Mineralocorticoid receptor antagonists in heart failure: an individual patient level meta-analysis

Background: Mineralocorticoid receptor antagonists (MRAs) reduce hospitalisations and death in patients with heart failure and reduced ejection fraction (HFrEF), but the benefit in patients with heart failure and mildly reduced ejection fraction (HFmrEF) or heart failure and preserved ejection fraction (HFpEF) is unclear. We evaluated the effect of MRAs in four trials that enrolled patients with heart failure across the range of ejection fraction.

Methods: This is a prespecified, individual patient level meta-analysis of the RALES (spironolactone) and EMPHASIS-HF (eplerenone) trials, which enrolled patients with HFrEF, and of the TOPCAT (spironolactone) and FINEARTS-HF (finerenone) trials, which enrolled patients with HFmrEF or HFpEF. The primary outcome of this meta-analysis was a composite of time to first hospitalisation for heart failure or cardiovascular death. We also estimated the effect of MRAs on components of this composite, total (first or repeat) heart failure hospitalisations (with and without cardiovascular deaths), and all-cause death. Safety outcomes were also assessed, including serum creatinine, estimated glomerular filtration rate, serum potassium, and systolic blood pressure. An interaction between trials and treatment was tested to examine the heterogeneity of effect in these populations. This study is registered with PROSPERO, CRD42024541487.

Findings: 13 846 patients were included in the four trials. MRAs reduced the risk of cardiovascular death or heart failure hospitalisation (hazard ratio 0·77 [95% CI 0·72-0·83]). There was a statistically significant interaction by trials and treatment (p for interaction=0·0012) due to the greater efficacy in HFrEF (0·66 [0·59-0·73]) compared with HFmrEF or HFpEF (0·87 [0·79-0·95]). We observed significant reductions in heart failure hospitalisation in the HFrEF trials (0·63 [0·55-0·72]) and the HFmrEF or HFpEF trials (0·82 [0·74-0·91]). The same pattern was observed for total heart failure hospitalisations with or without cardiovascular death. Cardiovascular death was reduced in the HFrEF trials (0·72 [0·63-0·82]) but not in the HFmrEF or HFpEF trials (0·92 [0·80-1·05]). All-cause death was also reduced in the HFrEF trials (0·73 [0·65-0·83]) but not in the HFmrEF or HFpEF trials (0·94 [0·85-1·03]). With an MRA, the risk of hyperkalaemia was doubled compared with placebo (odds ratio 2·27 [95% CI 2·02-2·56]), but the incidence of serious hyperkalaemia (serum potassium >6·0 mmol/L) was low (2·9% vs 1·4%); the risk of hypokalaemia (potassium <3·5 mmol/L) was halved (0·51 [0·45-0·57]; 7% vs 14%).

Interpretation: Steroidal MRAs reduce the risk of cardiovascular death or heart failure hospitalisation in patients with HFrEF and non-steroidal MRAs reduce this risk in patients with HFmrEF or HFpEF.

Funding: None.