Heart Failure With Preserved Ejection Fraction: New Treatments Provide 'Hope'

Clyde W. Yancy, MD, MSc; Ravi B. Patel, MD, MSc


March 28, 2022

Editorial Collaboration

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This transcript has been edited for clarity.

Clyde W. Yancy, MD, MSc: Hello. This is Clyde Yancy, professor and chief of cardiology at Northwestern University Feinberg School of Medicine and a longtime investigator and an author for the American College of Cardiology/American Heart Association guideline for the management of heart failure.

I'm delighted to have one of my rising-star colleagues with me today, Ravi Patel. Dr Patel has expressed and is executing a really profound interest in heart failure with preserved ejection fraction (HFpEF). We're taking advantage of his expertise and his growing awareness of this condition, as well as the benefit of his lens, which really formulates what the next generation anticipates in the treatment of patients with all forms of heart failure — in this case, we focus on HFpEF. As our discussant, Dr Patel will help us profile what we understand to be new and different about the treatment of HFpEF. Let me set things up.

We have the benefit now of a new universal definition that helps us understand who has heart failure and who doesn't. Importantly, it once again partitions heart failure according to the ejection fraction. This is a very important discussion. This isn't a nuance. This is actually a development. Yes, HFpEF still refers to heart failure with a left ventricular ejection fraction (LVEF) ≥ 50% that is a symptomatic condition.

Now, we understand that there is a newly defined phenotype, heart failure with mildly reduced left ventricular ejection fraction (HFmrEF) that is between 40% and 50%, inclusive of 41% and 49%. This enters into our conversation as well. There's another very important phenotype of patients, defined as heart failure with improved left ventricular ejection fraction (HFimpEF); those who previously had a very low ejection fraction of ≤ 40, and in response to evidence-based therapy with medicines and/or devices, now has realized a ≥ 10% improvement to > 40%.

When we begin to talk about HFpEF, and particularly when we think about the entry criteria for some of the clinical trials, we really are deciding that our cut point is at a LVEF > 40%. That dramatically changes the conversation. That's the first big point.

I'll take advantage of this opportunity to remind everyone about the history of HFpEF. For a long time, we've been frustrated. I've been the lead author for the guidelines, and we focus less on therapeutic interventions and more on addressing comorbidities and especially on prevention, particularly controlling blood pressure and rate response to atrial fibrillation, especially in older persons.

Only now have we been able to talk about specific interventions for HFpEF, and we still are without an agent that attenuates mortality. That gives us the set up where we've been historically, but also helps us understand from a point of definition and a contemporary context the correct patient population.

With that in mind, Dr Patel, welcome. Please tell everybody about yourself. Give us your credentials, and particularly, describe your scope of interest academically and clinically.

Ravi B. Patel, MD, MSc: Great, thanks so much for having me. My name is Ravi Patel. I'm a heart failure cardiologist at Northwestern University Feinberg School of Medicine. My primary clinical practice involves patients with — exactly, as you said, Clyde — HFpEF, that is LVEF ≥ 50%. This is also the basis of my research.

First Look at New Therapies

Yancy: Let's talk about the contemporary treatment of HFpEF. Let's set this up as we do as clinicians. Someone comes to see us. LVEF is 52%. It's an older woman with concomitant obesity and diabetes, and she is terribly symptomatic with limited exercise capacity and an unacceptable quality of life. Talk us through your evaluation process, how you want to approach this patient, and ultimately, what interventions you think would be best.

Patel: Great. I think that sounds like a great setup. This type of patient that you described is very typical of what we see in our HFpEF clinics: patients who are extremely debilitated from an exercise perspective. They're short of breath with limited activity and they can't do what they want to do on a day-to-day basis. When we see these patients in clinic, primarily, our perspective on treating these patients has changed within the past 2-3 years.

First, the PARAGON-HF trial demonstrated that in certain individuals with "heart failure with preserved ejection fraction," and I use that term in quotations based on the expanded universal definition discussed, sacubitril-valsartan may prove beneficial in reducing one's risk for a composite of heart failure hospitalization and cardiovascular death. [Editors' Note: In this trial, participants were randomly assigned to be treated twice daily with sacubitril-valsartan or valsartan alone. The primary composite outcome of total hospitalizations for heart failure and death from cardiovascular causes did not differ significantly between the two groups. There were fewer primary outcome events with sacubitril-valsartan than with valsartan, and the authors reported that an analysis of investigator-reported primary outcomes suggested a benefit of this therapy.]

Particularly in PARAGON-HF, we see that this exact patient that you've described may benefit from this medication. Women tended to benefit more than men in PARAGON-HF from sacubitril-valsartan. Second, there was an interaction by ejection fraction. That is, those individuals in PARAGON-HF who had ejection fractions slightly on the lower end of "normal" tended to benefit more from this medication as well. That differentiated by sex. This is a controversial aspect of the field and it is something that's evolving on a day-to-day or month-to-month basis.

Sacubitril-valsartan, I think, would be a medicine that could be of particular benefit in this patient. That was the first of the next few trials in HFpEF that started to yield potential new drug classes for HFpEF.

Yancy: Let's remind the audience that this is not a theoretical conversation, the FDA has extended the indication for the combination of sacubitril-valsartan to include symptomatic heart failure with an abnormal ejection fraction. Ostensibly, that's an ejection fraction < 60%.

We have an FDA indication. We have an evidence base that supports this, and we could go forward. Let's enrich the phenotype. This is a patient that is obese, probably has cardiometabolic parameters, the same symptomatology. You've given thought to sacubitril/valsartan. What's the next drug class that you might consider?

The Role of SGLT2 Inhibitors

Patel: The next drug class is one with which all aspects of cardiology have become more and more aware, and the HFpEF field is no stranger. With the results of the EMPEROR-Preserved trial we have, in the history of HFpEF clinical trials, our first positive trial, and a monumental moment. A trial evaluating the efficacy of empagliflozin (a sodium-glucose cotransporter 2 [SGLT2] inhibitor) vs placebo in HFpEF. This is the ideal patient who may benefit from this medicine.

EMPEROR-Preserved demonstrated a reduction in a composite endpoint of heart failure hospitalization and cardiovascular death. As you mentioned, Clyde, this efficacy was driven by a reduction in heart failure hospitalization. The class of SGLT2 inhibitors would be, certainly, a medicine that would provide much benefit not only from a reduction in heart failure hospitalization perspective, but a marked improvement in symptoms.

Yancy: That may be the most important thing because we've got yet another trial, CHIEF-HF, which demonstrated that we can uniquely improve quality of life. In the older patient, it may be that morbidity benefit, staying out of the hospital, and feeling better are really most important. We realize that there are more evidence points coming forward. We have another trial that we're anticipating. Tell us about the next trial with dapagliflozin.

Patel: Yes, absolutely. There has been, as you mentioned, the CHIEF-HF trial, which has shown a benefit from a quality-of-life perspective. Another drug in the same SGLT2 inhibitor class is dapagliflozin in the PRESERVED-HF trial, which also demonstrated an exercise benefit and a quality-of-life benefit.

Now, the question with dapagliflozin is whether it will show consistency in a reduction of hard clinical endpoints — heart failure hospitalization, cardiovascular death — and that will be demonstrated with the results of the ongoing DELIVER trial.

DELIVER is a unique trial. It's an extremely large HFpEF clinical trial similar to EMPEROR-Preserved. One aspect that is unique in DELIVER is the enrollment of patients with heart failure with recovered ejection fraction — a patient population for which we have limited data to support evidence-based therapies. DELIVER is enrolling a fair number of patients who had a lower ejection fraction that improved to > 40%, so it will give us a large amount of information.

Yancy: That gets us back to the opening statement that it's not nuanced. It really is a step forward when we consider not only the new definition, but these new descriptors and phenotypes of heart failure.

Let's wrap this up. We want to give the listener some strategies going forward. When you see the patient with symptomatic HFpEF, don't bemoan this, don't hang your head, don't wring your hands. We have some hope here. Why don't you summarize two or three takeaways of our discussion today?

Patel: Absolutely. First and foremost, considering sacubitril-valsartan in this population is paramount. In addition, we believe that SGLT2 inhibitors are and will become the standard of care in treating these patients, both from a symptomatic perspective and in reducing their clinical events and risk.

Additionally, don't forget about spironolactone. There are trials underway with regard to mineralocorticoid receptor antagonists, both spironolactone and a cousin of spironolactone, finerenone, which is being studied in the FINEARTS-HF trial. We do believe that spironolactone may benefit patients from a heart failure hospitalization perspective as well.

Last, as you mentioned, many of these patients have a huge comorbidity burden. Addressing that in a single visit is challenging, but certainly paramount to improving their symptoms and quality of life — whether it be weight loss, management of diabetes, or blood pressure control.

Yancy: I couldn't do a better job. I really want to thank you, Dr Patel, for helping us frame this contemporary perspective on the treatment of HFpEF. I hope that our listeners have been able to take away some very important caveats and can provide the kind of care to our patients that is consistent with best evidence and that is putting us in a better direction.

Thank you so much for having this conversation with me. I appreciate it.

Patel: Thanks for having me.

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