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Empagliflozin Improves Outcomes in HFpEF Patients

— "A major win" for heart failure with preserved ejection fraction, says editorialist

MedpageToday

Patients with heart failure with preserved ejection fraction (HFpEF) -- a notoriously difficult population to treat -- had a meaningful reduction in cardiovascular death and heart failure hospitalization when they received empagliflozin (Jardiance), the randomized showed.

At a median of 26.2 months follow-up, the relative risk of experiencing the composite endpoint of the trial was reduced by a relative 21% if the patients were on empagliflozin -- whether they were diabetic or not -- rather than placebo (P=0.0003), reported Stefan Anker, MD, of Charité Campus Virchow-Klinikum in Berlin, at this year's virtual .

"These results represent the first trial to show unequivocal benefits of any drug on major heart failure outcomes in patients with heart failure and a preserved ejection fraction," Anker said at an ESC press conference that featured the study.

"This benefit on the primary endpoint was consistently seen across all prespecified subgroups, including left ventricular ejection fraction, sex, and diabetes," he said. "And the primary endpoint result was particularly driven by a reduction in first and recurrent hospitalizations for heart failure by 27%, which again was highly significant."

Findings from the study were published simultaneously in the (NEJM).

Cardiovascular mortality was reduced by a non-significant 9%. "The results are driven by heart failure hospitalization reductions," Anker reported. Overall mortality was similar between arms, he noted.

He and his colleagues enrolled almost 6,000 patients in the study in which empagliflozin or placebo was added to standard-of-care therapy for chronic heart failure. The researchers sought patients for the study who had a left ventricular ejection fraction greater than 40%. These patients were symptomatic and had a kidney function estimated glomerular filtration rate of at least 20 ml/min.

"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," wrote Mark Drazner, MD, of the University of Texas Southwestern School of Medicine in Dallas, in an in NEJM.

"Ultimately, 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," he added.

The patients in the trial were an average 72 years old, about 45% were women, and about 49% had been diagnosed with diabetes.

"You can see that the Kaplan-Meier curve separates very early, within the first month already reaching significance," Anker said.

In addition, he said, the secondary endpoints also favored treatment with empagliflozin. Total heart failure hospitalizations -- the first and second events -- were reduced by 27% compared with the patients on placebo (P=0.0009).

The change in glomerular filtration rate was also slower with empagliflozin therapy (P<0.0001).

In response to questions from reporters, Anker said it was premature to determine if the treatment effects seen with empagliflozin were a class effect of other SGLT2 inhibitors, and that additional studies with other drugs in the class would be required before a blanket statement on the class could be made.

Kidney-Specific Effects

A second study that focused on the kidney-specific benefit of empagliflozin found that in patients with a higher ejection fraction, the benefits for renal function were attenuated, reported Milton Packer, MD, of Baylor College of Medicine in Dallas, and colleagues, in a in the same issue of NEJM.

They noted that SGLT2 inhibitors reduce the risk of serious adverse renal outcomes in type 2 diabetes, but the renal effects of these drugs in patients with heart failure remain uncertain.

"Although empagliflozin and dapagliflozin have been reported to slow the rate of decline in the estimated glomerular filtration rate (eGFR), changes in the eGFR slope may not predict the effects of these drugs on major renal outcomes," the researchers said.

They compared the results of the and the EMPEROR-Preserved trials and found that the effect on kidneys was greater among the patients who were sicker -- that is, with reduced ejection fractions.

"Our finding that ejection fraction influences the effects of empagliflozin on major renal outcomes is noteworthy, given that empagliflozin lowered the incidence of hospitalizations for heart failure to a similar extent in the EMPEROR-Reduced and in the EMPEROR-Preserved trials," Packer and co-authors wrote.

"In the EMPEROR-Preserved trial, the observed lack of benefit with respect to serious renal outcomes contrasts with the finding that empagliflozin slowed the decline in eGFR in that trial, suggesting that eGFR slope analysis has limitations as a surrogate for predicting the effect of drugs on renal outcomes in patients with heart failure," the team concluded.

  • author['full_name']

    Ed Susman is a freelance medical writer based in Fort Pierce, Florida, USA.

Disclosures

Anker reported financial relationships with Brahms GmbH, Vifor International, Abbott Vascular, Servier, Bayer, Boehringer Ingelheim, Novartis, and Cardiac Dimensions.

Drazner reported reimbursement to the University of Texas Southwestern School of Medicine for site conduct of DEFINE-HF, an investigator-initiated trial funded by AstraZeneca and conducted by Saint Luke's Mid America Heart Institute independent of the funding source.

Packer disclosed financial relationships with AbbVie, Amarin Pharma, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Casana, CSL Behring, Cytokinetics, Eli Lilly, Johnson & Johnson, Moderna, Novartis, ParatusRX, Pfizer, Relypsa, Salamandra, Teva, and Theravance Biopharma.

Primary Source

New England Journal of Medicine

Drazner M, et al "SGLT2 inhibition in heart failure with a preserved ejection fraction -- a win against a formidable foe" N Engl J Med 2021; DOI: 10.1056/NEJMe2113008.

Secondary Source

New England Journal of Medicine

Anker S, et al "Empagliflozin in heart failure with a preserved ejection fraction" N Engl J Med 2021; DOI: 10.1056/NEJMoa2107038.