UPDATED August 28, 2021 // The SGLT2 inhibitor empagliflozin achieved in EMPEROR-Preserved what no other agent could previously do: unequivocally cut the incidence of cardiovascular death or hospitalization in patients with heart failure and preserved ejection fraction (HFpEF).
Treatment with empagliflozin (Jardiance) led to a significant 21% relative reduction in the rate of cardiovascular death or hospitalization for heart failure (HHF), compared with placebo, among 5,988 randomized patients with HFpEF during a median 26 months of follow-up, proving that patients with HFpEF finally have a treatment that gives them clinically meaningful benefit, and paving the way to an abrupt change in management of these patients, experts said.
"This is the first trial to show unequivocal benefits of any drug on major heart failure outcomes in patients with HFpEF," Stefan D. Anker, MD, PhD, declared at the virtual annual congress of the European Society of Cardiology.
The 21% relative reduction, which reflected a cut in the absolute rate of the trial's primary composite endpoint of 3.3% compared with placebo, was driven mainly by a significant 27% relative reduction in the incidence of HHF (P < .001).
Empagliflozin treatment, on top of standard therapy for patients with HFpEF, also resulted in a nonsignificant 9% relative risk reduction in the incidence of cardiovascular death, but it had no discernible impact on the rate of death from any cause, said Anker, professor of cardiology at Charité Medical University in Berlin.
Concurrently with his talk at the meeting, the results were published online in the New England Journal of Medicine.
Practice Will Change "Quickly"
"This will definitely change our practice, and quite quickly," said Carlos Aguiar, MD, chair of the Advanced Heart Failure and Heart Transplantation Unit at Hospital Santa Cruz in Carnaxide, Portugal, who was not involved in the study.
Transition to routine use of empagliflozin in patients with HFpEF should be swift because it has already become a mainstay of treatment for patients with heart failure with reduced ejection fraction (HFrEF) based on evidence for empagliflozin in EMPEROR-Reduced.
A second sodium-glucose cotransporter 2 (SGLT2 ) inhibitor, dapagliflozin (Farxiga), is also an option for treating HFrEF based on results in the DAPA-HF trial, and the DELIVER trial, still in progress, is testing dapagliflozin as a HFpEF treatment in about 6,000 patients, with results expected in 2022.
About half of the patients in EMPEROR-Preserved had diabetes, and the treatment effects on HFpEF were similar regardless of patients' diabetes status. Empagliflozin, like other members of the SGLT2 inhibitor class, boosts urinary excretion of glucose and received initial regulatory approval as an agent for glycemic control in patients with type 2 diabetes.
Empagliflozin also has US approved marketing indications for treating patients with HFrEF whether or not they also have diabetes, and for reducing cardiovascular death in patients with type 2 diabetes and cardiovascular disease.
"We already use this drug class in cardiovascular medicine and to treat patients with type 2 diabetes, and we have been eager to find a treatment for patients with HFpEF. This is something that will be really significant," said Aguiar.
Heart failure clinicians have “become familiar prescribing” SGLT2 inhibitors following approval of HFrEF indications for some of these agents, noted Mary Norine Walsh, MD, a heart failure specialist with Ascension Medical Group in Indianapolis. The new results “are good news because there have been so few options” for patients with HFpEF, she said in an interview.
EMPEROR-Preserved "is the first phase 3 clinical trial that exclusively enrolled patients with heart failure and an ejection fraction of more than 40% to meet its primary outcome," and the results "represent a major win against a medical condition that had previously proven formidable," Mark H. Drazner, MD, said in an editorial that accompanied the published results.
The trial's findings "should contribute to a change in clinical practice given the paucity of therapeutic options available for patients with HFpEF," wrote Drazner, a heart failure specialist who is professor and clinical chief of cardiology at UT Southwestern Medical Center in Dallas.
Theresa A. McDonagh, MD, MBChB, who chaired the panel that just released revised guidelines from the European Society of Cardiology for managing patients with HF, predicted that empagliflozin treatment for patients with HFpEF will soon show up in guidelines. It will likely receive a “should be considered” ranking despite being a single study because of the impressive size of the treatment effect and lack of well-supported alternative treatments, she commented as a discussant of the trial during its presentation at the congress. If the DELIVER trial with dapagliflozin shows a similar effect, the recommendation would likely become even stronger, added McDonagh, a heart failure specialist and professor of cardiology at King’s College, London.
More Women Enrolled Than Ever Before
EMPEROR-Preserved enrolled adults with chronic HFpEF in New York Heart Association functional class II–IV and a left ventricular ejection fraction greater than 40% starting in 2017 at more than 600 sites in more than 20 countries worldwide including the United States. As background therapy, more than 80% of patients received treatment with either an ACE inhibitor or angiotensin receptor blocker (in some instances in the form of sacubitril/valsartan), more than 80% were on a beta-blocker, and about a third were taking a mineralocorticoid receptor antagonist, making them "very well treated HFpEF patients," Anker said.
One of the most notable features of enrollment was that 45% of participants were women, giving this trial the highest inclusion of women compared with all prior studies in patients with HFpEF or with HFrEF, said Walsh. “HFpEF is very prevalent in woman,” she noted, and having this high participation rate of women in the study increases its relevance to these patients. “It’s important to be able to tell women that patients like you were in the study so we can more easily apply the lessons from the trial to you. That can’t be stressed enough,” she said.
The primary outcome occurred in 415 (13.8%) of the 2,997 patients in the empagliflozin group and in 511 (17.1%) of 2,991 patients who received placebo (hazard ratio, 0.79; 95% confidence interval, 0.69-0.90; P < .001).
The study showed a safety profile consistent with prior experience with empagliflozin, Anker added.
Pooling EMPEROR-Preserved with EMPEROR-Reduced
The investigators who ran EMPEROR-Preserved designed the trial to closely parallel the EMPEROR-Reduced trial in patients with HFrEF, and they included a prespecified analysis (EMPEROR-Pooled) that combined the more than 9,700 patients in the two studies.
This showed a consistent and robust benefit from empagliflozin for reducing HHF across a wide spectrum of patients with heart failure, ranging from patients with left ventricular ejection fractions of less than 25% to patients with ejection fractions as high as 64%.
However, the analysis also showed that patients with ejection fractions of 65% or greater received no discernible benefit from empagliflozin, Milton Packer, MD, reported in a separate talk at the congress.
"The findings demonstrate the benefits of empagliflozin across a broad range of patients with heart failure who have ejection fractions of less than 60%–65%," said Packer, a researcher at Baylor University Medical Center in Dallas.
This apparent attenuation of an effect at higher ejection fractions "has been observed in other HFpEF trials, most recently in the PARAGON-HF trial" of sacubitril/valsartan (Entresto), he noted.
Additional analyses led by Packer showed that in patients with ejection fractions below 65%, the HHF benefit from empagliflozin consistently surpassed the benefit seen with sacubitril/valsartan in PARAGON-HF. But he recommended using both drugs in patients with HFpEF and an ejection fraction up to about 60%.
"If I had a patient with HFpEF, I would use both drugs as well as beta-blockers and mineralocorticoid receptor antagonists," he said during a press briefing.
Another finding from analysis of the EMPEROR-Reduced and EMPEROR-Preserved trials together was that patients with reduced ejection fractions showed a significant 49% relative reduction in the incidence of serious renal outcomes, but this effect was completely blunted in EMPEROR-Preserved.
"Ejection fraction influences the effects of empagliflozin on major renal outcomes," concluded Packer in a report on this analysis published simultaneously with the main EMPEROR-Preserved findings. "These data from the EMPEROR trials are unique. We have no comparable data from any of the other reported studies of SGLT2 inhibitors," he said.
EMPEROR-Preserved was sponsored by Boehringer Ingelheim and by Eli Lilly, the two companies that jointly market empagliflozin (Jardiance). Anker has received personal fees from Boehringer Ingelheim and from several other companies, and he has received grants and personal fees from Abbott Vascular and Vifor. McDonagh has had recent financial relationships with AstraZeneca, Novartis, Corpus, Pfizer, and Vifor. Packer has received consulting fees from Boehringer Ingelheim and from numerous other companies. Aguiar and Walsh had no disclosures.
European Society of Cardiology (ESC) Congress 2021. Presented August 27, 2021.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
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Cite this: EMPEROR-Preserved: Empagliflozin Scores HFpEF Breakthrough - Medscape - Aug 27, 2021.