The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial

Abstract

The sodium-glucose cotransporter 2 inhibitor empagliflozin reduces the risk of cardiovascular death or heart failure hospitalization in patients with chronic heart failure, but whether empagliflozin also improves clinical outcomes when initiated in patients who are hospitalized for acute heart failure is unknown. In this double-blind trial (EMPULSE; NCT04157751 ), 530 patients with a primary diagnosis of acute de novo or decompensated chronic heart failure regardless of left ventricular ejection fraction were randomly assigned to receive empagliflozin 10 mg once daily or placebo. Patients were randomized in-hospital when clinically stable (median time from hospital admission to randomization, 3 days) and were treated for up to 90 days. The primary outcome of the trial was clinical benefit, defined as a hierarchical composite of death from any cause, number of heart failure events and time to first heart failure event, or a 5 point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days, as assessed using a win ratio. More patients treated with empagliflozin had clinical benefit compared with placebo (stratified win ratio, 1.36; 95% confidence interval, 1.09-1.68; P = 0.0054), meeting the primary endpoint. Clinical benefit was observed for both acute de novo and decompensated chronic heart failure and was observed regardless of ejection fraction or the presence or absence of diabetes. Empagliflozin was well tolerated; serious adverse events were reported in 32.3% and 43.6% of the empagliflozin- and placebo-treated patients, respectively. These findings indicate that initiation of empagliflozin in patients hospitalized for acute heart failure is well tolerated and results in significant clinical benefit in the 90 days after starting treatment.

Fig. 1. Screening, randomization, and follow-up.

Flowchart of the double-blind EMPULSE trial (NCT04157751), in which 530 patients with a primary diagnosis of acute de novo or decompensated chronic heart failure, regardless of left ventricular ejection fraction, were randomly assigned to receive empagliflozin 10 mg once daily or placebo. This study was carried out at 118 centers in 15 countries.

Fig. 2. Primary efficacy outcome and components.

The stratified win ratio was calculated using a non-parametric generalized pairwise comparison within heart failure status strata; data are presented as the point estimate and 95% CI with a two-sided P value. For the components of the win ratio, the percentages do not reflect randomized comparisons. Please refer to Table 2 for the overall number of events and KCCQ-TSS data. *Hierarchical composite of death, number of HFEs, time to first HFE and change from baseline in KCCQ-TSS after 90 days of treatment.

Fig. 3. Primary efficacy outcome in all prespecified subgroups.

Win ratios were calculated using a non-parametric generalized pairwise comparison within subgroup strata; data are presented as point estimates and 95% CIs with two-sided interaction P values. No adjustments for multiple testing were made. HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.