EMPULSE: Empagliflozin improves outcomes in all Heart Failure admissions

Key Points:

• In the EMPULSE study, patients admitted with acute HF of any ejection fraction with or without diabetes were treated with either empagliflozin or placebo. The primary outcome was 90-day clinical benefit determined by a stratified “win ratio,” which included a comparison of death, HF events, time to first HF event, and change in baseline Kansas City Cardiomyopathy Questionnaire Total Summary Score (KCCQ). Secondary analyses included change in KCCQ from baseline, subgroup analyses of the primary endpoint by clinical characteristics including diabetes, and individual outcome components of the primary endpoint.
• Treatment with empagliflozin resulted in a reduction in the primary outcome, as well as a significant reduction in time to all-cause death or HF events. There was also a significant improvement in KCCQ score. The primary outcome was similar in patients with or without diabetes.

Patients with acute heart failure have high morbidity and mortality, facing high readmission and complication rates. Many recent trials have demonstrated the efficacy of SGLT2 inhibitors in reducing cardiovascular morbidity and mortality in chronic HF, including HFrEF (EMPEROR-REDUCED, DAPA-HF, etc) and HFpEF (EMPEROR-PRESERVED, PRESERVED-HF). More evidence is needed regarding the effect of SGLT2 inhibitors in acute HF; the SOLOIST trial demonstrated a reduction in combined CV death/HF hospitalizations in patients with worsening HF and diabetes, but more information is needed regarding acute HF patients without diabetes. In a breaking presentation at the 2021 American Heart Association Scientific Sessions today, Dr. Adriaan Voors (University Medical Centre Groningen, The Netherlands) and his team presented the results of the Empagliflozin in patients hospitalized for acute heart failure (EMPULSE) trial.

The EMPULSE study (NCT04157751) was an international multicenter randomized trial, conducted across 118 centers. Patients were treated with either a 10mg daily empagliflozin or placebo. All recruited patients were required to be currently hospitalized with acute HF, with any ejection fraction. Patients were required to be clinically stable, with an sBP>100 and no symptoms of hypotension, no increase in IV diuretic dosing, and no IV vasodilators or inotropic drugs within 6 hours. Patients were required to be randomized between 24 hours to 5 days after admission. Some relevant exclusion criteria included cardiogenic shock, major cardiac surgery, transcatheter cardiac procedure, or PCI within 30 days, T1DM, impaired renal function (eGFR<20), or history of DKA.

A total of 530 patients were randomized, with 265 in each group. 45% of patients were diabetic, and 67% had an EF <40%. Outcomes were assessed at 90 days. The primary outcome was clinical benefit at 90 days determined by an algorithm -derived “win ratio,” which was a hierarchical, stratified comparison of death, HF events, time to first HF event, and change in baselin

e Kansas City Cardiomyopathy Questionnaire Total Summary Score (KCCQ). Pre-specified secondary analyses included improvement in KCCQ >10 points, change in KCCQ from baseline, subgroup analyses of the primary endpoint by clinical characteristics including diabetes, and individual outcome components of the primary endpoint. Empagliflozin reduced the primary endpoint with a stratified win ratio of 1.36 (95% CI; 1.09-1.68, p=0.0054). The primary endpoint was similar in magnitude across subgroups, including de novo vs chronic HF, diabetes status, age (> or <70) and sex. There was no significant reduction in time to CV death or HF event, but there was a significant reduction in time to all-cause death or HF event in the empagliflozin group (HR 0.65, 95% CI (0.43-0.99), p=0.0423). There was also a significant reduction in change in KCCQ score in the empagliflozin group (4.5 point improvement, 95% CI (0.3-8.6), p=0.0347). No safety concerns were identified in the empagliflozin group other than a mild increase in genital infections (1.2% vs 0.4%), volume depletion (12.7% vs 10.2%) and hypoglycemia (1.9% vs 1.5%).

When discussing the implications of the study at the AHA, Dr. Voors stated: “Initiation of empagliflozin compared to placebo in patients hospitalized with acute HF resulted in a significant clinical benefit within 90 days. There were fewer deaths or HF events and an improvement in quality of life…and we didn’t see any safety concerns.”