JACC Heart Fail 2025 Jul 01;138:102479. doi: 10.1016/j.jchf.2025.02.025.

Interaction Between Aldosterone and Mineralocorticoid Receptor Antagonist: Findings From the EPHESUS Trial.

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BACKGROUND: Mineralocorticoid receptor antagonists (MRAs) block the activation of mineralocorticoid receptors by aldosterone, thereby mitigating cardiovascular risks. However, data on whether impact of aldosterone on outcomes differs with MRA use remain limited. OBJECTIVES: The study aims to explore the associations between baseline aldosterone, its changes and outcomes, and their interaction with eplerenone. METHODS: In a subset of the EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) trial, associations between baseline serum aldosterone concentrations, their changes from baseline to month 1, and outcomes were separately assessed in the eplerenone and placebo groups. The primary outcome was a composite of cardiovascular death or heart failure (HF) hospitalization. RESULTS: Among 453 patients (mean age: 62 ± 11 years; 75% male), baseline median serum aldosterone was 5.6 ng/dL (Q1-Q3: 3.1-9.2 ng/dL). Higher baseline serum aldosterone was associated with primary outcome in the placebo group (HR per 1 ng/dL: 1.04 ng/dL [95% CI: 1.02-1.07 ng/dL]; P = 0.002), but not in the eplerenone group (HR per 1 ng/dL: 0.99 ng/dL [95% CI: 0.93-1.05 ng/dL]; P = 0.64; P for interaction = 0.048), and these associations persisted after covariate adjustment (ie, prior HF history and renal function). At month 1, eplerenone increased serum aldosterone more than placebo (P < 0.001). High serum aldosterone changes (≥ median value) were associated with increased risk of primary outcome in the placebo group but not in the eplerenone group (HR: 3.48 [95% CI: 1.35-8.99]; P = 0.01 in placebo; HR: 0.81 [95% CI: 0.36-1.82]; P = 0.60 in eplerenone; P for interaction = 0.046), and these associations persisted after covariate adjustment. CONCLUSIONS: In patients with left ventricular systolic dysfunction and/or HF after myocardial infarction, higher baseline or rising aldosterone levels were associated with increased risk of HF events. However, eplerenone mitigated aldosterone-associated risks.

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