Clinically meaningful benefit seen in patients with EF >40%

Among symptomatic heart failure patients with ejection fractions above 40%, daily treatment with the sodium-glucose cotransporter 2 inhibitor empagliflozin reduced the composite endpoint of cardiovascular death and hospitalizations by 21% compared ot placebo, a finding that is being heralded as practice-changing for the treatment of preserved ejection fraction heart failure (HFpEF).

“This is a highly significant result with a P value of 0.0003,” EMPEROR-Preserved principal investigator Stefan D. Anker, MD, PhD, reported during the opening Hot Line Late-Breaking Clinical Trials session at the 2021 European Society of Cardiology (ESC) Congress. “This is also a clinically meaningful difference. This benefit on the primary endpoint was consistently seen across all pre-specified subgroups, including left ventricular ejection fraction and diabetes,” he explained at an ESC press briefing, which like the ESC meeting was presented in a virtual format.

’Unequivocal Benefit’

Anker explained that the primary endpoint result was “particularly driven by a reduction in first and recurrent hospitalizations for heart failure by 27% (P<0.0009)—Again, a highly significant result. These results represent the first trial to show an unequivocal benefit of any drug on major harmful outcomes in patients with heart failure and a preserved ejection fraction.”

Another secondary endpoint, slope of decline in glomerular filtration rate over time, was also significant (P<0.0001), he said.

Asked about cardiovascular mortality, Anker said there was a 9% reduction in mortality, but that was not significantly different than the outcome among controls. Of note, the empagliflozin heart failure benefit appeared to decrease at the highest ejection fractions.

As proof of the unequivocal benefit of empagliflozin, Anker shared a chart comparing results of earlier studies that sought a drug to treat HFpEF:

  • PARAGON-HF (2019), which tested sacubitril/valsartan, reported a 13% reduction in the combined endpoint of cardiovascular death and first or recurrent HF hospitalization, P=0.06.
  • TOPCAT (2014), which tested spironolactone, reported an 11% reduction in the combined endpoint P=0.14.
  • I-PRESERVE (2008), which tested irbesartan with a combined endpoint of all-cause mortality and HF hospitalization, reported a 5% reduction, P=0.35.
  • PEO-CHF (2006), which tested perindopril with a combined endpoint of all-cause mortality and HF hospitalization, reported an 8% reduction, P=0.55.
  • CHARM-Preserved, which tested candesartan with a combined endpoint of CV death and HF hospitalization, reported a 14% reduction, P=0.05.

Mary N. Walsh, MD, medical director of the heart failure and cardiac transplantation programs at Ascension St. Vincent Heart Center in Indianapolis, told BreakingMED that the EMPEROR-Preserved findings were “good news, because it means that these drugs can help all heart failure patients.” Earlier studies such as DAPA-HF and EMPEROR-Reduced had already provided evidence of SGLT2 inhibitors’ benefit in reduced heart failure with reduced ejection fraction (HFrEF), and Walsh noted that those results spurred “robust uptake [of SGLT2 inhibitors] among heart failure specialists. I can speak for general cardiologists or general internists.”

In the heart failure treatment community, SGLT 2 inhibitors, which were originally approved for treatment of diabetes mellitus,” are now considered the fourth pillar of heart failure management—ARNI, beta-blockers, MRA [mineralocorticoid receptor agonists], and SGLT2i.”

EMPEROR-Preserved enrolled 5,988 patients with class II-IV heart failure and ejection fraction more than 40%. They randomized 2,997 to empagliflozin 10 mg daily and 2,991 to placebo. All participants received optimal background therapy.

The average age of participants was 72; 45% were women; and 49% had type 2 diabetes.

Over a median of 26.2 months, a primary outcome event occurred in 415 of 2,997 patients (13.8%) in the empagliflozin group and in 511 of 2,991 patients (17.1%) in the controls. There were 407 hospitalizations in the empagliflozin arm versus 541 in the control group.

Anker said there were no new safety signals, and no evidence of increased risk of amputations, something that has been seen in some studies of SGLT2 inhibitors in diabetes.

A True Game-Changer?

Because empagliflozin is an FDA-approved drug—although it lacks a label indication for HFpEFBreakingMED asked Anker if he thought the EMPEROR-Preserved findings would prompt clinicians to immediately begin prescribing empagliflozin, and other drugs in the same class, for patients with HFpEF.

“For class effect decisions, typically you want at least three positive trials with different kinds of drugs,” he said. “So, I think it’s a bit premature to conclude this after one study. We should wait for the next big trial to report next year.”

ESC meeting chair Carlos Aguiar, MD, of Lisbon, a heart failure specialist who moderated the press conference, said he thought “that yes, I think this is practice changing. I expect to see an immediate impact of these findings.”

In an editorial that accompanied the EMPEROR-Preserved findings in The New England Journal of Medicine, Mark H. Drazner, MD, of the University of Texas Southwestern Medical Center in Dallas, left little doubt about the practice-changing potential of the findings. He wrote:

“The EMPEROR-Preserved trial is the first phase III clinical trial that exclusively enrolled patients with heart failure and an ejection fraction of more than 40% to meet its primary outcome, a result that represents a major win against a medical condition that had previously proved formidable.”

Noting that some ongoing trials of SGLT2 inhibitors are likely to confirm the benefits, he concluded that “[U]ltimately, the EMPEROR-Preserved trial should contribute to a change in clinical practice, given the paucity of therapeutic options available for patients with heart failure and a preserved ejection fraction.”

Walsh, who like Aquiar was not involved in the trial, agreed. “I think people can start prescribing this tomorrow morning, but the issue will be cost and trying to get it approved by insurers,” she said. Walsh, who is a past president of the American College of Cardiology, said she anticipates many battles with pharmacy benefits managers, “fights we have every day.”

The cost to the patient could be substantial, Walsh added. Currently, the GoodRx site lists the monthly cost of empagliflozin at $539.30.

  1. In a randomized, placebo-controlled trial of heart failure with preserved ejection fraction, treating patients with empagliflozin reduced the composite of cardiovascular death or hospitalization for heart failure by 21%.
  2. Be aware that the empagliflozin benefit observed in EMPEROR-Preserved was driven by a reduction in hospitalization. There was no significant reduction in heart failure mortality.

Peggy Peck, Editor-in-Chief, BreakingMED™

EMPEROR-Preserved was funded by Boehringer Ingelheim and Eli Lilly.

Anker reported grants from Vifor; personal fees from Vifor, Bayer, Boehringer Ingelheim, Novartis, Servier, Impulse Dynamics, Cardiac Dimensions, and Thermo FisherScientific; and grants and personal fees from Abbott Vascular, outside the submitted work.

Drazner reported income from St. Luke’s Mid America Heart Institute outside the submitted editorial.

Walsh had no disclosures.

Aguiar disclosed serving as an advisor or consultant for Bayer HealthCare Pharmaceuticals; Bristol-Myers Squibb Company; Daiichi Sankyo, Inc.; and Pfizer Inc. He served as a speaker or a member of a speakers bureau for Bayer HealthCare Pharmaceuticals; Bristol-Myers Squibb Company; Daiichi Sankyo, Inc.; and Pfizer Inc.


Cat ID: 204

Topic ID: 74,204,730,204,3,192,925,203