Effect Of Empagliflozin On Major Heart Failure Outcomes, Renal Function And Quality Of Life In Patients With Heart Failure With A Reduced Ejection Fraction, With And Without Sacubitril/valsartan

Abstract

Background SGLT2 inhibitors reduce serious heart failure events in patients with type 2 diabetes, and one trial with dapagliflozin that enrolled patients with mild heart failure and a reduced ejection fraction has reported benefits in patients without diabetes. Methods We randomized 3730 patients with chronic heart failure and an ejection fraction 40% or less and class II-IV heart failure, who were receiving appropriate and established drug and device treatments for heart failure. Patients were randomized to empagliflozin 10 mg daily or placebo and followed for a median of approximately 18 months. The primary endpoint of the trial is the time-to-first event analysis of the combined risk of cardiovascular death and hospitalization for heart failure, but the trial is also evaluating the effects of empagliflozin on renal function, cardiovascular death, all-cause mortality, recurrent hospitalization events and quality of life. By adjusting eligibility based on natriuretic peptide levels to the baseline ejection fraction, the trial enrolled higher-risk patients. By design, a majority of participants will have an ejection fraction 30% or less, the median N-terminal-proBNP will be nearly 2000 pg/ml, and the estimated annual placebo event rate is expected to be at least 15%. The trial is expected to accrue at least 820 primary endpoint events, and was designed to have 90% power to detect a meaningful reduction in the risk of the primary endpoint by empagliflozin. Results Enrollment and follow-up in the trial has been completed. The top line results will be available by the end of July and will be presented at the ESC (end of August). Our plan is to present the detailed results of the large subgroup receiving sacubitril/valsartan (this subgroup represents 20% of the participants), and we will present the effects of empagliflozin in patients receiving and not receiving neprilysin inhibitors across all outcomes measures. (None of these data will ever have been presented before.) We will also present (for the first time) a meta-analysis of the patients treated with sacubitril/valsartan across the DAPA-HF and EMPEROR-Reduced trials for major heart failure outcomes. Conclusion The EMPEROR-Reduced trial will add substantial and critically important new information about the role of SGLT2 inhibitors when added to existing treatments for chronic heart failure with left ventricular systolic dysfunction. The results of this trial will greatly influence whether SGLT2 inhibitors become an established standard of care for these patients and whether they add incrementally to sacubitril/valsartan.