Mount Sinai, New York, examined whether preterm birth is associated with an increased risk of stroke and its major subtypes in adulthood. The authors use the prenatal and birth information obtained from the Swedish Birth Register, which contains information for nearly all births in Sweden since 1973. The study cohort included over 2,200,000 singleton live births in Sweden from 1973 to 1994. These years were chosen to allow for sufficient follow-up into adulthood. The study cohort was examined for the earliest diagnosis of stroke from the time the participants turned 18 through September 31, 2015, and the maximum age of included population is 43 years. Stroke was identified using ICD codes from all primary and secondary diagnosis in the Swedish Hospital and Outpatient Registries and all deaths attributed to stroke in the Swedish Death Register.

Dr. Negar Asdaghi:         Cosibling analyses assess for potential shared, familial confounding factors, such as genetic and environmental factors, that could contribute to development of stroke. In 28 million person-years of follow-up, 4861, or 0.2% persons, were diagnosed with stroke between 18 to 43 years of age. The authors found that low gestational age at birth was associated with a significantly higher risk of first-time stroke in adulthood. In their adjusted model, as compared to those born at full-term, the hazard ratio for any stroke associated with early preterm, that is birth between 22 to 33 weeks of gestation, was 1.4, and the hazard ratio for late preterm, that is birth between 34 to 36 weeks of gestation, was 1.22, both of which were statistically significant. Interestingly, each additional week of gestation was, on average, associated with a 3% lower risk of first stroke in adulthood.

Dr. Negar Asdaghi:         Similar associations were found in men and women and for both hemorrhagic and ischemic strokes. These findings were only partially explained by shared genetic or environmental risks of preterm birth and stroke within families, suggesting important direct effects of preterm birth on risk of stroke. Multiple putative mechanisms that could potentially link preterm birth with increased stroke risk were discussed in the paper as well, including interaction of fetal angiogenesis during the critical developmental period leading to reduced capillary density and increased arterial stiffness, to persistently elevated levels of anti-angiogenic factors, which are correlated with increased blood pressure development and development of hypertension in adulthood. In summary, the study findings suggest that preterm birth should be recognized as a risk factor for stroke later in life, and survivors need early preventive evaluation and long-term clinical follow-up into adulthood to reduce their lifetime risk of stroke.

Dr. Negar Asdaghi:         The incidences of intracranial aneurysm and aneurysmal subarachnoid hemorrhage are high in postmenopausal women, suggesting estrogen may be protective against aneurysm formation or aneurysmal rupture. However, estrogen-containing hormone replacement therapy is also associated with an increased risk of other significant adverse outcomes, such as increased risk of breast cancer and ischemic stroke, and is not routinely recommended for primary prevention of chronic conditions in postmenopausal women. Isoflavones, a type of phytoestrogen, are plant-based, diet-derived compounds with properties similar to estrogen. Two types of isoflavones, genistein and daidzein, are found in soybeans, chickpeas, and lentils and are thought to be the most potent phytoestrogens that exert estrogenic activities with tissue and receptor specificity. Regular consumption of isoflavones has been shown to alleviate the vasomotor symptoms of estrogen deficiency and associated with reduced incidence of estrogen-dependent diseases in postmenopausal women. Daidzein, once ingested, is converted to its bioactive metabolite, equol, which preferentially binds to estrogen receptor beta, a receptor subtype responsible for the protective effect of estrogen against the formation and rupture of intracranial aneurysms.

Dr. Negar Asdaghi:         In the paper titled "Roles of Phytoestrogen in the Pathophysiology of Intracranial Aneurysm," Dr. Tomoki Hashimoto from the Barrow Aneurysm and AVM Research Center, Departments of Neurosurgery and Neurobiology, the Barrow Neurological Institute, and colleagues investigated whether the phytoestrogens daidzein and its bioactive form, equol, are protective against the formation and rupture of intracranial aneurysms in ovariectomized female mice. Intracranial aneurysms were induced by combining systemic hypertension and a single injection of elastase into the CSF at the right basal system. Ovariectomized mice were fed with an isoflavone-free diet. The systemic treatment with equol delivered via an implanted mini-osmotic pump in the treatment group (0.5 mg/kg/day) or vehicle (in the control group) began one week before aneurysm induction and was continued for four weeks thereafter. So, what they found was that equol treatment significantly reduced the incidence of aneurysm formation compared to vehicle, and there was a trend for equol-treated mice to have a lower incidence of aneurysmal rupture than control mice, while there was no difference in the blood pressure noted between the two groups.

Dr. Negar Asdaghi:         Furthermore, systemic treatment through equol decreased mRNA expression of proinflammatory cytokines, such as IL-6 and interleukin-1β. Importantly, equol seems to require estrogen receptor beta, as the observed protected effects of equol against aneurysm formation was not duplicated in ovariectomized estrogen receptor beta knockout mice. The authors further demonstrated that dietary daidzein reduced the incidence of aneurysm formation, an effect that was dependent on the conversion of daidzein to equol as the beneficial effect of this dietary supplement was abolished in mice that were fed vancomycin, which prevented the intestinal microbial conversion of daidzein to equol. In summary, this study showed that both dietary oral daidzein or the systemic use of its bioactive metabolite, equol, protect against aneurysm formation in ovariectomized female mice through the activation of estrogen receptor beta and subsequent suppression of inflammation. These results indicate a potential therapeutic value of phytoestrogen in prevention of intracranial aneurysm formation and related subarachnoid hemorrhage.

Dr. Negar Asdaghi:         Early recognition of stroke-like symptoms, combined with increased utilization of revascularization therapies, have greatly improved the clinical outcomes of patients with acute ischemic stroke, but have similarly resulted in an ever-growing demand on the stroke systems of care. In the era of endovascular thrombectomy, a prehospital scoring tool with predictive abilities for detection of a target vessel occlusion can greatly assist in the appropriate triage, transfer, and activation of the endovascular team for eligible patients, all the while preventing the inevitable fatigue that accompanies the overuse of the system by properly triaging out those who have a lower likelihood of needing endovascular therapy. For any scoring system used in the prehospital setting, the need for precision needs to be balanced with notions such as ease of administration, time consumption, and reproducibility, as decisions made in the field are invariably fast and frequently made in unstable situations. The Field Assessment Stroke Triage for Emergency Destination, or the FAST-ED scale, is one such stroke scale that meets many of the above-stated criteria in patients with stroke-like presentations to predict a possible large vessel occlusion.

Dr. Negar Asdaghi:         In the paper titled "Reliability of FAST-ED Scale Use by Paramedics: Mobile Stroke Unit First-Year Experience," Drs. Nirav Bhatt and Diogo Haussen and colleagues, from the Marcus Stroke and Neuroscience Center, Grady Memorial Hospital, and the Department of Neurology at Emory University School of Medicine in Atlanta, report on the reliability of the FAST-ED score in the prehospital setting when used by the paramedics in a mobile stroke unit. I'm joined now by Drs. Bhatt and Haussen to discuss this paper. Good afternoon, Nirav and Diogo. Thank you very much for joining us.

Dr. Nirav Bhatt:               Thank you so much for the invitation. I'm very happy to be here.

Dr. Diogo Haussen:         Thank you very much. It is a great pleasure to join you.

Dr. Negar Asdaghi:         Right. In this paper, the FAST-ED score was administered by the paramedics in a mobile stroke unit. So Nirav, to get us started, please tell us about the concept of a mobile stroke unit, how long it's been implemented in Atlanta, and what it means for patients with stroke-like symptoms who would possibly have a large vessel occlusion.

Dr. Nirav Bhatt:               The mobile stroke unit, or the MSU, is an ambulance equipped with a CT scanner and state-of-the-art telemedicine capabilities and is operated by the Grady Emergency Medical Services that covers majority of Metro Atlanta and many of its suburbs, caring for a population of a little over 500,000. It was specifically incorporated to expedite care amongst patients with suspected strokes and went into operations on 30th May, 2018, Monday through Saturday, 12 hours a day, 8 a.m. through 8 p.m. It is operated by a group consisting of an EMT driver, a paramedic, an emergency medicine registered nurse, and a CT technician. So, when a patient has symptoms suspicious for a stroke, the MSU is activated either through 911 dispatch or by an ALS ambulance crew evaluating a possible stroke alert patient in the field. After the initial stroke triage performed by the MSU crew, if there is a persistent suspicion for stroke, the patient is transferred to the MSU and a noncontrast CT scan of the brain is immediately performed.

Dr. Nirav Bhatt:               These CT images are transmitted via the telemedicine platform and are available for review by the vascular neurologist and neuroradiologist in real time. With the help of telemedicine technology, a remotely located vascular neurologist then examines the patient. So, with the help of telemedicine and CT scanner, it allows the remotely located vascular neurologist to identify patients who may qualify for IV alteplase, which is then administered in the MSU to qualifying patients, and these patients get subsequently transported to a stroke treatment center. Now, if the neurological exam is concerning for a large vessel occlusion and the non-contrast CT scan does not show corresponding early ischemic changes, these patients get transferred specifically to a comprehensive stroke center for consideration of thrombectomy. At our centers, some of these patients get directly transported to the neuro-angio suite for further imaging and possible thrombectomy. Thus, the MSU serve a very important goal of expediting critical neurological care for a stroke patient, not only by administering IV alteplase in the field to qualifying patients, but also early triage and transport of qualifying patients to the neuro-angio-suite and with earlier activation of neuroangiosuite.

Dr. Negar Asdaghi:         Perfect, Nirav. An important and a growing concept, bringing treatment to patients and helping with triaging them appropriately, as you mentioned, which I'm sure we'll see more of in the United States and across the world. Now, Diogo, over to you. Can you tell us about the FAST-ED score, its components, then about the reliability of FAST-ED score in the prehospital setting prior to your current study?

Dr. Diogo Haussen:         So, the landmark trials published in 2015 defined mechanical thrombectomy as this very effective and powerful treatment of large vessel occlusion stroke patients, and the clinical and the public health impact of this treatment are certainly highly dependent on the rapid triage of these folks into the appropriate destination. So, this involves the prompt identification of patients with severe symptoms by the emergency medical system personnel, and obviously the transportation of them for a thrombectomy capable center. So, some scales had been proposed earlier on, and the FAST-ED was then developed, and it aimed to help with the identification of patients with a higher probability of having a large vessel occlusion stroke. So, in 2017, we validated the scale on stroke patients that had undergone contrast-enhanced vascular images, which had not been done before, in this publication led by Fabricio Lima and Raul Nogueira in Stroke, in the Stroke journal.

Dr. Diogo Haussen:         So, this paper demonstrated that FAST-ED had higher accuracy than RACE and CPSS. The main limitation at the time was the fact that the FAST-ED score derived from the NIH Stroke Scale and, therefore, had to be validated in the field. The FAST-ED scale stands for the important features that are involved with stroke care and recognition and triage, such as facial palsy, arm weakness, speech changes, and time. Then we complimented this with findings of critical dysfunction illustrated by eye deviation and also denial/neglect. So, the FAST-ED has the following scoring system: So, facial palsy scored from zero to one; arm weakness from zero to two; speech changes, which is aphasia, from zero to two; time is just for documentation, but not for really any decision-making in terms of the scale itself. So, eye deviation goes from zero to two, and denial/neglect from zero to two, and again, was designed based on the items of the NIH Stroke Scale with higher predictive value for large vessel occlusion strokes. I think Nirav is going to discuss a little bit more about why we chose those cutoffs, but they're all designed in a specific way.

Dr. Negar Asdaghi:         Perfect. So a quick score that can be administered easily by different healthcare personnel. So, please tell us, before we go back to Nirav, about your paper's methodology. What were you hoping to expand on the existing knowledge with this paper?

Dr. Diogo Haussen:         I'm just going to repeat a few things, but our mobile stroke unit is equipped obviously with a CT machine and is staffed by an EMT driver and emergency medicine registered nurse, a paramedic, and a CT technician. So, a remote evaluation of patients by a vascular neurologist is then performed through this video-based telemedicine platform. The MSU, as he mentioned, is routinely accompanied by an Advanced Life Support–staffed ambulance, which responds to the suspected stroke calls, and sometimes then calls in or calls off the potential of our stroke code. And as part of this MSU evaluation, the FAST-ED is then administered by the MSU paramedic via the FAST-ED smartphone application that was designed. And then an independent NIH is performed by the registered nurse within the MSU. So, subsequently, the patient is transferred into the MSU itself and a non-conscious CT is performed. Once the scan is completed, the patient is evaluated by the vascular neurologist in a two-way video conference where the FAST-ED is then estimated by the physician.

Dr. Diogo Haussen:         So, all patients are then transferred to the comprehensive stroke center, where further evaluation, including vascular imaging, is performed. The vascular imaging data was formerly read by neuroradiology and then followed by an independent read by the vascular neurologist for the identification of large vessel occlusion strokes, which we define in this paper as an intracranial occlusion off the internal carotid, the M1 or the M2 branches of the middle cerebral artery or the basilar artery. The study encompassed our initial experience, which was from May of 2018 till August of 2019. And we have some other goals, but the initial experience was planned to allow us to investigate, once again, this most important feature, which is the potential reliability of the estimation of the FAST-ED score by paramedics in the field.

Dr. Negar Asdaghi:         Perfect. Thank you for this background, Diogo. Now Nirav, we're ready to hear about the study results.

Dr. Nirav Bhatt:               So, in the first 15 months of operation of the mobile stroke unit, we analyzed data on 173 eligible patients. We had an almost equal distribution of our patients in terms of gender. We had 52.6% females, and the majority of our patients were Black. We found that FAST-ED scores matched perfectly between paramedics and vascular neurologists 56% of the time, and there was only a zero to one point difference in 91% of the cases. Cases in which the discrepancy of the FAST-ED score between the paramedic and vascular neurologist was two points or higher were less than 9%. Overall, the intraclass correlation of FAST-ED score between the paramedic and the vascular neurologist was 0.94, indicating excellent interrater reliability.

Dr. Negar Asdaghi:         Thank you. You found a higher interrater reliability between the paramedics and vascular neurologists for scores of three or above on the FAST-ED scale. Higher FAST-ED scales also were more specific in terms of detection of a target vessel occlusion. How should your results be interpreted in our day-to-day practice, Nirav?

Dr. Nirav Bhatt:               That is correct. When vascular neurologists recorded a FAST-ED score greater than or equal to three, paramedics also recorded a FAST-ED score greater than or equal to three in 87.5% of the instances, and when a vascular neurologist recorded a FAST-ED score of greater than or equal to four, the paramedics also recorded a FAST-ED score of greater than or equal to four in 92% of the instances. This is suggestive that when the patients presented with a moderate to a severe stroke, that EMS paramedics were highly reliable in identifying the neurological severity of these patients. This provides a sound basis for more widespread utilization of FAST-ED as a simple and reliable tool that can be utilized by paramedics to identify stroke severity in the field.

Dr. Negar Asdaghi:         Thank you, Nirav. Simple indeed. I know Diogo briefly alluded to this, but can you also tell us a little more about how FAST-ED compares to the other prehospital scoring systems in terms of their interrater reliability and LVO prediction? And what should be our takeaway message from your paper?

Dr. Nirav Bhatt:               Yes, absolutely. So, just to give you an example, the Los Angeles Motor Scale, LAMS, tests for facial droop, arm drift, and grip strength, but does not really test for cortical signs. We know that a lot of patients with subcortical strokes will have those features, meaning facial droop, arm drift, and decreased grip strength. Similarly, while RACE is very similar to FAST-ED, it tests for leg weakness in addition to what FAST-ED does. It also puts a lot more emphasis on the facial droop as compared to FAST-ED. And with that, I want to draw your attention to a study that we cited in our paper where these scales were compared head to head, and while the accuracies of all the prehospital scales were found to be acceptable, the accuracy of RACE and LAMS were slightly higher than that of FAST-ED. However, it should be noted that in almost 35% of the cases, a complete FAST-ED score could not be reconstructed largely due to data and availability regarding patients' neglect.

Dr. Nirav Bhatt:               This percentage for data and availability for RACE was even higher, meaning we have to consider the feasibility of these scales when we recommend the widespread adoption of these scales into our communities. Overall, the takeaway from this entire study is we strongly believe that there needs to be a system in place for prehospital stroke triage in order to identify and transport the patients to the right destination rapidly. However, the choice of individual scales should be made after consideration of the geographical characteristics of a particular community, and also that experience and that comfort with the level of training required for reliable performance of each of these scales by the EMS personnel.

Dr. Negar Asdaghi:         Thank you so much, Nirav. More to come on this, I'm sure, in the future. Thank you for joining us on the podcast today.

Dr. Nirav Bhatt:               Thank you so much. It was our pleasure.

Dr. Negar Asdaghi:         Thank you, Drs. Nirav Bhatt and Diogo Haussen. Thank you for joining us on the podcast today, and we look forward to covering more of your work in the future. This concludes our podcast for the August 2021 issue of Stroke. Please be sure to check out the August table of contents for the full list of publications, including a special report on the safety of the mobile stroke units and a descriptive review of the amount of radiation exposure to the public, patients, and staff from these mobile units. With that, as our work to save every brain cell from ischemic and hemorrhagic damage continues, we invite you to stay alert with Stroke Alert.

Dr. Negar Asdaghi: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 6 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the July 2021 issue of Stroke: “Prevalence and Clinical Correlates of Intracranial Dolichoectasia in Individuals With Ischemic Stroke” and “Dose Escalation and Safety of Capsaicin for Cerebral Perfusion Augmentation.” She also interviews Dr. Osama Zaidat about his article “Impact of Age and Alberta Stroke Program Early Computed Tomography Score 0 to 5 on Mechanical Thrombectomy Outcomes.”

Dr. Negar Asdaghi:

1) Is intracranial dolichoectasia the new intracranial atherosclerotic disease?

2) What is the latest on collateral flow improvement through sphenopalatine ganglion stimulation in patients with acute ischemic stroke?

3) Is endovascular therapy futile in patients presenting with a low ASPECTS score?

These are the topics that we will cover in today's podcast. You're listening to the Stroke Alert Podcast. Stay with us.

Dr. Negar Asdaghi:         From the Editorial Board of Stroke, welcome to the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast.

Dr. Negar Asdaghi:         For the July 2021 issue of Stroke, we have a systematic review and meta-analysis of safety and efficacy of dual antiplatelet therapy with P2Y12 inhibitors and aspirin versus aspirin monotherapy in patients with mild ischemic stroke or high-risk transient ischemic attack, which I encourage you to review in addition to today's podcast.

Dr. Negar Asdaghi:         Later in the podcast, I have the pleasure of interviewing Dr. Osama "Sam" Zaidat, Professor of Neurosurgery and Neurology at Bon Secours Mercy Health Neuroscience Institute. Dr. Zaidat will speak to us about his work on endovascular therapy in patients presenting with a large ischemic core as determined by a low ASPECTS score on presentation. But first with these two articles.

Dr. Negar Asdaghi:         In the setting of acute ischemic stroke, intracranial large-vessel disease is often equated with processes which result in narrowing of the intracranial vessels, such as what is seen in the setting of intracranial atherosclerotic disease, or ICAD, where much research has focused on the degree of noumenal stenosis. Less is known about intracranial dolichoectasia, or IDE, which is characterized by ectasia, that is dilation, or dolichosis, which is increased length or tortuosity of the intracranial arteries.

Dr. Negar Asdaghi:         IDE can occur due to inflammatory, infectious, or genetic abnormalities. But much like its stenotic counterpart, or ICAD, most cases of IDE are diagnosed in the setting of uncontrolled vascular risk factors. Keeping in mind that the pathophysiology of ICAD and IDE are entirely different.

Dr. Negar Asdaghi:         Despite recent advances in recognition of IDE beyond an arteriopathy involving the basilar artery alone, the prevalence of IDE in patients with acute ischemic stroke is unknown, in part related to the lack of a unified diagnostic criteria for this condition. In this issue of the journal, Dr. Victor Del Brutto from the Division of Cerebrovascular Disease at the University of Miami and colleagues studied the prevalence and clinical correlates of IDE among 211 consecutive acute ischemic stroke patients admitted to a tertiary care hospital during a four-month period. IDE was defined as either ectasia or dolichosis of at least one proximal intracranial artery equal or greater than two standard deviations from the study population mean as measured by semi-automated segmentation method.

Dr. Negar Asdaghi:         So, what they found was that IDE was identified in 24% of stroke cases: a small percentage, which was only 5%, with only isolated ectasia; 9.5% with isolated dolichosis; and the rest with both ectasia and dolichosis. Anterior and posterior circulation were equally involved, but not surprisingly, the basilar artery was the single most common affected artery by IDE. After a complete stroke work-up, stroke was classified as cardioembolic in 25.5% of their population, large-artery atherosclerosis in 30%, small-artery occlusion in 14.5%, and undetermined in 25.5% of cases. Using cardioembolic stroke as a reference, the prevalence of IDE was significantly higher across strokes of undetermined etiology with odds ratio of 2.8. And there was a trend towards higher IDE prevalence in those whose stroke was classified as small-vessel disease.

Dr. Negar Asdaghi:         Furthermore, IDE was considered the most likely pathogenic mechanism in 6% of the entire cohort, which represented over 23% of strokes initially categorized as undetermined etiology and 21% of those with strokes categorized in small-vessel disease category, suggesting a likely causal correlation between parent vessel dolichoectasia and occlusion of the small vessel perforators in these patients.

Dr. Negar Asdaghi:         The authors concluded that IDE is an arteriopathy frequently found in patients with acute ischemic stroke and likely responsible for a sizable fraction of strokes initially categorized as undetermined etiology and those with small-vessel ischemic disease.

Dr. Negar Asdaghi:         The concept of freezing ischemic penumbra refers to either pharmacological or non-pharmacological interventions that aim to reduce tissue energy requirements for increased oxygen delivery and collateral perfusion to the tissue at risk for ischemia while awaiting revascularization therapies. Sphenopalatine ganglion, or SPG, electrical stimulation via an injectable implant had been previously shown to augment collateral flow and improve clinical outcomes in patients with acute ischemic stroke.

Dr. Negar Asdaghi:         The benefit of SPG stimulation is likely conferred not only from its potent collateral augmentation properties, but also from other mechanisms, such as blood-brain stabilization, direct neuroprotection and enhancement of neuroplasticity, though the need to implant the device diminishes its applications in the hyperacute stroke setting.

Dr. Negar Asdaghi:         Capsaicin, the pungent ingredient in hot chili peppers, is an SPG chemical stimulator, which affects the trigeminal vascular system, resolving in vasodilation and improved collateral flow. In the paper titled "Dose Escalation and Safety of Capsaicin for Cerebral Perfusion Augmentation: A Pilot Study," Dr. Juan Manuel Marquez-Romero from IMSS Institute in Mexico and colleagues completed a dose escalation study of capsaicin ranging from 33 to 165 micromole topically applied to the posterior surface of the subject's hemi-palate in 30 healthy volunteers. By applying capsaicin in the palate mucosa, the SPG can be stimulated directly through the greater and lesser palatine nerves while minimizing that pungent sensation.

Dr. Negar Asdaghi:         During the 20-minute applications, the investigators used transcranial Doppler to study various flow parameters, including the mean velocity, positivity index, and the CBF index, or cerebral blood flow index, over the middle cerebral artery. The median age of participants in the study was 21. All reported having consumed capsaicin in their diets sometimes in the past. So, what they found was, at baseline, TCD measurements and the calculations were all within normal limits. All the tested doses of capsaicin reduced augmentation of the MCA mean velocity while reducing the positivity index. The effects peaked between the five and the 10 minutes measurements and then returned to basal levels for all doses of capsaicin, except for the 66 micromole dose group, in which the effect remained stable with the same pattern. There were no side effects reported, and the investigators found no correlation between the perceived pungency and the dose of capsaicin administered.

Dr. Negar Asdaghi:         The authors noted that capsaicin appears to produce a hemodynamic response in the intracranial circulation, similar to the one achieved with SPG electrical stimulation. Understanding that this is data from a small pilot study, the results are hypothesis-generating at this point, and further research is required to measure the safety and efficacy of capsaicin in the elderly stroke population.

Dr. Negar Asdaghi:         Endovascular thrombectomy is an effective evidence-based treatment to improve outcomes in patients with acute ischemic stroke. Studies to expand the applications of this therapy to late-presenting patients, those with large ischemic cores, or distal occlusions are leading to major changes in clinical practice worldwide. Whether the ischemic core is measured by volumetric methods or by ASPECTS score, the presenting infarct core beyond which endovascular therapy is futile, or even potentially harmful, has not been established.

Dr. Negar Asdaghi:         So, the commonly encountered question in routine practice is whether thrombectomy should be offered to patients with presenting low ASPECTS. In other words, what are the characteristics of patients who continue to benefit from thrombectomy despite presenting with a large ischemic core? In the paper titled "Impact of Age and ASPECTS of 0 to 5 on Mechanical Thrombectomy Outcomes: Analysis From the STRATIS Registry," we learn about the outcomes of thrombectomy-treated patients stratified into low and high ASPECTS categories and the specific interaction between increasing age and low ASPECTS.

Dr. Negar Asdaghi:         I'm joined now by the first author of the paper, Dr. Osama "Sam" Zaidat, who's one of the principal investigators of the STRATIS Registry. Dr. Zaidat, of course, needs no introduction to our listeners. He's the past president of the Society of Vascular and Interventional Neurology. He's a leader in the field of neurointerventional therapists and currently is the neurology residency director and the endovascular fellowship director at the Bon Secours Mercy Health Neuroscience Institute. Welcome Sam. Welcome to our podcast. Thank you for joining us.

Dr. Osama Zaidat:           Thanks for having me. I really appreciate Dr. Negar and the Stroke journal team for featuring our research and our results and sharing it with your listeners today. Thank you for having me.

Dr. Negar Asdaghi:         Thank you very much. So, let's start by learning about the STRATIS Registry. Can we please hear an overview of the registry?

Dr. Osama Zaidat:           Yes, that's a good question because this is kind of the database where we really go and mine for questions that we still need answers for in the stroke field. For example, and specifically in the thrombectomy field, the STRATIS Registry was designed to evaluate post-marketing, real-life experience and results using Solitaire device stent retriever as the first mechanical thrombectomy choice. So, if you have enrolled a patient, that means the first attempt to take the clot out was using the Solitaire device for large vessel occlusion that presented with acute ischemic stroke.

Dr. Osama Zaidat:           We planned about 1,000 patients, so we needed a bigger patient population than the randomized trial. So, we have 1,000 patients treated with Solitaire device within eight hours from symptoms onset with large vessel occlusion presenting with acute ischemic stroke. To do that, we needed 55 medical centers with various clinical experience, various volume, and various operator experience because that really reflects a little bit of not a selection bias, meaning that data can be reproducible and can be validated across different spectrum of centers and neurointerventionalists and stroke neurologists for that matter.

Dr. Osama Zaidat:           This also, the aim of it — the spectrum — in addition to validate and reproduce randomized clinical trial data, to try to address questions that are hard to address with a clinical trial. For example, what's the outcome in nonogenarians? What's the outcome in tandem lesion? What's the outcome in different technique we use in the lab? What's the outcome of large infarct sites? Until we find the randomized trial, we can have some signals from those large registry to really inform future randomized trial.

Dr. Osama Zaidat:           So that's kind of the scope of the STRATIS Registry.

Dr. Negar Asdaghi:         Perfect. So truly a real-life, large cohort of endovascularly-treated patients, allowing us to look at the many aspects of this therapy in real life, rather than in a randomized setting.

Dr. Negar Asdaghi:         So, now coming to the current paper, we often think of low ASPECTS as a phenomenon of late presenters. Yet the current paper included endovascularly treated patients in a relatively early time window, within eight hours of symptom onsets. Please walk us through what percentage of your study patients actually had low ASPECTS, and what were their baseline characteristics as compared to high ASPECTS of patients?

Dr. Osama Zaidat:           That's an excellent question. STRATIS was basically a core lab adjudicated. So, independent, experienced core lab have read all the angiogram outcomes and have read all the CT scan, all the MRI, so he doesn't know about what's going on at 90 days functional outcome. And we wanted to restrict the analysis to the available baseline CT scan that was evaluated by the core lab, like you mentioned. So, from the 984 evaluable patients, only 763 patients, almost 75%, had the CT scan available for the core lab and the core lab blinded to the functional outcome and blinded to the angiographic outcome have read the ASPECTS.

Dr. Osama Zaidat:           So, this is a centrally read ASPECTS score by experienced interpreter that read them. So, 75% has available CT, or 763 patients. From those 763 patients, as a clinical practice out there, 92.5% had an ASPECTS of six to 10, consistent with the guidelines that we all treat on everyday basis. If the CT scan looks good, we treat. STRATIS is consistent with that. 92.5% had an ASPECTS of six to 10, or 706 patients. 7.5%, close to 8%, of the site had enrolled patients with low ASPECTS, or 57 patients have low ASPECTS, zero to five. So, about one out of maybe eight, less than one out of 10 patients, had low ASPECTS at the time the STRATIS was conducted between 2014 and 2016.

Dr. Osama Zaidat:           People were following the AHA/ASA guideline, with an ASPECTS of six to 10 the majority of the time, like in the STRATIS. It came up to 92% with ASPECTS and 8%, very low ASPECTS, for example.

Dr. Osama Zaidat:           So, kind of really what we like about the STRATIS, the real-life practice tried to adhere to the guideline for most of the time. However, we managed to find good sample size, 57, that people kind of did not necessarily, for one reason or another follow the guidelines.

Dr. Osama Zaidat:           And I feel like the first things, when you asked me the second question, the baseline characteristics, is there is a difference between the low ASPECTS group and the good ASPECTS. The first thing, really, that stand out-- the young age. So, the age was 62 years versus almost 69. So there's absolute difference of about seven years between low ASPECTS and good ASPECTS, six to 10 versus less than five. And the P value was significant. The listener can look at the paper, but it was a very statistically significant ASPECTS.

Dr. Osama Zaidat:           My feeling and my interpretation to this difference is that the physician felt, even with the low ASPECTS, he wanted to give the younger population a chance and take the clot out and see if they do well. So, I think they were more aggressive to take a low ASPECTS in a young patient than not necessarily offering them a mechanical thrombectomy, which probably mirrors what you do and what I would do in real life. If you have 55 years old and ASPECTS of four, you want to say, "Let me take the clot out and see how the functional status pans out." So, that's one thing.

Dr. Osama Zaidat:           The other difference, besides the difference in age, slightly more diabetic in the low ASPECTS, but it didn't reach statistical significance. Slightly less AFib than the ASPECTS of six to 10. What really also makes sense, besides the age, is the stroke scale, the stroke severity scale. The stroke severity scale was higher in the low ASPECTS, which makes sense. The infarct is completed, the patient had a worse stroke scale at baseline. So, their stroke scale was almost 20 versus 17, consistent with literature and the good ASPECTS. So, 17 in the good ASPECTS, the average score, and 20 in the low ASPECTS, slightly higher stroke severity scale.

Dr. Osama Zaidat:           What also makes sense in the low ASPECTS is you have more ICAT occlusion. When you have an ICAT occlusion, will lead to loss of collateral, will lead to more tissue, and more core infarct volume with a completed stroke.

Dr. Osama Zaidat:           So, I feel like also that's consistent. So, the difference between the baseline characteristic can be summarized with younger age, higher proximal occlusion, and more severe stroke than usual. And then the general anesthesia use was more often because now you have more severe stroke, now you have more core infarct volume, you are more likely to need anesthesia than not. So again, that's also consistent.

Dr. Osama Zaidat:           The onset to puncture time, because you may need more anesthesia, the patient was sicker to stabilize, the onset to puncture time was also more prolonged in the lower ASPECTS group versus the good ASPECTS.

Dr. Osama Zaidat:           So, those are the differences at baseline, Negar, as you can see. Not sure how you think about it, how you feel about them as well, but kind of the best way to explain them. But I'm curious also to hear your thought about them, if you have any comment or questions.

Dr. Negar Asdaghi:         Yeah, I think I want to repeat just what you said and the point you raised because it's, as you mentioned, it is not surprising to see that low ASPECTS patients are presenting with more severe strokes with higher NIH Stroke Scale, have more tandem occlusions or more proximal occlusions. They're obviously sicker patients. So, those differences were not surprising at all to a reader of your paper. What was surprising is that age gap that you mentioned within your low ASPECTS and high ASPECTS category, and that from the registry-based study is actually, exactly what you mentioned, is a signal that clinicians are more comfortable to push the guidelines boundaries in the younger population. That's something that has to be taken with a grain of salt, because we're not talking about a population-based study where we're comparing age groups between low ASPECTS and high ASPECTS. We're talking about a highly selected group of individuals who've already received endovascular therapy, and now we're comparing the age groups depending on their lower ASPECTS. So that's an important distinction that you beautifully outlined for our listeners.

Dr. Negar Asdaghi:         Now, coming to your primary outcomes, please tell us about the reperfusion rates in the study and comparing the low to high ASPECTS categories.

Dr. Osama Zaidat:           That's an excellent question, to try to see — in spite of you're taking the chances — and treating patients with low ASPECTS. How did they do functionally and angiographically? The angiographic outcome and revascularization success can be a surrogate of functional outcomes. So, let's try to review with your listeners and readers the reperfusion outcome, like you mentioned. If you look at the reperfusion outcome in the paper, and I direct the readers and the listeners to Table 2. Specifically, what stands out is the rate of complete reperfusion because that's the one with the highest difference and significance between the two groups, which is TICI 3. The frequency of obtaining TICI 3 was 83 patients out of 662 that had an angiographic outcome with a good ASPECTS was zero out of the 55 patients; none of them had a TICI 3 complete occlusion.

Dr. Osama Zaidat:           What's really astonishing in the result is the fact that there's a statistical difference between complete reperfusion, TICI 3, between the low ASPECTS group and cohort versus the good ASPECTS cohort of six to 10, and the theory and explanation, one of the explanations at least that may be plausible, is the fact that you probably had a good collateral in the good ASPECTS to have less core infarct, and the good collateral reduced the clot length, because the pial flow goes all the way backward into the clot in a retrograde fashion and makes it probably more likely to have a successful removal of the clot and hence achieving a TICI 3.

Dr. Osama Zaidat:           So, but overall, if you just lump TICI 2b or higher, the standard definition of successful reperfusion as TICI 2b or higher, there was no statistical difference between the group. It was 85.5% in the low ASPECTS and 87.6% in the good ASPECTS group. So, that was not statistically different.

Dr. Osama Zaidat:           When we looked at the first-pass effect, there was a trend toward more first-pass effect in the good ASPECTS group, but 61% and 57% in the low ASPECTS. That's defining first pass as TICI 2b from the first attempt, and not TICI 3, for example.

Dr. Osama Zaidat:           So again, you can see that your success of reperfusion probably related to the ASPECTS in an indirect way, as a surrogate of collateral. Poor collateral tissue dies quickly, low ASPECTS and higher core infarct volume, and hence low success of reperfusion, but again, the only statistical significance here is in the complete reperfusion and TICI 3.

Dr. Osama Zaidat:           So, if you kind of evaluate if the reperfusion outcome translated to a difference in the functional outcome, yes, indeed. In the low ASPECTS group, three out of 10 patients achieved independence at 90 days, or to be precise, 28.8% of that cohort and population had mRS of zero to two at 90 days in comparison to 59.7% in the good ASPECTS group.

Dr. Osama Zaidat:           So, it's almost six out of 10 patients in the good ASPECTS versus three out of 10 patients in the low ASPECTS group. Still, they achieved a good outcome because we don't have a control group, but in comparison to the good ASPECTS, it's lower outcome, as you can see on Table 2, as well.

Dr. Osama Zaidat:           The mortality is higher; it's almost 31% in the low ASPECTS versus 13.4% in the good ASPECTS group. The symptomatic hemorrhage rate was 7% versus almost 1% only in the good ASPECTS group. So, functional outcome across the board is lower than the good ASPECTS, but since this is not a randomized trial, we don't know if doing nothing to those low ASPECTS will necessarily yield similar results.

Dr. Osama Zaidat:           So, it could be better than control, but clearly it's the likelihood of the patient doing better correlates with a better ASPECTS, which we all kind of already know, but we want to try to identify the group beyond which, like you started, Dr. Negar, beyond which the mechanical thrombectomy may be futile.

Dr. Negar Asdaghi:         Right. So a very unfortunate vicious cycle almost, that those who needed the first-pass effect, TICI 3 perfusion the most actually ended up achieving it less than their high ASPECTS counterpart, as you mentioned. And again, it's important to understand that these observations are based on an observational large registry study.

Dr. Negar Asdaghi:         Now, you found an important interplay between age and low ASPECTS in the clinical outcomes from thrombectomy in your study. Can you please elaborate on those findings?

Dr. Osama Zaidat:           Absolutely. That's an excellent question because that's kind of the unique part of our research and our paper is we're trying to really combine the low ASPECTS with another variable that we all know as a clinician and people who treat stroke on a daily basis, that influence outcome. If you combine two poor predictors of good functional outcome. A good predictor that they could predict the outcome one way or another in either direction, good or bad outcome, you know ASPECTS was one of them, and age. So, we wanted to see if there's a threshold beyond which, if you combine the two, you can identify the patients that are almost less likely to benefit and the resources and the, if you may say, the resources and the message to the patient and their families should be with this consideration to try to provide guidance to the clinician nowadays.

Dr. Osama Zaidat:           So, based on the previous data, we kind of wanted to really trichotomize the age into young, less than 65, 65 to 75, and 75.

Dr. Osama Zaidat:           There is enough signal in the literature out there that 75 with low ASPECTS is a good cutoff to see. And indeed, we looked at that and we compared those three cohorts. We compared less than 65, 65 to 75, and more than 75 in the low ASPECTS group to see which one stands out. Now, the sample size is fairly small. So, I want to caution the reader and the listener to us today that this is a good signal, this is a good hypothesis-generating result; however, it needs to be reproduced in, again, large sample size and see if other researchers and investigators can have similar results.

Dr. Osama Zaidat:           What we've found in this group of more than 75 and less than 65, I feel like the equipoise should remain between 65 and 75, but less than 65 is probably beneficial more than 75. Unfortunately, we could not find a strong signal of good functional outcome in those people more than 75.

Dr. Osama Zaidat:           We had 12 patients; none of them achieved (mRS of) zero to two at 90 days, 0% at zero to two. And their mortality was close to 60%, and their symptomatic hemorrhage was close to 15%. So, when you treat a low ASPECTS (zero to five), and they are older than 75, the current data or the current signals suggest that the likelihood of good outcome is 0%, if you consider good outcome as (mRS) 0-2, and the likelihood of mortality close to 60%. More than half of them will die, and the likelihood of symptomatic hemorrhage is going to be higher, close to 16%.

Dr. Osama Zaidat:           So, that's the cohort that we have to be very cautious about. I think the younger cohort had even better outcome than the overall zero to five. If you recall, from the previous question of Dr. Negar, discussion that the overall was 28.8%. If you restrict the analysis to the young, they have probably a good plasticity, good recovery, good rehab potential. If you look at those less than 65, their mRS zero to two went up to 44.8%, which is decent, acceptable, functional outcome in those young patients, and their mortality went down from 30% or 31% to 20%, and the symptomatic hemorrhage from 7% to 6%. So, it seems that there is a good signal in those less than 65 for being aggressive and try to provide them with a therapy, less aggressive with 75, and in between, where we really have no clear answer, and their mRS score was close to 20% versus 44 and 0%. So 44%, 18%, and 0%; less than 65, 65 to 75, and older than 75.

Dr. Osama Zaidat:           Hopefully, this will shed the light and make the decision-making in the middle of the night probably more informed to the best of our knowledge nowadays.

Dr. Negar Asdaghi:         Right. And how do these rates, the symptomatic intracerebral hemorrhage rates and mortality rates, compare in the low ASPECTS group as compared to those reported from the randomized trials?

Dr. Osama Zaidat:           This is an excellent question because the randomized clinical trial had the advantage of having a control group, and the HERMES meta-analysis in all patient-level meta-analysis have looked at the CT ASPECTS. However, they combined it with the MRI ASPECTS, so kind of a heterogeneous population. It's not exactly the same, like the STRATIS low ASPECTS study that we're discussing today, and they have a very small sample size. What they found in that group from three to five, that 31%, so almost identical- if you think about -it to our outcome in the ASPECTS group. HERMES group didn't go to the 24 hour; they did up to six hours. Maybe the ESCAPE was 12 hours, the only one with the expanded time window, but interesting that their three to five ASPECTS had a good outcome of mRS zero to two at 31% versus 16% in the tPA group with an absolute difference about 15%.

Dr. Osama Zaidat:           So, again, our result is consistent with the HERMES patient-level meta-analysis. However, in the (ASPECTS) zero to two group, they found the futility in the zero to two. They found 0%  (90 day mRS) in the mechanical thrombectomy. We didn't have that much of a sample size of zero to two (ASPECTS), and we didn't obtain a 0% (90 day mRS) similar to them, but we did obtain a 0% (mRS) if you are zero to five (ASPECTS) and older than 75. They have not really looked at the intersection and the interaction with the age like we looked at it, for example. So again, in their trial, the three to five (ASPECTS) is consistent with the ASPECTS with our low ASPECTS trial at 28.8% (90 day mRS) versus 31% in the HERMES meta-analysis, for example.

Dr. Osama Zaidat:           MR-CLEAN group, however, even they have a better outcome, zero to four (ASPECTS), than us and HERMES, at about (90 day mRS) 36.7%. Their sample size was very small, less than 30 patients in the whole cohort, almost half the size of our sample size. So MR-CLEAN showed also, so if you think about it, the registry is close to 30% (mRS of 0-2 at 90 days), the randomized trial 31% to 35%. So, we are within the confidence interval of what's the likelihood of good outcome, which is almost one-third of the patients with low ASPECTS would have a good outcome.

Dr. Osama Zaidat:           The good news that the standard care therapy with tPA gives you half of that outcome almost. So, there's a good signal that future randomized trial may be positive if they follow the STRATIS registry, HERMES, or MR-CLEAN data.

Dr. Negar Asdaghi:         So, Sam, very important information and percentages to keep in mind as we counsel patients and family members, especially those elderly patients we see with large ischemic cores and low ASPECTS in the early timeframe from stroke onset.

Dr. Negar Asdaghi:         I know you alluded to the future randomized trials, but I want to end with our takeaway message from your study, and how do you see these randomized trials in low ASPECTS population unfolding in the future?

Dr. Osama Zaidat:           I mean, this is an excellent question that has two aspects about it. One is, can we use some of this data to guide us nowadays until we have future randomized trial? And I think each patient is individual, each family's individual family. I want the listener and the readers to take their time to explain the data to the patient. They have to keep in mind that there is a small sample size and also how definitive they feel about their reads with ASPECTS score, how definitive they feel about the large core infract, and is this plus minus one, is five the cutoff, in the elderly? Is it four or zero?

Dr. Osama Zaidat:           So, I think if you are confident that your score may be zero to three, and the patient is more than 75, is more justifiable, kind of, at that extreme and to say this is less likely to benefit (from endovascular therapy) based on collective data.

Dr. Osama Zaidat:           Again, without randomized trial, it's hard to strongly send a message, don't treat them (endovascularly) and futile. But based on HERMES, based on our analysis, extreme ASPECTS in older than 75, probably you have to be cautious taking them to the (cath) lab, for example. Now that's been said, the future trial will answer that. We are running the randomized trial ourself, myself and my co-PI, Dr. Albert Yoo, are doing an international TESLA trial. We are close to 125 patients randomized from two to five ASPECTS score and up to 85 years of age. So, we have almost 60-plus randomized in each arm, and we are hoping if we continue at this rate in the next two years to complete the enrollment and have some answer.

Dr. Osama Zaidat:           Our sample size-it's an adaptive design trial called TESLA Trial--and our sample size is 300 patients. In Germany, there is an ongoing Tension trial. In U.S., there is another trial that mixed a CT scan with the perfusion for large core infarct called SELECT 2. That's ongoing, as well. And then a fourth trial, which is the IN EXTREMIS trial in France, that also going to answer it, and hopefully we can do a meta-analysis among those four large core infarct trials.

Dr. Osama Zaidat:           Some of them allowed diffusion MRI, as well as CT scan; some of them allowed perfusion. And this way, if we combine all our data together, we can have probably a more reliable and precise answer to this important clinical question that has been identified by the National Institutes of Health [inaudible 00:36:43] as priority number one for thrombectomy following what we know so far. It's ranked as the next question that needs answer.

Dr. Negar Asdaghi:         Dr. Sam Zaidat, congratulations on this work, and we look forward to the completion of TESLA results and the results of other randomized trials. Thank you for being with us today.

Dr. Osama Zaidat:           Thank you for having me, and I appreciate the listener tuning in, and I appreciate the ASA and the journal team for having me. This is on behalf of my co-authors, the sponsor of the registry. Thank you very much.

Dr. Negar Asdaghi:         Thank you. Now, before we end the July podcast, I want to draw your attention to a special invited report prepared by the Stroke Council Leadership on behalf of the American Heart and Stroke Associations on diagnosis and management of cerebral venous sinus thrombosis, or CVST, with vaccine-induced immune thrombotic thrombocytopenia.

Dr. Negar Asdaghi:         This report is to heighten clinicians' awareness regarding the six cases of CVST, with thrombocytopenia in patients who received the Johnson & Johnson vaccine in the United States. Similar thromboembolic events were reported in Europe following the administration of AstraZeneca vaccination. These are adenoviral vector–containing vaccines, which are mechanistically different from the mRNA SARS-CoV-2 vaccines produced by Pfizer and Moderna.

Dr. Negar Asdaghi:         The putative mechanism of vaccine-induced thrombotic thrombocytopenia is believed to be related to the leakage of DNA from the adenovirus-infected cells that subsequently binds to the platelet factor 4 and triggers the production of auto-antibodies against platelets.

Dr. Negar Asdaghi:         The authors emphasize that while we wait for further research on the causal nature of the relationship of vaccines to CVST with thrombocytopenia, it is important to keep in mind that the reported risk of CVST associated with COVID-19 infection itself is far greater than that associated with vaccination.

Dr. Negar Asdaghi:         And with that, we conclude our podcast for the July 2021 issue of Stroke. On behalf of the Editorial Board, I want to thank you all for listening and a special thanks to our healthcare providers and clinicians who continue to work on the front lines of this pandemic. We hope that you find this information useful, and until our next podcast, stay alert with Stroke Alert. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

Stroke Alert June 2021

On Episode 5 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the June 2021 issue of Stroke: "Preexisting Mild Cognitive Impairment, Dementia, and Receipt of Treatments for Acute Ischemic Stroke” and “Body Mass Index in 1.9 Million Adolescents and Stroke in Young Adulthood.” She also interviews Dr. Shyam Prabhakaran, from the University of Chicago, about his article "Predictors of Early Infarct Recurrence in Patients With Symptomatic Intracranial Atherosclerotic Disease."

Dr. Negar Asdaghi:

1) Do people with mild cognitive impairment receive the same quality of stroke care as their cognitively normal counterparts?

2) Is there a causative relationship between the alarming rise in adolescent obesity and the rise in the incidence of stroke under the age of 50?

3) What are the independent predictors of radiographic recurrence in patients with symptomatic intracranial atherosclerotic disease?

These are the topics that we will cover in today's podcast. You're listening to the Stroke Alert Podcast. Stay with us.

Dr. Negar Asdaghi:                        From the Editorial Board of Stroke, welcome to the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. For the June 2021 issue of Stroke, we have a range of publications that cover a variety of topics from activation of neuroinflammatory pathways and intracerebral hemorrhage to predictors of outcome in patients with mild and rapidly improving ischemic stroke, which I encourage you to review, in addition to our podcast. Later in today's podcast, I have the privilege of interviewing Dr. Shyam Prabhakaran from University of Chicago on his work with various radiographic biomarkers as predictors of outcome in patients with symptomatic intercranial atherosclerotic disease. But first, with these two papers.

Dr. Negar Asdaghi:                        In the United States, one in five adults over the age of 65 have mild cognitive impairment, and one in seven have a formal diagnosis of dementia. With our aging population, these numbers are estimated to triple by year 2050. Prior studies suggest that patients with dementia are less likely to receive evidence-based stroke care as compared to those with normal cognition. Less is known about the quality of stroke care amongst patients with mild cognitive impairment. In their paper titled "Preexisting Mild Cognitive Impairment, Dementia, and Receipt of Treatments for Acute Ischemic Stroke," Dr. Deborah Levine from Departments of Neurology and Internal Medicine at the University of Michigan and colleagues studied the quality of care in acute ischemic stroke patients with mild cognitive impairment, or MCI, and preexisting dementia as compared to patients with normal cognition.

Dr. Negar Asdaghi:                        This was a cross-sectional analysis of prospectively obtained data on adults with acute ischemic stroke included in the Brain Attack Surveillance in the Corpus Christi project from 2008 to 2013. Primary outcome of the study is a composite quality measure of defect-free care calculated by dividing the number of treatments that a patient received by the number of treatments they were eligible to receive. Defect-free care was defined as receipt of seven stroke performance measures when eligible, and included administration of IV tPA, use of antithrombotic therapy by end of hospital day two, administration of DVT prophylaxis, assessment for rehabilitation, discharge on antithrombotic therapy, discharge on lipid-lowering therapy, and discharge on anticoagulation therapy for atrial fibrillation.

Dr. Negar Asdaghi:                        Amongst 836 adults included in this study with a median age of 65, 58%, that's over half of the patients in this study, had some degree of cognitive impairment prior to their presenting stroke. 44% of patients with preexisting dementia received defect-free care as compared to 55% with either normal cognition or mild cognitive impairment. The difference, they did not reach statistical significance after adjusting for the sex, vascular comorbidities, and BMI in multivariate analysis. However, preexisting MCI remain an independent factor to be negatively associated with receipt of IV tPA echocardiogram and assessment for rehabilitation. Similarly, after adjusting for all confounders, preexisting dementia remained negatively associated with receipt of antithrombotic therapy by day two, lipid-lowering therapy at discharge, and receiving an echocardiogram. The authors highlighted their findings as a call to action to improve the overall delivery of stroke care and measures to all stroke patients, and caution that disparities noted in their study might contribute to differences in post-stroke outcomes, such as functional disability and recurrent stroke in the growing population of patients with mild cognitive impairment and dementia.

Dr. Negar Asdaghi:                        Having a stroke at a young age has profound personal, societal, and economic implications. For the young stroke survivors, a long life expectancy after stroke, and the cost of long-term care pose huge challenges to healthcare systems, which are different than that encountered in the elderly stroke population. Over the past two decades, the incidence of ischemic stroke has substantially increased in the young, with adults under the age of 50 now comprising 10% of all ischemic stroke cases. This comes in parallel with the continuous rise in the prevalence of adolescent obesity in many Western countries, but the association between the two remains unclear. In the current issue of the journal, Dr. Aya Bardugo from the Department of Military Medicine, Hebrew University, in Jerusalem, and colleagues studied the association of adolescent body mass index, or BMI, with first stroke event in young adults as part of a nationwide population-based study of 1.9 million adolescents, followed for a cumulative 9.48 million person-years. BMI values were categorized in five groups of underweight, low-normal, high-normal, overweight, and obese.

Dr. Negar Asdaghi:                        So, what they found was that the incident rate of any stroke and ischemic stroke increased gradually across the five BMI categories. Importantly, the hazard ratio for ischemic stroke became significant, even in the high-normal BMI group at 1.4, and increased to 2 for the overweight and 3.5 in the obese category. Though a similar increase in the rate of hemorrhagic stroke was noted, there was no significant association between BMI and hemorrhagic stroke in the study. Not surprisingly, many vascular risk factors, including high blood pressure and diabetes, were also elevated in the higher category BMI adolescents. However, alarmingly, these trends remain significant even after adjustment for age, sex, sociodemographic factors, and when the data was limited to otherwise healthy adolescents, those without diabetes and those without high blood pressure. Overall, the authors found that overweight and obese adolescents had approximately two- to threefold increased hazard for ischemic stroke that could present prior to the age of 30 irrespective of sex, race, ethnicity, and socioeconomic status.

Dr. Negar Asdaghi:                        The authors detailed various mechanisms in which increased adolescent BMI may lead to stroke in the young, including progressive risk of large vessel intra and extracranial atherosclerotic disease, increased cardiovascular disease, and a shift to young onset heart failure and atrial fibrillation, as well as a strong association with being high BMI in children and adolescents, and that of obesity in adults. These findings are important observations as we face a growing epidemic of childhood and youth obesity worldwide with the potential to increase the future burden of stroke in young adults.

Dr. Negar Asdaghi:                        Intracranial atherosclerotic disease, or ICAD, is an important cause of ischemic stroke worldwide. In addition to neurological deficits caused by index event, patients with ICAD remain at high risk for development of recurrent ischemic events. The risk of clinical recurrence is estimated to be between 12% to 20% at one year based on prior studies, despite best medical management. But recent studies have shown that up to 25% of patients with symptomatic ICAD have evidence of radiographic recurrence on follow-up MRI imaging.

Dr. Negar Asdaghi:                        Who will remain stable and who will have more events with symptomatic ICAD is a common question that practicing clinicians struggle with in routine practice. The Mechanisms of Early Recurrence in Intracranial Atherosclerotic Disease, or the MYRIAD study, aimed to get us closer to that answer. Joining me now is Dr. Shyam Prabhakaran, Professor of Neurology and Chair of the Department of Neurology at the University of Chicago, who was one of the principal investigators of the MYRIAD study and the first author of the paper in the current issue of the journal titled "Predictors of Early Infarct Recurrence in Patients With Symptomatic Intracranial Atherosclerotic Disease." Good afternoon, Shyam. Thank you for joining us.

Dr. Shyam Prabhakaran:              Thank you, and good afternoon to you.

Dr. Negar Asdaghi:                        Thank you. Shyam, can you please start by telling us how MYRIAD's design was different from prior studies of symptomatic ICAD? And what were the main objectives of the study?

Dr. Shyam Prabhakaran:              Sure, so MYRIAD was conceived as a study to really unravel and study the mechanisms of recurrent stroke after symptomatic ICAD presentation. Prior studies, I think, have really helped in many ways, obviously to understand the natural history of the disease, including through clinical trials, where we learned about the different interventions that could be applied, medical and endovascular, through WASID and then SAMMPRIS. However, both of those studies, which provided probably the bulk of information about the disease in multi-center study, did not really focus on mechanisms, per se, understanding it through biomarkers, understanding whether certain subsets of patients have higher or lower risk of recurrence. So, MYRIAD was conceived to try to tackle that particular aspect of research that we felt was understudied.

Dr. Negar Asdaghi:                        Yes, thank you. Traditionally, as you mentioned, the location and the degree of stenosis have been considered as important radiographic factors to predict outcomes in symptomatic ICAD. MYRIAD looked at many more imaging biomarkers than just degree of stenosis and the location. Can you please elaborate on those radiographic biomarkers that were included in MYRIAD?

Dr. Shyam Prabhakaran:              Yeah. So, again, MYRIAD wanted to explore these imaging biomarkers, and we split them into three categories. One was biomarker of antegrade flow. What would help us understand the amount or volume of flow through a particular diseased artery? And we used quantitative MRA for that, which is a technique that's been around a long time, a phase contrast MR approach, to get vessel-specific flow measurements. And aim two thought of the distal flow beyond the stenosis and aimed to look at two types of imaging biomarkers that might answer the question of flow in the distal territory, one through perfusion imaging. So looking at CT or MR perfusion, but MR was the one that we selected, where we would measure the tissue flow through Tmax measurements, and then the other using TCD, transcranial Doppler, and vasomotor reactivity testing of the distal arterials. So that was aim two. Can we look at those biomarkers potentially as predictors of recurrence? And then the third was emboli detection, so the plaque vulnerability or instability biomarker. So, could we look at distal emboli in the territory and assess its role in predicting recurrence? So, those were really the main biomarkers tied to the objectives of the grant.

Dr. Negar Asdaghi:                        Perfect. So, obviously, great, and a comprehensive various biomarkers looking at different imaging predictors of early recurrence. We're excited to hear about your primary results. So, what did your study find?

Dr. Shyam Prabhakaran:              So, in MYRIAD, we enrolled 105 subjects who had symptomatic intercranial stenosis at 10 centers across the US. And we were able to track them for both the primary outcome, which was stroke in the territory of the stenosis, clinical stroke at one year, and the secondary outcome, which was radiographic occurrence of new infarcts on six- to eight-week MRI. So that was a prespecified outcome. In the primary analysis of the clinical outcome, we did find a fairly high rate of recurrent events. Roughly 10% of patients in the cohort had a recurrent clinical event at one year, consistent with findings from, say, SAMMPRIS, which with maximum medical or aggressive medical management found a roughly 12% recurrence. So, we were able to confirm that there is a high rate of clinical recurrence. However, none of the biomarkers that we were looking at, quantitative MRA, profusion imaging, transcranial Doppler for BMR or emboli detection were predictors of the clinical outcome at one year. So, that was our main results.

Dr. Shyam Prabhakaran:              Our secondary outcome was recurrent infarcts on study-specific research MRIs performed at the sites, and looked for recurrences compared to baseline MRIs that were performed at the time of their index stroke or TIA. So, in this paper, we were really interested in looking at whether there were any specific predictors of recurrent radiographic infarct, and that really was an interest of ours because we did find such a high rate of radiographic recurrence. Roughly 24% of our cohort had a recurrent infarct on brain imaging at six to eight weeks. So, we recognized right away that this is potentially an unrecognized phenomenon, that there's potentially an excess of radiographic events to clinical events. And there could be, obviously, a potential consequence of this radiographic accumulation of disease. Particularly, it might be important to prevent those radiographic occurrences in the future if they are affecting an individual's performance on cognition or even physical function as a result of accumulating lesions. So, we were really interested in seeing whether there were some early predictors of this six- to eight-week recurrence that we saw at a high rate. So, the paper looked at clinical factors, as well as imaging factors, that were available in the MYRIAD cohort, really trying to delve into a model that we could use to identify a subset that is at the highest risk of these early recurrent infarcts.

Dr. Negar Asdaghi:                        Right, so very, very important findings. So, just to reiterate for our listeners, one in four patients in your study had evidence of radiographic recurrence despite clinically seemingly having no clinical events. So, this clinical radiographic dissociation would have absolutely gone unnoticed had it not been for these early MR images that were performed in the study. So, I want to clarify this from a pathophysiological standpoint. Is it hypoperfusion, plaque rupture, or both? Based on your results, what is the driving factor in development of new ischemia in symptomatic ICAD?

Dr. Shyam Prabhakaran:              So, one of our main findings here, which is reported in this paper, is that those with multiple infarcts at their index stroke, so a pattern on diffusion-weighted imaging that was more than a singular infarct lesion, was a strong, independent predictor of having a recurrent event, recurrent infarct at six to eight weeks. And the part that isn't really highlighted in the paper, but is true, is the other factor that was co-mingled with multi-lesion, multi-infarct and index was borderzone pattern. They were co-linear, and they were essentially the same patients who were borderzone also had multiple lesions. So, one way we've interpreted this, and I can speak to a little bit about the different biomarkers that were studied in addition to the infarct pattern, but one way we've interpreted this is that multi-lesions can probably fall under two subsets.

Dr. Shyam Prabhakaran:                           It could either be in this borderzone pattern, where you have multiple lesions due to hypoperfusion mechanisms, typically within either cortical or internal borderzones. And that may be then telling us about a mechanism of low flow. On the other hand, some of these patients could also have scattered lesions that are embolic in etiology and suggest a plaque that was unstable and potentially showered at their index event, resulting in that pattern that we saw. So, both of them probably are mixed in. We're favoring the borderzone because they were so co-linear that that probably was the more likely mechanism. And we're probably concerned that that could also be a factor that leads to early recurrence because flow failure typically is associated with critical hypoperfusion and imminent recurrence.

Dr. Shyam Prabhakaran:              But, interestingly, in the paper, we talk about this, none of the specific prespecified biomarkers that were looking at flow, perfusion imaging, vasomotor reactivity were significant by themselves as predictors of recurrent infarct. So, it's a little hard for us to know why. It could be that the technology that we use, perfusion imaging, is still not quite picking up the kind of flow failure that we need to. Maybe it's more subtle than even we found because we looked at different cut points of Tmax and other parameters on perfusion imaging, and yet, we're not able to find a cutoff that was predictive, likewise with vasomotor reactivity. So, it could be that those are not quite good enough surrogates of hypoperfusion. And yet, borderzone or multi-infarct patterns may have been a surrogate of hypoperfusion. So, I think the short answer here is that it could be both mechanisms, plaque instability and hypoperfusion, although we're maybe favoring hypoperfusion because there was a strong co-linearity with borderzone pattern.

Dr. Negar Asdaghi:                        Understood. Now Shyam, recurrent events on maximum medical therapy, this is not what we like to hear. Where do you see the future of symptomatic ICAD therapy? Now in your view, is there a role for interventional treatment or other therapies in a select group of ICAD patients?

Dr. Shyam Prabhakaran:              I think that's really where we still face real challenges. I think the work done by many of the investigators before us on maximum medical therapy and interventional therapies have found, obviously, that there are some benefits to the medical approaches that we now consider standard of care. The dual antiplatelet therapy, the lipid-lowering therapy, the lifestyle management that SAMMPRIS also implemented and successfully showed some benefits of physical activity. So, those things clearly matter. And yet, the clinical event rate is still very high, and the radiographic event rate is even higher. So, you have this real challenge facing clinicians and patients of a disease that has a very high rate of recurrence, much higher than the other subtypes of ischemic stroke, and certainly higher than, say, AFib patients even, where we sometimes obviously are concerned and adopt strategies to lower risk. So, we are in a position, I think, today where we have to go back to the well and think about novel strategies.

Dr. Shyam Prabhakaran:              Now, flow is a component of this, and I do think that SAMMPRIS, albeit now almost a decade ago, tested an interventional approach. It may be worth revisiting interventional strategies. Of course, we know from endovascular therapy for ischemic stroke, try once and fail, and try again, and you might find a different result because technologies get better, practitioners, proceduralists get better. So, that's one angle that I think people are very interested in, is whether or not an interventional approach for flow failure patients is a path forward. And that, I think, will get a lot of attention in the years to come with new studies that are being designed.

Dr. Shyam Prabhakaran:              I think the other important point here is that aggressive medical management in the current day and age may still have room for improvement. Maybe the drugs that we're using, especially with DAPT and lipid-lowering therapies, they're not as quick or necessarily universally responsive for every patient. So, we know that about clopidogrel, that there's a certain rate of non-responders. We could probably do better than that with other choices, antiplatelet choices or even anticoagulant choices, which are being considered. And we know that lipid-lowering therapy with statins works well, but perhaps PCSK9 drugs could be considered in this population to lower cholesterol levels even more rapidly and more aggressively. So, all of these, I think, should be on the table as we move forward.

Dr. Negar Asdaghi:                        Dr. Shyam Prabhakaran, thank you for joining us on the podcast today. We look forward to having you back here and covering more of your work in the future.

Dr. Shyam Prabhakaran:              Thank you for having me.

Dr. Negar Asdaghi:                        Thank you. And this concludes our podcast for the June 2021 issue of Stroke. Please be sure to check out the June table of contents for the full list of publications, including an important update from the American Stroke Association and the Stroke Council on how cerebrovascular disease is expected to temporarily fall from the fifth to the sixth leading cause of death in the United States in 2020. Sadly, this is not because of advances in stroke prevention and therapies, but rather because mortality from COVID-19 will displace stroke as a leading cause of death, a grim reminder of the year we put behind us and the many lives lost to this global pandemic. And yet we look ahead with hope, and with the promise that science has the power to resolve and the ability to push the human race forward. Every small step, every question will get us closer to learning more, answering more and knowing more. So, as we end this podcast today, we look forward to asking more at our next, and our promise to stay alert with Stroke Alert. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 4 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two featured articles from the May 2021 issue of Stroke: “Association of Serum IL-6 With Functional Outcome After Intracerebral Hemorrhage” and “SARS-CoV-2 and Stroke Characteristics: A Report from the Multinational COVID-19 Stroke Study Group.” This episode also features a conversation with Dr. Alvaro Garcia-Tornel Garcia-Camba to discuss his article “Ischemic Core Overestimation on Computed Tomography Perfusion.”

Dr. Negar Asdaghi:

1) Can a pro inflammatory marker predict the hematoma size and clinical outcomes in patients with intracerebral hemorrhage?

2) What are the characteristics of stroke patients infected with coronavirus?

3) Is ischemic core reliably represented by the current established cerebral blood flow thresholds on CT perfusion imaging? Or are we underestimating the importance of perfusion overestimating the ischemic core?

We will discuss these topics in today's podcast. You're listening to Stroke Alert Podcast. Stay with us.

Dr. Negar Asdaghi:                                     From the Editorial Board of Stroke, welcome to the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. For the May 2021 issue of Stroke, we have an exciting program today, as we cover topics from the predictive role of inflammatory markers in intracerebral hemorrhage to characteristics of stroke patients infected with SARS-CoV-2 virus. Later in the podcast, I have the privilege of interviewing Dr. Alvaro Garcia-Tornel Garcia-Camba from Autonomous University of Barcelona on the topic of ischemic core overestimation by CT perfusion imaging. I hope you enjoy our podcast.

Dr. Negar Asdaghi:                                     Intracerebral hemorrhage is an aggressive form of stroke with high morbidity and mortality rates. Increased systemic inflammation may be correlated with more severe neurological presentation, larger hematoma volume, and worse clinical outcome in these patients. Elevated levels of interleukin 6, or IL-6, have been found in the experimental models of ICH and may represent a therapeutic target to reduce the inflammatory response in ICH if similar findings were replicated in clinical studies of patients with ICH.

Dr. Negar Asdaghi:                                     In the May issue of the journal, in the study titled “Association of Serum IL-6 With Functional Outcome After Intracerebral Hemorrhage,” Dr. Kevin Sheth from Department of Neurosurgery at Yale University and colleagues performed a pre-specified exploratory analysis of the patients enrolled in the FAST trial, testing the association of admission levels of serum IL-6 with baseline neuroimaging and functional outcome at 90 days.

Dr. Negar Asdaghi:                                     But just a reminder for our listeners that FAST trial was a multicenter randomized trial of the recombinant factor VIIa administered in two doses versus placebo in patients with spontaneous nontraumatic intracerebral hemorrhage presenting within three hours of symptom onset.

Dr. Negar Asdaghi:                                     So, in the current analysis, amongst 841 patients enrolled in the trial, 66% were included who had both baseline IL-6 measurements and the follow-up modified Rankin Scale on day 90. Patients were stratified into four quartiles based on their admission IL-6 serum levels from low/normal in quartile one to very high levels in quartile four. And their baseline characteristics, neuroimaging and outcomes were then compared.

Dr. Negar Asdaghi:                                     So, what they found is that patients with a poor outcome, defined as modified Rankin Scale of four or higher at 90 days, had a higher median admission IL-6 level than those with a favorable outcome. In their multivariate analysis, for each one nanogram per liter increase in IL-6 level, there was a 30% increase in the odds of a poor functional outcome after adjustment for various factors, such as age, intracerebral hemorrhage volume, baseline Glasgow Coma Scale, presence of intraventricular hemorrhage, hematoma expansion, ICH location, and recombinant factor VIIa treatment allocation.

Dr. Negar Asdaghi:                                     So, a higher IL-6 level at baseline was also found to be independently associated with higher baseline hematoma volume and was a predictor of perihematomal edema, an association that was stronger in patients with lobar rather than subcortical  ICH.

Dr. Negar Asdaghi:                                     Now, whether there is a causal relationship between IL-6 and outcomes in ICH, and importantly, whether the growing number of anti-IL-6 therapies have a role in the reduction of inflammation and improvement of clinical outcome in this population, are important subjects to consider and study in the future. So please stay tuned.

Dr. Negar Asdaghi:                                     We now move on to our next paper, examining the characteristics of stroke in COVID-positive patients. In the study titled “SARS-CoV-2 and Stroke Characteristics: A Report from the Multinational COVID-19 Stroke Study Group,” Dr. Ramin Zand from Geisinger Neuroscience Institute and colleagues from across the globe examine the characteristics of COVID-infected patients with neuroimaging-confirmed stroke from 71 centers across 17 countries. Patients were included in the study if presented to the hospital with stroke-related chief complaints and asymptomatic COVID infection, or had a stroke while being hospitalized for COVID, or patients with stroke-related admission who had confirmed prior diagnosis of COVID infection.

Dr. Negar Asdaghi:                                     A total at 432 stroke patients were included in the study. 75% of those had acute ischemic stroke, 21% with intracerebral hemorrhage, and the remainder had cerebral venous sinus thrombosis. The authors found that, in general, stroke characteristics and subtypes were different in COVID-infected patients as compared to non-COVID stroke patients based on the prior population-based studies for both ischemic and hemorrhagic stroke. Notably, amongst COVID-infected patients with acute ischemic stroke, a third had only asymptomatic COVID. They had an overall male predominance with a young median age, and that a quarter of ischemic stroke patients were younger than 55 years of age, and a similar percentage had no known identifiable vascular risk factors. Among those with available vascular imaging, close to 50% had evidence of a large vessel occlusion on vascular imaging. In considering the etiology of stroke as defined by the TOAST classification, only 10% of COVID-positive stroke population had small vessel disease in contrast to typically 30% of the general ischemic stroke population.

Dr. Negar Asdaghi:                                     Now, when considering the hemorrhagic stroke, despite smaller number of patients included in the study, similar differences in general classification of hemorrhagic stroke patients was noted. Specifically, 25% of hemorrhagic strokes had evidence of subarachnoid hemorrhage, over two thirds of which was non-aneurysmal, a much higher percentage than that reported amongst non-COVID infected patients. A third of hemorrhagic strokes in this population is related to cerebral venous sinus thrombosis, an observation that is in keeping with the general notion that COVID infection can create a hypercoagulable state.

Dr. Negar Asdaghi:                                      In summary, this study adds to the growing literature regarding the complex interplay between COVID infection and vascular disease, and the importance of understanding how this virus may play a role in clinical presentation of stroke.

Dr. Negar Asdaghi:                                      Various imaging modalities, including diffusion-weighted imaging, MR perfusion, and CT perfusion, are used to define the extent of ischemic core in patients presenting with acute ischemic stroke. In contrast to restrictions and delays associated with acquisition of an MRI study in the acute setting, CT perfusion is readily accessible with relatively fast acquisition times and is easily incorporated in the stroke-alert workflow. As a treating stroke neurologist, you make the decision not to proceed with endovascular therapy in an otherwise eligible patient due to presence of a large volume of ischemic core, as measured by CT perfusion, only to find out that perfusion overestimated the ischemic core. How often do we encounter this scenario? And what are the factors associated with ischemic core overestimation as determined by CT perfusion? Joining me now is Dr. Alvaro Garcia-Tornel Garcia-Camba from Autonomous University of Barcelona, who's the first author of the study titled “Ischemic Core Overestimation as Measured by CT Perfusion: Collateral Status, Time and Its Interaction.” Good afternoon, Alvaro. Thank you for joining us from Barcelona.

Dr. Alvaro Garcia-Tornel Garcia-Camba: Good afternoon, Negar. It is a pleasure to be interviewed in a Stroke Alert Podcast to talk about our work with you.

Dr. Negar Asdaghi:                                      Great, Alvaro. Endovascular treatment is routinely offered to patients with a target intracranial occlusion, or between 6 to 24 hours from symptom onset, or those without a known time of onset if they're determined to have a small ischemic core. Can you walk us through the evolution of stroke endovascular therapies from time-based to imaging-based decision-making, please?

Dr. Alvaro Garcia-Tornel Garcia-Camba: Yeah, well, I remember when I started my neurology training, that was nearly 10 years ago, that the most important biomarkers that we took into account in decision making was time and stroke severity. For decades, time had been the tool to select patients for thrombolysis. It was no different for patients that were considered for endovascular treatment at the beginning. And we did a variety of scales and scores for acute stroke infarct assessment on non-contrast CT and MRI, like ASPECTs score and the routine use of non-invasive angiographics tests for the selection of patients with large vessel occlusion and the new generation stent-retrievers, and in basic framework for patient selection started to grow, and this led to positive progress for endovascular treatment trials back in 2015. Perfusing imaging developed in parallel with SWIFT-PRIME and EXTEND-IA being the early window trials that used perfusion imaging to select patients for endovascular treatment, with the aim to estimate the ischemic core, the already infarcted tissue, and penumbra, the ischemic tissue that is still viable if reperfusion is achieved, on computed tomography perfusion as an effort to mimic the accuracy of diffusion imaging MRI core estimation. Multiple studies for the development of thresholds applied to computed tomography perfusion role data to estimate core and penumbra using diffusion imaging as the gold standard. And the mismatch concept was the finite and it was successfully applied in the extended window that was above six hours in DEFUSE 3 trial.

Dr. Alvaro Garcia-Tornel Garcia-Camba: And DAWN trial, the other late window endovascular treatment trial, used a slightly different approach using the core clinical measurements, taking into account clinical severity and age rather than the penumbral tissue to select patients for endovascular treatments. Both the studies had positive results and a number needed to treat comparable to early imaging trials. And we have learned in the past years that time is one of the most important prognostic factors in patients with an acute stroke. But the clock runs at different speeds depending on the specific patient that we evaluate. Tissue analysis on imaging is the way to calibrate this state.

Dr. Negar Asdaghi:                                      Thank you, Alvaro, for this nice review of the literature. Can you please tell us about the concept of ischemic core overestimation, specifically by CT perfusion? What was known in the literature before, and what prompted you to look into this in more detail in the current study?

Dr. Alvaro Garcia-Tornel Garcia-Camba: Well, we consider ischemic core overestimation is present when the estimated score by computed tomography perfusion imaging is actually larger than the real core, which is the not salvageable tissue at the time of imaging. Most of the studies that have focused on computed tomography perfusion accuracy considered both types of error, that the estimated score is larger or smaller than actual real core normal using diffusion imaging as the ground truth. We wanted to focus on overestimation because of two reasons. The first one is because it might deny endovascular treatment for patients in which reperfusion might lead to better outcomes. And because the ground truth is that the core should increase its size over time, not decrease. The study that prompted me to further investigate on this concept was an article that was published back in 2017, that is ghost infarct core concept that it was published by the unit that I work in nowadays.

Dr. Alvaro Garcia-Tornel Garcia-Camba: And this is the two main factors succeeded with overestimation. In this case was slightly different because they consider core overestimation to be when the estimated core was 10 milliliters larger than the follow-up infarct where reperfusion that was achieving more than 50% of reperfusion after endovascular treatment for more than mTICI 2B or earlier imaging in time. We consider the main limitation of this specific study was the small size because it only included 70 patients. And that the software used for computed tomography perfusion analysis was not as validated at this time as RAPID is, the one that is used in our actual study.

Dr. Negar Asdaghi:                                      Right. Now, very important concept to keep in mind, especially because RAPID is now used worldwide everywhere in many institutions. And as you mentioned, we make therapeutic decisions based on volumetric assumptions of ischemic core that's given to us by RAPID. Alvaro, we're excited to hear about your study. Can you please tell us about your patient population, and how you define ischemic core and CT perfusion, and what measures were used to determine the final ischemic volume in your study?

Dr. Alvaro Garcia-Tornel Garcia-Camba: Well, we included 407 patients from a single center retrospective database that was from 2014 to 2019. They had to have an anterior circulation intracranial large vessel occlusion, including in portions of M1, M2 of middle cerebral artery or terminal intracranial carotid artery occlusion. And they had to have baseline computed tomography perfusion, and they must have achieved reperfusion after endovascular treatment that we have defined as mTICI 2B at the end of the procedure, with a follow-up non-contrast CT at 24-48 hours, in order to measure the final infarct volume.

Dr. Alvaro Garcia-Tornel Garcia-Camba: Patients with unwitnessed stroke onset were included, and the estimated core and hypoperfusion intensity ratio that it's a perfusion imaging output that it strongly correlates with collateral flow were determined using RAPID automated software with default thresholds. That is a relative reduction of cerebral flow below 15%* as compared to contralateral hemisphere for estimated core and the ratio of tissue with a Tmax delay above 10 seconds in areas with a Tmax delay above six seconds for hypoperfusion intensity ratio.

Dr. Alvaro Garcia-Tornel Garcia-Camba: The final infarct that was the ground truth for comparison was calculated as the mean from two observers’ measurements using a semiautomatic method for non-contrast CT and patients with a parenchymal hemorrhage type 2 hemorrhagic transformation on follow-up imaging were excluded from the analysis. Ischemic core overestimation was considered when estimated core was larger than final infarct volume.

Dr. Negar Asdaghi:                                      Perfect. Can you please tell us about the main findings of the study?

Dr. Alvaro Garcia-Tornel Garcia-Camba: We found out that ischemic core overestimation is a phenomenon that is more prevalent in patients with earlier window time and that the influence of poor collateral status are measuring using hypoperfusion intensity ratio with a cutoff point of 0.4. Previously as stated to discriminate between good and [inaudible 00:16:02] collaterals was stronger in patients with earlier window time. Patients with poor collateral status in the first four hours window had twice the odds of ischemic core restoration, as compared to patients that presented above four hours from symptom onset.

Dr. Negar Asdaghi:                                      Very interesting, Alvaro. CT perfusion overestimated the volume of ischemic core in 20% of your study population. What was the median volume of core overestimation, and what were the factors associated with this overestimation in your multivariate analysis?

Dr. Alvaro Garcia-Tornel Garcia-Camba: 83 patients presented with ischemic core overestimation. The median volumetric overestimation was 12 milliliters with an interquartile range of 56 milliliters. Apart from hypoperfusion intensity ratio and time from onset to imaging, terminal internal carotid occlusion location and complete reperfusion that was more than 90% of the people with modified TICI 2C–3 were independently associated with ischemic core overestimation on multivariate analysis. Within the [inaudible 00:17:12] and independent association with time from imaging to reperfusion, a variable that had been previously reported to influence the accuracy of core overestimation on computed tomography perfusion, and we believe that differences in baseline characteristics between the studies and the low variability in imaging reperfusion time in the core will explain why it was not statistically significant.

Dr. Negar Asdaghi:                                      Very important findings, Alvaro. Just reminding clinicians to pay attention to factors such as location of the occlusion and, as you mentioned, the hypoperfusion intensity ratio, in addition to the volume of the tissue with relative cerebral blood flow of less than 30% to define the ischemic core. So, definitely many important learning factors for all of us here. Alvaro, I want to finish by just a question that in routine clinical practice, CT perfusion is not commonly performed in those under six hours. And yet ischemic core overestimation seems to be a phenomenon most notably found in earlier presenters. So, what is the clinical implication of the ischemic core overestimation by CTP in late presenters?

Dr. Alvaro Garcia-Tornel Garcia-Camba: Well, the rate of ischemic core overestimation was low in patients presenting above four hours from symptom onset. And I do not personally believe that clinically relevant overestimation is present in late presenters with witnesses at the stroke onset. Nonetheless, a high proportion of this population with late presentation do not actually have a clear symptom onset times. And it was witnessed in this group of patients, they [inaudible 00:18:46] not to perform in the vascular treatment for a large score on CTP only should be carefully taken given the results of our study. As taken solely in accountable volumetric estimation of core on computed tomography perfusion might lead to deny treatment to patient that could benefit from it.

Dr. Negar Asdaghi:                                      Very important, Alvaro. Again for our listeners, keep that ischemic core overestimation in mind when relying on CT perfusion in waker-upers and those with ischemic stroke of unknown time of onset. So, Alvaro, please tell us what's the most important takeaway message from your study, and what does the future hold for you in terms of your research?

Dr. Alvaro Garcia-Tornel Garcia-Camba: Well, it's a global message. I believe that contemporary perfusion imaging construct is based on fixed thresholds to estimate ischemic core. Those thresholds rely on [inaudible 00:19:37] patients with relatively small cores and early imaging. These models might have overfitted to those specific population characteristics. Different studies, including ours, have pointed that the accuracy of computed tomography perfusion core estimation is dependent on many variables. Some of them are known at the time of imaging, like degree of the perfusion after endovascular treatment or time from imaging to reperfusion. In order to improve our prediction accuracy for both core and prognosis estimation, further research should be focused on a multi-parametric approach that takes into account both clinical and imaging parameters, not only imaging parameters.

Dr. Negar Asdaghi:                                      Dr. Alvaro Garcia-Tornel Garcia-Camba, thank you for joining our podcast, and we look forward to covering more of your work in the future. And this concludes our podcast for the May 2021 issue of Stroke. Please be sure to check out the May table of contents for the full list of publications, including original contributions on clinical and basic and translational sciences, brief reports, editorials, comments and opinions, and much more. And remember that every breakthrough in science started somewhere from an idea that was then cultivated with care, determination, perseverance, and collaboration. A simple idea that someone might've heard somewhere in passing or on a podcast. So, keep working on your ideas, and until our next podcast, stay alert with Stroke Alert.

*Dr. Alvaro Garcia-Tornel Garcia-Camba confirmed following the interview that “15%” should be “30%.”

On Episode 3 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two featured articles from the April 2021 issue of Stroke. This episode also features a conversation with Dr. Simon Nagel, from Heidelberg University in Germany, to discuss his article “Predictors for Failure of Early Neurological Improvement After Successful Thrombectomy in the Anterior Circulation.”

Dr. Negar Asdaghi:                      

1) Is Andexanet a cost-effective treatment for the reversal of coagulopathy in factor Xa-associated intracranial hemorrhage?

2)  Are statins safe and efficacious in secondary prevention of stroke in the elderly population?

3)  What are the predictors of futile recanalization amongst successfully treated patients with endovascular therapy?

We have the answers to the above and much more in today's podcast. You're listening to Stroke Alert Podcast. Stay with us.

Dr. Negar Asdaghi:                       From the Editorial Board of Stroke, welcome to the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. For the April 2021 issue of Stroke, we have an exciting program today where I have the privilege of interviewing Dr. Simon Nagel from Heidelberg University in Germany on predictors of failure of early neurological improvement or futile recanalization after successful thrombectomy. But first I want to review these two interesting articles.

Dr. Negar Asdaghi:                       Factor Xa inhibitors, such as apixaban, edoxaban and rivaroxaban, are commonly used for prevention of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation. Bleeding is a serious adverse consequence of treatment with anticoagulants, including factor Xa inhibitors, with intracranial hemorrhage representing the most devastating form of such adverse events.

Dr. Negar Asdaghi:                       Anticoagulant-associated intracranial hemorrhage typically results in larger hematoma volumes, higher risk of expansion, and worst clinical outcomes as compared to their spontaneous counterparts and requires immediate reversal of coagulopathy. Andexanet alfa is a recombinant modified factor Xa protein which is an effective antidote to reverse this coagulopathy, though it comes with an increased risk of thromboembolic events, either from Andexanet itself or delayed or lack of resumption of anticoagulation in the setting of intracranial hemorrhage.

Dr. Negar Asdaghi:                       It is important to note that the estimated cost of Andexanet is between $25-50,000 US dollars, depending on the standard versus high dose used, and this medication is currently not available in many countries, including in Canada, and even in the United States, it's still not accessible in many centers mainly due to its high cost. Now, when Andexanet is not available, the non-specific antidote of prothrombin complex concentrate, or PCC, is used, carrying an approximate cost of $4-8,000 US dollars, depending on the dosage used.

Dr. Negar Asdaghi:                       PCC, which is a combination of various clotting factors, together with protein C and protein S, have a limited efficacy and reversal of Xa inhibitors coagulopathy. In the absence of randomized control trials to directly compare Andexanet to PCC, there remains a significant gap in knowledge with regards to comparative efficacy, adverse events, and cost-effectiveness of these therapies for life-threatening bleeding, specifically intracranial hemorrhage, in the setting of Xa inhibitor use.

Dr. Negar Asdaghi:                       In the current issue of the journal, Dr. Andrew Micieli and colleagues from the Division of Neurology, Department of Medicine, Universities of Toronto and Calgary, in Canada, did a comparative analysis between Andexanet and PCC in a study titled “Economic Evaluation of Andexanet Versus Prothrombin Complex Concentrate for Factor Xa-Associated Intracranial Hemorrhage.” Using a patient population on chronic factor Xa inhibitor treatment, when presenting with an intracranial hemorrhage, the authors applied a probabilistic Markov model over a lifetime horizon for each patient to evaluate the cost and benefits if either Andexanet or PCC was administered to reverse the coagulopathy.

Dr. Negar Asdaghi:                       Estimates of outcomes, dosing, and administration protocols for Andexanet were derived from the ANNEXA-4 study and from the UPRATE study for the PCC. These are two previously published large cohorts of treatment for these agents, respectively.

Dr. Negar Asdaghi:                       So, what they found was an overall reduction in the occurrence of fatal intracranial hemorrhage with Andexanet therapy, estimated around 18%, as compared to PCC, estimated at 34%, specifically if the antidote was administered in the first cycle, which is the first 30 days following intracranial hemorrhage. This, of course, came at a cost of a higher thromboembolic event rate measured as composite outcome of myocardial infarction, TIA stroke, deep vein thrombosis or pulmonary embolism of approximately 10% in the Andexanet-treated group as compared to 5% in the PCC-treated group.

Dr. Negar Asdaghi:                       Now, the cost analysis of the study is very interesting. The authors found that Andexanet, for its incremental effectiveness in gaining quality-adjusted life year, had an incremental cost over PCC. This cost-effectiveness ratio was close to $220,000 US dollar per quality-adjusted life year gain for Andexanet.

Dr. Negar Asdaghi:                       And as such, as things stand today, this therapy is not cost-effective and represents low value for reversal of factor Xa–associated intracranial hemorrhage over the standard of care, which is PCC. So, this study provides an important insight, not only for the physicians, but also for health policymakers, as they critically evaluate the merits of Andexanet therapy compared to the current standard of care.

Dr. Negar Asdaghi:                       So, moving on now from oral anticoagulants to statin therapies and other medication commonly used in the secondary prevention of ischemic stroke, the second article we will discuss today in our podcast looks at the use of statins poststroke in the elderly population. About a third of stroke patients are over the age of 80, and with the aging population and increased life expectancy, this proportion is estimated to double by year 2050.

Dr. Negar Asdaghi:                       Stroke survivors who are over the age of 80 have increased 30-day and one-year mortality rates and remain at higher risk for recurrent cardiovascular events as compared to their younger counterparts. Statin therapy has been shown to reduce the risk of composite cardiovascular events in stroke survivors, but randomized data regarding their safety and efficacy in the elderly population is limited.

Dr. Negar Asdaghi:                       Treatment with statin is not without its own challenges in the elderly population. These patients are more likely to be on multiple medications that can interact with statins, and there's also some evidence that the frail population may be more prone to statin side effects such as muscle pain, risk of rhabdomyolysis, increased blood glucose levels, increased risk of diabetes, and liver problems that have all been reported in the setting of statin use.

Dr. Negar Asdaghi:                       In this issue of the journal, Drs. Lefeber and colleagues from the Department of Geriatrics in Utrecht University in Utrecht, Netherlands, study this subject in their paper titled “Statins After Ischemic Stroke in the Oldest: A Cohort Study Using the Clinical Practice Research Datalink Database.” This was a retrospective analysis of over 5,900 patients aged 65 years and older who were hospitalized and then discharged for a first ischemic stroke during a 17-year study period from 1999 to 2016 who were not on statin prescription in the year prior to their index hospitalization.

Dr. Negar Asdaghi:                       The authors compared the primary outcome, which was a composite of recurrent stroke, myocardial infarction, and cardiovascular-related mortality, within the elderly patients, those over the age of 80, to the younger population, those over 65 but under 80 years of age, based on the number of years that they had a statin prescription poststroke. That is comparing at least two years of statin prescription time with no statin treatment or less than two years of prescription time compared to no treatment at all.

Dr. Negar Asdaghi:                       So, what they found was that 53% of their population were actually over the age of 80, and in over half of these elderly patients, a statin was prescribed within 90 days of the index date. And not surprisingly, 38% of this elderly population had moderate to severe frailty, an index that has been linked to statin intolerance and its common myalgia side effect. Now, in terms of their main finding, more than two years of statin prescription compared to no statin prescription was significantly associated with a lower risk of the primary endpoint for both the over and the under 80 age groups.

Dr. Negar Asdaghi:                       This association remained true in their adjusted model, not only for the primary outcome, but also for all-cause mortality rates, which was significantly lower in the statin-treated patients. After a correction for the mortality rate of close to 24% during the first two years, the number needed to treat for reduction of composite recurrent stroke, myocardial infarction, and cardiovascular-related mortality was 64 and the number needed to treat for reduction of all-cause mortality was 19 in the group over 80 on a statin prescription during a median follow-up of 3.9 years.

Dr. Negar Asdaghi:                       So, in the absence of data from randomized controlled trials, this study provides reassuring results regarding the efficacy of statins in reduction of cardiovascular events in the patients aged 80 and older, keeping in mind that a third of the elderly population in the study was significantly frail, at risk for development of possible statin-related adverse effects.

Dr. Negar Asdaghi:                       Much has changed in the field of reperfusion therapies since the publication of the positive results of the thrombectomy trials in 2015. Advances in patient selection processes, rapid access to advanced neuroimaging, the use of newer generations of thrombectomy devices, and improvement in systems of care have all played important roles in the growing success of endovascular therapy.

Dr. Negar Asdaghi:                       But even with today's rigorous selection criteria and fast thrombectomy timelines, there remains a significant proportion of endovascularly treated patients in whom the successful radiographic recanalization do not translate into early neurological improvement. In our previous podcast, we report how the odds of favorable outcomes with thrombectomy decreases with an increase in the number of retrieval attempts during the procedure amongst successfully recanalized patients. Today, we dive deeper and look into other independent variables that may predict odds of futile recanalization.

Dr. Negar Asdaghi:                       Joining me now is Dr. Simon Nagel from Department of Neurology at Heidelberg University Hospital in Germany, who is the senior author of the study titled “Predictors for Failure of Early Neurological Improvement After Successful Thrombectomy in the Anterior Circulation.” Good morning, Simon, and thank you for joining us.

Dr. Simon Nagel:                           Good morning, or even good evening, from Germany. Thank you, Negar. It's a pleasure to be here, of course, especially in these times when you don't get to personally speak to a lot of international colleagues.

Dr. Negar Asdaghi:                        That's great, Simon. Can you start us off, please, with some background on futile recanalization? What do we know about this medical work, and what prompted you to look into this topic in more detail?

Dr. Simon Nagel:                           I guess, in most studies, futile recanalization is defined as a technically successful recanalization by a TICI score of 2b upwards, but an outcome on day 90 of only three to six points on the modified Rankin scale. And many papers have examined a selected number of parameters for the association with futile recanalization being either clinical, radiological, laboratory or procedural, which is why we wanted to be very comprehensive in our approach by including 38 different variables from the above-mentioned spectrum in our own analysis from our monocentric registry in Heidelberg.

Dr. Negar Asdaghi:                        Perfect, so a very important concept to keep in mind in light of the increased demand to perform endovascular therapy. So, can you tell us, you alluded to it, but can tell us a bit more about the study design, the population you studied, and specifically why you choose failure of early neurological improvement at the time of discharge as opposed to that more conventional outcome measure of modified Rankin scale at day 90 poststroke?

Dr. Simon Nagel:                           That's a good point, Negar, and you're right, we did maybe choose an unconventional end point since the definition of early neurological improvement is usually based on the NIHSS at 24 hours, but this study was driven from a very clinical perspective, that is the one from the stroke physician on the ward who is receiving the patient after the procedure, after all the acute decisions have been made. And then we have to do our best during the following days managing the complications, the deficit, and finding out why the stroke happened in the first place, until the patient is then either discharged home or back to the referring facility or to a normal board or to rehabilitation.

Dr. Simon Nagel:                           But a considerable amount of patients, we found, did not improve until this discharge, although the procedure was a technical success. So some reasons for that are obvious, but some of them are not, and we wanted to find more about this, especially since early neurological improvement has been proposed as a surrogate for good outcome later on.

Dr. Negar Asdaghi:                        Right. So we're very excited, Simon, to hear about the main study results. What were some of the predictors of failure of early neurological improvement in your study, and were you at all surprised by any of those developments?

Dr. Simon Nagel:                           A lot of known factors that have been previously described to show an association with early neurological improvement or failure of that were found in our univariate analysis, namely 21 of 38, but only a few remained independent predictors after selecting with the elastic net approach and logistic regression modeling. Some of them are obvious by definition, which is symptomatic intracranial hemorrhage. Then, of course, the ASPECTS on follow-up was a predictor, and this obviously beat the baseline ASPECTS and also potentially the collateral score, which was significant in univariate analysis, but we included also over 20% of patients with a premorbid disability of more than two on the Rankin scale so premorbid condition was an independent predictor.

Dr. Simon Nagel:                           We had eight patients with end stage renal failure in our analysis, so we did include that as well, and dialysis is a very strong predictor of failure of early neurological improvement. But also, admission glucose was, so higher levels of that, and then procedural parameters like reaching thrombolysis. So, if you do imply this, this was a factor that was positively associated with early neurological improvement. And then, also, the time from groin puncture to final recanalization was associated, so the longer it took, and this obviously beat also the stent retriever attempts in the analysis, the longer it took, the more likely that it was that failure of early neurological improvement was observed. And last but not least, general anesthesia was associated with that, but there is a sense of bias in this analysis because we have a SOP that we generally perform awake sedation. That means only patients that are not eligible for that, that are not doing well, will be treated under general anesthesia, so this variable has to be interpreted with caution.

Dr. Negar Asdaghi:                        So, very interesting, Simon. I want to emphasize to our listeners that in your study, 20%, that is one in five successfully recanalized patient, did not clinically improve post-thrombectomy up until discharge. This is a considerable percentage to keep in mind. Now, in our day-to-day practice, many of us also accept a TICI 2b as a measure of a successful recanalization. In your study, you included a more rigorous definition of successful recanalization. How do you think your results would have changed had you included those who have achieved a TICI 2b, and why did you exclude that population?

Dr. Simon Nagel:                           According to the mTICI definition, 2b means that more than half of the previously occluded vessel is reperfused, which also means that almost 50% is not. That might have been a success in the advent of thrombectomy and when this was defined in 2013, but I don't think it's adequate to call this a successful recanalization these days. When this was re-defined by David Liebeskind in 2018 with a eTICI score, 2b is still not considered anything more than two-third of the territory, and only 2c is a nearly complete reperfusion, leaving just 10% of the vessel territory occluded or not reperfused.

Dr. Simon Nagel:                           This is why we thought it is a more appropriate definition of successful thrombectomy, and this is what we think should be attempted in day-to-day practice. In our cohort, almost 50% achieve TICI 2c or 3, and if we would have included 2b, 83% of patients would have achieved that. I can't tell you what our analysis would have looked like if we included 2b, it might have been different, but I can tell you that that would require a new analysis of the data.

Dr. Negar Asdaghi:                        Yes, and we keep that in mind for sure that the new way of definition is to keep 2c or better. So Simon, I agree that definitely your study has given us a clear roadmap regarding early outcome expectations in patients undergoing thrombectomy. What should be our final take-away from your study?

Dr. Simon Nagel:                           I guess, before I can tell you, you have to bear in mind that this is a monocentric retrospective analysis, hence, there is bias to be expected, and choosing a different definition of early neurological improvement then may be useful, might have given us a different result. It is also important to be clear from what perspective you are looking at the data. For example, this analysis does not necessarily help with predictors for outcome that help you make a decision if you should treat the patient or not since we included many parameters that are not yet available at that point in time when you need to make the decision to treat the patient.

Dr. Simon Nagel:                           But, I think it's fair to say that you should, according to our results, apply thrombolysis whenever indicated, that you should be as quick as possible with your procedure, and that you should manage blood sugar well, as well as other medical complications, and that you should not expect too much early improvement in case the patient has a premorbid condition or if the motor cortex is involved, which was also a significant outcome, which I didn't mention earlier, and, of course, by definition, if symptomatic hemorrhage occurs.

Dr. Simon Nagel:                           Hemorrhagic transformations, on the other side, do not seem to independently influence failure of early neurological improvement.

Dr. Negar Asdaghi:                        Dr. Simon Nagel, it's always a pleasure speaking with you, and thank you for being with us. And this concludes our podcast for the April 2021 issue of Stroke. And as I leave you today, I want to remind us all that for every minute left untreated a brain under an ischemic attack loses an average of 1.9 million neurons. So whether you're just starting off or you're a well-established clinician or researcher in the field of vascular neurology, your work and that of your colleagues are part of a quest to save the most valuable commodity of human life, which is the brain, and, for that, we're proud to review your work in stroke and highlight the best in vascular neurology in our future podcasts. So until our next podcast, stay alert with Stroke Alert.

On Episode 2 of the Stroke Alert podcast, host Dr. Negar Asdaghi highlights two featured articles from the March 2021 issue of Stroke. This episode also features a conversation with Dr. Joan Montaner from Neurovascular Research Laboratory at the Universitat Autònoma in Barcelona, Spain, to discuss his article “D-Dimer as Predictor of Large Vessel Occlusion in Acute Ischemic Stroke.”

Dr. Negar Asdaghi:           Can your microRNA profile predict your future risk of stroke?

Is stroke that wake-up call to finally live a healthier lifestyle, better diet, exercise more, and stop smoking?

Can a simple blood test improve our clinical predictive models for presence of a large vessel occlusion in patients with suspected ischemic stroke?

We have the answers and much more in today's podcast. You're listening to Stroke Alert. Stay with us.

Dr. Negar Asdaghi:           From the Editorial Board of Stroke, welcome to the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami, Miller School of Medicine, and the host of the monthly Stroke Alert Podcast. In today's podcast, I'm going to interview the senior author of the study on the values of D-dimer and predicting the presence of large vessel occlusion in stroke. But first with these two articles.

Dr. Negar Asdaghi:           DNA noncoding sequences and introns, once thought to represent the, quote, junk DNA, quote, have been found to play an important role in the modulation of gene expression at the post transcriptional level through coding for regulatory molecules, such as microRNAs, or miRNA. Whether the presence of certain miRNAs can signal a future risk of development of stroke is unknown. In their paper titled “Circulatory MicroRNAs as Potential Biomarkers for Stroke Risk: The Rotterdam Study,” Dr. Michelle Mens and colleagues from the Department of Neurology, University Medical Center, in Rotterdam, Netherlands, discuss their findings related to microRNA samples collected between 2002 and 2005 from over 1900 stroke-free participants of the Rotterdam Study. Participants were assessed for incident stroke through continuous monitoring of medical records until January 1, 2016.

Dr. Negar Asdaghi:           At baseline, using next-generation sequencing, they measured expression levels of over 2083 miRNAs in plasma samples. During a mean follow-up of close to 10 years, the incidence of stroke was 7% in their study population, and they found, in total, 39 miRNAs were at least nominally related with that incidence of stroke. In their fully adjusted model, they found significant association between expression level of three particular microRNAs and risk of stroke, with the hazard ratio ranging between 1.1 to 2.6. Interestingly, the area under the curve for the longitudinal predictive models improved when the miRNA data was added to the vascular risk factor model. And in conclusion, they found miRNA 6124, 5196-5p and 4292 were associated with future risk of stroke in their population. The elevated levels of these miRNAs may serve as plasma biomarkers for predicting future risk of stroke in combination with other known vascular risk factors for stroke.

Dr. Negar Asdaghi:           So, speaking of vascular risk factors, let's move on to our second paper for today's podcast. There's a growing emphasis on adherence with pharmaceutical interventions, such as diabetic and blood pressure treatments, statin therapy, to control the risk factors for stroke and prevent recurrent vascular events. All the while, the non-pharmaceutical interventions, such as smoking cessation, diet control, and increased physical activity, seem to represent the somewhat easy or implied aspect of our secondary preventive efforts. But how well are stroke survivors doing with regards to making these healthy lifestyle modifications? In the March issue of Stroke, Dr. Chelsea Liu and colleagues from Johns Hopkins School of Public Health presented their findings on lifestyle and behavioral changes pertaining to cardiovascular health in the study titled, “Change in Life’s Simple 7 Measure of Cardiovascular Health After Incident Stroke: The REGARDS Study.”

Dr. Negar Asdaghi:           So, this was a population-based, epidemiological study of over 7,000 stroke-free participants between 2003 and 2007, who had data on Life's Simple 7, what the author called “LS7 measures,” which studied seven different domains. Four of them behavioral, including smoking, diet, physical activity, body mass index, and three medication-controlled, including blood pressure, total cholesterol, and fasting glucose, both at study entry and their follow-up visit. At which point, either they did not have a stroke or had an ischemic stroke and were included if that stroke had happened more than one year before the follow-up visit. And so the study authors hypothesized that those with a stroke would have had a significant improvement in their Life's Simple 7 data poststroke as compared to the stroke-free participants.

Dr. Negar Asdaghi:           But what they found was completely the opposite. At 10 years follow-up, a total of 149 patients had suffered a stroke in their study. On a scale of zero to 14 at study entry, all participants scored low or relatively low in these seven simple measures, but those participants who would ultimately suffer a stroke scored significantly lower at baseline. What was alarming, though, was that after adjusting for all confounders, at follow-up, participants who had experienced an ischemic stroke showed a significantly further decline in their total LS7 score at 10-year follow-up. And the greatest declines were noted in behavioral domains, most notably physical activity and diet scores. The authors noted a non-significant improvement, in other words, improvement in weight in the BMI score among stroke survivors, but they caution that that may indeed be actually related to muscle loss, a downstream effect of decreased physical activity poststroke, rather than representing active dietary interventions with weight loss. So, in summary, this important paper highlights, on a population level, the urgent need for behavioral interventions to improve secondary prevention after a stroke event up and beyond our efforts to improve medication adherence.

Dr. Negar Asdaghi:           So now moving on from secondary preventative measures to the acute phase, our next paper discusses ways in which we can improve our diagnostic accuracy in the acute setting. Identification of large vessel occlusions is the first step in determining patients' eligibility for endovascular thrombectomy, a highly effective treatment to improve outcomes in acute ischemic stroke. But without vascular imaging, which may not be readily available in the small or community hospitals, the decision to transfer patients to thrombectomy-capable centers is entirely dependent on clinical scales, which, as we all know, may have suboptimal sensitivity and specificity. So the question is, could a simple blood test improve the predictive capabilities of our current clinical scales for presence of a target LVO, or large vessel occlusion? Joining me now is Dr. Joan Montaner from Neurovascular Research Laboratory at the Universitat Autònoma in Barcelona, who is the senior author of the study titled “D-Dimer as Predictor of Large Vessel Occlusion in Acute Ischemic Stroke.” Good morning, Joan, all the way from the sunny Florida to the beautiful Barcelona. Good to have you with us, and thank you for joining us.

Dr. Joan Montaner:         Hello. Nice to talk with you on blood biomarkers for stroke management.

Dr. Negar Asdaghi:           Thank you, Joan. Your study touches on the importance of improving the ways in which the systems of care are set up in triage and transfer of patients with thrombectomy-capable centers. Can you please tell us briefly about the stroke systems of care in Catalonia where you practice and where your study is based out of? And what clinical scales are currently used for transfer of patients with suspected acute stroke to a comprehensive stroke center?

Dr. Joan Montaner:         Yes, Catalonia, it's a region of about 7.5 million inhabitants. And when we did this study, most of the comprehensive stroke centers were located in Barcelona itself, in the capital. So it's true that there are several areas of the region that are far away from Barcelona. It took more than two hours to bring some patients from those distant regions to Barcelona. That's why we began to use these clinical scales that you are talking about. Mainly they are RACE, it's like a simplification of the NIHSS subscale. And, in fact, a large study RACE card that was presented last year in the European Stroke Conference was done to try to see if we could, by using these scales, RACE, select the right patients to come directly to the thrombectomy centers instead of going to the closest hospital. But, unfortunately, the results were neutral. So, we were a little bit disappointed, and we think, as you were saying, that these neurological scales are suboptimal, probably not enough sensitivity and specificity for identifying LVO. That's why we think that these biomarkers could improve the accuracy of those scales.

Dr. Negar Asdaghi:           Perfect. I totally agree with you. And now, before you tell us about the biomarkers, can you just briefly tell us about the Stroke-Chip study, your study population, and what prompted you to look at these various biomarkers that you addressed in the paper?

Dr. Joan Montaner:         Stroke-Chip was a lot, it was really a massive collaborative effort among all the public hospitals in this network here in Catalonia. We were able to collect more than 1,300 patients in this particular study that we are talking about. Dr. Anna Ramos-Pachón and Elena Cancio were leading the analysis on the relation of these biomarkers with LVO. But I have to say that this was not the original intention of our study. Really, and perhaps we were naive at that time, we were looking for biomarkers to differentiate ischemia from hemorrhagic strokes or from stroke mimicking conditions to try to give TPA or TNK in the ambulance. But, as I was saying, perhaps that was a little bit naive, and we know how difficult that would be and perhaps with some liabilities. That's why it came this idea of, "Well, if we use those markers, not for giving a drug in the ambulance, but for doing triage and sending the patient to the right hospital, that could be more simple and more useful even."

Dr. Negar Asdaghi:           Thank you very much. Can you briefly tell us about the study? What were your inclusion criteria?

Dr. Joan Montaner:         Well, in this study, we selected all consecutive acute stroke patients attending the stroke unit of all these hospitals. We were including all stroke suspicions, if their symptoms onset happened within six hours. So, it's really hyperacute patients. And we were able to collect, like this, more than 1,300 patients. And then at the hospital, with the angio CT or duplex, we were able to categorize those with LVO, and we measured a panel of different biomarkers in the blood stream of those patients and trying to associate which of these markers were related with having or not having an LVO.

Dr. Negar Asdaghi:           Very interesting. So tell us, please, your study’s main finding?

Dr. Joan Montaner:         The main finding, what we liked more, let's say, of our results was that some of those markers, specifically NT-proBNP and D-dimer, were really high among patients with a large vessel occlusion. When we combined these results, for example, having high levels of D-dimer, those patients above fourth quartile of D-dimer with more stroke severity, patients with NIH of more than 10, the accuracy was really good. It was very specific, 93% specificity, 34% sensitivity, to predict an LVO. So this means that without almost any mistake, you select more than one third of the patients that have an LVO, that could be very useful. To bring those patients, we were talking from far away of these thrombectomy centers, to the right place. And perhaps we could be doing a thrombectomy one or two hours before with these technologies.

Dr. Negar Asdaghi:           Perfect. So basically, just to reiterate what you're saying, is that D-dimer, as non-specific as it is and as important as it is to note that it can be elevated in the setting of aging or increase NIH Stroke Scale severity, this increase in D-dimer noted in patients with LVO was just not a factor of just age simply or increased severity of the stroke scale. Can you tell us about your multivariate analysis and what other factors you adjusted for in your final model?

Dr. Joan Montaner:         You are right that D-dimer can be modified by many things, as you were saying. That's why we took a lot of care about the multivariate analysis and all factors, all clinical factors that were related with LVO were included in the model. And finally, only eight NIH Stroke Scale scores D-dimer and the vast history of atrial fibrillation were included in the model. Odds ratio for D-dimer was 1.59 that I think it's quite acceptable. And it's true that in that model, NT-proBNP was not included anymore, probably because it's related with a fee. So, that's something interesting if perhaps in the ambulance, you don't know about the story, the history of a patient, of a fee, we could use NT-proBNP, so I think this opens the possibility of using different clinical neurological scales biomarkers in combination to make the prediction of LVO.

Dr. Negar Asdaghi:           Yes. Very, very exciting results for sure. So what is our main takeaway from your study? Are we thinking that D-dimer or a particular level of elevations of D-dimer will one day become the, quote, Troponin equivalent of LVO for stroke?

Dr. Joan Montaner:         Well, it sounds nice, but I know it's several technical issues here. You are right that there is variability among labs in the measurement of D-dimer so now what we are doing is really, in a prospective study called BIO-FAST in the south of Spain, in Seville, in a large network of ambulances, we are measuring D-dimer, but in a rapid fashion with a rapid point of care test in the ambulance itself. We think that we are not going to have a magic biomarker. Not that Troponin you are talking about. Probably we need to combine it with others. We think that the marker of brain damage would add a lot on top of D-dimer, probably D-dimer is very good for the clot burden, but we think other markers could improve the accuracy of the test. And we are measuring them together with these. Our dream would be really to have cost utility study in the future and to see if really we are able to randomize patients based on these biomarkers in the ambulance, will have an impact on outcome if we are able really to do thrombectomies much faster.

Dr. Negar Asdaghi:           Well, we certainly look forward to covering your future studies on this topic of biomarkers. Dr. Joan Montaner, thank you for joining us and congratulations on your work.

Dr. Joan Montaner:         Thanks a lot.

Dr. Negar Asdaghi:           And this concludes our podcast. Don’t forget to check online for the full list of publications, including two papers on the state of pediatric thrombectomy and a study on the association between stroke and subsequent risk of suicide that are published online ahead of their presentations at the International Stroke Conference. Until our next podcast, stay alert with Stroke Alert.

On Episode 1 of the Stroke Alert podcast, host Dr. Negar Asdaghi highlights two featured articles from the February 2021 issue of Stroke. This episode also features a conversation with Drs. Fabian Flottmann and Matthew Maros from the Department of Diagnostic and Interventional Neuroradiology, University Medical Center, in Hamburg, Germany, to discuss their article “Good Clinical Outcome Decreases With Number of Retrieval Attempts in Stroke Thrombectomy: Beyond the First-Pass Effect.”

Dr. Negar Asdaghi:          Are women more likely to suffer from stroke than men?

Are oral anticoagulants safe in atrial fibrillation patients with a prior history of GI bleeding?

Does pregnancy increase the risk of intracerebral hemorrhage in patients with cavernous malformation?

Does the number of retrieval attempts during thrombectomy affect the outcomes of stroke patients in whom successful reperfusion is achieved?

In today's podcast, we address some of these topics and much more. You're listening to the Stroke Alert Podcast. Stay with us.

Dr. Negar Asdaghi:         From the Editorial Board of Stroke, welcome to the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami, Miller School of Medicine, and the host of the monthly Stroke Alert Podcast. We're starting our podcasts with the February 2021 issue of the journal, which also features a special section on Go Red for Women stroke, a comprehensive American Heart Association platform to improve the vascular health of women globally. I hope you enjoy it.

Dr. Negar Asdaghi:         Cavernous malformations or cavernomas are angiographically called vascular abnormalities, which can pose an increased risk for intracerebral hemorrhage. Cavernomas can have diverse neurological presentations ranging from mild neurological symptoms to seizures, but in some cases may remain entirely asymptomatic and are diagnosed incidentally as part of routine neuroimaging completed for other reasons. Earlier studies had reported higher rates of intracerebral hemorrhage from cavernomas during pregnancy, and have postulated a hormone-related increased expression of vascular endothelial growth factor or basic fibroblasts growth factors to explain this increased rate. Subsequent studies, however, have failed to demonstrate either progesterone or estrogen receptors in cavernomas. So the question is, should presence of cavernous malformation, whether symptomatic or asymptomatic, influence the reproductive choices of women of childbearing age? In the “Influence of Pregnancy on Hemorrhage Risk in Women With Cerebral and Spinal Cavernous Malformations,” Dr. Nycole Joseph and colleagues from the Departments of Neurology and Neurosurgery from Mayo Clinic Rochester in Minnesota evaluated 365 pregnancies and 160 women with brain or spinal cord cavernomas. They found that during the cumulative 402 years of study follow-up, the risk of hemorrhage amongst non-pregnant patients in the study was 10.4% per year. They found only four patients with clinical hemorrhage during pregnancy, all of which resulted in the cavernomas being first diagnosed. None of the hemorrhages occurred during delivery, and all of the four patients had functionally independent outcomes by three months. Importantly, they found that no patient who became pregnant after the diagnosis of cavernous malformation had a hemorrhage while pregnant. They had a total of 33 pregnancies in the study, including one patient who had previously bled during a prior pregnancy and also patients with brainstem lesions and those who presented with hemorrhage at diagnosis. Both of these are factors for hemorrhage in cavernomas.

So, in summary, in this prospective study, pregnancy did not increase the risk of hemorrhage in women with a known brain or spinal cord cavernous malformation. And the vaginal delivery was safe in this population. The authors concluded that the presence of cavernous malformation should not influence the reproductive choices in women or their type of delivery.

Now, speaking of hemorrhage risk, let's move on to our next paper on anticoagulation therapy in patients with atrial fibrillation. The decision to start anticoagulants for atrial fibrillation can often be challenging in those who have suffered from a prior gastrointestinal bleeding. Prior studies have shown that the non–vitamin K antagonist oral anticoagulants, or NOACs, can carry a comparable and, in some cases, even a higher risk of GI bleed than warfarin. It should be noted that patients with a prior GI bleed were generally excluded from the pivotal randomized control trials that approved NOACs.

And importantly, the risk of bleeding may also be higher in certain race/ethnic groups, such as the Asian population. In the article titled “Non–Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and Prior Gastrointestinal Bleeding,” Dr. Soonil Kwon from the Department of Internal Medicine, Seoul National University Hospital, in Seoul, Republic of Korea, studied over 42,000 anticoagulant–naïve patients with nonvalvular atrial fibrillation and prior GI bleed from 2010 to 2018 as part of a retrospective, observational cohort study in Korea. They evaluated the risk of ischemic stroke, major bleeding and combined outcomes in this population. What they found was that, not surprisingly, close to 60% of patients were initiated on a NOAC, with rivaroxaban leading dabigatran, apixaban, followed by edoxaban in terms of frequency of agents used. Just over 40% of patients were started on warfarin. Now, over the study follow-up, when they looked at the safety by looking at major bleeding rate and effectiveness by assessing ischemic stroke rates, NOACs generally did better as compared to warfarin, resulting in 39% risk reduction in recurrent stroke, 27% risk reduction in major bleeding and 34% risk reduction in composite outcomes as compared to warfarin.

And the rates of upper and lower GI bleed were similar in NOACs versus warfarin users. NOACs still did better as compared to warfarin amongst patients who suffered from GI bleed as they had a lower transfusion rates and shorter hospital stay. NOACs were also associated with lower risks of fatal clinical outcomes except for fatal GI bleed. So the authors concluded that contrary to some of the prior reports, NOACs may be a better option than warfarin for stroke patients and atrial fibrillation patients with prior GI bleed.

Dr. Negar Asdaghi:         Moving from secondary prevention to acute stroke therapy, our last article discusses how the technical details of endovascular thrombectomy may affect the outcomes in patients with ischemic stroke. So, achieving a successful reperfusion is the cornerstone of improving clinical outcomes in patients undergoing endovascular therapy, but how many retrieval attempts should be made by the interventionist to obtain that desired successful reperfusion is still unclear. Importantly, if successful reperfusion is ultimately achieved, it's still not clear if there's a relationship between the number of retrieval attempts and favorable clinical outcomes.

 Joining me now are doctors Fabian Flottmann and Matthew Maros from the Department of Diagnostic and Interventional Neuroradiology, University Medical Center, in Hamburg, Germany, who are the first and senior authors of the study titled “Good Clinical Outcome Decreases With Number of Retrieval Attempts in Stroke Thrombectomy: Beyond the First-Pass Effect.”

Good morning from Florida, and good afternoon, Fabian and Máté, in Germany. Thank you for joining us.

Dr. Fabian Flottmann:    Thank you very much, Negar, for the nice introduction. Good afternoon from Hamburg. At the moment, it's really, really cold here. It's -4 degrees Celsius. I can't translate it to Fahrenheit, but it's pretty cold, let me assure you. And thank you very much for having us today.

Dr. Negar Asdaghi:         It's great to have you. So I start with Fabian. This is a very interesting and timely study as we're learning more that the way in which we achieve a goal in acute stroke reperfusion therapies is almost as important as the goal itself. Can you tell us a bit about the background of your study, Fabian, and why you felt the need to look at these granular details, which unfold inside the angio suite during endovascular thrombectomy?

Dr. Fabian Flottmann:    Of course, that's a question that's highly relevant for a neurointerventionalist. This research topic developed from our clinical practice, because quite often we have the situation in the angiography suite, where we try to open a vessel, a patient with a large vessel occlusion, and everything is very easy if the vessel opens after one retrieval attempt, because everybody is happy and you can end the procedure. But what happens if the vessel doesn't open? Then you try again. And what happens if the vessel doesn't open? You try it again, and so on and so on. So the question is, when should you stop? And we ask ourselves, are these maneuvers that we do, like three or four or five maneuvers, are they as successful or as beneficial for the patient as the first maneuver?

We did an analysis of our data in Hamburg, and that led to the first paper that we published in Stroke in 2018. And our finding was that the third or fourth retrieval, they were successful in achieving recanalization, but the clinical outcome of those patients was not as good as those patients that you opened with just one retrieval attempt. That was the first finding that we had with our data and our center. And then in the same year, the first pass effect was described. The first pass effect, being the finding that the first retrieval attempt is the most important for the patient. This data was very interesting. And then there were other publications that said, no, there's no connection between the number of retrieval attempts and the clinical outcome. So, as always, in science, when there's more than one opinion, things begin to get interesting. And we said we want to investigate this further. And we decided to do a multicenter study with more patients. And we decided to look at each retrieval attempt separately, to not look just at a first retrieval attempt versus the others, but at each retrieval attempt.

Dr. Negar Asdaghi:         So interesting indeed. Please tell us, before you tell us about the study findings, about the German Stroke Registry. How many years has the registry been active, and how many centers are involved, and please walk us through your study population and the selection process of your study?

Dr. Fabian Flottmann:    Germans Stroke Registry. It's a systematic observational registry study from Germany. It's academic, it's independent, prospective, multi-central, there are 25 centers who participate in this registry. And its goal is to have a systematic evaluation of endovascular stroke treatment in Germany. There are stroke centers from all around the country who consecutively enroll their patients. All patients with an intention to treat in the angiography suite are included. All the patient data are collected at the center and all these data are then centralized and we have a central quality check. And what is important that we also try to include the clinical follow-up information for every patient at day 90. So, the modified Rankin Scale at day 90 is also included. And in our work, we did an analysis of the first 2,600 patients of this German Stroke Registry, and our goal was to eliminate bias. So, for example, we wanted to include data on the stroke severity, the NIHSS score, the amount of early infarction, the ASPECTS score and the location of occlusion, the age of the patient. We selected all the patients that had these data entered. So, we were able to select about 1,200 patients from the German Stroke Registry that fulfilled our inclusion criteria for the present study. To our knowledge, this is the largest multicentric, retrospective study that investigated this effect of retrieval attempts on clinical outcome.

Dr. Negar Asdaghi:         This is really nice because we are really not used to getting granular details and radiographic details in such large numbers. So, the multicenter nature and the large number of patients included in your study are certainly important strengths of your paper, and that should be noted. Now, Matthew, over to you. Please tell us the main findings of the paper.

Dr. Matthew Maros:     So, one specialty of our applied methodology is that we used a generalized mixed-effects models, if we didn't know logistic regression framework. That means that our target variable was the mRS90 and the good functional outcome, defined by zero to two scores by mRS. We also implied this framework to be comparable to the HERMES meta-analysis by Goyal et al. And we investigated, in our primary analysis, the effect of age, the baseline stroke severity NIHSS score, ASPECTS score, and also the main explanatory variable that we investigated was the successful reperfusion at N-th retrieval attempt. And we found that, so as one would expect, a younger age and the less severe stroke clinical manifestation, like NIHSS score, was inversely associated with a good functional outcome. So, younger patients and less severe stroke were associated with a favorable outcome. And also, a less severe ischemic changes on a non-contrast head CT, so ASPECTS score eight, nine or ten, were also independent predictors for a good function outcome at 90 days. Our main finding was that the success at the first, second, or third retrieval attempts were significantly and independently associated with a good functional outcome. And interestingly, the effect of the consecutive retrieval attempts were gradually diminishing from an odds ratio from six (around) to three.

Dr. Negar Asdaghi:         This is interesting. So, basically, what you found is that you go in with the first attempt, second and third, you don't achieve that successful recanalization. If you achieve your successful reperfusion after the third attempt, it's good, but not so good, meaning that it doesn't translate to that beautiful, favorable outcome at 90 days as it did for the first three attempts.

Dr. Matthew Maros:      So, for four or more retrieval attempts, this positive effect on the outcome has flattened, so the curve is more like a sigmoid curve that was asymptotic to a virtual threshold.

Dr. Negar Asdaghi:         Understood. So, I find it very interesting that this decline in the odds of favorable outcome, despite successful reperfusion, was not simply a factor of time, meaning that, if you tried once and you achieve reperfusion right away, it's so much faster. And of course, time is brain, but if you try five times, it would take longer. It is interesting in your results and your multivariate analysis that even if you adjusted for the factor of delay in time, the results persisted. Could you please tell us about your multivariate analysis and what other factors and co-founders you adjusted for?

Dr. Matthew Maros:      Exactly. So, as a sensitivity analysis, we also included the time from groin puncture to flow restoration and also sex, and also to be almost identical or highly similar to the model applied in the HERMES meta-analysis. We also included the site of the intracranial occlusion and better intravenous thrombolysis was administered or not. And in the sensitivity analysis, we had almost 90% of our dataset. So almost a thousand one hundred patients. And we found that all the effects of age and NIHSS score stayed significant, and also the effect of the first, second and third retrieval attempts associated with good functional outcome at 90 days were also significant. While interestingly, the effect of intravenous thrombolysis, and also the ASPECTS score, had diminished, but also just narrowly escaped a significant threshold. And interestingly, the effect of time, so time from groin puncture to flow restoration, seemed to be not relevant or be interpreted that way, that the number of retrieval attempts and the effect that we see is not a surrogate of time, that it simply takes longer to perform the interventions, but it's the true effect of achieving recanalization at a certain attempt.

Dr. Negar Asdaghi:         So, what should be our takeaway from your study, Fabian? Is three that magic number? Are we asking the interventionalist to stop the procedure after the third retrieval attempt if they're unsuccessful, and what should the future hold in terms of studies on this project?

Dr. Fabian Flottmann:    That's the most important question. Of course, we have to keep in mind that every patient and every intervention is different. The decision to continue or stop the thrombectomy procedure is a very important decision, which is taken by the neurointerventionalist together with his team. And they will take into account multiple factors, including patient's biography, medical history at time from symptom onset, image data, and so on. Our study can provide some guiding information when making this decision. And yes, three could indeed be called a magic number in the following sense. We would like to encourage interventionalists to make at least three attempts in case of persistent occlusion, because we can see a clear benefit even when reperfusion is achieved after the third attempt. Then, in patients with younger age and/or, for example, a good ASPECTS score, even more retrieval attempts are probably warranted regardless of IV thrombolysis, site of occlusion and potentially increased procedure time.

Of course, in all these retrospective studies, a bias remains. We don't know why the procedure was stopped in each case. The best thing would be a randomized controlled trial with the following design. You could, in case of persistent occlusions, after two retrievals, randomize to continue or to stop the procedure. And then we would know what the right answer is. So, taken together, our study suggests that in EVT for anterior circulation strokes, at least three retrieval attempts should be performed in cases of persistent occlusion, and up to five attempts of beneficial association with good clinical outcome is expected.

Dr. Negar Asdaghi:         Doctors Fabian Flottmann and Matthew Maros, thank you very much for joining us and congratulations on this work. And this concludes our podcast today. Don't forget to check the February table of contents for the full list of publications, including original contributions, brief reports, editorials, and our special section on Go Red for Women stroke. Until our next podcast, stay alert with Stroke Alert.