Initiation of eplerenone vs. spironolactone and all-cause mortality in HFrEF: linked database study

Mineralocorticoid receptor antagonists are recommended as part of guideline-directed medical therapy for heart failure with reduced ejection fraction (HFrEF). The comparative effectiveness of spironolactone and eplerenone, however, remains uncertain.

This was a non-interventional database study using nationwide Danish health registries, 1 January 2020 to 30 June 2025. Patients aged ≥45 years with HFrEF (ejection fraction ≤40%) initiating eplerenone or spironolactone were included. An active-comparator, new-user design and inverse-probability-of-treatment weighting based on propensity scores was used. The primary outcome was all-cause mortality. Secondary outcomes included cardiovascular mortality, heart failure hospitalization, and their composite. Weighted hazard ratios (wHRs) were estimated using Cox proportional hazards models. A total of 4550 patients initiating eplerenone and 6651 initiating spironolactone were included. Median follow-up was 2.3 years. There were 571 deaths in the eplerenone group (5.0 per 100 person-years) and 1168 in the spironolactone group (7.0 per 100 person-years). A lower risk of death was observed with eplerenone [wHR, 0.83; 95% confidence interval (CI), 0.75–0.93], corresponding to an absolute rate difference of −1.10 per 100 person-years (95% CI, −0.50 to −1.70). For secondary outcomes, wHRs were 0.89 (95% CI, 0.81–0.98) for cardiovascular death or heart failure hospitalization, 0.79 (95% CI, 0.67–0.92) for cardiovascular death, and 0.97 (95% CI, 0.87–1.09) for heart failure hospitalization. Effect estimates were attenuated in per-protocol analyses.

In this large nationwide study, initiation of eplerenone was associated with lower risks of all-cause and cardiovascular mortality compared with spironolactone, with findings suggesting a contribution of better treatment persistence.