Empagliflozin's HFpEF Efficacy Catalyzes Redefinition of HF

Mitchel L. Zoler, PhD

September 22, 2021

Groundbreaking results from the EMPEROR-Preserved trial did more than establish for the first time that a drug, empagliflozin, has clearly proven efficacy for treating patients with heart failure with preserved ejection fraction (HFpEF). The results also helped catalyze a paradigm shift in how heart failure thought leaders think about the role of ejection fraction for making important distinctions among patients with heart failure.

EMPEROR-Preserved may also be the final nail in the coffin for defining patients with heart failure as having HFpEF or heart failure with reduced ejection fraction (HFrEF).

This new consensus essentially throws out left ventricular ejection fraction (EF) as the key metric for matching patients to heart failure treatments. Experts have instead begun suggesting a more unified treatment approach for all heart failure patients regardless of their EF.

'Forget About Ejection Fraction'

"We encourage you to forget about ejection fraction," declared Milton Packer, MD, during discussion at a session of the annual scientific meeting of the Heart Failure Society of America. "We certainly encourage you to forget about an ejection fraction of less than 40%" as having special significance," added Packer, a lead investigator for both the EMPEROR-Reduced and EMPEROR-Preserved trials (which researchers combined in a unified analysis with a total of 9,718 patients with heart failure called EMPEROR-Pooled), and a heart failure researcher at Baylor University Medical Center in Dallas.

"The 40% ejection fraction divide is artificial. It was created in 2003 as part of a trial design, but it has no physiological significance," Packer explained. A much better way to distinguish systolic and diastolic heart failure is by strain assessment rather than by ejection fraction. "Strain is a measure of myocardial shortening, a measure of what the heart does. Ejection fraction is a measure of volume," said Packer. "Sign me up to get rid of ejection fraction," he added.

"Ejection fraction is not as valuable as we thought for distinguishing the therapeutic benefit" of heart failure drugs, agreed Marvin A. Konstam, MD, professor of medicine at Tufts University and chief physician executive of the CardioVascular Center of Tufts Medical Center, both in Boston, who spoke during a different session at the meeting.

"It would easier if we didn't spend time parsing this number," ejection fraction, commented Clyde W. Yancy, MD, professor of medicine and chief of cardiology at Northwestern Medicine in Chicago. "Wouldn't it be easier if we said that every patient with heart failure needs to receive one agent from each of the four [pillar] drug classes, and put them in a polypill" at reduced dosages, he proposed, envisioning one potential consequence of jettisoning ejection fraction.

The four pillar drug classes, recently identified as essential for patients with HFrEF but until now not endorsed for patients with HFpEF, are the sodium-glucose cotransporter 2 (SGLT2) inhibitors, such as empagliflozin (Jardiance); an angiotensin receptor blocker neprilysin inhibitor compound such as sacubitril/valsartan (Entresto); beta-blockers; and mineralocorticoid receptor antagonists such as spironolactone and eplerenone.

An Opportunity for 'Simpler and Easier' Treatments

"This is an opportunity to disrupt the way we've been doing things and think about something that is simpler and easier," said Yancy, who chaired some of the panels serially formed by the American Heart Association and American College of Cardiology to write guidelines for treating heart failure. "An approach that would be easier to implement without worrying about staggering the start of each drug class and an incessant focus on titrating individual elements and taking 6 months to get to a certain place."

Results from EMPEROR-Preserved and the combined EMPEROR-Pooled analysis triggered these paradigm-shifting sentiments by showing clear evidence that treatment with empagliflozin exerts consistent benefit — and is consistently safe — for patients with heart failure across a spectrum of EFs, from less than 25% to 64%, though its performance in patients with HFpEF and EFs of 65% or greater in the EMPEROR-Preserved trial remains unclear.

The consequence is that clinicians should feel comfortable prescribing empagliflozin to most patients with heart failure without regard to EF, even patients with EF values in the mid-60% range.

The EMPEROR-Preserved results showed a clear signal of attenuated benefit among patients with an EF of 65% or greater "on a population basis," stressed Packer. "But on an individual basis, ejection fraction is not that reproducible, so measuring ejection fraction will not help you determine whom to treat or not treat. "

"There is significant variability" measuring EF using the most common modality, echocardiography, noted Javed Butler, MD, an EMPEROR coinvestigator who also spoke at the meeting session. A person with a measured EF of 65% could actually have a value that may be as low as 58% or as high as about 72%, noted Butler, who is professor and chair of medicine at the University of Mississippi, Jackson. The upshot is that any patient diagnosed with heart failure should receive an SGLT2 inhibitor "irrespective of their ejection fraction," Butler advised.

"Ejection fraction is very crude, and probably not sufficient to identify a phenotype," for treatment, said Yancy. "The real takeaway may be that we need to revisit what we call HFrEF, and then let that be the new standard for treatment."

"Is [an EF of] 60% the new 40%?" asked Packer, implying that the answer was yes.

Results From Several Trials Suggest Redefining HFrEF

The idea that patients without traditionally defined HFrEF — an EF of 40% or less — could also benefit from other classes of heart failure drugs has been gestating for a while, and then rose to a new level with the August 2021 report of results from EMPEROR-Preserved. Two years ago, in September 2019, Butler, Packer, and a third colleague advanced the notion of redefining HFrEF by raising the ejection fraction ceiling in a published commentary.

They cited the experience with the angiotensin receptor blocker candesartan in a post hoc analysis of data collected in the CHARM-Preserved trial, which showed a strong signal of benefit in the subgroup of patients with EFs of 41%-49%, but not in those with an EF of 50% or higher. This finding prompted Konstam to express doubts about relying on EF to define heart failure subgroups in trials and guide management in a commentary published more than 3 years ago.

Another crack in the traditional EF framework came from analysis of results from the TOPCAT trial that tested spironolactone as a treatment for patients with HFpEF, according to the 2019 opinion published by Butler and Packer. Once again a post hoc analysis, this time using data from TOPCAT, suggested a benefit from the mineralocorticoid receptor antagonist spironolactone in patients with heart failure and an EF of 45%-49% (45% was the minimum EF for enrollment into the study).

Recently, data from a third trial that tested sacubitril/valsartan in patients with HFpEF, PARAGON-HF, showed benefit among patients with EFs below the study median of 57%. This finding led the Food and Drug Administration in February 2021 to amend its initial approval for sacubitril/valsartan by removing a specific EF ceiling from the drug's indication and instead saying that patient's receiving the drug should have a "below normal" EF.

Writing in a recent commentary, Yancy called the FDA's action on sacubitril/valsartan "reasonable," and that the subgroup assessment of data from the PARAGON-HF trial creates a "new, reasonably evidence-based therapy for HFpEF." He also predicted that guideline-writing panels will "likely align with a permissive statement of indication" for sacubitril/valsartan in patients with HFpEF, especially those with EFs of less than 57%.

The idea of using an SGLT2 inhibitor like empagliflozin on all heart failure patients, and also adding agents like sacubitril/valsartan and spironolactone in patients with HFpEF and EFs in the mid-50% range or lower may take some time to catch on, but it already has one influential advocate.

"If a patient has HFpEF with an EF of less than 55%, use quadruple-class therapy," summed up Butler during the HFSA session, while also suggesting prescribing an SGLT2 inhibitor to essentially all patients with heart failure regardless of their EF.

The EMPEROR-Preserved and EMPEROR-Reduced trials and the EMPEROR-Pooled analysis were sponsored by Boehringer Ingelheim and Lilly, the companies that jointly market empagliflozin (Jardiance). Packer has had financial relationships with BI and Lilly and numerous other companies. Konstam has served on data monitoring committees for trials funded by Boehringer Ingelheim and by Amgen, Luitpold, and Pfizer, and has been a consultant to Arena, LivaNova, Merck, SC Pharma, and Takeda. Yancy had no disclosures. Butler has had financial relationships with Boehringer Ingelheim and numerous other companies.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.


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