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Empagliflozin in patients with HFpEF reduced by 21% the risk of cardiovascular death or heart failure hospitalization across all prespecified subgroups, including those with/without diabetes.
In patients with heart failure with preserved ejection fraction (HFpEF), empagliflozin reduced by 21% the risk of a composite endpoint of cardiovascular (CV) death or hospitalization for heart failure, a benefit that was independent of ejection fraction or diabetes status.
The findings were presented today in a “Hot Line” clinical trial session at the European Society of Cardiology (ESC) Congress 2021 and published simultaneously in the New England Journal of Medicine.
The highly anticipated results reflect full analysis from the EMPORER-Preserved trial for which preliminary topline data were presented in July. EMPORER-Preserved is the investigational successor to EMPORER-Reduced which showed that empagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor reduced the risk of CV death or hospitalization for heart failure in patients with heart failure and reduced ejection fraction (HFrEF). The latter trial results were published in NEJM in October 2020.
"For people with heart failure with preserved ejection fraction, the reality is that so far there are no clinically proven treatments we can offer that would make a significant impact on their condition," said Professor Stefan Anker, EMPEROR-Preserved principal investigator and heart failure cardiologist at Charité Berlin, Germany, in a statement from Eli Lilly and Company.
“This [sic] data brings hope for millions of patients suffering from heart failure with a preserved ejection fraction. The primary endpoint was similarly improved in all subgroups of patients, in men and women, with and without diabetes, and regardless of their ejection fraction and kidney function level. This underlines the breadth of empagliflozin's efficacy and its potential overall impact."
For the phase 3 EMPEROR-Preserved trial, Anker et al randomized 5,988 patients with NYHA class II to IV heart failure and an ejection fraction >40% to empagliflozin 10 mg once daily or placebo, both administered on a background of standard therapies. Participant’s mean age was 72 years; 45% were women; mean left ventricular ejection fraction (LVEF) was 54%. The study cohort was drawn from 622 medical centers in 23 countries.
Patients were required to have an estimated glomerular filtration rate (eGFR) of ≥20 mL/min/1.73 m2 and either structural heart disease or a hospitalization for heart failure within the past year. Also required was an elevated N-terminal pro B-type natriuretic peptide (NT-proBNP) concentration (>300 pg/mL in patients without atrial fibrillation [AF], >900 pg/mL in patients with AF). Approximately half (49%) of patients had diabetes.
The study’s primary endpoint was a composite of CV death or hospitalization for heart failure. There were 2 secondary outcomes specified: the first, hospitalizations for heart failure, including first and recurrent events; and the second, the rate of decline in eGFR during study treatment.
Median follow-up for the trial was 26 months during which a primary composite 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 placebo group (hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.69–0.90; p<.001).
According to the study authors, the effect was related primarily to a lower risk of hospitalization for heart failure in the treatment group—407 admissions occurring in the empagliflozin group vs 541 in the placebo group (HR, 0.73; 95% CI, 0.61-0.88; P <.001).Cardiovascular death occurred among 219 (7.3%) patients randomized to empagliflozin and 244 (8.2%) randomized to placebo, a reduction, researchers emphasize, that did not reach statistical significance (HR, 0.91; 95% CI, 0.75-1.09).
The effects on the primary outcome were observed across all prespecified subgroups, including patients with or without diabetes and those with LVEF of <50%, 50% to <60%, or ≥60%.
Analysis of data for the secondary outcomes found, as noted above, that total number of hospitalizations for heart failure was lower with empagliflozin than with placebo. Empagliflozin also was associated with a slower rate of decline in renal function vs placebo, by 1.36 mL/min/1.73 m2 per year (P <.0001).
Reporting results for safety investigators said that serious adverse events occurred in 1,436 patients (47.9%) in the empagliflozin group and in 1,543 patients (51.6%) in the placebo group. Adverse events leading to discontinuation of treatment occurred in 571 patients (19.1%) in the empagliflozin group and in 551 patients (18.4%) in the placebo group. In patients treated with empagliflozin uncomplicated genital and urinary tract infections and hypotension were more common.
Mark Drazner, MD, clinical chief of cardiology and medical director of the LVAD and cardiac transplantation program at UT Southwestern Medical Center, writing in an editorial accompanying the study in NEJM said,
“The EMPEROR-Preserved trial 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, a result that represents a major win against a medical condition that had previously proved formidable… 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.”
Reference. Anker SD, Butler J, Filippatos G, et al for the EMPEROR-Preserved Trial Investigators. Empagliflozin in heart failure with a preserved ejection fraction. NEJM. Published online August 27, 2021. August 27, 2021 DOI: 10.1056/NEJMoa2107038