Routine Spironolactone in Acute Myocardial Infarction — CLEAR (NEJM 2025)

Authors, Journal, Affiliations, Type, DOI

• Authors: Jolly SS, d'Entremont MA, Pitt B, Lee SF, Mian R, Tyrwhitt J, Kedev S, Montalescot G, Cornel JH, Stanković G, Moreno R, Storey RF, Henry TD, Mehta SR, Bossard M, Kala P, Bhindi R, Zafirovska B, Devereaux PJ, Eikelboom J, Cairns JA, Natarajan MK, Schwalm JD, Sharma SK, Tarhuni W, Conen D, Tawadros S, Lavi S, Asani V, Topic D, Cantor WJ, Bertrand OF, Pourdjabbar A, Yusuf S; for the CLEAR Investigators
• Journal: New England Journal of Medicine 2025;392:643–52
• Affiliations: Population Health Research Institute, McMaster University, Hamilton, Canada (coordinating centre); 104 centres in 14 countries
• Type: International, investigator-initiated, prospective, randomised, double-blind, placebo-controlled trial; 2×2 factorial design (spironolactone vs placebo × colchicine vs placebo); spironolactone arm reported here
• DOI: https://doi.org/10.1056/NEJMoa2405923

Overview

The CLEAR trial enrolled 7,062 AMI patients who had undergone PCI (95.1% STEMI; 4.9% large NSTEMI with ≥1 high-risk feature) at 104 centres in 14 countries between February 2018 and November 2022, randomising them to spironolactone 25 mg daily or placebo in a 2×2 factorial design with colchicine. Over a median follow-up of 3 years, spironolactone did not reduce either primary composite endpoint — CV death or new/worsening HF (HR 0.91; P=0.51) or the 4-component MACE composite (HR 0.96; P=0.60). A hypothesis-generating on-treatment analysis showed trends toward benefit (HR 0.79 and 0.83), suggesting adherence may modulate the drug effect. Gynecomastia (2.3% vs 0.5%), modest eGFR reduction (−1.8 ml/min/1.73m²), and a modest hyperkalemia excess (1.1% vs 0.6%) were the main adverse effects.

Keywords

Spironolactone, mineralocorticoid receptor antagonist, aldosterone antagonism, acute myocardial infarction, STEMI, percutaneous coronary intervention, heart failure, cardiovascular outcomes, randomised controlled trial, CLEAR

Key Takeaways

Background and Rationale

• Mineralocorticoid receptor antagonists (MRAs) reduce mortality in chronic HFrEF (RALES: spironolactone 30% all-cause mortality reduction) and in post-MI HFrEF (EPHESUS: eplerenone 15% RRR for death/CV death)
• Higher aldosterone levels post-MI are associated with increased mortality, providing biological rationale for extending MRA use beyond HFrEF
• ALBATROSS (n=1,603; MI without HF; spironolactone vs placebo): overall neutral, but a STEMI subgroup (n=1,229) showed significant mortality reduction — generating the hypothesis for CLEAR
• CLEAR aimed to determine whether routine spironolactone is beneficial in all post-MI patients, not just those with HFrEF

Trial Design

• 2×2 factorial design: spironolactone vs placebo AND colchicine vs placebo (colchicine arm published separately)
• Initially STEMI only; protocol amended April 2020 to include large NSTEMI with ≥1 risk factor (LVEF ≤45%, diabetes, multivessel CAD, prior MI, or age >60 years)
• Spironolactone 25 mg daily initiated as soon as possible after index PCI
• Double-blind, with blinded independent endpoint adjudication committee
• Coordinated by the Population Health Research Institute, McMaster University

Patient Characteristics

• 7,062 patients enrolled; 3,537 spironolactone, 3,525 placebo
• Mean age 61 years; 20.4% women; 9.0% prior MI; 0.8% prior HF; 18.5% diabetes
• 95.1% STEMI; 4.9% NSTEMI
• Median time from MI onset to randomisation: 26.8 hours (IQR 15.9–42.4)
• Baseline characteristics well balanced between groups
• LVEF data were not systematically collected — subgroup analysis by EF not possible

Primary Outcomes

• Primary outcome 1 — CV death or new/worsening HF (total events, Prentice–Williams–Peterson model):
  • Spironolactone: 183 events (1.7 per 100 patient-years)
  • Placebo: 220 events (2.1 per 100 patient-years)
  • Adjusted HR (competing risks): 0.91 (95% CI 0.69–1.21; P=0.51) — NOT significant
• Primary outcome 2 — First occurrence of CV death, MI, stroke, or new/worsening HF (time-to-event):
  • Spironolactone: 280/3,537 patients (7.9%)
  • Placebo: 294/3,525 patients (8.3%)
  • Adjusted HR (competing risks): 0.96 (95% CI 0.81–1.13; P=0.60) — NOT significant

Secondary Outcomes

• New or worsening HF alone: 58 patients (1.6%) vs 80 patients (2.3%); hazard ratio 0.68 (95% CI 0.49–0.96) — significant on time-to-first-event analysis; after competing-risk adjustment: HR 0.77 (95% CI 0.55–1.08) — no longer significant
• CV death: HR 0.98 (95% CI 0.74–1.27) — neutral
• All-cause mortality: 3.3% both groups; HR 0.98 (95% CI 0.76–1.27) — neutral
• Factorial interaction (colchicine × spironolactone): no significant interaction for either primary outcome (P=0.23 and P=0.23)

On-Treatment Analysis (Pre-Specified)

• Higher discontinuation in spironolactone group: 28.0% vs 24.4%
• On-treatment primary outcome 1: 131 vs 179 events; HR 0.79 (95% CI 0.63–1.00) — approaching significance
• On-treatment primary outcome 2: 204 (5.8%) vs 250 (7.2%); HR 0.83 (95% CI 0.69–1.00) — approaching significance
• This generates the hypothesis that better adherence (lower dropout) might reveal a clinically meaningful benefit

Blood Pressure Effect

• Systolic BP at 1 year: 126.9 mmHg vs 129.7 mmHg (mean difference −2.8 mmHg; 95% CI −3.6 to −2.0)
• Diastolic BP at 1 year: 77.5 mmHg vs 78.9 mmHg (mean difference −1.3 mmHg; 95% CI −1.8 to −0.8)
• BP reduction was observed at all time points throughout follow-up

Safety

• Hyperkalemia (K >5.5 mmol/L) leading to discontinuation: 1.1% vs 0.6% — higher with spironolactone
• Composite renal outcome (renal death/dialysis/transplant/sustained eGFR drop ≥40%): 1.0% vs 1.2% (OR 0.84; NS)
• eGFR at 1 year: 88.5 vs 90.2 ml/min/1.73m² (mean difference −1.8; P<0.001) — statistically significant reduction but modest
• Gynecomastia: 2.3% vs 0.5% (P<0.001) — the most common dose-specific spironolactone adverse effect
• Serious adverse events: 7.2% vs 6.8% — similar overall

Subgroup Analysis

• No significant interactions across prespecified subgroups: age, sex, MI type (anterior STEMI vs other), baseline K, hypertension history, COVID-19 era, geographic region
• Incidence of primary outcomes was consistent across all subgroups (no compelling subgroup with differential benefit)

Contextual Comparison With Related Trials

• RALES (HFrEF NYHA III/IV; LVEF ≤35%): spironolactone 30% all-cause mortality reduction, 35% HF hospitalisation reduction — positive
• EPHESUS (MI + LVEF <40% + HF or DM): eplerenone 15% RRR for death and HF hospitalisation — positive
• ALBATROSS (MI without HF; n=1,603): overall neutral; STEMI subgroup n=1,229 showed mortality benefit — hypothesis-generating
• EMPACT-MI (empagliflozin post-MI, high-risk): primary endpoint neutral (HR 0.90; P=0.21); HF hospitalisation alone reduced — parallel null result in the same era
• PARADISE-MI (sacubitril/valsartan): primary endpoint neutral; exploratory total HF events reduced — same era challenge of improving outcomes post-MI
• All three recent trials (CLEAR spironolactone, EMPACT-MI, PARADISE-MI) suggest modern post-MI care has substantially reduced residual risk, limiting the power of trials to detect incremental pharmacological benefit

Limitations of the Document

• Underpowered: Despite sample size increase from 4,000 to 7,000, event rate was lower than anticipated (4% vs 9–15% projected), reducing power; cannot exclude clinically meaningful RRR of ≤30%
• Type II error possible: 95% CIs for the primary outcomes include risk reductions of 27–31% — potentially clinically important if true
• High discontinuation rate: 28% in spironolactone vs 24% in placebo; may have attenuated the ITT treatment effect as supported by on-treatment analysis
• No LVEF data: Spironolactone benefit may be more pronounced in patients with reduced EF; inability to stratify by EF is a significant limitation
• Women underrepresented: 20.4% female (lower than real-world STEMI incidence); sex-specific effects unknown
• STEMI-dominant population: 95.1% STEMI, limiting generalisability to NSTEMI
• Factorial design cross-interference: Colchicine-related GI side effects may have increased discontinuation of the blinded spironolactone tablets, introducing non-random attrition

Key Concepts Mentioned

• concepts/Mineralocorticoid-Receptor-Antagonists-Post-MI — spironolactone 25 mg daily in unselected AMI; ITT negative; on-treatment trends
• concepts/Beta-Blocker-Post-MI — parallel post-MI pharmacotherapy question; same era of challenging older assumptions
• concepts/SGLT2-Inhibitors-in-CKD — EMPACT-MI as parallel null result for empagliflozin post-MI
• concepts/Colchicine-in-Cardiovascular-Disease — CLEAR colchicine arm (published separately); anti-inflammatory approach also neutral

Key Entities Mentioned

• entities/Acute-Coronary-Syndrome — CLEAR defines the role of spironolactone in unselected AMI
• entities/HFrEF — RALES and EPHESUS context for positive MRA evidence in HFrEF
• entities/Finerenone — class comparison: nonsteroidal MRA with a different profile

Wiki Pages Updated

• wiki/sources/spironolactone-ami-clear-nejm-2025.md — created (this file)
• wiki/concepts/Mineralocorticoid-Receptor-Antagonists-Post-MI.md — created
• wiki/entities/Acute-Coronary-Syndrome.md — updated: MRA/spironolactone section added
• wiki/sourceindex.md — updated
• wiki/wikiindex.md — updated