Mineralocorticoid receptor antagonists in heart failure with mildly reduced or preserved ejection fraction: a systematic review and meta-analysis of safety and clinical outcomes

Background

The role of mineralocorticoid receptor antagonists (MRAs) in heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) remains uncertain, in part due to heterogeneous trial results and concerns regarding hyperkalemia and renal dysfunction. Recent randomized trials conducted in the context of contemporary background therapy warrant an updated evaluation of the balance between safety and clinical outcomes in this population.

Methods

We conducted a systematic review and meta-analysis of randomized controlled trials comparing spironolactone, eplerenone, or finerenone with placebo in patients with HFmrEF or HFpEF. Four trials met inclusion criteria: FINEARTS-HF, TOPCAT, Aldo-DHF, and RAAM-PEF. The primary analyses focused on safety outcomes, specifically hyperkalemia (serum potassium ≥5.5 mmol/L) and worsening renal function, defined according to trial-specific criteria. Secondary analyses evaluated severe hyperkalemia (≥6.0 mmol/L), treatment discontinuation, and clinical efficacy. The key efficacy outcome was the composite of time-to-first worsening heart failure event or cardiovascular death. Risk ratios (RRs) for binary outcomes were pooled using random-effects models, while hazard ratios (HRs) for time-to-event outcomes were pooled using inverse-variance methods. Statistical heterogeneity was assessed using the I² statistic.

Results

Across four randomized trials encompassing patients with HFmrEF/HFpEF, MRA therapy was associated with a significantly higher risk of hyperkalemia compared with placebo (RR 2.06, 95% CI 1.76–2.42; I²=0%). MRAs were also associated with an increased risk of worsening renal function despite heterogeneity in renal definitions across trials (RR 1.74, 95% CI 1.35–2.24; I²=0%).

In contrast, MRA therapy was associated with a significant reduction in the composite outcome of time-to-first worsening heart failure event or cardiovascular death (HR 0.86, 95% CI 0.79–0.93; I²=0%). This benefit appeared to be driven predominantly by reductions in worsening heart failure events rather than cardiovascular mortality. Severe hyperkalemia was uncommon, and treatment discontinuation due to adverse events varied across studies without a consistent excess risk.

Conclusions

In patients with HFmrEF or HFpEF, MRA therapy confers a modest but significant reduction in worsening heart failure events, alongside predictable increases in potassium and renal adverse events These findings clarify efficacy–safety trade-offs across steroidal and nonsteroidal MRA eras, emphasizing careful patient selection, close laboratory monitoring, and individualized risk–benefit assessment, rather than routine, uniform use in HFmrEF/HFpEF.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.