From early success with ACE inhibitors to breakthroughs with ARNI and SGLT2-inhibitors, the journey continues

BreakingMED Conversations is a video series featuring informal conversations with leading experts on issues dealing with diagnosis and clinical management of a variety of clinical conditions. In this Conversation, Clyde W. Yancy, MD, of Northwestern University’s Feingold School of Medicine in Chicago, discusses the evolution of medical management of heart failure...

Peggy Peck: I’m Peggy Peck. I’m Editor-in-Chief at BreakingMED and this is part of a video series that we call Conversations. I’m talking today with Dr. Clyde Yancy, who is the Director of Cardiovascular Medicine at Northwestern’s Feinberg School of Medicine in Chicago. He is also a deputy editor of JAMA Cardiology. He is a world-renowned expert in heart failure. Welcome, Dr. Yancy.

Clyde Yancy, MD: Thank you, Peggy. I’m delighted to be with you and be part of these conversations.

Peck: I started covering heart failure in 2001 with a trial that was called Val-HeFT. I’ll be honest, I didn’t know a whole lot about heart failure, but I was being told prior to it being reported that this was going to make a really big difference in medical management of heart failure. I’d like you to just comment a little bit about Val-HeFT. It looked at valsartan. That’s why it’s called Val-HeFT, valsartan, which is an angiotensin receptor blocker. Let’s start at that point.

Yancy: Well, that’s really a wonderful place to start, but I have a perspective that actually predates that a bit.

I started working in heart failure as an investigator as an early career physician in 1990, just shortly after the V-HeFT I trial was released. We need to remember that heart failure was one of those early adaptations of the randomized control trial in cardiovascular science, in cardiovascular medicine. I won’t say it was the first, but one of the earliest ones where we actually set up studies with true, placebo-controlled questions. We began to at least understand better methods of exploration. Out of all of this effort emerged the stunning breakthrough with the CONSENSUS Trial and ACE inhibitors, the SOLVD studies, both prevention and treatment, and we begin to realize that this condition for which we had nothing but despair. There was a glimmer of hope that some therapies targeted not hemodynamics, lowering pressure and improving ejection fraction, but interrupting biology were actually potentially effective. Then along comes Val-HeFT that says here is another way to interrupt the Renin-Angiotensin-Aldosterone System (RAAS) to do so with fewer side effects and to provide an option for patients that couldn’t tolerate the ACE inhibitor.

As time went on, we realized that the ACE inhibitor probably had a predominant benefit, but then we also had another, if you will, a eureka moment that was not for the good. Everything halted after we discovered the beta-blockers in the first study using mineralocorticoid antagonists. We had these three foundational drugs: RAAS inhibition, evidence-based beta-blockers, and mineralocorticoids. But once the 2000s hit, we really had a progressive series of failure, after failure, after failure, ironically aligned with heart failure. We really had nothing but a few potentially therapeutic agents, but not what we really hoped.

I think that as we go forward—and we can talk about this some more—the journey in heart failure has been enlightening. It’s been courageous in some regards, but what’s most important is that it’s been impactful, it’s been effective, and now we’re at a very different place. But yes, those early years lots of struggle introducing methods more than anything else.

I think the most important thing about that era, Peggy, the most important thing, was this fundamental shift from targeting hemodynamics as an outcome in our interventions to targeting biology. I would argue that that really was the door that, once it was open, allowed us to be where we are today. We should always endorse those early trials because of the courage to shift our thinking from hemodynamics to science.

Peck: To me, in terms of medical management, the really big breakthrough moment came with PARADIGM, sort of aptly named PARADIGM Heart Failure. Which is, to me, ironic, because I so often heard investigators say this is a paradigm shift, and I would think to myself, “Oh, yeah, a paradigm shift.”

But PARADIGM comes along and here you have sacubitril/valsartan versus enalapril in a trial. And you do get what appears to be a mortality benefit in reduced ejection fraction heart failure. When that was reported in 2014 at the ESC and it was simultaneously published in The New England Journal of Medicine, I can recall crowds and crowds of people standing around and listening to experts talk about this. I can remember having the crowd stand back, while I was doing video interviews, so that I could actually interview investigators on this. There was that level of excitement.

You were one of the people that I talked to at the time, and you were very enthusiastic. That drug, however, was not FDA approved at the time. Just 9 months later, I believe, it did get approval. I’d like to talk a little bit about the impact in clinical care and also how rapidly it was adapted just to use this drug.

Yancy: Let’s make three observations about what I would like to call the contemporary era. Many of us in 2014 opined that this was the introduction of a new day. It was just that profound a discovery. I think that in fact it was the introduction of a new dawn because we’ve had a number of positive trials that have evolved since then. Let’s say that’s the first big thing.

Next, let’s say it was an introduction of a therapy, the clinical benefit of which we are still trying to fully capture. It looks as if there is a reduction in sudden cardiac death events, a reduction in hospitalization, and extension of the longevity of life, and improvement in quality of life, albeit with some exposure to issues of hypertension. We have yet another very powerful tool now.

But I think the third piece really is in keeping with the theme I have been establishing. Again, the original, the predicate, heart failure trials were amongst the first to use randomization. The trials in heart failure were amongst the first to take the shift from anatomical or hemodynamic targets to science. Then this particular trial may have been one of the very first to ever challenge the conventional approach in medicine we typically take.

This is the first time we actually challenged conventional medicine and we are willing to deconstruct would it become now a theorem, no longer a hypothesis, and challenge it with something that was potentially better. I think those are important contributions because it really enabled our courage to explore things very differently going forward. I was one of the ones that loudly proclaimed this is a new day in 2014. But when I look back on it, I think it was a new dawn and we have continued to reap benefits over the last 7 years in a wonderful way.

Peck: But one of the issues, as I mentioned, that drug was not FDA approved at that time. One of the slams, if you will, against this is that it’s not been picked up. It’s not been widely adapted initially. Some people said it was because you didn’t have hospitals… they didn’t start the drug in hospitalized patients. There was a follow-up trial looking at it, starting it… because I guess there are data that support if you start something in the hospital, you’ll get better adherence to the therapy doing that. I just want to get a sense of that lag time and where we are now. Where are we now? How widely used do you think it is now?

Yancy: Well, it’s considerably better. I like to take the longer lens. I like to reflect on how long it took for ACE inhibitors to be incorporated in conventional medical regimens for reduced of heart failure. I know, as one of the investigators involved in the first positive studies using evidence-based beta-blockers of heart failure and as part of a core of investigators and clinician sciences who were tasked with communicating this to the community, I still remember the harsh pushback, the criticism of advocating for therapy that traditionally had been contraindicated. Then we come up with something that has unseated an agent that it took nearly 15 years to become embedded. We have always had to deal with this kind of clinical inertia. I think the real challenge, Peggy, it’s not really a specific issue with the ARNI compound. I think the real challenge is a challenge that exists today, how do we overcome clinical inertia when a new therapy emerges? We have seen it with ICDs. We are seeing it now with SGLT2 inhibitors. It is something inherent in the way that practitioners, physicians especially, incorporate new therapies. There is always a bit of tentativeness. They know the data, but they’re concerned about how will this respond, how will this work in my patients. It’s that my-patient question that continues to be top of mind for many physicians and many physicians still practice medicine from an experiential perspective. Yes, they know the data, but it really is based on what they have observed.

Peck: Well, I’m glad that you mentioned SGLT2 inhibitors because here is an interesting thing. With Sacubatril/ Valsartan, the PARADIGM trial was followed up in 2019 with the PARAGON-HF Trial, which was looking at preserved ejection fraction heart failure. That was 60%, or as some people call it mid-range, but I believe it was above 45 or above 40…

Yancy: Above 45.

Peck:: … above 45 up to 60 and looking for benefit. It did not meet its endpoint. The investigator at the time said it missed it. It was so close, missed by 7 cases was, I believe, the number. There was a trend that looked like it did meet the end point if you looked at a sub study in women. The sweet spot appeared to be 57%, that that seemed to be where things happened at that point.

That was reported in 2019 in Paris. Then at the same meeting, added to the program at the very last minute, became an SG LT-2 inhibitor trial, DAPA-HF. That was the one that had people dancing in the streets of Paris. Because it did everything and it combined it with… in some cases, some of the patients were actually taking the optimum therapy. The optimum background did include the ARNI therapy as well. They showed a benefit for hospitalization and a mortality benefit, a drug that was approved already out there. It’s already… You can write a script for it for if you are… talk about what happened then. This was the first time, by the way, when I interviewed you that you talked to me about heart failure as a continuum, is that maybe we need to step away from these numbers and look at this whole syndrome of disease.

Yancy: Well, that’s exactly right because the findings from WHF, and I continue to congratulate John McMurray on really a stunning study that has fundamentally changed the practice of medicine, really demonstrated that in addition to realizing yet another truly beneficial therapy it was important to really take a step back and think about what’s going on here. Because, once again, here is heart failure helping us appreciate that there is a certain complexity to this abnormal biology that leads to clinical LV dysfunction and symptomatic heart failure. It’s not just the RAAS system. It’s not just the sympathetic nervous system. It’s certainly not just ventricular modeling. There are other components that when managed well improve the outcomes.

I think that as we celebrate this benefit, we have to also question the mechanism, not because we are circumspect, but because we want to know what are we manipulating now. Why is it so much better? Can we capture this biology, refocus our efforts and target that biology for even better outcomes?

It really is a beautiful story when you go from the beginning, where we introduce randomized control trials, you go to the shift to where we focus on science and now you have yet a different shift, the shift that goes beyond the knowledge we previously had about the syndrome itself. We’re getting into a dimension that for lack of a better word probably is in metabolism of the myocardium, not in the hemodynamics, not in the ultra-structural components, but in the metabolism of the metabolic [INAUDIBLE 00:16:42] myocardium. That’s hypothetical, but that may be where the truth resides.

If we think about PARAGON-HF, there is even yet another contribution from heart failure. You realize that the sub-study pre-specified that show the efficacy of the RNA compound at the median LVF or lower has now since been the basis upon which a new drug indication has been granted by the FDA, one of the few times that a secondary outcome of an otherwise neutral trial has driven a new label indication. Lots of dynamics about the FDA and how that all has come about. I have an editorial in press right now about this whole thought process.

But nevertheless, another introduction arguing that sometimes there is more actionable data in a randomized control trial than just the top line results and maybe there is a way that we can get more traction out of studies than we have in the past. Again, heart failure leading the way. Once again, we have these great tools. As I said, this dawn that was introduced in 2014 continues to deliver.

A word about the data for women because it really does connect well with the final question you wanted me to address, like what is normal? We don’t know because normal has been defined by an ejection fraction and very malleable dynamic component. On any given day, Peggy, I can load your ventricle in a way that can make your ejection fraction go very low and I can unload your ventricle in a way that will make it go very high. Knowing exactly where your normal is it’s very difficult. Think about population normals.

We are beginning to realize other parameters, particularly strain, as a more precise way of thinking about the integrity of ventricular function. We are beginning to recognize that those that have extensively with a ejection fraction of 60 or greater, or 55 or greater, many times they have strain parameters consistent with systolic dysfunction.

Here is the point. Whether it’s in women or patients with HFpEF, we’re beginning to understand that the way in which we have identified and calibrated ventricular function is crude. We need to let research evolve new ways of understanding ventricular function so that our therapies can more capably match the phenotype. It may be the cardiac MRIs. How we get their strain almost surely is often of some benefit and maybe the natriuretic peptides can tell a story as well.

But we’ve really gone from A to Z with this where we had nothing, we introduced a new way of doing clinical trials, we introduced the focus on science, we were willing to challenge the conventional standards, we had eruptive discoveries, and now we’ve extended our discoveries into a new field that may explain the biology of LV dysfunction and clinical heart failure like we’ve never done before. We are beginning to challenge things like what is a normal EF. Is EF still a relevant parameter? It meets all the definitions, but does it do anything else? Stay tuned because heart failure is on this journey. The dawn was 7 years ago. The day is as we see it now. I think we have more runway. I think we have more discovery left to go. I have a nine o’clock call. I’m so sorry.

Peck: It’s always a pleasure to speak with you and I always enjoy your views in our conversations. Thank you very much.

Yancy: Thank you, Peggy. I really appreciate it.

Peggy Peck, Editor-in-Chief, BreakingMED™

Cat ID: 3

Topic ID: 74,3,730,3,914,192,925