Circulation January 29, 2019 Issue

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts of Circulation on the Run. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             And I am Greg Hundley, also associate editor from VCU Health Systems in Richmond, Virginia.

Dr Carolyn Lam:                So, have you ever wondered in patients with atrial fibrillation and stable coronary artery disease beyond a year of coronary stenting, can you safely just continue on oral anticoagulation without antiplatelet therapy? Well, if you've ever wondered that ... I sure have. I'm sure you have too, Greg. Our feature paper this week does discuss this, so you have to stay tuned. But for now, Greg, what are your picks from this week's issue?

Dr Greg Hundley:             I've got a couple to discuss. The first is Patrick Hsieh from Taipei, Taiwan, and really is evaluating the gut microbiota and how that affects cardiac repair after myocardial infarction. I mean, who would've thought to chase an idea like this? But what this investigative team did is they had mice, so this was a basic science experiment, and they treated them seven days prior to ligation of their left anterior descending artery that would induce a myocardial infarction. They treated them seven days prior with ampicillin, metronidazole, neomycin, and vancomycin. What were they trying to do? Totally obliterate any bacterial load within their GI system. Then, they ligated that coronary artery, and at 21 days, they looked at histopathologically what was happening.

                                                And you know what they found? Those where they wiped out the bacterial load, they had increased cardiovascular events. And importantly, myocardial rupture was very high in this group of mice. Also those mice, they had reduced heart rate, and mechanistically what had occurred is there was a reduction in our immune monocytes that were trying to infiltrate the peri-infarct. They weren't there. They were not in those peri-infarct zones. And so, the thought here is that removal of the favorable microbiota in the gut can actually be harmful in the setting of myocardial infarction.

Dr Carolyn Lam:                Fascinating. So, microbiome as our pals. But wait a minute. I mean, how can you say it's from elimination of the microbiome versus some kind of effect of the antibiotics itself?

Dr Greg Hundley:             Yeah, that's a great question, Carolyn. The way they did this is they took another group of animals, and they supplemented them with lactobacillus probiotic, like the stuff we get in the grocery store. And those animals, they did not suffer any of the adverse cardiovascular effects. So, it really points to an important role of our gut microbiota. You know, and what do they do? They basically ferment these carbohydrates that we ingest, and produce short chain fatty acids that are a substrate for these mononuclear cells to help infiltrate those infarct zones. So, really exciting basic science question that this group examined.

Dr Carolyn Lam:                I love that you picked a basic science paper, and I love that you made even me understand it so well. Okay, but what I have is a clinical trial. So, it's the REDUCE-MVI trial, which is the first randomized trial comparing maintenance treatment with ticagrelor or prasugrel after a primary PCI. So, this is from Dr van Royen and colleagues. They're from Radboud University Medical Center in the Netherlands. Basically, they figured that despite successful restoration of epicardial vessel patency with primary PCI, coronary microvascular injury does occur in a large proportion of STEMI patients, and of course, adversely affects outcomes. Now, ticagrelor has been reported to increase plasma adenosine levels, which may have a protective effect on the microcirculation. So, the authors randomize 110 STEMI patients following revascularization to maintenance therapy with ticagrelor versus prasugrel, with the primary outcome being microvascular injury at one month as determined by the index of microcirculatory resistance in the infarct related artery.

                                                What they found was that there was no difference in the extent of microvascular injury and in the extent of infarct size by cardiac MRI at one month after the primary PCI. The attributed pleiotropic benefits of ticagrelor through the adenosine metabolism pathway actually could not be confirmed in the STEMI population, as plasma adenosine levels were actually not increased in the patients treated with ticagrelor.

Dr Greg Hundley:             So, what does this mean for the use of adenosine and its role?

Dr Carolyn Lam:                I suppose you're also asking, you know, is the adenosine hypothesis really out here? This is a study that really suggests we have to question it, but there are some limitations that we perhaps should keep in mind when we think about this. So first, before primary PCI, all patients were loaded with ticagrelor because this was standard of care in the participating centers. That, of course, could have modified microvascular injury already at the index event. Now, a second important thing is that the study may have been underpowered. There was a greater than anticipated variability in that primary outcome of index on microcirculatory resistance.

                                                The relatively low rates of risk factors, the small infarct size, the preserved ejection fraction could all have influenced this IMR values, as well as the potential effects of the pharmacological intervention. And furthermore, the natural recovery of microvascular dysfunction over time may have diluted the positive effects. And of course, selection bias is inevitable in a trial. And so, you know, although this really questions the adenosine hypothesis, there are still caveats to these results.

Dr Greg Hundley:             Very good. So, Carolyn, I've got another study to sort of go over, and this is from Dan Modin from the University of Copenhagen. And it's really addressing this issue. We all in the fall, do we all get our flu shots? And could that be helpful in patients with heart failure? You know, the ACC, the AHA, and the ESC all suggest flu shots, but there's actually no guideline to recommend. So, what did these investigators do? They looked in Denmark, and from the period of January of 2003 to June of 2015, they identified 134,048 subjects. And they looked at the vaccination status for those with a diagnosis of heart failure that were greater than 18 years in age. 55% percent of these were men. And then, they also looked at ICD-10 codes for cardiovascular events.

                                                Now, they examine the dates of when you had your vaccination, how frequently, what were your comorbidities cardiovascular-wise, medication use, etc. And what they observed is that those individuals that had more than one vaccination ... So, basically annual vaccinations for a three year period, they had an 18% reduction in all death, and a 19% reduction in cardiovascular death.

Dr Carolyn Lam:                So, is this all heart failure patients? Are there specific subgroups that we should be targeting?

Dr Greg Hundley:             At our institution, they really get on us. If we don't have our flu shots in September, I mean, they threaten to withhold everything, or maybe October. Well, interesting that you asked that question. Those individuals that had flu shots in the September to October window did much better than those individuals that had their vaccination November, December, or actually later in January. And the second group that benefited were the individuals that actually had annual vaccinations. So, if periodically you say, "Oh, I'm going to get it this year, but then I'm not going to get it two years from now." Not so good. It was those individuals that had those vaccinations annually.

Dr Carolyn Lam:                You know, Greg, it's making me question too, because here I am in a tropical island. We actually don't have seasons. So, what does that mean for us? That's one thing. And then, do we need even randomized trials now?

Dr Greg Hundley:             Yeah, I think you're right there, Carolyn, because first of all, you know the investigators targeted this because 50% of heart failure exacerbations are actually triggered by some sort of respiratory infection. So, that was kind of the thought behind this. But we do have to be careful about looking at this longitudinal data and making predictions or developing guidelines. A couple of reasons why. It could be that those that come in for annual vaccinations at the time points, well, maybe they also come in for more frequent heart failure visits with their doctor. So, it's not cause and effect.

                                                And in fact, there was another study, Get with the Guidelines heart failure study, and it actually showed no association. So, more work really needs to be done in this area. And just to point out quickly, there is a current randomized trial going on called Invested, and it's looking at different types of vaccinations, trivalent versus quadrivalent. They're underway in those with heart failure. And so, there's a lot more work in this area. But it was interesting getting it that old "get your flu shot," and it looks like at least longitudinally in cohort studies could be beneficial. And if you are going to do it, do it every year and get that September, October. So, Carolyn, what about your next paper?

Dr Carolyn Lam:                So, Greg, my second paper is another trial. It's the radio sound hypertension trial, this time focusing on renal denervation. In fact, it's the first trial to compare three different techniques and technologies for catheter-based renal denervation. It's from Dr Lurz from Heart Center Leipzig in Germany. And what they did is, they randomized 120 patients with resistant hypertension to three arms. Either one, radiofrequency, renal denervation of the main renal arteries. Two, radiofrequency renal denervation of the main renal arteries and the side branches and accessories. Or three, an endovascular ultrasound-based renal denervation of the main renal artery. The primary endpoint was change in systolic daytime ambulatory blood pressure at three months. In the end, endovascular ultrasound-based renal denervation was the winner over radiofrequency ablation of the main arteries, with or without ablation of the side branches.

Dr Greg Hundley:             Carolyn, does this mean that renal denervation is coming back? Are we going to actually start thinking about this as a viable option to treat those with longstanding hypertension?

Dr Carolyn Lam:                Greg, this was exactly addressed by an editorialist, Dr Ram from UT Southwestern and Apollo Hospitals and Apollo Medical College in India. Beautiful editorial. Basically, even with the publication of these new data, it is difficult to predict whether renal denervation is firmly back on track. You see, some caveats should be mentioned, including that in this trial, only patients with large renal arteries were chosen for this study. And patient enrollment was rather selective.

                                                For example, out of 1,884 patients screened, only 120 patients met the inclusion criteria. And then, importantly, in a few patients, the reduction in systolic blood pressure was really impressive, close to 40 millimeters mercury. But the majority of responders had a more modest effect, and in about 30%, there was no change in blood pressure.

                                                So, one of the ultimate things we need to learn to do is to identify the so-called hyper-responders from the non-responders. So, lots more work needs to be done in renal denervation.

                                                That brings us to a close of our little chat. Can't wait for our feature discussion coming right up.

                                                Our feature paper today deals with a very important topic in a very frequently encountered group of patients. And they're the ones with concomitant stable coronary artery disease and atrial fibrillation. You see, these are patients at high risk of both ischemic and bleeding events, and therefore, it's critical to identify the right antithrombotic regimen with the optimal benefit ratio, since this is going to be lifelong therapy. Now, interestingly, despite recommendations in the guidelines and consensus documents, there has been no randomized controlled trial evaluating oral anticoagulation with and without antiplatelet therapy in patients with atrial fibrillation and stable coronary artery disease beyond one year of coronary stenting. I mean, Greg, I didn't even realize that we didn't have a randomized control trial. Did you?

Dr Greg Hundley:             Absolutely, Carolyn. And, you know, this is an important issue, because we have a lot of patients coming to the cath lab that have atrial fibrillation, and what is going to be the recommended anticoagulant and antiplatelet combination? And so, it's really time for a randomized trial.

Dr Carolyn Lam:                I know, and luckily for us, that's exactly what this issue's feature paper does. And I'm so pleased to welcome to the show Dr Satoshi Shizuta from Kyoto University Graduate School of Medicine, Japan, as well as associate editor Dr Shinya Goto from Tokai University in Japan. We're so proud to be publishing the OAC-ALONE trial, even though we understand it was a difficult trial. Tell us, what were the results?

Dr Satoshi Shizuta:           As you know, the results were somewhat inconclusive because of pretty much a combination of patient enrollment. Initially, we scheduled to enroll 2,000 patients during 12 months, but patient enrollment speed was extremely slow, much slower than expected. So, we extended the patient enrollment period from 12 months to 38 months. But finally, we could only enroll 696 patients, about one-third of the initially planned patients. The result was around 50% rate of primary end point during 2.5 years of follow up. And the hazard ratio of [inaudible 00:15:01] strategy, as compared with OAC plus APT was 1.16 with a 95 confidence interval of 0.79 to 1.72.

                                                So, in conclusion, our study failed to establish no inferiority of OAC-ALONE to combination therapy of OAC plus antiplatelet therapy in patients with AF and stable coronary artery disease beyond one year after stenting in terms of primary endpoint of death, MI, or stroke. So, this study was underpowered and inconclusive. So, future larger studies require to establish the optimal antithrombotic regimen in this same patient population.

Dr Carolyn Lam:                Thanks so much. Shinya, you've been thinking about this, too, and the performance of such a difficult trial. Did you have anything to add or to ask?

Dr Shinya Goto:                So, first of all, I would to congratulate Satoshi and the group. They have completed a very interesting randomizing trial. As Greg mentioned, there is two kind of patient who lead to coronary artery disease and atrial fibrillation, especially after, you know, one year after stenting. So, taking a look at coronary artery disease with atrial fibrillation, we don't have the established standard of care yet. So, Satoshi know, it is a long-time study. So, I understand the rich colored nature of the patient in this kind of trial. So, what is the most difficult point increased to encourage the patient in this long-term trial?

Dr Satoshi Shizuta:           We think that difficulty reflects substantial reluctance of most cardiologists to withdraw antiplatelet therapy, single antiplatelet therapy from stented patients, even the patients treated with oral anticoagulation for atrial fibrillation. So, that is the most important point.

Dr Shinya Goto:                You have already showed in this paper myocardial infarction recurrence of stents thrombosis. Not a huge problem in this kind of patient population, you know? Stroke is a bigger problem, mortality, not including cardiovascular is also the problem. So, you have suggested, you have a strong kind of mind, is it? And single antiplatelet therapy necessary after stenting. Your results are underpowered but still suggest how always you know would be enough in stable CAD patients with atrial fibrillation.

                                                I would congratulate you again.

Dr Satoshi Shizuta:           Thank you.

Dr Greg Hundley:             Satoshi, I have a quick question. So, in the randomization process, how can you achieve the physicians managing the patients to administer the anticoagulant therapy to guideline levels, particularly when they are also prescribed antiplatelet therapy? I noticed that in the editorial on this manuscript that was a concern, and suggesting that in future studies that the therapy really be defined, and not so much open label administration at the discretion of the prescribing physician. What are your thoughts on that?

Dr Satoshi Shizuta:           I agree with you, but in this kind of study, randomizing whether or not to withdraw a drug is very difficult to conduct. Financial support is limited, and in such situation, double blind placebo controlled trial is very difficult to conduct. As you know, several years ago, a loose trial was published in the Lancet. And also in the loose trial, the study design was open level, and also in the PCI and [inaudible 00:19:48], I think the study design was not blinded but open. In this paper figure two, our control level was set as a dependent based on the Japanese guidelines. In the Japanese guidelines, target IR was set as 1.6 to 2.6, a little bit lower than Western golden standard for elderly patients older than 50 years. And same 2.0 to 3.0 in patients younger than 70 years.

                                                And in that criteria, as you can see, if you get 2A of paper, the therapeutic range was extremely high. 76% in the OAC-ALONE group, and also 73% in the OAC plus APD group. We can clearly understand that the intensity of oral anticoagulation was different between the two groups. Most of the OAC-ALONE group, OAC was controlled with ionine level higher than 2.0. On the other hand, in the OAC plus APD group, the ionine level was mostly controlled between 1.6 to 2.2 or .5 or so. So, this is a great big limitation of the study. But even in this limitation, the bleeding events, there was numerical excess in the OAC plus APD group. And, regarding the TEMI major bleeding, there was a trend toward increased major bleeding in the OAC plus APD group. If the intensity of OAC was the same, of course, I am convinced that even in this underpowered sample five, the major bleeding will be statistically higher in the OAC plus APD group.

Dr Carolyn Lam:                Thank you so much Satoshi for really taking us under the hood, and showing us all the myriad of considerations that occurred to perform this trial.

                                                This is Greg and Carolyn. Thank you for joining us on Circulation on the Run. Don't forget to tune in again next week.

                                                This program is copyright American Heart Association 2019.