COMMENTARY

Calling Time on the Failure in Heart Failure

An Interview With Clyde Yancy, MD

Interviewer: Robert A. Harrington, MD; Interviewee: Clyde W. Yancy, MD, MSc

Disclosures

April 24, 2019

Robert A. Harrington, MD: Hi. This is Bob Harrington from Stanford University, here on theheart.org | Medscape Cardiology. At the end of last year, Mike Gibson and I did a podcast on some of the big developments in cardiology in 2018 that had occurred during the year, and then we did a second podcast on what we were looking forward to in 2019.

Both of us are interventional cardiologists and we talked a lot about ischemic heart disease, interventional cardiology, and new technologies like digital and artificial intelligence. But it was pointed out to us that we were a little thin on our coverage of heart failure.

https://twitter.com/NMHheartdoc/status/1096480540809707521

I think the criticism was warranted because this is one of the most important diseases, syndromes, and sets of patients that all of us who practice cardiology are faced with. It's important to review new thinking and observations that were made in 2018. In addition, it's critically important to review things being done to help us understand the heart failure patient, mechanisms associated with heart failure development, and, most of all, therapies that might benefit these patients.

I'm thankful for the criticism from my good friend and colleague, Clyde Yancy, and for his joining us today to discuss heart failure. Clyde is professor of medicine and the chief of the Division of Cardiovascular Medicine at Northwestern University Feinberg School of Medicine, where he also serves as the vice dean of diversity. Clyde, thank you very much for joining us today on Medscape Cardiology.

Clyde W. Yancy, MD, MSc: Bob, I'm delighted to be a part of this conversation and to work with you and your colleagues at Medscape Cardiology. Even though my first outreach to you was almost tongue-in-cheek, I really was insistent on having an opportunity to express the heart failure voice—not because we think there should be fair billing, but because there is something to say. As we think about the aggregate data that have come forward since 2018 and what we expect in 2019, there is reason for a lot of excitement in heart failure.

I've even recently recorded a piece saying that maybe heart failure is becoming "sexy." A play on words, obviously, but it is intriguing and interesting, and we want to help promulgate that message as much as we can, so thanks for this opportunity.

Burden of Heart Failure in Society

Harrington: You are the perfect person to discuss heart failure, given your clinical and research background, but also given your role in the development of the heart failure guidelines over the past few editions. Let's start with the overarching comments. Give us a sense of the burden of heart failure in the United States.

Yancy: This is an excellent way to begin because we have recited statistics for decades. We keep saying that 5 million people or so have heart failure, but what we know now is that heart failure, for the most part, is a disease or a condition of becoming older. The successes we've achieved with acute ischemic syndrome, valvular heart disease, and now hypertension are coming together to amplify this signal on heart failure.

We believe that by 2025 to 2030, that number of 5 or 6 million will be between 8 and 10 million. Now we're talking about a public health crisis and a huge consumption problem for our healthcare resources. It really shifts our awareness to trying to understand how we got here and determining whether we can do anything to prevent it.

Prevention

Harrington: Let's jump right into prevention. Since we thought that ischemic heart disease might lead to at least one syndrome of heart failure, we used to think that prevention of heart failure was really around dealing with atherosclerotic disease. You have been pointing out lately that there are important issues around a heart-healthy lifestyle and the intersection of diabetes, obesity, and hypertension that are driving heart failure. Why don't you talk about some of the new developments in thinking about the prevention of heart failure?

Yancy: This is the critical piece for everyone who is listening: Ostensibly, we can prevent heart failure. That has more heft to it than you think, because what we've known all along is that we don't have a cure for the condition that occurs. We can improve outcomes for certain. Once heart failure occurs, it fundamentally redefines the trajectory of life and living for the person affected. Getting to the patient before that negative inflection point happens on their life trajectory could not be more important.

We've known since 1971 that there was an unbelievably tight alignment between a history of hypertension and the development of heart failure. Those data came from the seminal landscape observations in Framingham.[1] They have been endorsed time and time and time again. The critical new piece of information is a direct output from the SPRINT trial.[2] If we target an out-of-clinic blood pressure of ≤ 120/80 mm Hg or an in-clinic blood pressure of 130/80 mm Hg in those at increased cardiovascular risk, we are able to reduce the incidence of new-onset heart failure requiring hospitalization by nearly 40%.

In my mind, that is a huge pause moment, because there is something fundamental about becoming so sick from heart failure that you require hospitalization. It changes everything. Nothing can be more important than getting there early. When we further backfill this imperative to get there early and start disease-modifying drugs and lower blood pressure as appropriate, we now have an unbelievably growing dataset that says biomarker screening can help us better discriminate who might benefit from a more aggressive assessment of ventricular function and early initiation of therapy.[3]

There is much excitement about this opportunity to prevent heart failure, and that is just focusing on hypertension.

Harrington: The SPRINT data are very compelling and there are many reasons to be more aggressive in our treatment of blood pressure. When you walk patients through the things that they can prevent by better treatment of their hypertension, heart failure really resonates with them, doesn't it?

Yancy: Absolutely, because you know what? One in five Americans will get heart failure during their lifetime. This is not a disease about them; it's a disease about us. Everyone knows someone with heart failure. Physicians have been consulted formally and informally about this condition, so it really does reflect an everyday book of knowledge that we need to possess.

It goes to the next level because, remember that the important new guidelines on hypertension[4] articulate that lifestyle adjustment is the first, second, and third step unless blood pressure is extremely elevated. This intersects so well with what we're talking about in regard to heart failure. Life's Simple 7, which has been extant since 2010, now has a fairly good dataset to indicate that people who incorporate those seven attributes into their daily life and living have dramatically reduced likelihood of having heart failure.[5,6]

We can extend this to diabetes and understand that we have new therapies that are consistently showing a signal—not of cardiovascular harm or even neutrality, but of benefit (benefit being defined as a reduction in the instance of heart failure).[7] Now we can pull three powerful switches to prevent heart failure: adequate control of blood pressure; incorporation of lifestyle adjustment; and when diabetes is present, utilization of new therapies that have been consistently shown to reduce the incidence of heart failure.

To think that you can prevent someone from the consequences of heart failure is cause for excitement.

Harrington: You could not be more right about the data on sodium glucose cotransporter-2 (SGLT2) inhibitors and diabetes. This was not anticipated when the trials began. Most of these big diabetes trials were looking to see if the new therapies did not cause cardiac harm. This finding on the reduction of heart failure emerged very consistently across the datasets.

This is a perfect example of clinical data driving bench scientists to go back and say, "This observation appears to be real. Let's now search for the mechanism so we can understand it and pursue new directions to help our patients."

Yancy: It was so fun when we first saw these data. My lens was thinking about heart failure: "Eureka! We have another tool in the tool chest!" And your lens was as a clinical trialist: "Huh? We need to figure this out."

It came together so that we now have three different datasets in the same drug class—three different datasets[7,8,9] that say the signal is real and that it's worth our attention.

Best Practices: Some Good and Some Sobering News

Harrington: I would like to touch on treatment of the patient with reduced ejection fraction (HFrEF) and treatment of the patient with preserved ejection fraction (HFpEF)—not broadly but just a couple of key issues in each.

Let's do HFrEF first. Boy, there was a lot of evidence over the past year, finding that doing simple things like adhering to guideline-directed medical therapy is still pretty valuable.

Yancy: Let me show you the goalpost in this discussion because this really is another seminal piece of information for our listeners to capture. We know that when best practices are exercised, the outcomes can be better than we ever thought.

That is really good news.

The other part of this goalpost, which is the opposite end of the spectrum, is very sobering. Despite the fact that we've got well-articulated guidelines supported by robust evidence, real-world application of these evidence-based strategies fails miserably. In patients eligible for guideline-directed medical therapy as derived from the recently released CHAMP-HF registry, only 25% were on one of each of the three drug classes of a renin-angiotensin system (RAS) inhibitor, an evidence-based beta-blocker, and a mineralocorticoid antagonist.[10] Only 1% were on a candidate drug from each drug class given at the doses prescribed in the clinical trials. That is an enormously big missed opportunity.

[M]aybe right now we don't need another major breakthrough at the bench; maybe we need a breakthrough at the pill bottle.

There are some themes our listeners can walk away with. Number one, there are ways to prevent heart failure; and number two, let's keep it simple and do the things we know will work to make a difference.

Harrington: As I talk to cardiology fellows and other young clinical scientists, I point out all the time that health services research implementation science is a really hot area because of the data you have just shared. We don't necessarily need everybody studying brand-new therapies. We need some people who are very engaged with the tools of implementation science. Are you talking to your trainees about those topics?

Yancy: Absolutely. We are training our trainees to take a deep dive into those topics. We have young fellows focused on wearable technologies and some becoming expert in bioinformatics. We are trying to understand how we can use data. How can we make it so that the electronic health systems that we all bemoan actually can enable? Is there a way we can do this? Can we build crisp decision tools that will make it so much easier to screen patients and identify those that are candidates for evidence-based therapy, and introduce the right prompts to make all this happen? We are fully invested because we realize that maybe right now we don't need another major breakthrough at the bench; maybe we need a breakthrough at the pill bottle. If we can make that happen, it could be a big difference.

Mitral Regurgitation, Atrial Fibrillation

Harrington: I completely agree with you. Let's quickly do a nod to our interventional colleagues and discuss treatment of mitral regurgitation (MR) and treatment of atrial fibrillation (AF). There were potentially big findings over the past year to aid in the HFrEF population.

Yancy: I knew the world was beginning to spin differently when all of a sudden the interventional world was inviting me to their meetings and wanted commentary on heart failure. I was like, "Whoa, stop the presses. Something just happened here." It's precisely because these new interventions that appear to be quite impactful are selectively improving the trajectory of those with heart failure.

We're thinking about the re-apposition of mitral valve leaflets in the setting of severe MR that goes beyond that which seems appropriate. We're talking now about functional MR and being able to fundamentally improve outcomes. That is great information. COAPT data[11] need to be celebrated as a major contribution. Then, getting back to implementation, how do we go beyond that group of really skilled clinical trialists who perform COAPT and make it broadly available to the community for the right patient? More of a tangent, how do we identify the right patient, given that our data are in contradistinction from MITRA-FR[12] in the European space?

Then we think about AF. We're still trying to wrestle with this. We know that the concurrent presence of AF in heart failure is "badness," as we used to say back in the Deep South. When we think about how can we modify that pairing and improve outcomes, ablation makes sense. But before ablation, it was really about rate control in the setting of AF, less so than rhythm control.

We have two signals—and I'll emphasize signals now—that ablation might be beneficial in the setting of heart failure when AF is present.[13] I'm on the AF guideline writing committee; we wrestled with the dataset and we came back with the best response we could. It's a class IIb recommendation, meaning highly selected, uncertain of the real benefit, but something that goes into your decision tree.

We'd like to see that signal become more crisp. I am reassured from the CABANA quality-of-life data,[14] led by your former colleague and my friend, Dan Mark, that quality of life does improve after ablation for AF. I think that is smart because that is really why we send patients for ablation. Patients want to feel better. Let's call it a day; we can help patients feel better. Those are two device findings that intersect.

I knew the world was beginning to spin differently when all of a sudden the interventional world was inviting me to their meetings...

Harrington: It's really important that we're starting to bring together disciplines outside of "the traditional group" to care for the heart failure patient.

Yancy: It's excellent because that means that everybody needs to get involved in screening for heart failure now. We will have to build different systems of care and different referral patterns, but that is all for the good. Look at what has happened with aortic stenosis; it's not a quiet diagnosis anymore. Everybody has their antenna raised and it's helping patients. Hopefully we can do the same thing.

You made an important statement about HFpEF, and I don't want to miss the opportunity to let all the listeners know that 2019 is a big year for HFpEF. Results of PARAGON-HF,which is testing the angiotensin receptor–neprilysin inhibitor with valsartan in the setting of HFpEF, will come out probably in the second half of the year, maybe coincident with European Society of Cardiology or with the American Heart Association meeting in November. Boy, no matter what the results are, they will make a difference.

If it is another negative trial, it really will tell us to hit the kill switch and that we have to completely start over and further dissect this condition into its component parts. A hint or signal, especially if positive, will be a moment for us to celebrate, much like we've celebrated with some of the recent trials, because it will have direct clinical application. That is really important.

Harrington: I've been really impressed by the work of your colleague, Sanjiv Shaw, and how he has made a compelling case that HFpEF is not a disease but is multiple diseases or multiple syndromes.[15] I look forward to seeing more of that work. My guess is that as we think about precision-based medicine, we're going to see diseases reclassified and recategorized, and then we're going to look for therapies within those categorizations. I'm very excited by that work.

Yancy: I agree with you and would take it to the next level, because you and I both are in situations where we train medical students, residents, and fellows. What a beautiful model to share with others, because here is a physician that we've been able to shepherd through all of these phases. Look at the extraordinary contributions, whether it's phenomapping in HFpEF, creating an interatrial shunt for those who have HFpEF with pulmonary hypertension, or dealing with infiltrated diseases like amyloid cardiomyopathies.

It's just stunning, as someone who still has a teacher's DNA somewhere buried inside of me, to see a student, now a mature faculty member, really emerge owning so much of one particular space. That makes coming to work worthwhile.

Mid-Range Ejection Fraction

Harrington: There are a lot of lessons there. As we close, let's discuss the midrange ejection fraction (EF), because until I started hearing you at some of the meetings, I was not even aware of the phrase "heart failure with midrange ejection fraction." Would you want to first describe it for the audience? Tell us what is hot in this area and what they might expect in 2019.

Yancy: Heart failure with midrange EF is defined as EF > 40% but < 50%.[16] It's not just a quirk of having one eye open and one eye closed in the echo lab. There is something unique about being in that midrange, particularly when the path the patient has followed to get into that midrange started off with HFrEF. That is what has so many of us enthused.

What is happening in about 15% of patients with HFrEF that allows them to respond so robustly to evidence-based therapy and end up with a residual ejection fraction > 40%? As you point out in thinking about outcome sciences, the entire consistency of the signal demonstrates that when that event occurs, the outcomes are better. There are fewer hospitalizations and better survival.

We want to enable this, right? It's been a great opportunity for us to understand who those patients might be. Can we identify it a priori? But as we get excited about the science, as we discriminate that there is this new phenotype, we have a major reason to be careful because we know that every clinician has seen one or two cases (and lots of cases in my practice) where people get better.

Do you just say, "Wow, we dodged this; it's a great thing"? What happens when the patient says, "Okay, I feel better and you tell me the numbers are better, so do I have to take all this medicine?" And then you have this blank stare.

We now have the data from TRED-HF.[17] We helped in the orchestration of the study and the messaging when the study came out in the Lancet. It was important to demonstrate that even in those people where there was overwhelming evidence that they truly were better (I'm being careful with my words saying "better," not "recovered"), within 8 weeks after the medicines were systematically withdrawn by protocol, over 40% had recrudescent heart failure.

This whole concept of failure in the phrase 'heart failure' is not obligatory.

The word is not "recovered"; the word is "remission," akin to the cancer parallels, and that is okay because the outcomes are so much better and the patients are better. We're excited about this because we want to know how you go from being low to midrange. Can we manipulate this? Can we reaffirm that the patient will do better? Can we also understand what is the least burdensome medical profile that we need to maintain so that the patient is less encumbered but still has the benefit of having improved?

We already know not to discontinue implantable cardioverter defibrillator therapy because they are still at risk for sudden death. It's exciting because it gives us something new to discuss or explore, but also it gives patients hope.

This whole concept of failure in the phrase "heart failure" is not obligatory. It is not obligatory. Many of us are stridently in favor of finding a way to take failure out of the discussion until we get into the advanced clinical syndromes.

That very nomenclature probably has handicapped us for several decades. We have enough tools now where we can say that the failure in heart failure is no longer obligatory.

Harrington: That is a great way to end, because the discussion that has been taking place and led in part by you is that words do matter. And the words that we use to convey information to our patients really matter. Given that we have ways now to prevent heart failure, to treat various syndromes of heart failure, and to think about the development of new therapies, while at the same time applying known therapies, the future is really bright. Your community, which has really been working hard over the decades to deal with this big patient population, deserves a lot of credit for sticking with it.

Clyde, I'm going to have you back to do some of the other topics that we've discussed. Maybe one we will discuss is the salt debate.[18] How we think about salt versus the totality of nutrition is a whole other topic for heart failure prevention and treatment.

Yancy: I can't wait to have that conversation.

Harrington: I want to thank my friend and colleague, Clyde Yancy, professor and chief of the Division of Cardiology at the Northwestern University Feinberg School of Medicine, where he's also the vice dean of diversity. Clyde, thank you for joining us, and thank you, the listener, for spending some time with us to talk about heart failure.

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