Heart Failure Podcast

Nuanced Management of Heart Failure With Reduced Ejection Fraction (HFrEF): Select Patients

Michelle M. Kittleson, MD, PhD; Gregg Fonarow, MD


January 10, 2023

This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.

Michelle M. Kittleson, MD, PhD: Welcome to Medscape's InDiscussion series on heart failure. I'm your host, Dr Michelle Kittleson. This is episode two of our 12-part series, in which we first look at the six core challenges and issues affecting patient care, while our final six episodes tackle special concerns. Today, we'll discuss outpatient management of heart failure with reduced ejection fraction (HFrEF), with a focus on therapies indicated in special situations, [as a core challenge]. We all know that optimal quadruple therapy for HFrEF should be in the water supply — the ARNI (angiotensin receptor–neprilysin inhibitor), the evidence-based beta-blocker, the MRA (mineralocorticoid receptor antagonist), and the SGLT2 (sodium glucose cotransporter 2) inhibitor. But what about the other therapies out there? Where do they fit in our heart failure toolbox? For expert guidance on the use of ivabradine, vericiguat, isosorbide dinitrate/hydralazine, and transcatheter mitral valve edge-to-edge repair in patients with HFrEF, we've invited Dr Gregg Fonarow. He is the interim chief of the UCLA Division of Cardiology in Los Angeles, California. He also directs the Ahmanson-UCLA Cardiomyopathy Center and co-directs UCLA's Preventive Cardiology Program. Welcome, Gregg. I'm delighted to have you.

Gregg Fonarow, MD: Thanks so much, Michelle. It's really a pleasure to be with you here.

Kittleson: Let's start this discussion with a little bit about you. How did you know you wanted to work with patients with heart failure? What keeps you engaged today?

Fonarow: When I was first training as a resident in internal medicine at UCLA, these were among the most challenging patients I encountered throughout my residency. At that time, we had such limited options for these patients. We could control symptoms, [but] it wasn't entirely clear we had any medications that could alter their natural history and extend survival, and I was inspired by that challenge. Under the mentorship of Lynne Warner Stevenson, I decided to do a heart failure fellowship in general cardiology and was completely hooked.

Kittleson: Amazing. We all owe you and Dr Stevenson so much for our current understanding of the amazing armamentarium of therapies we have today. What a great lesson in the beauty of mentors to inspire you to career heights. Let's take a deep dive into these therapies. When should you reach for them? When should you pass? Let's talk first about ivabradine. Tell us about the mechanism, the evidence, and the guidelines. When do you use ivabradine in clinical practice?

Fonarow: Ivabradine is a really interesting form of therapy. It is derived from the remarkable findings for certain evidence-based beta-blockers having the most dramatic reduction in all-cause mortality seen and, of course, the mechanisms for that benefit. Beta-blockers have a multitude of benefits, which include blocking the dilatory effects of epinephrine and norepinephrine but also reducing heart rate. What we're seeing in the large trials that showed 34% or 35% mortality reduction is that at least some of that benefit seemed to correspond to the reduction in heart rate.

Ivabradine specifically targets the I f [I funny ] channel on the sinoatrial node, and it lowers heart rate. It doesn't have the adverse hemodynamic effects of beta-blockers and is very well tolerated. The SHIFT trial decided to test this on top of what, at the time, was background beta-blocker therapy — at least to the extent that clinicians thought was maximally tolerated — and patients were in sinus rhythm and still had a resting heart rate of 70 or greater. The SHIFT trial demonstrated approximately a 20% relative risk reduction in cardiovascular death and heart failure hospitalization, but it was mainly from the benefits driven by a robust reduction in heart failure hospitalization incremental to background therapy. The benefits were particularly evident for those with resting heart rates of 77 or above. The lessons there are as follows: Here is a therapy that is beneficial but additive to foundational therapies, with every effort made to initiate and uptitrate, if well tolerated, the beta-blocker. It really has a benefit, though, in particular patient populations — so, those on maximally tolerated beta-blockers in whom the resting heart rate is 77 or above.

The other group commonly overlooked are those who cannot get on or tolerate any dose of a beta-blocker and tend to move on to other therapies. Here's a drug that can be used in these patients, is well tolerated, and lowers their risk by subgroup analysis about a 15% shift. They were on no beta-blocker therapy and had on the order of a 40% reduction in the composite endpoint. Now, it's a subgroup analysis, but I think it really fits with the mechanism.

Certainly, atrial fibrillation patients don't benefit from this drug. So, don't just start a low dose of a beta-blocker and then reach for this. But here is a drug we can use to meaningfully reduce the risk of hospitalization. In fact, heart failure mortality was reduced by 26% in this trial. It's an important therapy that gets a class IIa recommendation in the guidelines, but it's for select patients and on top of foundational medical therapies for HFrEF.

Kittleson: Dr Fonarow says it best; that was perfect. I think we should all remember that when you reach for the clicker on your mouse, in your electronic medical record to prescribe ivabradine, you should feel a little tingle on the back of your spine and ask yourself, "Have I maximized the beta-blocker first?" If you have, and the patient's heart rate is still above 70, or 77 for ideal benefit, then your conscience is clear, and you move forward. Excellent. Now, we move on to isosorbide dinitrate/hydralazine. Tell us, who's the ideal patient to receive this therapy?

Fonarow: Yes, that's such a great question, and the honest answer is that we haven't fully defined that. If you go back to the original V-HeFT study, there were hints of benefit overall, but it really wasn't clear and by its prespecified P value wasn't even quite significant when compared with an ACE (angiotensin-converting enzyme) inhibitor. In V-HeFT II, the ACE inhibitor was a clear winner. In looking back at those trials, the subgroup of patients who identified their race as Black had a 49% or 50% reduction in the endpoints, whereas in the other patients, there was not even a hint of benefit. The traditional use had been in patients who couldn't be on neurohormonal antagonists or had significant renal dysfunction that was limiting the use of an ACE inhibitor or angiotensin receptor blocker.

The A-HeFT trial, though, gave us valuable insights — particularly in those self-identified as African American on background triple neurohormonal antagonists as well tolerated. You did see this pretty significant reduction in composite endpoint mortality and improvement in quality of life. So, that's really the group in whom this drug can be utilized. There are challenges, though. It's taken either twice a day, or if you're not using the fixed-dose combination, it can be three or four times a day. There can be headaches and tolerability problems. The ideal population is those who are on foundational medical therapy or self-identify as Black, and for whom this is an important additional therapy. For those of other races, we really don't know for sure. We've looked at some observational data to try to find the ideal candidate for this drug who's non–African American, and have not seen any benefit associated with its use in non-African American subsets. So, this is a challenging class of drug. I should also say having a race-based indication for the drug has been very controversial and has limited its use. There's still more to learn. The guidelines give the drug a class I recommendation for self-identified African American patients with HFrEF on background medical therapy who are still symptomatic to be treated with hydralazine nitrates. In other patient subgroups, it's a much lower class IIb "selective" or "consider" type of indication.

Kittleson: Perfect. I think it comes down to that same "tingle in the back of your spine" when you're clicking the button to prescribe the medication. It is not a knee-jerk soundbite that if you are a Black American with HFrEF, you get isosorbide dinitrate/hydralazine. No, it's if you are a Black American with HFrEF who is already maximized on the best quadruple therapy and you still have blood pressure room to go — and there may be patients who still do — then and only then do you reach for isosorbide dinitrate/hydralazine based on the evidence and guidelines we have. Now, moving on to a newer kid on the block — vericiguat. Tell us about this medicine. The VICTORIA trial showed us a reduction in the composite of heart failure hospitalization and cardiovascular death. Yet, it receives a relatively weak class II indication in the guidelines — that is, "may be considered." Why no love for vericiguat? Who do you think should be on it?

Fonarow: That's such a great question. Our evidence base here is evolving. This is, you know, a soluble guanylate cyclase agonist, really trying to augment that system and in some ways counteracting the dilatory vasoconstricting neurohormones but downstream. It was safe, it was well tolerated, but it was studied in a specific population — those hospitalized with worsened heart failure recently or on background medical therapy at the time, who then started on the vericiguat therapy, which was really safe and very well tolerated. But the overall composite endpoint was a 10% relative risk reduction, which is less than we've seen with some of the other drugs that are utilized and have been considered foundational.

There were also some interesting subgroup analyses, in which the quartile with higher N-terminal pro–B type natriuretic peptide (NT-proBNP) levels was above approximately 5000. The hazard ratios actually were above one and a signal, potentially. Again, not something we can completely pin down. This is a drug that may be considered for reducing cardiovascular death or heart failure hospitalization in appropriate select patients. SGLT2 inhibitors weren't around at the time the trial was being conducted, so there is a question as to how much additive benefit may be there. It's for those reasons I think the guidelines were relatively conservative with the class IIb recommendation. But that doesn't mean that for the select patients who have had recent worsening of heart failure despite optimal background therapy, or in whom you've optimized therapy and they remain symptomatic, it shouldn't be considered. There wasn't much seen as far as quality-of-life improvements, so that's a consideration. Cost-effectiveness and those other aspects are still being explored. But this does represent an additional therapy. However, we really want to know about milder outpatients with heart failure. Could there be a role for this drug in those patients? There is a large trial that's been organized, so more information's going to be available that will strengthen our evidence base and help us better define who is the ideal candidate for vericiguat.

Kittleson: Again, we have this "tingle on our spine." We must remember that these therapies, as you noted, are not foundational. They are complementary. They're not the Thanksgiving turkey that is de rigueur. It's the cranberry relish you may need on the side. We've run the risk of polypharmacy, so we should be very careful about which drugs we give our patients. The other point I'd like to amplify is that these are sick patients. They are symptomatic with HFrEF and have had prior hospitalization, so vericiguat may be the first step, but it shouldn't be the last. This sick population also needs a discussion now about advanced therapy. So, when you're reaching for ivabradine because your patient can't tolerate a beta-blocker or you're reaching for vericiguat because they've been hospitalized, these are sentinel events that speak to potential advanced heart failure, in which more things need to be done. Would you say that's fair?

Fonarow: I agree. We really need to feel that any hospitalization for heart failure or any worsening of heart failure, even in the outpatient arena, is a sentinel event, in which we need to look at a patient's therapies, and we need to make sure the foundational therapies have been initiated and their dosing optimized. With any medication that was stopped, was it stopped for an absolute contraindication, or should we try to reintroduce it? And then optimize those therapies, but also think, "Okay, what else is necessary?" What are the potential precipitating factors or comorbidities that could potentially be managed in a way that will further improve outcome? Why are we considering these additional adjunctive therapies?"

Kittleson: Now we're going to move a little bit away from the pills and into the interventional world of transcatheter edge-to-edge repair — TEER, as it's called in the guidelines of the mitral valve — a catheter-based procedure. Tell us the theory of why it should work, the evidence for when it works, and when it doesn't work. What do the guidelines say?

Fonarow: This evolution is so interesting. Some of the earliest models for creating heart failure in the lab were to damage the mitral valve. If you cause severe MR (mitral regurgitation) in the animal models, they will reproducibly develop a nonischemic cardiomyopathy and worsened heart failure. There's been a long-standing theory: This extra volume overload, concomitant with having moderately severe or severe MR, leads to adverse remodeling and further neurohormonal activation in the worsened heart failure state. There have been attempts to demonstrate through surgical repair of the mitral valve that outcome could be improved. The data weren't from good randomized controlled trials; they were really mixed and very controversial. They never ultimately demonstrated the evidence base.

Then, with the edge-to-edge repair, transcatheter-based therapy, we could reproducibly reduce that MR, the nonmechanical functional MR we see in our patients with ischemic and nonischemic cardiomyopathy and heart failure. We had a MITRA-FR study, the results of which were relatively neutral, and then the remarkable benefits in the COAPT trial. I think what distinguishes the COAPT trial is that there was a dedicated effort to truly optimize guideline-directed medical therapy again and again, as well as optimizing volume status, and to reassess the MR, making sure these patients still had medically refractory, moderately severe, or severe MR. When doing that, you saw these remarkable benefits, the number needed to treat to save a life was five. You saw these incredible early reductions in hospitalizations compared with optimal medical therapy alone. So, it really defines a patient population that can benefit from this treatment. But what's so important is the multidisciplinary team that's truly optimized the care of this patient population. Each of our guideline-directed medical therapies can reduce MR. So, if you can be on a medication and achieve this, that's the way to do it. But if you've really optimized the meds, the volume status, and technically, you get a good result, we see this remarkable early profound magnitude and meaningful benefits — improvement in quality of life, reduction in hospitalizations, reduction in rehospitalizations, and meaningful extension of survival. So, the reason for a class I–type recommendation is that the guideline is for the appropriate patient. So much of it depends on all the work by that multidisciplinary team to select the right patient, achieve the good outcome, and ensure the maintenance of those medications.

Kittleson: It's such a fascinating story on every level — not just the science of it, but the overall lessons we learn from randomized clinical trials. We're all taught in medical school that in the hierarchy of evidence, there's nothing like a randomized controlled trial to uncover the truth. But it all depends on who you enroll in that trial. What an amazing lesson. MITRA-FR might have taken patients who, as you noted, were too sick, too far gone, and their ventricles were too dilated; their ejection fractions were too low; and their pulmonary artery pressures were too high. Or, the study might have taken patients who were too well. Investigators didn't bother to try to fix this dynamic volume-sensitive, afterload-sensitive lesion by optimizing them before they went in. How lucky we are that COAPT and MITRA-FR both happened, so we'll know when it works and when it doesn't. Remember that tingle in the back of your spine — when you reach for prescribing ivabradine or isosorbide dinitrate/hydralazine or vericiguat. Well, you should feel a full-on shock to the system when you want to send someone for the transcatheter edge-to-edge repair of their mitral valve because this is a huge intervention. Although it's very well tolerated, when you want to do something interventional to a patient, you really want to make sure they'll benefit from it. So, I think you couldn't have put it more beautifully.

Fonarow: Yes, I would add that emphasis: It's the team, right? Because one physician seeing a patient doesn't have that full aspect. Even then, the advanced practice nurses are working to make sure the patient really adheres to the regimen and is monitoring their volume status. Then, the noninvasive imagers give us that valuable monitoring information to help guide the procedure — if that patient is the appropriate candidate. All of that is so critically important. It just reinforces the value of that true multidisciplinary team in managing these patients.

Kittleson: So, what's the one thing you want listeners to do differently after hearing this podcast?

Fonarow: I want to emphasize what you started off with, which was covered in episode one of this podcast — that the foundational guideline-directed medical therapy is so critical and time critical. In the past, we've taken a more lackadaisical approach that we could start one medication at a low dose, go slowly, and focus on just that medication, so we have the leisure time to then start the second medication and then get around to the third medication. The challenges there are when clinical inertia takes over, and a lot of the subsequent lifesaving medications get overlooked or don't get uptitrated. We don't have that leisure time. These medications all work within days of initiation. Thus, if we're waiting even 30 days to start one or more of these meds, events can happen that we could have prevented. We have seen that we can start these therapies at low dose simultaneously or in very rapid sequence and get these very early remarkable benefits and get the patient off on the right course with marked improvement in their functional capacity, reduced risk of hospitalization, and improvement in ejection fraction where they may not require an ICD (implantable cardioverter defibrillator) they otherwise would have. And, of course, we see the remarkable early cumulative benefits in all-cause mortality. So, whether you like to refer to them as the Fantastic Four, quadruple therapy, comprehensive disease-modifying medical therapy, or guideline-directed medical therapy, the key is getting a patient on these therapies early, uptitrate if well tolerated, and then build from there for these select patients who still continue to be symptomatic or haven't experienced a full response.

Kittleson: So, what we've learned today is that comprehensive, foundational, quadruple therapy is the absolute baseline essential element. After that, if your patient is on maximally tolerated beta-blocker, with a heart rate over 70 and no atrial fibrillation, you can reach for ivabradine. If they are self-described as African American and symptomatic with blood pressure room after maximum doses of quadruple therapy, you're allowed to reach for isosorbide dinitrate/hydralazine. If they have been optimized on quadruple therapy as tolerated and are hospitalized, you may consider vericiguat. If — and only if — your multidisciplinary team approach to optimization has resulted in persistent moderate to severe symptomatic MR with appropriate ejection fraction, left ventricular size, and pulmonary artery systolic pressure criteria, you are allowed to refer the patient for transcatheter edge-to-edge repair.

There are so many highlights into the subtleties that can help our patients feel better and live longer. Dr Fonarow, thank you so much. It's been such a pleasure.

Fonarow: Thank you, Dr Kittleson.

Kittleson: Thanks for joining us for this 12-part conversation on heart failure. There's much more ahead in the coming episodes. I'm Dr Michelle Kittleson for Medscape InDiscussion.


The Use of β-Blockers in Heart Failure With Reduced Ejection Fraction

I funny Channel Inhibitors: An Emerging Option for Heart Failure

Ivabradine and Outcomes in Chronic Heart Failure (SHIFT): A Randomised Placebo-Controlled Study

Effect of Vasodilator Therapy on Mortality in Chronic Congestive Heart Failure

A Comparison of Enalapril With Hydralazine–Isosorbide Dinitrate in the Treatment of Chronic Congestive Heart Failure

Neurohormonal Activation in Heart Failure With Reduced Ejection Fraction

Combination of Isosorbide Dinitrate and Hydralazine in Blacks With Heart Failure

Hydralazine and Isosorbide Dinitrate in Heart Failure

Vericiguat in Patients With Heart Failure and Reduced Ejection Fraction

Soluble Guanylate Cyclase as an Emerging Therapeutic Target in Cardiopulmonary Disease

A Study of Vericiguat (MK-1242) in Participants With Chronic Heart Failure With Reduced Ejection Fraction (HFrEF) (MK-1242-035) (VICTOR)

Percutaneous Repair or Medical Treatment for Secondary Mitral Regurgitation

Transcatheter Mitral-Valve Repair in Patients With Heart Failure

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