Mineralocorticoid Receptor Antagonists Associated With Reductions in Hospitalizations and Death Among Patients With Heart Failure

Is the treatment of heart failure with steroidal or nonsteroidal mineralocorticoid receptor antagonists associated with decreased heart failure hospitalizations and cardiovascular death?

The individual patient level meta-analysis confirms that steroidal mineralocorticoid receptor antagonists (spironolactone and eplerenone) reduce hospitalizations in patients across heart failure types and reduce cardiovascular death and all-cause mortality in patients with heart failure with reduced ejection fraction. The nonsteroidal mineralocorticoid finerenone (Kerendia) reduces mortality risk for patients with mildly reduced or preserved ejection fraction. There is a concomitant absolute increase of approximately 1.5 percentage points for severe hyperkalemia. (Level of Evidence = 1a)

The authors present an individual patient level meta-analysis (13,846 participants) of four large studies of treatment with mineralocorticoid receptor antagonists vs placebo for the reduction of hospitalizations for heart failure and cardiovascular death in patients with heart failure with reduced ejection fraction (HFrEF; 40% or less), heart failure with mildly reduced ejection fraction (41%–49%), and heart failure with preserved ejection fraction (HFpEF; 50% or more). The study included two steroidal mineralocorticoid receptor antagonists (spironolactone and eplerenone) and one nonsteroidal mineralocorticoid receptor antagonist (finerenone). The latter was used in trials focused on patients with heart failure with mildly reduced ejection fraction and HFpEF because it did not demonstrate benefit in patients with HFrEF in the TOPCAT trial, one of the studies included in the meta-analysis. Baseline characteristics were balanced among groups. The primary outcome was time to first hospitalization for heart failure or cardiovascular death.

There was heterogeneity among studies regarding treatment effects for the composite end point of greater benefit for HFrEF than for heart failure with mildly reduced ejection fraction and HFpEF (pooled hazard ratio [HR] = 0.66; 95% CI, 0.59–0.73 vs HR = 0.87; 95% CI, 0.79–0.95). The benefit of mineralocorticoid receptor antagonists for cardiovascular death as a separate end point was significant for HFrEF, but not heart failure with mildly reduced ejection fraction or HFpEF (HR = 0.72; 95% CI, 0.63–0.82 vs HR = 0.92; 95% CI, 0.60–1.05, respectively). It was similar for all-cause mortality. The effect of mineralocorticoid receptor antagonists for total heart failure hospitalizations was significant (for HFrEF: relative risk [RR] = 0.60; 95% CI, 0.52–0.69; for heart failure with mildly reduced ejection fraction and HRpEF: RR = 0.82; 95% CI, 0.74–0.90). Safety outcomes were assessed for patients who received at least one dose of mineralocorticoid receptor antagonists. Severe hyperkalemia, defined as greater than 6.0 mmol/L, was higher with mineralocorticoid receptor antagonists than placebo (odds ratio = 2.27; 95% CI, 2.02–2.56; absolute risk difference = 1.5%).

Study design: Meta-analysis (randomized controlled trials)

Funding source: Self-funded or unfunded

Setting: Various (meta-analysis)

Reference: Jhund PS, Talebi A, Henderson AD, et al. Mineralocorticoid receptor antagonists in heart failure: an individual patient level meta-analysis. Lancet. 2024;404(10458):1119-1131.