Colchicine in Acute Myocardial Infarction (CLEAR Trial)

Authors, Journal, Affiliations, Type, DOI

• Authors: Sanjit S. Jolly, Marc-André d'Entremont, Shun Fu Lee, Rajibul Mian, Jessica Tyrwhitt, Sasko Kedev, Gilles Montalescot, Jan H. Cornel, Goran Stanković, Raul Moreno, Robert F. Storey, Timothy D. Henry, Shamir R. Mehta, Matthias Bossard, Petr Kala, Jamie Layland, Biljana Zafirovska, P.J. Devereaux, John Eikelboom, John A. Cairns, Binita Shah, Tej Sheth, Sanjib K. Sharma, Wadea Tarhuni, David Conen, Sarah Tawadros, Shahar Lavi, Salim Yusuf, for the CLEAR Investigators
• Journal: New England Journal of Medicine
• Affiliations: Population Health Research Institute, McMaster University, Hamilton, Canada (lead); 104 centres across 14 countries
• Type: International, investigator-initiated, multicenter, prospective, randomized, double-blind, placebo-controlled trial (2×2 factorial design — colchicine component reported here)
• DOI: https://doi.org/10.1056/NEJMoa2405922

Overview

The CLEAR trial (CLEAR SYNERGY OASIS-9) randomized 7,062 patients with acute MI to colchicine 0.5 mg/day or placebo in a 2×2 factorial design (also testing spironolactone vs placebo). Over a median 3-year follow-up, colchicine did not reduce the composite primary outcome of CV death, recurrent MI, stroke, or unplanned ischemia-driven revascularization (HR 0.99; 95% CI 0.85–1.16; P=0.93). Colchicine confirmed its anti-inflammatory effect (CRP reduced by 1.28 mg/L at 3 months) and increased diarrhea (10.2% vs 6.6%), but failed to translate biological activity into clinical benefit. This null result challenges the ESC Class IIa recommendation and FDA approval for colchicine in coronary artery disease, both issued before these data were available.

Keywords

Colchicine, acute myocardial infarction, STEMI, NSTEMI, anti-inflammatory therapy, CRP, secondary prevention, MACE, cardiovascular outcomes, CLEAR trial

Key Takeaways

Trial Design and Population

• 2×2 factorial design: colchicine vs placebo AND spironolactone vs placebo; colchicine results reported here (spironolactone results published separately)
• Enrolled between February 2018 and November 2022 at 104 centres in 14 countries
• Initially STEMI only; protocol modified April 2020 to also include high-risk NSTEMI with PCI + ≥1 risk factor (LVEF ≤45%, diabetes, multivessel CAD, prior MI, or age >60 years)
• Baseline characteristics: mean age 61 years; 20.4% women; 9.0% prior MI; 18.5% diabetes; 95.1% STEMI, 4.9% NSTEMI
• Colchicine dosing: initially weight-based (≥70 kg: 0.5 mg twice daily; <70 kg: 0.5 mg once daily for first 90 days); simplified to 0.5 mg once daily throughout from September 2020 after COLCOT results
• Median time from symptom onset to randomization: 26.8 hours; median time to first dose: 1.6 hours post-randomization
• Median follow-up: 3.00 years; 25.9% in colchicine and 25.5% in placebo discontinued trial regimen

Primary Outcome — Null Result

• Primary composite (CV death, recurrent MI, stroke, or unplanned ischemia-driven revascularization): 322/3,528 (9.1%) colchicine vs 327/3,534 (9.3%) placebo — HR 0.99 (95% CI 0.85–1.16; P=0.93)
• No significant interaction with spironolactone factorial (P=0.96 for interaction)
• 649 total first primary-outcome events — exceeds the >600 threshold above which spurious trial results are rare by prior meta-analysis

Secondary Outcomes — Consistently Null

• CV death, recurrent MI, or stroke: 241 (6.8%) vs 250 (7.1%) — HR 0.98 (95% CI 0.82–1.17)
• CV death: 3.3% vs comparable in placebo — HR consistent with null
• All individual components of primary and secondary outcomes appeared similar between groups
• On-treatment analysis consistent with intention-to-treat analysis
• Results consistent across all prespecified subgroups (age, sex, diabetes, vessel disease, STEMI/NSTEMI, eGFR, COVID era)
• One exception: patients ≥70 kg who received twice-daily colchicine in first 3 months showed a signal for lower event rate (HR 0.68; 95% CI 0.46–0.99) — exploratory, not confirmatory

Anti-Inflammatory Effect Confirmed

• CRP at 3 months (n=1,384 colchicine, n=1,419 placebo): least-squares mean difference −1.28 mg/L (95% CI −1.81 to −0.75) — colchicine had statistically significant biological activity
• This biological-clinical dissociation (lower CRP, no MACE benefit) is a key finding

Safety

• Diarrhea: 10.2% colchicine vs 6.6% placebo (P<0.001) — expected pharmacological effect
• Serious adverse events: no difference between groups
• Serious infections: no difference (no excess pneumonia as seen in COLCOT)
• Noncardiovascular death: 45 (1.3%) in colchicine group — numerically lower than placebo (directionally opposite to meta-analysis concerns about non-CV mortality with colchicine)

Comparison with Prior Colchicine Trials

• COLCOT (n=4,745; post-MI within 30 days): 23% RRR in MACE (HR 0.77; P=0.02) — positive result
• LoDoCo2 (n=5,522; stable CAD): 31% RRR in primary composite — positive result
• CHANCE-3 (n=8,345; acute ischemic stroke): No effect on stroke (HR 0.98); short treatment duration (90 days) may explain
• CONVINCE (n=3,154; ischemic stroke; 34 months): No effect on composite vascular outcome (HR 0.84; 95% CI 0.68–1.05)
• CLEAR, CHANCE-3, and CONVINCE represent the three most recent colchicine trials — all neutral
• The reason for divergence between COLCOT/LoDoCo2 (positive) and CLEAR/CHANCE-3/CONVINCE (neutral) remains unexplained

Limitations of the Document

• Women (20.4%) and racially/ethnically diverse groups underrepresented relative to real-world MI incidence
• 26% discontinuation rate — higher than anticipated (12.5%); sensitivity on-treatment analysis was consistent but power reduction cannot be excluded
• Protocol change mid-trial from twice-daily (weight-based, first 90 days) to once-daily dosing — the twice-daily subgroup showed a signal (HR 0.68) but was not prospectively powered for this comparison
• Adherence assessed only by patient self-report; pill counts not feasible during COVID-19 pandemic
• Gout incidence not assessed as an outcome
• 95% STEMI (predominantly acute plaque rupture physiology) — may not generalise to stable ASCVD or mixed MI populations
• Missing vital status in 45 patients (0.6%) — most likely missing at random

Key Concepts Mentioned

• concepts/Colchicine-in-Cardiovascular-Disease — primary subject; CLEAR is the largest acute-MI colchicine RCT
• concepts/Inflammation-in-Atherosclerosis — biological rationale for anti-inflammatory therapy in ACS
• concepts/Multivessel-PCI-STEMI-Timing — context: 95% STEMI population undergoing PCI

Key Entities Mentioned

• entities/Acute-Coronary-Syndrome — trial population; colchicine as post-MI therapy
• entities/Chronic-Coronary-Disease — implications for COR 2b recommendation update

Wiki Pages Updated

• wiki/sources/colchicine-ami-clear-nejm-2025.md — created (this file)
• wiki/concepts/Colchicine-in-Cardiovascular-Disease.md — created
• wiki/entities/Acute-Coronary-Syndrome.md — updated colchicine section and contradictions
• wiki/entities/Chronic-Coronary-Disease.md — updated colchicine section and contradictions
• wiki/sourceindex.md — updated
• wiki/wikiindex.md — updated