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Circulation on the Run

Feb 3, 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 Centre and Duke National University of Singapore.

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

Dr Carolyn Lam: Greg, this issue is full of super interesting papers, many of which were presented as late-breaking presentations at the American Heart Association, like the feature paper that sacubitril/valsartan across the spectrum of ejection fraction in heart failure, where this was really analyzed across the landmark PARADIGM and PARAGON trials. I'm sure everyone's looking forward to hearing about it, but before we talk about that, I want to share some more very interesting results from a very important trial, the REDUCE-IT trial.

So, as some background, some trials have found that patients from the United States derive less benefit than patients enrolled outside the United States. And this was the reason that there was a pre-specified subgroup analysis of the REDUCE-IT trial, which really is the reduction of cardiovascular events with icosapent ethyl-intervention trial, and this analysis was conducted to determine the degree of benefit of icosapent ethyl in the United States.

So, Greg, do you remember what the REDUCE-IT trial was about?

Dr Greg Hundley: Well, Carolyn, I think REDUCE-IT randomized 8,179 statin-treated patients with triglycerides between 135 and 500 milligrams per deciliter and LDL cholesterol levels between 40 and 100 milligrams per deciliter and a history of atherosclerosis or diabetes to Icosapent Ethyl, four grams per day or placebo. And the primary endpoint, I believe, was cardiovascular death, nonfatal myocardial infarction, non-fatal stroke, coronary revascularization or hospitalization for unstable angina. Hah!

Dr Carolyn Lam: Wow, Greg, you pass that quiz, like maybe you had a cheat sheet answer.

Dr Greg Hundley: All right, Carolyn, tell us now what did REDUCE-IT USA find?

Dr Carolyn Lam: This was from a corresponding author, Dr Deepak Bhatt, from Brigham and Women's Hospital Heart and Vascular Center, and his colleagues and they found that in the United States Icosapent Ethyl at four grams a day produced large and significant reductions in multiple ischemic endpoints including cardiovascular death, myocardial infarction, stroke, coronary revascularization, and hospitalization for unstable angina. Furthermore, REDUCE-IT US demonstrated that Icosapent Ethyl provided a statistically significant 30% relative risk reduction and a 2.6% absolute risk reduction in all-cause mortality. The risk benefit profile of Icosapent Ethyl was highly favorable with an overall safety and tolerability profile virtually identical to placebo.

Dr Greg Hundley: Wow, Carolyn. So, this does have important implications for us in the US, very nice. Thank you for that lovely quiz. So, Carolyn, I'm going to switch now and talk about a paper from Roddy Walsh from Amsterdam in the Netherlands. In this study, the investigators defined the frequency of rare variation in 2,538 patients with dilated cardiomyopathy across protein-coding regions of 56 commonly tested genes and compared this to both 912 confirmed healthy controls and a reference population of 60,706 individuals to identify clinically interpretable genes robustly associated with dominant monogenetic dilated cardiomyopathy.

Dr Carolyn Lam: Wow, wow. That's a huge study. So what did they find?

Dr Greg Hundley: Okay, Carolyn. So overall rare variants in 12 genes potentially explain 17% of cases in the outpatient clinical cohort representing a broad range of adult patients with dilated cardiomyopathy and 26% of cases in the diagnostic referral cohort enriched in familial and early onset dilated cardiomyopathy. And so, practically speaking, by analyzing two dilated cardiomyopathy cohorts with distinctive patient profiles, the authors were able to comprehensively evaluate the genetic basis of dilated cardiomyopathy and identify variant classes that were particularly associated with early-onset disease. By restricting analyses to validated and interpretable genes and variant classes, the authors hoped in this study to increase the accuracy and reduce the uncertainty associated with genetic testing in dilated cardiomyopathy.

Dr Carolyn Lam: Very nice, very practical information. Well, my next paper is, I have to admit a super favorite topic of mine, and that is sex differences in heart failure. Now as a reminder to everybody, women represent over half of patients with heart failure with heart failure preserved ejection fraction, and there are multiple effective drug and device therapies for HFrEF, or heart failure reduced ejection fraction, but none approved for HFpEF. Thus, there is a greater so-called failure therapeutic deficit in women compared to men. So, does the recently presented PARAGON trial provide answers?

Dr Greg Hundley: Ah, Carolyn, you were involved in the PARAGON trial. Maybe tell us a little bit about that first to help us get oriented.

Dr Carolyn Lam: I would love to. So PARAGON compared sacubitril/valsartan with valsartan in patients with HFpEF. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes, and the trial overall narrowly missed this primary outcome. However, an intriguing result in PARAGON was a significant sex-by-treatment interaction. And this was explored further in the current pre-specified subgroup analysis of outcomes by sex, which was reported by John McMurray from University of Glasgow and his colleagues.

Dr Greg Hundley: Ah, so I'm interested. What was this interaction?

Dr Carolyn Lam: Ah, so here is how the interaction work. Now, remember this was multi-variably adjusted significant in a pre-specified large subgroup of PARAGON. And what we found was that as compared with valsartan, sacubitril/valsartan seem to reduce the risk of heart failure hospitalization more in women than in men. Now, while the possible sex-related modification of this effect of treatment has potential explanations, the current study really cannot provide a definitive mechanistic basis for this finding.

Dr Greg Hundley: Very interesting. So, perhaps then, in heart failure preserved ejection fraction, sacubitril/valsartan could be very helpful in women.

Dr Carolyn Lam: Yes, and perhaps especially those with each ejection fraction in the lower ejection fraction range. And that is coming up in our future discussions, so let's not preempt it. You got another paper, Greg?

Dr Greg Hundley: Absolutely, Carolyn. My next paper is from Professor Irene Lang at the Medical University of Vienna, and it's related to microvascular disease and chronic thromboembolic pulmonary hypertension and hemodynamic phenotyping and histomorphometric assessments. So, Carolyn, pulmonary endarterectomy is the gold standard for treatment of patients with operable chronic thromboembolic pulmonary hypertension. However, persistent pulmonary hypertension after PEA or endarterectomy remains a major determinant of poor prognosis.

Dr Carolyn Lam: Ah, so are there any possible solutions to this?

Dr Greg Hundley: Well, Carolyn, today it is thought that a concomitant small vessel arteriography in addition to major pulmonary artery obstruction may play an important role in the development of persistent pulmonary hypertension and survival after pulmonary endarterectomy. One of the greatest unmet needs in the current preoperative evaluation is to assess the presence severity of small vessel arteriopathy.

Dr Carolyn Lam: Huh, that makes a lot of sense. So what did the authors do? What they find?

Dr Greg Hundley: Okay. Well, Carolyn, they had 90 patients with 49 of them receiving lung wedge biopsies for validation. So, in analyses incorporating receiver operating characteristic curves, pulmonary vascular resistance measures and larger arterial upstream resistance beds predicted persistent pulmonary hypertension after pulmonary endarterectomy, and certain values identified patients with poor prognosis after endarterectomy. Therefore, perhaps this form of analysis could be helpful in establishing prognosis in these patients and perhaps suitability for future interventions.

Dr Carolyn Lam: Wow, very interesting. Well, we were saying this issue's full of very important papers, and that also includes research letters. There's a research letter by Dr Cannon talking about evaluating the effects of canagliflozin on cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease according to baseline HbA1c, including those with an HbA1c less than 7%. And these are very interesting results from the CREDENCE trial that was also presented at the American Heart Association.

There's a research letter by Dr Jackevicius on the population impact of generic valsartan recall in Ontario, Canada, that really highlights the potential burden and risks associated with recalls of chronic oral medications used by large populations. And in Cardiology News, Bridget Kuehn talked about cardiovascular risk biomarkers, high-sensitivity cardiac troponin T and NT-proBNP and talked about how these two biomarkers may help clinicians stratify which patients may benefit the most from therapies for hypertension or diabetes. And this was according to a pair of studies presented, again, at the American Heart Association.

Dr Greg Hundley: Well, Carolyn, that's quite a nice review. I've got just a couple more papers to discuss. There's a perspective piece from Dr Ben Levine and colleagues from UT Southwestern that discusses whether a simple physical exam and maneuvers could actually supplant tilt-table testing. He provides arguments as to whether we should continue with tilt-table testing given the high rate of false positives. And then lastly, from the Mailbag, Dr Shuyang Zhang from Peking Union Medical College Hospital and the Chinese Academy of Medical Sciences provides a letter to the editors regarding a prior publication on the clinical applicability of the awareness of androgen-deprivation therapy's effects on ventricular repolarization. And Dr Joe-Eli Salem from Vanderbilt University provides his response.

Well, Carolyn, how about onto that feature?

Dr Carolyn Lam: Let's go. Our feature discussion today is all about left ventricular ejection fraction. Ah, that measure we both love and hate in the world of heart failure, I think. And this paper is truly remarkable, in my opinion. It is the look at the effect of sacubitril/valsartan across the spectrum of left ventricular ejection fraction in the PARADIGM and PARAGON trials. And I'm just so pleased to have none other than the first and corresponding author, Dr Scott Solomon, from Brigham and Women's Hospital and Harvard Medical School, as well as our Senior Associate Editor, Dr Biykem Bozkurt, from Baylor College of Medicine as well.

Scott, could you start by telling us about this analysis and why the opportunity to do such a special analysis in this paper?

Dr Scott Solomon: This was a really fantastic opportunity because, as you know, we did these two trials, PARADIGM and PARAGON, not at the same time but essentially in series. PARADIGM was a trial of patients with heart failure reduced ejection fraction, so ejection fraction of 40%, and PARAGON was a study of patients with heart failure with preserved ejection fraction. And the interesting thing is that, with the exception of ejection fraction, the criteria for enrolling patients in these trial was virtually the same.

In other words, we enrolled patients with signs and symptoms of heart failure, some elevation in natriuretic peptides, and we followed them. So it's really an extraordinary dataset of 13,195 patients in whom we can look at heart failure across that full spectrum of ejection fraction. We haven't been able to do this really since the CHARM study, which enrolled about 8,000 patients across the spectrum of ejection fraction. And it gave us an opportunity to look at a number of things including the effect of sacubitril/valsartan across that full spectrum of ejection fraction.

Dr Carolyn Lam: Great. And, Scott, you want to tell us what you found?

Dr Scott Solomon: When we pooled 13,195 patients, and by the way, this was a pre-specified analysis that we had decided to do prior to unblinding PARAGON. We see that if we put them all together, all these patients together, and just treat them as one group, we see that for every endpoint that we looked at, whether heart failure, hospitalization and cardiovascular death, cardiovascular death, all-cause mortality, whether we look at the time to first event endpoints or the total number of heart failure hospitalizations, we see a significant benefit in patients receiving sacubitril/valsartan compared to patients receiving either enalapril in the PARADIGM study or valsartan in the PARAGON study.

Now, what we also saw though, and this is probably most important, is that there appears to be an attenuation of the treatment effect as ejection fraction rises. Now we know that patients with higher ejection fractions tend to have a lower frequency of these events such as heart failure, hospitalization and cardiovascular death. But we also see here that as ejection fraction goes up that the benefit of sacubitril/valsartan appears to wane, especially when you get over about 60, an ejection fraction of about 60%. We've looked at this in categorical ways and also looking at a continuous spline analysis throughout the entire spectrum.

Dr Carolyn Lam: Yeah, I love that, and I just need to point every listener right now to figures 3 and 4 of your paper. I have a feeling we're going to be seeing these figures in a lot of talks and cited everywhere. Biykem, could I bring you in on this? What are the implications of something like this?

Dr Biykem Bozkurt: The interesting findings from the pooled data are, first, support of what we had seen in PARADIGM, meaning the lower the EF, the more the benefit or the higher the benefits. And as we had seen in PARAGON, which did not show an improvement in the combined endpoint with treatment with sacubitril/valsartan in patients with heart failure with preserved ejection fraction. In the pooled analysis as the EF got higher, there didn't seem to be any benefit, but the interesting, perhaps group of patients that the pooled analysis allowed us to have a deeper dive into was heart failure with mid-range EF. And we can crudely perhaps define this as ejection fraction between 40 and 50%. And by certain analyses, which again this is in the post-hoc and also in a continuous analysis and a specific analysis and a cubic spline analysis, it appeared that the benefit extended into those individuals with mid-range ejection fraction.

Again, we need to keep several points in consideration. One is ejection fraction can vary over time and is not a very precise measurement. There's definitely inter-reader as well as intra-reader variability and is not a good mayor of contractile performance. And we tend to actually have a significant amount of a specific infiltrative cardiomyopathies in that EF range, which tend to be excluded from usual clinical trials. And with that caveat, having kept this in mind, it's also important to recognize from cohorts and population-based studies, about 10 to 20% of our patients currently reside in that have HeFmrEF or heart failure with mid-range EF status. And thus the findings are intriguing, hypothesis generating and also encouraging that we may see perhaps benefits with RAS antagonism in individuals that do have LV systolic dysfunction.

And probably, if this is persistent and a clear reflection of a phenotype that reflects itself as reduced ejection fraction, probably the patient may benefit. Again, these results may need to be supported by future studies, and also we need to keep in mind that infiltrative cardiomyopathies, such as amyloidosis or sarcoidosis or others, were not included in these studies.

Dr Carolyn Lam: Thank you, Biykem. Go ahead, Scott.

Dr Scott Solomon: Carolyn, I agree with many of Biykem's points. I think that this middle range, and you and I kind of coined that term, heart failure with mid-range injection fraction, a number of years ago. The problem, of course, is knowing where that range exactly is, and I think that some people believe it's 40 to 50%, but we know that these are very arbitrary cutoffs. The data from the pooled analysis in PARAGON, in particular, do suggest that the patients who have evidence of some degree of left ventricular dysfunction seem to benefit from sacubitril/valsartan. Now, this is not a completely novel finding because we saw that in patients who received candesartan in the CHARM study and in patients who received spironolactone in the TOPCAT trial that the greatest benefit was observed in the patients in that middle range of ejection fraction, again, below what we would normally consider the normal range. Normal might be 55% or 55% in men and women.

And that gets me to the other thing that I think is really worth mentioning here, which is that we found that the range of benefits does vary by sex, so that women seem to derive greater benefit to a higher ejection fraction than men. We can see that here in figure 4, looking at these two curves that there really does appear to be a difference between men and women. Women overall derive greater benefit in the PARAGON study, it appeared than in men. So I think that the fact that there's biologic plausibility here that patients with cardiac function that is not normal seem to benefit from therapies that we know benefit patients with heart failure with reduced ejection fraction, that patients with ejection fraction that was in this middle range also do appear to benefit from sacubitril/valsartan as we think they did in other studies of other agents that we know work in patients with lower ejection fraction.

Dr Carolyn Lam: Indeed, Scott. You've just pointed out my favorite figure of all, that figure 4. You know how I feel about sex differences and pointing them out. I would love to ask for Biykem's thoughts on it.

But in the meantime, just to emphasize how important findings like these are because it makes us question the cutoffs that we use to define heart failure groups, makes us question is midrange more mildly reduced ejection fraction like we're also writing about. And I think really makes us question, for example, the 2016 ESC Guidelines that say that mid-range ejection fraction should be treated like preserved ejection fraction. Well, maybe this could be really game changing here in that we actually think now this group should be treated more like reduced ejection fraction. So, really, congrats on this incredible paper.

Biykem, what do you think of those sex differences? I have to point out, I love your editorial, which everyone should read.

Dr Biykem Bozkurt: It's very intriguing, very interesting point. The benefits from sacubitril/valsartan was interestingly similar for both sexes at lower EF levels. Women's benefit compared to men's benefit for low EF was comparable; they were not different. But women seem to confer a benefit at higher EF ranges and by this continuous analysis all the way up to the 50 to 60% range, which is very, very interesting. And as to what were the phenotypes of the women compared to men at that range, women were older, had more obesity, less CAD, and of course, at all ranges they usually tend to have a higher baseline EF.

And, interestingly, even though we may state that maybe women may have more systolic dysfunction at higher EF quantification ranges or may have a different phenotype than men for HFpEF, maybe a more clear or pure heart failure phenotype, heart failure with preserved EF phenotype than men. The interesting things were the NT-proBNP levels were lower for women, though the symptoms were a little bit higher, and the benefit seemed to be higher even though the KCCQ scores were not different. So, even though we did have lesser sort of filling pressures for women and perhaps other surrogates for improvement did not seem to differ, and also biological metabolites, such as urinary cyclic GMP to creatine ratios, were not different in women.

So, if we were to think of whether there were biological differences, whether there were differences in NT-proBNP levels or delta changes over time or the urinary cyclic GMP levels, they were not different in women versus men. So, we still have many other substrates for neprilysin. I mean there could be other substrates, such as adrenomedullin or bradykinin or substance P that may be differentially metabolized for women compared to men, and we don't have the data on those. But again, it's very interesting to see this upper scale of EF benefit being higher in women compared to men. So, we don't have any other either biological or other surrogate markers for benefit for women, either for the HFpEF or HFrEF being than different than men.

Dr Carolyn Lam: Biykem, I just love the way you so carefully dissected that, and it's so reflected in that editorial that you and Justin Ezekowitz wrote entitled Substance and Substrate. So I'm going to make sure all readers look for it. We could go on forever. I mean I just was struck, that figure 4, also is really similar if we look at what normally ejection fraction is for women versus men with increasing age. We also see that women are supposed to have higher ejection fractions as they age compared to men at any age. So it's just intriguing to me, but you're right. I think hypothesis generating.

Scott, I'm going to give you the last word.

Dr Scott Solomon: I'm pretty confident that there are biologic differences between men and women. I just don't necessarily know what they are with respect to heart failure, preserved ejection fraction, but I think we're going to be spending a lot of time and effort trying to sort this out. We're pretty confident that the finding of a weighing of benefit with ejection fraction is a real one and that the benefit in this middle range is an important one to pay attention to because I agree with what you said, Carolyn. If we had been thinking about heart failure with reduced ejection fraction as something that went up to a higher level 25 years ago, we would probably have treated a lot more patients with therapies that we now know to benefit patients with heart failure with reduced ejection fraction. So, I think this data helps us rethink how we parse up heart failure and hopefully, ultimately will lead to changes how we treat patients.

Dr Carolyn Lam: Well, listeners, you heard it right here on Circulation on the Run. Thank you so much, Scott and Biykem, for joining us, and don't forget to tune in again next week.

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