COMMENTARY

Heart Failure With Reduced Ejection Fraction: Advances in Management

Javed Butler, MD, MPH, MBA; Biykem Bozkurt, MD, PhD; Alanna A. Morris, MD, MSc

Disclosures

June 13, 2022

Editorial Collaboration

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This transcript has been edited for clarity.

Javed Butler, MD, MPH, MBA: Greetings. I am Dr Javed Butler. I serve as the president of the Baylor Scott & White Research Institute in Dallas, Texas, and also as professor of medicine at the University of Mississippi in Jackson, Mississippi.

Along with me to discuss advances in management of patients with heart failure with reduced ejection fraction (HFrEF) are two of my respected colleagues and friends. First, Dr Biykem Bozkurt.

Biykem Bozkurt, MD, PhD: Thank you, Javed. This is Biykem Bozkurt, professor of medicine at Baylor College of Medicine in Houston, Texas. I'll turn it over to Alanna.

Alanna A. Morris, MD, MSc: Hi. I'm Dr Alanna Morris. I'm an associate professor of medicine at Emory University in Atlanta, Georgia.

Butler: Great to have both of you. Who better to start this discussion than Dr Bozkurt, who is vice-chair of the writing committee for the 2022 ACC/AHA/HFSA Guideline for the Management of Heart Failure? There is so much activity there. Biykem, can you enlighten us about what's new in the guidelines?

New Agents and Updated Guidelines

Bozkurt: Thank you, Javed. First and foremost, we have first-line quadruple therapy, which now includes sodium-glucose cotransporter 2 (SGLT2) inhibitors, in addition to beta-blockers, mineralocorticoid receptor antagonists (MRAs), and renin-angiotensin system (RAS) inhibition with angiotensin receptor-neprilysin inhibitor (ARNI) in patients with New York Heart Association (NYHA) class II to III heart failure or angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) in patients with NYHA class II to IV heart failure.

The first-line therapy now includes these four classes, and these are agents that have been shown to be beneficial in the reduction of cardiovascular death and heart failure hospitalization. All patients, regardless of how stable they look, should be optimized with this quadruple therapy.

Butler: Biykem, can I unfold this a little bit more with you? Is there any particular focus on how to sequence these four therapies? Does it depend on the clinical situation or the clinician?

Bozkurt: In the guidelines, we did not specify the sequencing of one agent over the other, but we did specify the necessity to uptitrate and optimize as quickly as possible. We also mentioned that the optimization can be achieved with 1- to 2-week titration.

The critical concept to keep in mind is that, yes, the sequencing and which agent to initiate first can be individualized according to specific etiology and patient factors, such as their hemodynamic characterization, acuity of illness, and other indications they may have, such as kidney disease and/or other etiologies. Importantly, regardless of which one to start with, the concept is to optimize the four classes as quickly as possible.

Butler: Great. We know from registry data that, even before the era of SGLT2 inhibitors, and until 3 years ago, when the standard of care was triple therapy, many patients were not getting appropriate therapy. Now it's quadruple foundational therapy, so that's one point — that we really need to do well in implementing the proper therapy.

Alanna, let me bring you in. We also know for a fact that in the clinical trial setting, even on a very good baseline therapy in an SGLT2 inhibitor arm (in other words, quadruple therapy), there was a significant residual risk for the patient. If somebody is continuing to have symptomatic heart failure on standard of care, are there any new therapies otherwise for those patient populations?

Morris: Absolutely. I think the guidelines give us some hint as to what else we can use. For example, there is a new agent named vericiguat that has made it to these guidelines, and we can use this compound in patients who've had recent worsening heart failure, defined by a recent heart failure hospitalization or the requirement for intravenous (IV) diuretics. This is probably many of our patients. As you mentioned, Javed, this could potentially be patients who are on four-drug therapy and yet still have some residual risk that's defined by those two events.

We also want to think about non-heart failure–related comorbidities, if you will. For example, many of our patients have iron deficiency, with or without anemia, and the guidelines encourage us to replete those patients with intravenous iron. For many years, many of us have been using oral iron, and we really want to try to use IV iron because we've shown some very significant improvements in functional status and quality of life.

We also know that for some of our patients, as Biykem mentioned, who have chronic kidney disease or other comorbidities that limit our ability to uptitrate some of the old but good renin-angiotensin aldosterone system (RAAS) inhibitors, we now have evidence for some of the potassium binders. We have a couple of those that we can use to try to lower potassium levels in patients who are at risk for hyperkalemia, which will allow us to use some of the RAAS inhibitors that we know improve morbidity and mortality in these patients who are very high risk.

Butler: There is a large amount of interest about inotropes. Can you talk a little bit about omecamtiv mecarbil?

Morris: Omecamtiv mecarbil has not quite made the guidelines. Maybe Biykem can educate us as to what the thoughts were from the guideline committee as to what we should do with that agent or what we might expect to see in the future.

Defining Heart Failure

Butler: Let me ask you one more question. The folks who think about heart failure all the time, like us, we think about these classifications for heart failure and its evolution. But there's confusion in the primary care setting about whether to divide heart failure into two categories or three categories.

Can you tell us the universal definition and the classification of heart failure — where things stand right now?

Bozkurt: In terms of our approach to heart failure, it's becoming standardized. A universal definition of heart failure has defined a person with heart failure as an individual with symptoms and signs that are attributable to structural and/or functional cardiac abnormality, corroborated by evidence of increased filling pressures, either by elevated natriuretic peptide levels and/or objective evidence of increased filling pressure, either noninvasively and/or by hemodynamic characterization.

Now, in the guidelines, we're very much harmonized with this concept, with the recognition that either left ventricular systolic dysfunction or elevated filling pressures, especially in a mildly reduced or preserved ejection fraction, is useful.

Classification, according to ejection fraction, is very much harmonized both in the universal definition and in the guidelines and is defined as HFrEF, heart failure with mildly reduced ejection fraction (HFmrEF), heart failure with preserved ejection fraction (HFpEF), or heart failure with improved ejection fraction (HFimpEF).

Classes for stages of heart failure also are revised both in the universal definition and in the heart failure guidelines with terminology that is better understood by patients and nonspecialists. They include at risk for heart failure for stage A; pre–heart failure for stage B, which now includes elevated biomarkers even in the absence of symptoms defining the pre–heart failure stage; simple or symptomatic heart failure for stage C; and advanced heart failure for stage D. All of these classes now have specific recommendations in the guidelines.

Butler: Let's dig into the guidelines. We are focusing on novel therapies. Alanna mentioned vericiguat and IV iron. Omecamtiv mecarbil is one of the new medications — I guess it's not in the guideline — and potassium binders. Also, for patients with persistent symptoms, there are some oldies — not necessarily novel therapies — like digoxin and hydralazine nitrates.

Can you tell us what the guidelines are saying about these agents and what they say about heart failure with mildly reduced ejection fraction?

Bozkurt: After the first step of optimization of quadruple core therapies, we do have a step 2. In patients who self-identify as African American or Black, hydralazine and isosorbide dinitrate are indicated as a class 1 recommendation. Then, one should consider the implantable cardioverter-defibrillators and cardiac resynchronization therapy devices. Additional therapies can be considered among patients with HFrEF once the core therapies are optimized; these include ivabradine in patients with a heart rate ≥ 70 beats/min despite an optimal dose of beta-blockade — that's a class 2A recommendation — or digoxin may be considered to reduce hospitalizations or the oral soluble guanylate cyclase stimulator may be considered to reduce heart failure hospitalization and cardiovascular death as a class 2B recommendation. Polyunsaturated fatty acids and the potassium binders in the setting of hyperkalemia when using RAAS inhibitors are also class 2B recommendations. The whole art of how to optimize these therapies will need to be individualized.

We have specific recommendations for comorbidities. In diabetes, we have the SGLT2 inhibitors, optimal treatment of hypertension, IV iron for iron deficiency anemia, and consideration of atrial fibrillation catheter ablation for those individuals whose symptoms can be attributed to atrial fibrillation in the setting of heart failure as optimization considerations.

For HFmrEF, in the aftermath of the EMPEROR-Preserved trial, we now have SGLT2 inhibitors as a class 2A recommendation. For the other agents, which relied on post hoc analyses of former trials, we have class 2B recommendations for ACE inhibitors, ARBs, ARNI, MRAs, and beta-blockade. So, again, the HFmrEF now includes the SGLT2 inhibitors as a class 2A indication and other agents as a class 2B indication.

We do not have omecamtiv mecarbil in the guidelines, in part because it's not FDA-approved. For an agent to be included in the guidelines, it needs to be FDA-approved. Even though in the GALACTIC-HF trial, the evidence or the outcome of cardiovascular death and heart failure hospitalization achieved significance in patients with symptomatic heart failure. There was also evidence of heterogeneity. Those with a lower ejection fraction (< 28%) appear to have more benefit. Thus, I think we will need to wait for further information as to whether this agent will be a good option for individuals with very advanced heart failure and low ejection fraction.

Butler: This is incredibly helpful information, Biykem. We're running out of time. Let me have a wrap here and give the last word to Alanna.

Alanna, an open-ended question: Can you give our audiences some hints or advice about "how to"? How to implement these therapies? How to use them in combinations? Just some general advice from a practical, clinical perspective.

Morris: The first piece of advice is to avoid clinical inertia. Biykem gave us a hint a few minutes ago that we want to get these drugs on board at low dose as opposed to using time to titrate to high dose as we've seen in the past. We want to try to get all four drugs on board as quickly as possible and perhaps bring patients back to clinic in 1-2 weeks, either by telemedicine or an in-person visit, to really try to get all four of these drugs on board as part of patients' regimens.

If patients still have persistent heart failure symptoms, think about some of the other drug therapies that we talked about that are beyond those four foundational pillars of therapy. Again, the idea is for us to try to be as aggressive as we can as clinicians. We now have so many different drug options to choose from, it is really up to us to try to get these patients on all of these therapies.

Butler: We will end with those sage words and that advice. Thank you very much. I really appreciate learning from you and hope this was of help to our audiences and to the patients whom they take care of. Thank you very much, Alanna. Thank you very much, Biykem.

Bozkurt: Thank you.

Morris: Thank you, Javed.

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