Circulation February 2, 2021 Issue

This week feature a Double Feature of Discussions. In our first discussion, author Larry Allen and Associate Editor Justin Grodin discuss the article "An Electronically Delivered, Patient-Activation Tool for Intensification of Medications for Chronic Heart Failure with Reduced Ejection Fraction: The EPIC-HF Trial." Then in our second discussion, author Benjamin Scirica and Associate Editor Sandeep Das discuss the Research Letter "Digital Care Transformation: Interim Report From the First 5000 Patients Enrolled in a Remote Algorithm-Based Cardiovascular Risk Management Program to Improve Lipid and Hypertension Control."

TRANSCRIPT BELOW

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, I'm Dr. Carolyn Lam associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Dr. Greg, I really love these double features that we have in 2021. Let me tell you about the first one. We are going to be talking about the EPIC heart failure trial. That's the electronically delivered patient activation tool for intensification on medications in HFrEF. Very important results.

Dr. Greg Hundley:

Yes, Carolyn. And the second feature is going to evaluate an algorithm based cardiovascular risk management program to improve lipid and hypertension control. But before we get to the double feature, how about we grab a cup of coffee and start with some of the other articles in the issue?

Dr. Carolyn Lam:

My coffee is right here and I want to talk about, guess what? SGLT2 inhibitors again for this first paper. Dapagliflozin, as we know, reduces the risk of end stage renal disease in patients with chronic kidney disease. We saw that in the DAPA-CKD trial. However, the primary and secondary preventive effects of SGLT2 inhibitors on cardiovascular outcomes have not been studied in patients with chronic kidney disease, with and without diabetes.

Dr. Greg Hundley:

Well Carolyn, remind us a little bit, what were the end points in the DAPA-CKD trial?

Dr. Carolyn Lam:

Okay, well yes. DAPA-CKD as a reminder, randomized more than 4,000 participants with chronic kidney disease to dapagliflozin, 10 milligrams daily or placebo. The primary endpoint was a composite of sustained decline in GFR of more or equal to 50% or end stage kidney disease or kidney or cardiovascular death. The secondary end points were a kidney composite outcome, the composite of hospitalization for heart failure or cardiovascular death and all cause death. Now the current paper is a pre-specified subgroup analysis where authors led by Dr. John McMurray from University of Glasgow, divided patients into primary and secondary prevention subgroups according to the history of cardiovascular disease. And results showed that dapagliflozin reduced the risk of the primary composite outcome to a similar extent in the primary and secondary prevention groups. This was also true for the composite of heart failure hospitalization or cardiovascular death and all cause mortality. The combined cardio renal benefits of SGLT2 inhibitors in patients with chronic kidney disease with and without diabetes therefore are substantial, whether there is history of cardiovascular disease or not.

Dr. Greg Hundley:

Not very nice, Carolyn. Well, my paper comes from Dr. Pradeep Natarajan and his colleagues at the Massachusetts General Hospital. And Carolyn, this study evaluated whether premature menopause is associated with CHIP. For our listeners, CHIP stands for clonal hematopoiesis of indeterminate potential and it is the age related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy. And previously it's been shown associated with accelerated atherosclerosis.

Dr. Carolyn Lam:

Yikes. Greg, is pretty much our menopause associated with CHIP?

Dr. Greg Hundley:

Well Carolyn, the investigators, among 19,606 women, they identified 418 or 2.1% with natural premature menopause and 887 or four and a half percent with surgical premature menopause. Premature menopause, especially the natural premature menopause was independently associated with CHIP among post-menopausal women. Natural premature menopause, therefore may serve as a risk signal for predilection to develop CHIP and CHIP associated cardiovascular disease.

Dr. Carolyn Lam:

Interesting. Okay. Well, my next paper really provides the first evidence for endogenous induction of type-1 protein kinase A disulfide formation in the heart and this occurring after ischemia and re-profusion in both humans and mice.

Dr. Greg Hundley:

Ah Carolyn, so tell us more about this interesting paper.

Dr. Carolyn Lam:

Well, this is from Dr. Simon from University of Oxford and colleagues who used high spatial and temporal resolution imaging modalities in conjunction with an interesting redox dead type-1 protein kinase A knock-in mouse model and demonstrated that disulfide modification targets this type-1 protein kinase A to the lysosome where it acts as a gatekeeper for two poor channel mediated calcium release and prevents inappropriate triggering of calcium release from the sarcoplasmic reticulum. In the post ischemic heart, they found that inhibition of lysosomal calcium release by these oxidized molecules was crucial for limiting infarct size and preserving cardiac function during re-profusion. All this thus offering a novel target for the design of cardio-protective therapeutics. This is discussed in an editorial by Doctors Westenbrink, Nijholt, and deBoer from University Medical Center Groningen.

Dr. Greg Hundley:

Thanks, Carolyn. Very nice. Well, my last paper comes from Dr. Nicholas Marston and colleagues from the TIMI study group at Brigham and Women's Hospital of the Harvard Medical School. Carolyn, genome wide association studies have identified single nucleotide polymorphisms or SNIPs that are associated with an increased risk of stroke. The authors sought to determine whether a genetic risk score could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors across five trials involving the spectrum of cardiometabolic disease.

Dr. Carolyn Lam:

Interesting. And these genetic risk scores are very hot. What did they find?

Dr. Greg Hundley:

Thanks, Carolyn. Among 51,288 subjects across the five trials, a total of 960 subjects had an ischemic stroke over a median follow-up of two and a half years. Across a broad spectrum of subjects with cardiometabolic disease, a 32 SNIP genetic risk score was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation, but lower CHA2DS2-VASc two scores, the genetic risk score identified patients with risk comparable to those with higher CHA2DS2-VASc two scores.

Dr. Carolyn Lam:

Wow, that really is impressive. Well, guess what? We've got some other articles in today's issue. There's a beautiful White Paper about the definitions and clinical trial design principles for coronary artery chronic total occlusion therapies and this from the CTOARC consensus recommendations by Dr. Rinfret and colleagues from McGill University. There's a Research Letter entitled, The Randomized Control Trial to Evaluate the Effect of Dapagliflozin on Left Ventricular Diastolic Function in Patients with Type II Diabetes. And this is from Dr. Hong and colleagues from Yonsei University College of Medicine in Korea.

Dr. Greg Hundley:

Thanks, Carolyn. Well I have an exchange of letters from Doctors Albiero and Xie regarding the previously published paper, Patent Foramen Ovale Could be a Source of Paradoxical Embolism and Lead to Adverse Outcomes in Hospitalized Patients with COVID-19 Pneumonia and DVTs.” There's also a Perspective piece to the 2020 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease from Dr. Bavry. And finally Carolyn, Dr. Tung has an ECG Challenge entitled, “Narrowing the Differential Diagnosis for a Wide Complex Tachycardia.” Well, how about we get on to both of our double features.

Dr. Carolyn Lam:

Let's go, Greg.

Dr. Greg Hundley:

Well listeners, we are here for our first feature discussion and we have with us today, Dr. Larry Allen from University of Colorado and our own associate editor, Dr. Justin Grodin from University of Texas Southwestern Medical School in Dallas, Texas. Welcome gentlemen. Larry, could you walk us through the background that really formulated your hypothesis? And then what was the hypothesis that you wanted to test with your study?

Dr. Larry Allen:

Well, thanks again for having me. I'm a heart failure doctor. The research group that I work with has spent a lot of time on patient empowerment and think about medication prescribing for HFrEF as shared decision making. Thinking about this as a discussion between the patient and me, rather than me deciding what to do. As you know, patients are now coming into the office because they've seen direct to consumer advertising around medications, but typically those are very biased. They're advertisements that are for only patented drugs. And what I'm really trying to think about is what is my patient's overall regimen in terms of heart failure?

Dr. Larry Allen:

And so we developed a tool which was a three minute video to tell patients that they should come into their visit and be excited to have discussions about their medicines and then a one page checklist that basically said, "Here's what an optimal regimen of medicines looks like for a patient with heart failure and reduced ejection fraction and nobody's really on a perfect regimen, but these are all the possibilities that you could have." Our hypothesis was that if we delivered that to patients before the clinic visit, that it would lead to better prescribing of these drugs. Essentially we imparted on a randomized trial within our healthcare system to do that and that's what we're discussing today, the results of the EPIC heart failure trial.

Dr. Greg Hundley:

Very nice, Larry. Tell us a little bit, what patients did you enroll in your trial? And then what outcomes did you work to assess?

Dr. Larry Allen:

We're part of the UC Health System, which has 12 hospitals, but a number of cardiology clinics across the front range of Colorado. Our entire system is on a single instance of the EPIC electronic health record so we're now able to essentially automatically identify all the patients in our system who have HFrEF. We generated lists of patients who had HFrEF who were going to see a cardiology provider in clinic and then we identified them ahead of time, enrolled them in the study prospectively. And the enrollment was for them to agree to be randomized in the study and then for us to be able to collect data on them.

Dr. Larry Allen:

The patients were kind of a wide range of HFrEF. They were an average of 65 years old, about 70% of the patients were male and reflected the race and ethnicity of Colorado with 11% Blacks and about 7% Hispanics. And everybody in the study had an ejection fraction of 40% or less on their last echocardiogram or other recent cardiac study. And then they were randomized to either get this three minute video sent to them as an email or as a text link that kicked them over to the one page checklist. And then we had them come in. A 145 patients came to clinic having got the information and a 145 patients just came to clinic like usual.

Dr. Greg Hundley:

Very nice. What did you find, Larry? What were your results?

Dr. Larry Allen:

Yeah, so we found not surprisingly that the majority of patients who were in usual care had no change to their medical regimen. What we found in the patients who received the EPIC heart failure three minute video and checklist, we saw about a 19% absolute increase in intensification of guideline directed medical therapy. And then we found that most of that was actually an increase in beta blocker dose prescribing. To some extent, the cheapest therapy that could be increased on a drug that people are already on.

Dr. Greg Hundley:

Very good. Well Justin, we'll turn to you. Help us put the results from Larry's work in the context of A, management of patients with heart failure and reduced ejection fraction and then also B, tell us a little bit about what attracted you to this article and maybe even where you see some of this going next.

Dr. Justin Grodin:

Thanks, Greg. And Larry, obviously I want to echo Greg's comments by thanking you for your submission. This was a paper that we thought obviously very highly of. Greg, for your first point, we've got novel therapies, but really one of the major issues now is not can we find a newer, better drug? I think we've all come to this realization, it's scalability and implementing these therapies into our regular practice, like beta blockers, RAS inhibitors and mineralocorticoid receptor antagonists. And as Larry said, the problem now is not the quality of our therapies, it's really scaling it and getting it to everyone. It's also increasing these therapies to optimum dosages in patients that can tolerate it over time.

Dr. Justin Grodin:

And then, to answer your second question, I think some of the things that struck us by this was that this is a wonderfully simple intervention that truly does empower patients. The majority of our interventions to optimize medical therapy has been targeting the physicians, the APP, the nurses, et cetera. This is beautiful in that it empowers the patient and we are putting the ball in their court. And I think to kind of dovetail with your third question, this is a health system clinical trial and I think that tells us a few things. I think one, it provides the framework on how one could perhaps implement that in their health systems. And we'll have to see if this is something that could translate to other health systems across the country or multiple centers. But I think really the intrigue with this work is that it all comes back to empowering the patients.

Dr. Greg Hundley:

Very nice.

Dr. Larry Allen:

Greg, I wanted to just add one thing that in the heart failure community, there's this argument going back and forth about whether the lack of optimization of guideline directed medical therapies is due to intolerance or whether it's due to therapeutic inertia. And one of the things I like about this study is on face value, we're empowering patients, but the fact that by asking patients to get involved in prescribing decisions, I think one of the take home messages is that this is partially about therapeutic inertia and that as clinicians, we have a lot of things we're dealing with. And if patients come in to the clinic visit and they're motivated to make these changes actually, we can intensify the therapy.

Dr. Greg Hundley:

Very good. Larry and Justin, both one at a time here quickly, in the last minute that we have, what do you see as the next study, Larry, that needs to be performed in this space?

Dr. Larry Allen:

I see two things quickly. One is, as Justin mentioned, validating that this kind of intervention, while simple can be pragmatically deployed in other health systems and in other contexts. The second thing is how do we integrate this kind of small intervention with the larger overall care of patients? One of the concepts that I've talked a lot about over the years with others, including Len Stevenson, is this concept of an annual heart failure review, where rather than seeing people on multiple short visits where we tackle small issues, we actually create a little bit of time to stand back and take a global view of heart failure therapy and how that heart failure therapy fits into the goals of care for the patient, the other medical problems they have and where they're headed.

Dr. Greg Hundley:

Very good. Justin, anything?

Dr. Justin Grodin:

Greg, I have to agree with Larry. I think he hit the nail on the head with his first comment. At least for me from an editorial standpoint is really we like to see how generalizable this is and really this implemented in other health systems. I think that's the logical next step. I can tell you, at least from our discussions at our medical center about this manuscript since it's been published at Circulation is, is there something like this we could implement in our own health system? Or in the health systems that we're affiliated with?

Dr. Larry Allen:

And I would just add that this research and the intervention was funded by the American Heart Association under the strategically focused research network for heart failure and so we've made the interventions public they're online at the research website we have, patientdecisionaid.org.

Dr. Greg Hundley:

Well fantastic. Well listeners, we want to thank Dr. Larry Allen from University of Colorado and our associate editor, Dr. Justin Grodin from UT Southwestern, for bringing us this article, demonstrating a process that facilitates patient physician interactions to improve the administration of guideline based therapy to patients with heart failure and reduced ejection fraction. And so we're going to wind up this feature discussion and we will head to our next feature.

Dr. Greg Hundley:

And we have with us Dr. Benjamin Scirica from Brigham and Women's Hospital and our own associate editor, Dr. Sandeep Das from UT Southwestern. Benjamin, could you tell us a little bit about the background information that you used to formulate your hypothesis that you wanted to test for this study?

Dr. Benjamin Scirica:

Thanks so much first for the invitation. It's a great honor to obviously be in Circulation and to be part of this podcast. We started with the recognition that in our practice, which is similar, I think to a lot of the United States, we are not doing as good a job as we could in terms of care for a lot of the chronic cardiovascular conditions we see. And hypertension and high cholesterol are one of those clear areas where we know there are very good guidelines with clear indication for therapy in specific situations and that these drugs that are available are predominantly generic. But when we looked at our registries, we found that we were not doing as well as we thought. We felt that there are a lot of reasons for that.

Dr. Benjamin Scirica:

A lot of it was based on the fact that for something good to happen, the right thing to happen, you have to have a patient and a doctor in the same room, the doctor has to recognize that there's a problem. They have to know that there is something they can do about it. They have to be able to convince the patient or educate the patient that they should start this new therapy. They have to know how to start the therapy and then have the ability to follow up and make sure that there is longitudinal care for these chronic diseases.

Dr. Benjamin Scirica:

And that's a lot to ask for any of us when we have 15 minutes to see the patient, we may only see the patient a couple times a year at most. And so we felt that our hypothesis is, could we design a program, would be delivered remotely, that would not require a doctor in the middle of all of these decisions and that we could scale by using lower cost resources, non-licensed healthcare coordinators or navigators and pharmacists who could follow very clear treatment algorithms to be able to identify patients and prescribe the right medicines to patients at the right time, based on their cardiovascular risk.

Dr. Greg Hundley:

What was your study design? And what was your study population?

Dr. Benjamin Scirica:

This is an active, ongoing quality improvement program where our hypothesis is that by doing this, we could improve patients' lipids and cholesterol prescriptions compared to prior. And we did some analysis and we saw that a lot of these patients had not been on optimal therapy for many years, even though they've been in our system. With the limitations of not having randomization, we identified these patients and through different clinics in the different hospitals, and would either have patients referred to us by providers or more commonly go and find them within the registries and identify the patients and contact them and have them enter our program where they would usually take somewhere between eight to 12 weeks to be actively managed, to get to their goals and then they'd enter a maintenance program. The report that we do now is that the story of the first 5,000 patients who we enrolled in our program of whom about 35% were still in management at the time we presented these ongoing results.

Dr. Greg Hundley:

Roughly how old were these participants? And what was the breakdown in terms of gender or sex distribution?

Dr. Benjamin Scirica:

We found that about 12% were over 75 years old, a little over half were female. We had 71% who are non-Hispanic Caucasian and 8% who were non-English speaking. In terms of their cardiovascular risks, about a third of the patients had established cardiovascular disease, about a quarter of the patients had diabetes and about a third had an LDL of more than 190 milligrams per deciliter, but no history of ASCVD or diabetes. And then for hypertension, we really would take anybody whom the physician felt required further blood pressure management, because their blood pressure was over 130 over 85.

Dr. Greg Hundley:

And what did you find?

Dr. Benjamin Scirica:

We found that of the 5,000 patients that we enrolled, about 4,000 were in the lipid program, a little over 1,400 we're in the hypertension program, so some patients were in both programs and in the lipid patients, in those patients who achieved maintenance, we increased lipid therapy, any lipid lowering therapy, from about 78% up to 97%. And that was predominantly through statins but we doubled the use of ezetimibe from 9% to 17%. We saw a small increase in PCSK9 inhibitor use from 1% to 3%. And if we looked at LDL reductions, it was a 52 milligram per deciliter reduction in LDL from an average LDL of a 125 down to 73 in those folks who achieved maintenance. For blood pressure, again, in those patients whom we successfully treated who are about 600 patients, we saw a 14 millimeter systolic blood pressure reduction and a seven millimeter mercury diastolic blood pressure reduction.

Dr. Greg Hundley:

Wow. Well Sandeep, what drew your attention to this? And then also, how do you put the context of these results with others that really are working in this wing of data science in cardiovascular medicine?

Dr. Sandeep Das:

Great question. We have a large body of literature that suggests that the use of these fantastic evidence based therapies like statins, like blood pressure medications is poor and we really struggle to improve those numbers. I wanted to applaud Ben and his group for really taking on, in a robust way, an important topic and subject. The other thing that really attracted me to this study, there was a hypertension expert here named Ron Victor back when I first started as a fellow. Fantastic researcher and he did a project called Colloquia called the Barbershop Project about leveraging pharmacists and barbers to improve the blood pressure control of African American men in the community.

Dr. Sandeep Das:

The idea is that you get out there, you got to go to where the patients are rather than expecting them to come to you. And you got to figure out ways to engage them, activate them, get them to participate in their own care. A fantastic study, but the one thing that always, we discuss that study, the thing that always jumps out is, well how do you scale it? How do you use it in a real practice? To me was also a very exciting aspect to this. The goal is to take steps to generalize from clinical trials to real world practice, because we got to get this to patients.

Dr. Greg Hundley:

Very nice. Well Ben, coming back to you, what do you see as next steps for your research here? And then even in the field?

Dr. Benjamin Scirica:

The first is, are there other disease areas we can do this in? I think the second part is how to test different techniques to try to improve the ability to scale it to broader populations and keep the cost down. And I think it is a combination of trying to find the right tools, whether they're digital or not and the right techniques to be able to activate patients, educate them, such that they are asking the question, "How come I'm not on these medicines? How come I'm not on this?" And I think we could do a lot in terms of AB testing in there. The part that I think is challenging in these healthcare studies and quality improvement studies, is that randomization would be great. How can we do it streamline? Do we need to get consent? Can it just be that approved drug A can be tested against approved drug B because there is clear equipoise. And I think by doing that, we could lower the bar for really pragmatic randomization in practice and be able to have much more rapid cycles of improvement and optimization on therapy.

Dr. Greg Hundley:

Very good. Sandeep, do you have anything to add?

Dr. Sandeep Das:

I'll echo Dr. Scirica's called arms here that we need to have a way to do this, do trials in this space pragmatically. I agree with that strongly. I did have a few thoughts on next directions. I work in a population of the urban poor of Dallas County with a lot of my clinical time and these patients have poor health literacy so I think that one question, not question but suggestion or comment to Ben and his group would be to think hard about how you would expand this to lower resource setting or to people that would be a little harder to reach. And even as sort of an aspirational goal, how do you expand it into the community? The other question that I would have is how much of this can we get by with adherence interventions? It's one thing to prescribe, but it's another thing to figure out how to get people to adhere to meds.

Dr. Greg Hundley:

Very nice. Well listeners, we want to thank Dr. Ben Scirica for Brigham and Women's and Dr. Sandeep Das from UT Southwestern, bringing us this really interesting research that has been providing early results of a remotely delivered pharmacist led lipid and hypertension management strategy that dramatically increased medication compliance and improved hypertension control and lipid management.

Dr. Greg Hundley:

On behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2021.