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Circulation on the Run

Feb 24, 2020

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. 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, director of the Pauley Heart Center at BCU Health in                                                     Richmond, Virginia.

Dr Carolyn Lam: So Greg, guess what? We are going to be discussing predicting the benefit of evolocumab therapy in patients with atherosclerotic disease using a genetic risk score. That's our featured paper this week coming from the results of the FOURIER trial. I bet you can't wait to discuss it, but I'm not going to let us until we talk about some of the papers in today's issue. Do you have one?

Dr Greg Hundley: Yes, Carolyn, but first I'm going to get a cup of coffee because there's a lot of data in this one. This study is from the ODYSSEY trial and it involves alirocumab and it's from Dr Charles Paulding. Remember Carolyn, the ODYSSEY trial was a randomized double-blind placebo-controlled trial comparing alirocumab, a PCSK9 inhibitor or placebo in 18,924 patients with acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin treatment. And the primary endpoint of this trial comprise death from coronary artery disease, non-fatal MI, ischemic stroke, or unstable angina requiring hospitalization. Now Carolyn, this is a sub-study and it was performed an A genome wide polygenic risk score for coronary artery disease comprising 6,579,025 genetic variants. And they were evaluated in 11,953 patients with available DNA samples. Analysis of the MACE risks, all those outcomes together, was performed in placebo treated patients while treatment benefit analysis was performed across all the patients.

Dr Carolyn Lam: Ooh, so what did they find?

Dr Greg Hundley: Well, Carolyn, both the absolute and relative reduction of MACE by alirocumab compared to placebo was greater in high versus low PRS patients. Those genetic, polygenetic risk scores combined in the patients. There was an absolute reduction by alirocumab in high versus low PRS groups of 6% and 1.5% respectively, and relative risk reduction in the alirocumab of 37% in the high PRS group versus 13% in the low PRS group. And so Carolyn, these results suggest the possibility of an independent tool for risk stratification using sort of precision medicine by selecting those using these genetic constructs, who may be more likely to benefit from this form of therapy.

Dr Carolyn Lam: Wow Greg, that is really interesting. I genuinely think that our world is moving towards precision medicine and this really, really speaks to remember that feature paper also talking about genetic risk scores, but from the FOURIER trial. But before we get to that, I've got a basic science paper. Now this one provides insights into the mechanisms underlying age related hypertension. And it's from Dr Ying Yu and colleagues from Tianjin Medical University who hypothesize that since proinflammatory cytokines increase in T lymphocytes with aging and prostaglandin D2 suppresses T helper 1 cytokines through the D-prostanoid receptor 1, that this axis in T cells may play a role in age related hypertension.

Dr Greg Hundley: Ah, Carolyn. What did they find in this study?

Dr Carolyn Lam: Prostaglandin D2 biosynthesis and D-prostanoid receptor 1 expression, were both markedly decline in CD4 positive T cells from older humans and aged mice. D-prostanoid receptor 1 depletion in these CD4 positive T cells, exaggerated age dependent blood pressure elevation in mice by increasing tumor necrosis factor alpha and interferon gamma secretion. Whereas its over expression showed the opposite effect and its activation suppressed TH1 cytokines. These results really indicate that D-prostanoid receptor 1 and its downstream pathway may serve as an attractive immuno-therapeutic target for age dependent hypertension.

Dr Greg Hundley: Oh wow. Very insightful Carolyn. Well, I've got a basic science paper to go over and it's from professor Kinya Otsu from Kings College London. This study addresses the mechanism of ongoing inflammation within the hearts of patients with cardiomyopathy. The study involves the assessment of Regnase-1 and RNAs involved in the degradation of a set of pro inflammatory cytokine messenger RNAs in immune cells. And the study involves the role of Regnase-1 in non-immune cells such as cardiomyocytes.

Dr Carolyn Lam: Wow.

Dr Greg Hundley: The degradation of cytokine messenger RNA by Regnase-1 and cardiomyocytes plays an important role in restraining sterile information in failing heart. Once the inflammatory cascade gets going, this is that constant inflammation that's ongoing. In addition, the Regnase-1 mediated pathway might be a therapeutic target to treat patients with heart failure as adeno-associated virus 9 mediated cardiomyocyte targeted gene delivery of Regnase-1 or administration of anti-IL-6 receptor antibody, attenuated the development cardiomyopathy induced by severe pressure overload in wild type mice.

Dr Carolyn Lam: Wow, that's really interesting. I find this whole field of inflammation in heart failure of course, of key interest, but I'm going to next tell you about the results of the FUEL trial, which is the Fontan Udenafil Exercise Longitudinal trial.

Dr Greg Hundley: Tell us about the Fontan operation.

Dr Carolyn Lam: Aha, I thought you may ask, Greg. Well, the Fontan operation to remind us all, really creates a total cavopulmonary connection and a circulation in which the importance of pulmonary vascular resistance is therefore magnified. Over time, the circulation needs to deterioration of cardiovascular efficiency associated with a decline in exercise performance. This FUEL trial and reported this time by David Goldberg and colleagues from the Children's Hospital of Philadelphia was a phase 3 clinical trial, which randomized 400 patients with Fontan physiology from 30 sites in North America and the Republic of Korea. The participants were randomly assigned to Udenafil at 87.5 milligrams twice daily or placebo. And the primary outcome was the between group difference in change in oxygen consumption with peak exercise.

Dr Greg Hundley: Hmmm, very large important trial it seems like Carolyn. What did they find?

Dr Carolyn Lam: Treatment with Udenafil did not result in a significant increase in peak oxygen consumption, which was the primary outcome, but did result in improvements in measures of exercise performance at the anaerobic threshold, which was a secondary outcome. Udenafil was well tolerated with side effects limited to those previously known to be associated with phosphodiesterase type 5 inhibitors.

These results and future perspectives are discussed an editorial called FUELing the Search for Medical Therapies in Late Fontan Failure, by Doctors Gewillig and De Bruaene.

Dr Greg Hundley: Very nice, Carolyn. Now how about the rest of the journal?

Dr Carolyn Lam: Oh well I want to tell you about this in-depth review by Dr Rosenkranz and it's entitled, Systemic Consequences of Pulmonary Hypertension and Right-Sided Heart Failure. Very intriguingly, talking about non-cardiac features, as well as cardiac, of right heart failure, a real, real must read with beautiful figures.

In the cardiovascular case series we discuss a case of left ventricular non-compaction and cardiogenic shock by Dr Shenoy. There are also two research letters I want to tell you about one by Dr Gillinov on the accuracy of the Apple watch for detection of atrial fibrillation. And this time looking at the Apple watch series 4, which interestingly employs electrodes to generate a single lead ECG and provides two mechanisms for rhythm assessment. Won't tell you more. You got to pick up this beautiful letter.

The next is by Dr Mazer on the effect of empagliflozin on erythropoietin levels IN stores and red blood cell morphology in patients with type II diabetes and coronary artery disease. And this really provides evidence to suggest that SGLT 2 inhibition with empagliflozin may stimulate erythropoiesis via an early increase in erythropoietin production in people with diabetes.

Dr Greg Hundley: You know Carolyn, we just keep hearing more about EMPA and DAPA and they are just going to really pave the way I think for a whole new class of agents that we're going to be using frequently.

I've got a couple letters in the mailbox and one is by Sugimoto and Taniguchi regarding the article, Internal Versus External Electrical Cardioversion of Atrial Arrhythmia in Patients with Implantable Cardio Defibrillators, a randomized clinical trial. And then also there's another research letter by Dr Hiroshi Sugimoto from Kobe Red Cross Hospital with a response by Jakob Lüker from University of Cologne.

What a great issue. How about we proceed to that feature article?

Dr Carolyn Lam: You bet.

Can a genetic risk score identify individuals who will derive greater benefit from PC SK9 inhibition? Well guess what? We're going to find out now in our feature discussion. So pleased to have with us the first and the corresponding authors of our feature paper, Dr Nicholas Marston and Dr Christian Ruff, both from the TIMI study group in Brigham and Women's Hospital and Harvard Medical School and also to have our lovely associate editor, Dr Svati Shah from Duke University in Durham, North Carolina. Welcome everyone.

Nick, could I get you started with telling us about this exciting analysis that you did from the FOURIER trial?

Dr Nicholas Marston: The FOURIER trial was a 27,000 patient cardiovascular outcomes trial that studied the PC SK9 inhibitor, evolocumab and it demonstrated a significant reduction in major adverse cardiovascular events in patients who had established atherosclerotic disease. And in the study, there was a 15% relative risk reduction and a 2% absolute risk reduction, which earned it a class 2 recommendation for very high-risk patients with atherosclerosis in the recent cholesterol management guidelines. And what we've done in previous lipid trials is we studied the interactions between genetic risk and treatment benefit. For example, in 2015 we showed that patients with high genetic risk, those in the top 20% of genetic risk, had the greatest benefit from statin therapy in terms of both absolute and relative risk reductions. And so now we have the opportunity with evolocumab and data from the FOURIER trial to ask the same question of PC SK9 inhibitor. That is, could a genetic risk score identify patients who will drive a greater treatment benefit and we hypothesize that like statins, there would in fact be a significant interaction between genetic risk and therapeutic benefit.

Dr Carolyn Lam: That's so cool Nick. But could I ask, the question always comes, is it nature versus nurture? And so I really love the way that you dealt with the clinical risk factors as well. Could you maybe walk us through that and then tell us the results?

Dr Nicholas Marston: Yes, absolutely. We for this study, kind of had two objectives. One was to look at risk prediction and then the other look at treatment benefit and using a genetic risk score for both. However, we wanted to go further than just use the genetic risk score. We wanted to incorporate clinical risk factors since that's how we would do it as physicians in the clinic. We would have not just genetic risk data in front of us but also clinical data. And so when we were grading a patient's risk using genetic risk, we also factored in if they had multiple clinical risk factors. And what we found by combining both genetic and clinical risk was that there was a significant gradient of risk across these risk categories.

That is patients who were without high genetic risk and without multiple clinical risk factors actually had no benefit from evolocumab over the 2.2-year follow-up period. However, those without high genetic risk, but who did have multiple clinical risk factors, derived an intermediate benefit. About a 13% relative risk reduction and 1.4% absolute risk reduction. And then it was the high genetic risk group, independent of whether or not they had multiple clinical risk factors that had the largest benefit from evolocumab with a relative risk reduction of 31%, absolute risk reduction of 4% and the number needed to treat of 25. And that's actually a twofold greater benefit than was seen in the overall FOURIER trial population.

Dr Carolyn Lam: That's really stunning results. Now I know Svati's going to have questions for us, so maybe I should invite you Svati, just put these results into context and let the audience know what we were thinking as editors when we saw this brilliant paper.

Dr Svati Shah: Yeah, thanks Carolyn. And I think Nick has done a fantastic job of describing the exciting results from this paper and just kind of taking a step back to help the audience understand what we're talking about when we're talking about genetics. For decades, we've been trying to figure out the genetics of heart disease and we're not talking about the genetics of things that are really rare like long QT syndrome, but the genetics of just common complex heart diseases. And amongst the scientific community, we've tried all different ways of sort of analyzing these data and so I want to make sure that everybody who's listening understands the novelty of really looking at these polygenic risk scores. Where we have now come to understand that it's not a single gene, it's not even two genes, that it's multiple variants and multiple genes and when they're combined, that's when you really have the power to understand how it might be useful in terms of how we take care of patients.

Really important with how Nick and Christian have laid out this really nice paper as well as their prior work in statins, is that not only did they show that these polygenic risk scores are associated with cardiovascular outcomes or even different amongst whether you get treated with the drug or whether you don't, but really importantly they're getting it clinical utility, not only with regards to showing that they compare it to a clinical risk score, but really showing that if you use these polygenic risk scores, you can identify patients who may derive the greatest benefit from PC SK9 inhibitors. And importantly in their paper, they show that if you have low polygenic risk score and low clinical risk score, you may not derive benefit from PC SK9 inhibitors. With all the caveats that this is a secondary prevention population, so I really applaud Christian and Nick and his team for the nice work that was done.

Dr Carolyn Lam: Oh, couldn't agree more, Svati. You know what I was very struck with too, because some people go, I may have a genetic risk. Maybe I could undo it or somehow overcome it with my clinical risk factors. And that's why I really appreciated that they showed that it was additive, and genetics still matter even if you have risk factors and vice versa. That was really cool. Christian, could I ask you to maybe describe a bit, what kind of genetic risk score this was and maybe perhaps point out some of the limitations therefore of what you studied.

Dr Christian Ruff: As Svati mentioned, this is really a quickly evolving field. We now have the ability to either genotype or sequence all of the variation that makes us different from one another. Our susceptibility to disease as well as our potential benefit for treatment. We had for this study, looked at several different risk scores. The one we focused on was a coronary artery disease genetic risk score that had 27 different variants that had been shown to predict having a cardiac event, both in primary and secondary populations. And we have previously identified patients who may have been at a higher risk who received greater benefit from statin therapy. And in this study, we actually compared this 27 variant genetic risk score with actually a much larger score of over six million variants. And interestingly, the two scores performed fairly similar with respect for risk prediction. One of the big questions going forward is, we have lots of ways to develop genetic risk scores, how many different variants do we need? What more information do we have with more complicated scores?

And I think Svati really hit on a really critical point is that really this study is really layering in genetic risk on top of clinical risk factors, which we can easily assess at the bedside. And I think what's reassuring to patients is that not only is genetic risk able to give us much more information for prognosis, but that this risk is modifiable. People think that their genetic risk, they're sort of born with it and there's nothing that they can do about it. But in this study, as Nick pointed out, even over a very short period of time with powerful lipid lowering therapy with a PC SK9 inhibitor, we essentially reduced these patients at high genetic risk to the risk of the very low risk patients on placebo. I think this is a reassuring message that genetics plays an important role for risk prediction and it identifies patients who we might target for more intensive therapy and that we can potentially reduce that risk even though that risk is based on the DNA that they're born with.

Dr Carolyn Lam: Indeed. That's a great point. And Svati, I'm sure you were thinking along those lines when you invited that beautiful editorial by Doctors Daniel Raider and Michael Levin. But Svati, would you like to comment on your thoughts on, is this ready for prime time?

Dr Svati Shah: I think that's the key question. What Christian and Nick and his team have done is take us a big step forward in how we use these polygenic risk scores. I think there still are many skeptics amongst the genetic scientific community about, well great, you can look at 27 variants and some of these polygenic risk scores, you're looking at a million things. How do we actually use that to take care of patients?

I actually want to turn this back, that question back around Carolyn, and I'd like to ask Christian next, what are the next steps? There are a lot of cardiologists who if you're listening to this podcast, should we all run out and get our patient's genotype to order this genetic chip so that we can figure out what their polygenic risk score is?

Dr Christian Ruff: Yeah, that's a great question and I could start off and then hand off to Nick, but I think one of the key questions is obviously there are a lot of genetic risk scores and I don't think as a field that we've come up with which one we really should implement in clinical practice. There's still a lot of fine tuning and figuring out which score gives us the most amount of useful information.

And then I think as something that you had mentioned that these scores are generated in both a healthy cohort population and now, we're looking at it in clinical trials and there's no sort of reference. Like when we have a blood test and we say, "If your hemoglobin A1C is above or below this number that means that you have diabetes." And we haven't figured out, what are the actual thresholds that you use for these genetic risk scores that you can implement broadly across different patient populations. There's still a lot of work that needs to be done to make these scores ready for prime time. This is really setting the stage. Is this something that we should be doing? And I think these studies and others say that the data looks great that we should be doing this, but we haven't yet figured out the logistics of which score and how do we actually reference to population.

Dr Nicholas Marston: Yeah, I agree with Christian definitely that we need to figure out what's the optimal genetic risk tool and for which population and what the cut points are. And then I think another piece that's going to be very important moving forward is doing a lot of this work and studying in non-European ancestry and cohorts and populations. Because most of the work done so far in discovery has been in databases such as the UK Biobank. And that limits us in our analyses to European ancestry patients. And so, I think for this to go to prime time, we want to be able to offer it to all of our patients. And so that means making sure we have scores that fit all populations, not just primary and secondary, but also all different types of ancestry.

Dr Carolyn Lam: Oh, I'm so glad you mentioned that, Nick. That was exactly on my mind coming from Asia. And the other thing of course, would be cost effectiveness of these approaches. Oh my goodness. I wish we had all the time in the world to talk about this more. The implications are enormous, but just let me thank you on behalf of all of us for publishing this remarkable paper in Circulation.

Audience, you've been listening to Circulation on the Run. Don't forget to tune in again next week.

Dr Greg Hundley: This program is copyright, the American Heart Association 2020.