September 29, 2025BMC Cardiovascular DisordersOpen Access

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

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Why the study?

MRAs are established for HFrEF, but their benefits in HFmrEF/HFpEF and agent-specific profiles required clarification across heart failure phenotypes and agents.

Do mineralocorticoid receptor antagonists reduce the composite of hospitalization for heart failure or cardiovascular death in patients with heart failure compared to placebo?

Structured PICO

Do mineralocorticoid receptor antagonists reduce the composite of hospitalization for heart failure or cardiovascular death in patients with heart failure compared to placebo?

Population

20,699 adults with heart failure from 6 RCTs (HFrEF: n=11,253; HFmrEF/HFpEF: n=9,446). Mean ages ranged from mid-60s to early 70s, 30-50% female, diabetes prevalence approximately 30-40%. Most patients were on ACE inhibitors (or ARBs) and beta-blockers.

Intervention

Mineralocorticoid receptor antagonists (MRAs) as a class (including spironolactone, eplerenone, and finerenone)

Comparator

Placebo

Outcome

Composite of hospitalization for heart failure (HHF) or cardiovascular deathcomposite

MRAs significantly reduce the composite of heart failure hospitalization or cardiovascular death across the spectrum of ejection fractions, though mortality benefits are predominantly seen in HFrEF.

Limitations

Small number of trials limits definitive assessment of publication bias
Potential underreporting of non-significant adverse events for safety endpoints

Implication

Supports MRA use across the HF spectrum to reduce HF hospitalization or CV death; extends RCT evidence beyond HFrEF.

Abstract

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. 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). 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). 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.