CLEAR Colchicine
(2025)Objective
To assess whether colchicine reduces cardiovascular events when initiated after acute myocardial infarction (MI).
Study Summary
• Primary composite outcome (CV death, MI, stroke, ischemia-driven revascularization): no difference between colchicine 0.5 mg daily and placebo at 3 years median follow-up
Intervention
International, multicenter, 2x2 factorial randomized controlled trial. Patients with STEMI or large NSTEMI underwent PCI and were randomized to colchicine 0.5 mg daily vs placebo. Adjustments made mid-study to use once-daily dosing. Trial also included spironolactone randomization (reported separately).
Inclusion Criteria
Patients with STEMI or large NSTEMI undergoing PCI and meeting at least one risk factor: LVEF ≤45%, diabetes, multivessel CAD, prior MI, or age >60.
Study Design
Arms: Colchicine vs Placebo
Patients per Arm: Colchicine: 3528; Placebo: 3534
Outcome
• Primary Endpoint: 9.1% (colchicine) vs 9.3% (placebo); HR 0.99 (95% CI 0.85–1.16; P=0.93)
• CRP at 3 months: Mean difference -1.28 mg/L favoring colchicine (P<0.001)
• Diarrhea more frequent in colchicine group (10.2% vs 6.6%, P<0.001)
• No significant differences in serious infections or total events.
• CRP at 3 months: Mean difference -1.28 mg/L favoring colchicine (P<0.001)
• Diarrhea more frequent in colchicine group (10.2% vs 6.6%, P<0.001)
• No significant differences in serious infections or total events.
Bottom Line
Colchicine did not reduce cardiovascular events over 3 years but lowered C-reactive protein and increased diarrhea.
Major Points
- Large randomized trial with 7,062 patients post-MI using a 2×2 factorial design (colchicine vs placebo × spironolactone vs placebo) across 104 centers in 14 countries.
- No difference in primary composite outcome of CV death, MI, stroke, or ischemia-driven revascularization (HR 0.99, 95% CI 0.85–1.16, P=0.93) — a definitively negative trial.
- C-reactive protein reduced by −1.28 mg/L at 3 months, confirming anti-inflammatory effect — but this biomarker reduction did not translate to clinical benefit.
- Contradicts COLCOT (2019, post-MI colchicine positive) and LoDoCo2 (2020, chronic CAD positive), raising questions about whether anti-inflammatory benefit is timing-dependent, dose-dependent, or population-specific.
- Dosing protocol changed mid-trial from weight-based twice-daily to once-daily 0.5 mg, potentially diluting any early high-intensity anti-inflammatory window.
- Increased diarrhea with colchicine (10.2% vs 6.6%, P<0.001) but no excess in serious infections, serious GI events, or serious adverse events overall.
- Unexpected signal for reduced non-cardiovascular death (HR 0.68, P<0.05), though not prespecified and likely a chance finding given multiple comparisons.
- High discontinuation rate (26%) may have attenuated any true treatment effect — on-treatment sensitivity analysis similarly showed no benefit.
- The 2×2 factorial design with spironolactone allowed independent assessment; no significant interaction between the two interventions detected.
- Predominantly STEMI population (95.3%) — limits generalizability to NSTEMI or unstable angina and may explain divergence from COLCOT (which included both).
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled, 2x2 factorial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 7062
- Follow-up
- Median 3.0 years
- Centers
- 104
- Countries
- 14 countries
Primary Outcome
Definition: Death from cardiovascular causes, MI, stroke, or ischemia-driven revascularization
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 9.3% | 9.1% | 0.99 (0.85–1.16) | 0.93 |
Limitations & Criticisms
- Underrepresentation of women (20.5%) and racial/ethnic minorities — limits generalizability to diverse populations.
- Higher-than-expected discontinuation rate (26%) may have attenuated any true treatment effect below detectable thresholds.
- Mid-trial protocol change from weight-based twice-daily to once-daily 0.5 mg dosing complicates dose-response interpretation and may have diluted the early anti-inflammatory window.
- Contradicts COLCOT and LoDoCo2 without a clear mechanistic explanation — raises fundamental questions about the reproducibility of colchicine's cardiovascular benefit.
- Predominantly STEMI population (95.3%) — results may not apply to NSTEMI or unstable angina, limiting the trial's scope for broader secondary prevention.
- The 2×2 factorial design with spironolactone introduces interpretive complexity despite no detected interaction between the two treatments.
- CRP reduction confirmed pharmacologic activity but failure to improve outcomes challenges the inflammation hypothesis as a therapeutic target in acute MI.
- No assessment of gout incidence during follow-up, missing an opportunity to evaluate a common colchicine co-benefit.
- COVID-19 pandemic overlap during enrollment (2018–2022) may have affected event rates, follow-up completeness, and healthcare access patterns.
Citation
Jolly SS, et al. N Engl J Med 2025;392:633–642.