Efficacy and safety of mineralocorticoid receptor antagonists in heart failure: a meta-analysis of randomized controlled trials

Abstract

Background: Mineralocorticoid receptor antagonists (MRAs) are established for heart failure with reduced ejection fraction (HFrEF), but their benefits in mildly reduced/preserved EF (HFmrEF/HFpEF) and agent-specific profiles require clarification. This meta-analysis aimed to evaluate the efficacy, safety, and benefit-risk profiles of MRAs across heart failure phenotypes and agents.

Methods: This meta-analysis synthesized data from randomized controlled trials (RCTs). The primary outcome was a composite of hospitalization for heart failure (HHF) or cardiovascular death. Secondary outcomes included HHF, cardiovascular/all-cause mortality, and safety endpoints. Subgroup analyses examined heart failure phenotypes and MRA agents. Benefit-risk was quantified via Number Needed to Treat/Harm (NNT/NNH).

Results: Data from six RCTs (FINEARTS-HF, EPHESUS, EMPHASIS-HF, J-EMPHASIS-HF, TOPCAT, RALES; n = 20,699) were synthesized. MRAs significantly reduced the primary composite outcome (HR = 0.79, 95% CI 0.71-0.88; P < 0.001; NNT_2.24yr =22.4), with consistent effects across demographic subgroups. Reductions were also observed in cardiovascular mortality (HR = 0.82, NNT_2.24yr = 45.5), sudden cardiac death (HR = 0.78, NNT_2.24yr = 67), HHF (HR = 0.76, NNT_2.24yr = 25), and all-cause mortality (HR = 0.84, NNT_2.24yr = 39.1). Safety analyses revealed increased risks of hyperkalemia (K⁺ >5.5 mmol/L: OR = 2.29, NNH_2.24yr = 12.7), hypotension (OR = 1.52, NNH_2.24yr = 23.3), and renal impairment (creatinine ≥ 2.5 mg/dL: OR = 1.63, NNH_2.24yr = 49.2), alongside a decreased risk of hypokalemia (K⁺ < 3.5 mmol/L: OR = 0.52, NNT_2.24yr = 17.3). Subgroup analyses demonstrated significant mortality benefits in HFrEF (cardiovascular mortality HR = 0.77; all-cause mortality HR = 0.78), although hospitalization benefits extended to both HFrEF and HFmrEF/HFpEF. Eplerenone demonstrated significant mortality reduction (cardiovascular mortality HR = 0.81; all-cause mortality HR = 0.83), while spironolactone only showed significant HHF reduction (HR = 0.73).

Discussion: MRAs significantly reduce composite cardiovascular outcomes across heart failure phenotypes, with mortality benefits predominantly in HFrEF. Eplerenone appears to offer stronger mortality advantages, while spironolactone is more effective in reducing hospitalizations. These findings support phenotype- and agent-specific strategies to optimize the benefit-risk profile of MRA therapy in heart failure.

Keywords: Eplerenone; Finerenone; Heart failure with preserved ejection fraction; Heart failure with reduced ejection fraction; Mineralocorticoid receptor antagonists; Number needed to treat; Spironolactone.