Mineralocorticoid Receptor Antagonists After Myocardial Infarction

Definition

Mineralocorticoid receptor antagonists (MRAs) — including the steroidal agents spironolactone and eplerenone, and the nonsteroidal agent finerenone — competitively block aldosterone at the mineralocorticoid receptor. Aldosterone levels rise acutely after MI and are associated with increased post-MI mortality, providing the biological rationale for MRA use. The key clinical question is whether MRA benefit, firmly established in patients with reduced ejection fraction (HFrEF) or established HF, extends to all post-MI patients regardless of EF or HF status.

Key Concepts

Established Positive Evidence (HF-Restricted Populations)

RALES — Spironolactone in Chronic HFrEF (1999)

• n=1,663; NYHA III/IV chronic HF; LVEF ≤35%; spironolactone 25 mg vs placebo
• All-cause mortality: 30% relative risk reduction (primary endpoint; P<0.001)
• HF hospitalisation: 35% reduction
• Landmark trial establishing spironolactone as a cornerstone of HFrEF management
• (Rating: very high; see entities/HFrEF)

EPHESUS — Eplerenone in Post-MI HFrEF (2003)

• n=6,642; LVEF <40% + HF or diabetes mellitus post-MI; eplerenone vs placebo
• All-cause mortality: 15% relative risk reduction (P=0.008); CV death/HF hospitalisation: 13% RRR (P=0.002)
• Demonstrated that selective MRA benefit extends to the post-MI setting — in patients with reduced EF and either HF or diabetes
• Guideline-endorsed: MRA after MI with EF <40% is Class I/A (ESC/AHA/ACC)
• Key limitation: restricted to patients with EF <40% + comorbidity — does not apply to unselected AMI

Hypothesis-Generating Evidence for Broader AMI Use

ALBATROSS — Spironolactone in AMI Without HF (2016)

• n=1,603; MI without established HF (all comers); spironolactone vs placebo; 6 months
• Primary composite endpoint: neutral overall
• STEMI subgroup (n=1,229): significant mortality reduction — hypothesis-generating
• Limitations: small sample, short follow-up; STEMI subgroup was not pre-planned as the primary analysis unit
• Motivated the CLEAR trial

Definitive Evidence Against Routine Use in Unselected AMI

CLEAR — Spironolactone in Unselected AMI Post-PCI (NEJM 2025) — LARGEST RCT

• n=7,062; 104 centres; 14 countries; Feb 2018–Nov 2022; 2×2 factorial design (spiro + colchicine); 95.1% STEMI, 4.9% NSTEMI; spironolactone 25 mg daily vs placebo; median follow-up 3 years (sources/spironolactone-ami-clear-nejm-2025, rating: very high)
• Primary outcome 1 (CV death or new/worsening HF, total events): HR 0.91 (95% CI 0.69–1.21; P=0.51) — NOT significant
• Primary outcome 2 (MACE composite: CV death, MI, stroke, or new/worsening HF): HR 0.96 (95% CI 0.81–1.13; P=0.60) — NOT significant
• No significant differences across any prespecified subgroups (age, sex, MI type, baseline K, hypertension, COVID era, geography)
• LVEF data not collected — unable to assess EF-based subgroup
• On-treatment analysis (hypothesis-generating): primary outcome 1 HR 0.79 (95% CI 0.63–1.00); primary outcome 2 HR 0.83 (95% CI 0.69–1.00) — both approaching but not reaching significance, driven by 28% discontinuation in spironolactone group vs 24% placebo
• New or worsening HF component: HR 0.68 (0.49–0.96) on time-to-first-event — significant in unadjusted analysis; HR 0.77 (0.55–1.08) after competing-risk adjustment — no longer significant
• Blood pressure: −2.8 mmHg systolic, −1.3 mmHg diastolic at 1 year (consistent anti-hypertensive effect)

Safety Profile of Spironolactone in AMI (CLEAR Data)

• Gynecomastia: 2.3% vs 0.5% (P<0.001) — most distinct adverse effect; dose-related; androgen receptor off-target effect
• Hyperkalemia (K >5.5 mmol/L requiring discontinuation): 1.1% vs 0.6% — modest excess
• eGFR at 1 year: −1.8 ml/min/1.73m² vs placebo (P<0.001) — statistically significant but modest; no excess renal hard outcomes (composite renal outcome 1.0% vs 1.2%; NS)
• Serious adverse events: 7.2% vs 6.8% — similar overall

Where Does MRA Fit in the Post-MI Landscape?

Comparison of MRA Agents

• Spironolactone: Steroidal; also blocks androgen/progesterone receptors → gynecomastia, breast tenderness, menstrual irregularity; cheap; RALES trial drug
• Eplerenone: Steroidal but more selective for mineralocorticoid receptor → less gynecomastia; EPHESUS/EMPHASIS-HF trial drug
• Finerenone: Nonsteroidal; highest receptor selectivity; no sex steroid effects; lower hyperkalemia risk than steroidal MRAs; positive in HFpEF/HFmrEF (FINEARTS-HF) and CKD (FIDELIO-DKD/FIGARO-DKD); not yet tested in acute MI setting

Contradictions / Open Questions

• CLEAR (unselected AMI, negative, n=7,062) vs EPHESUS (MI + HFrEF, positive, n=6,642): The key distinction is LVEF and HF status — EPHESUS restricted to EF <40% + HF/DM; CLEAR enrolled all comers without EF requirement and found no benefit. Because CLEAR did not collect LVEF data, it cannot confirm whether the EF <40% subgroup would have benefited. The mechanistic conclusion is that MRA benefit in AMI is EF- and HF-dependent, not a class effect across all AMI patients.
• On-treatment HR 0.79/0.83 vs ITT HR 0.91/0.96 — adherence confound: The on-treatment analysis in CLEAR approaches significance despite the ITT being clearly negative. The 28% discontinuation rate in the spironolactone group (vs 24% placebo) likely diluted the ITT effect. Whether higher adherence (achievable with better tolerability drugs like eplerenone or finerenone) would tip the result into significance is untested. A dedicated adherence-enhanced trial might be warranted.
• Finerenone as the candidate for future AMI trials: CLEAR used spironolactone, which has significant non-mineralocorticoid side effects (gynecomastia, androgen blockade) that may have driven higher dropout. Finerenone has shown kidney and CV benefits in CKD (FIDELIO-DKD/FIGARO-DKD) with better tolerability. Whether finerenone in unselected AMI would produce different results from spironolactone is an open question.
• Era effect — lower-than-expected event rates: CLEAR and concurrent post-MI trials (EMPACT-MI, PARADISE-MI) all enrolled with anticipated higher event rates than observed. Modern post-MI management (potent antiplatelets, high-intensity statins, complete revascularization) has dramatically reduced residual risk, limiting the absolute benefit achievable with any additional agent.
• HF component signal: New or worsening HF was numerically lower in spironolactone (58 vs 80 patients; HR 0.68) — time-to-first-event significant before competing-risk adjustment. The anti-congestion effect is biologically plausible (aldosterone drives sodium retention and myocardial fibrosis). Whether spironolactone delays HF development in higher-risk subgroups (anterior STEMI, diabetes, elevated BNP) remains exploratory.
• ALBATROSS STEMI subgroup vs CLEAR overall negative — subgroup hypothesis not confirmed: ALBATROSS suggested STEMI-specific benefit driving the hypothesis for CLEAR. CLEAR enrolled 95% STEMI patients yet found no benefit overall — the ALBATROSS STEMI subgroup finding was not replicated at scale.

Connections

• Related to entities/Acute-Coronary-Syndrome — CLEAR defines role of spironolactone post-AMI; EPHESUS defines eplerenone in AMI+HFrEF
• Related to entities/HFrEF — RALES and EPHESUS established MRA as cornerstone of HFrEF therapy; CLEAR does not challenge this
• Related to entities/HFpEF — TOPCAT (neutral) and FINEARTS-HF (positive for finerenone) are HFpEF MRA trials
• Related to entities/Finerenone — nonsteroidal MRA with distinct profile; potential future AMI candidate
• Related to concepts/Beta-Blocker-Post-MI — parallel era-defining trials challenging historic post-MI pharmacotherapy assumptions
• Related to concepts/SGLT2-Inhibitors-in-CKD — EMPACT-MI as parallel null result in same post-MI prevention space
• Related to concepts/Potassium-and-Ventricular-Arrhythmias — POTCAST demonstrates K 4.5–5.0 target reduces VA; MRA subgroup effect suggests K-mediated mechanism may partly explain RALES/EPHESUS benefit

Sources

• sources/spironolactone-ami-clear-nejm-2025 — CLEAR (NEJM 2025): largest RCT spironolactone in unselected AMI; negative ITT