Mineralocorticoid receptor antagonists in heart failure with preserved (and mildly reduced) ejection fraction: a comparative review of spironolactone and finerenone

Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of all heart failure presentations and remains associated with substantial mortality, ranging from 15% at 1 year to nearly 75% within 5-10 years following hospitalization. Mineralocorticoid receptor antagonists (MRAs), which blunt maladaptive activation of the renin-angiotensin-aldosterone system and thereby attenuate myocardial fibrosis, sodium retention, inflammation, and progressive ventricular remodeling, have been explored as a mechanistically grounded therapeutic strategy in HFpEF. Spironolactone, the most extensively studied steroidal MRA, was evaluated in the TOPCAT trial involving 3445 patients with symptomatic HFpEF or heart failure with mildly reduced ejection fraction; however, the trial did not demonstrate a significant overall benefit, while treatment was associated with increased rates of hyperkalemia and worsening renal function. Moreover, concerns regarding trial design, conduct, and marked regional heterogeneity in outcomes have further complicated interpretation, contributing to ongoing uncertainty regarding the role of spironolactone in routine HFpEF management. In contrast, finerenone, a non-steroidal MRA with greater receptor selectivity than spironolactone, demonstrated favorable outcomes in the FINEARTS-HF trial, which enrolled 6001 patients with symptomatic heart failure and left ventricular ejection fraction ≥40%, significantly reducing worsening heart failure events and cardiovascular death (rate ratio 0.84; 95% CI, 0.74-0.95), with consistent effects across the ejection fraction spectrum. Despite these findings, the substantially higher cost of finerenone compared with spironolactone may limit its accessibility and real-world use, particularly in resource-limited settings, and the absence of head-to-head randomized trials precludes definitive conclusions regarding comparative efficacy, safety, and cost-effectiveness; future studies should th