Empagliflozin beneficial in heart failure patients with a reduced and preserved ejection fraction

Empagliflozin reduces the risk of a composite of cardiovascular death or hospitalisation for heart failure in patients with heart failure and a preserved ejection fraction (HFpEF) with or without diabetes, according to a study presented at the European Society of Cardiology (ESC) Congress.

EMPEROR-Preserved, published in the New England Journal of Medicine, evaluated the effects of sodium-glucose co-transporter 2 (SGLT2) inhibition in HFpEF patients with and without diabetes.

The number of patients who needed to be treated with empagliflozin to prevent one primary outcome event during a median study period of 26 months was 31 (95% CI 20-69). The effects on the primary outcome were observed across all prespecified subgroups, including patients with or without diabetes and those with a left ventricular ejection fraction of less than 50%, 50% to less than 60%, or 60% or more.

The total number of hospitalisations for heart failure was also lower with empagliflozin than with placebo. The rate of decline in eGFR was slower in the empagliflozin group compared with the placebo group.

Empagliflozin has potential to become a new standard treatment for HFpEF patients

Principal investigator Professor Stefan Anker of Charité University Hospital Berlin, Germany said: “Empagliflozin convincingly reduced the combined risk of cardiovascular death or hospitalisation for heart failure in patients with heart failure and a preserved ejection fraction, with and without diabetes. This drug has the potential to become a new standard treatment for these patients, who currently have few therapeutic options.”

The trial enrolled 5,988 symptomatic HFpEF patients (left ventricular ejection fraction over 40%) with and without type 2 diabetes from 622 centres in 23 countries.

Patients were required to have elevated N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations (over 300pg/mL in patients without atrial fibrillation and over 900pg/mL in patients with atrial fibrillation) along with evidence of structural changes in the heart or documented history of heart failure hospitalisation.

Participants were randomised in a 1:1 ratio to receive empagliflozin 10mg daily or placebo, on top of all appropriate treatments for HFpEF and comorbidities. The primary outcome and the first two secondary outcomes were included in a hierarchical testing procedure. The primary endpoint was a composite of cardiovascular death or hospitalisation for heart failure.

The first secondary outcome was hospitalisations for heart failure, including first and recurrent events. The second secondary outcome was the rate of decline in the glomerular filtration rate (eGFR) during study treatment. The average age of participants was 72 years and 45% were women. The average ejection fraction was 54%.

During a median follow-up of 26 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 placebo group (6.9 vs. 8.7 events per 100 patient-years; hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.69-0.90; p=0.0003); this effect was mainly related to a lower risk of hospitalisation for heart failure in the empagliflozin group.

Regarding safety, 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. Uncomplicated genital and urinary tract infections and hypotension were more common in patients treated with empagliflozin.

Pooled analysis

The EMPEROR-Reduced trial previously showed that empagliflozin reduced the risk of cardiovascular death or hospitalisation for heart failure in patients with heart failure and a reduced ejection fraction.

A pooled analysis of the two trials has demonstrated the beneficial effects of empagliflozin in patients with heart failure with a reduced and preserved ejection fraction. The current analysis pooled the results of these two trials on an individual patient level. This was possible because of the similarities between both studies. The trials were carried out in parallel with nearly identical protocols, case report forms, investigative sites, and administrative committees.

Both trials evaluated the effects of empagliflozin versus placebo in a randomised and double-blind fashion in patients with established heart failure receiving all appropriate treatments. Empagliflozin or placebo was given for an average of 24 months.

The major difference was the enrolment of patients with heart failure and an ejection fraction of 40% or less in EMPEROR-Reduced and patients with heart failure and an ejection fraction of more than 40% in EMPEROR-Preserved.

Principal investigator Dr Milton Packer of Baylor University Medical Center, Dallas, US, said: “This analysis was prospectively designed and we developed a statistical plan before any patient was recruited in either trial. The evaluation was alpha-protected, meaning that the endpoints were statistically powerful and unbiased because by specifying the pooled analysis in the individual trials it was protected from an inflated false positive error rate.”