Long-term trials of colchicine for secondary prevention of vascular events: a meta-analysis

Low-dose colchicine added to guideline-directed therapy reduces long-term major adverse cardiovascular events without increasing mortality.

Background

Inflammation is a key driver of atherothrombosis. Building on prior trials (e.g., COLCOT, LoDoCo2) and new data from acute myocardial infarction and post-stroke populations, this meta-analysis reassesses the long-term efficacy and safety of low-dose colchicine for secondary prevention of vascular events.

Patients

• Total: 21,800 adults with clinically manifest vascular disease randomized in 6 RCTs (colchicine n=10,871; control n=10,929).
• Populations: post-myocardial infarction (COLCOT, CLEAR-SYNERGY), acute coronary syndrome (COPS), stable coronary artery disease (LoDoCo, LoDoCo2), prior non-cardioembolic ischemic stroke or high-risk TIA (CONVINCE).
• Baseline: mean age 60–67 years; approximately 20% women overall; >90% on statins; higher hypertension prevalence and female representation in stroke trial.

Intervention

Low-dose colchicine 0.5 mg once daily, added to guideline-directed medical therapy.

Control

Placebo or no colchicine, on top of guideline-directed medical therapy.

Outcome

• Primary efficacy: Major adverse cardiovascular events (MACE) = cardiovascular death, myocardial infarction (MI), ischemic stroke, urgent coronary revascularization.
• Secondary efficacy: Each MACE component.
• Safety: Serious adverse events including all-cause and non-cardiovascular mortality, infections, pneumonia, hospitalizations for gastrointestinal events, and incident cancer.

Study Design

Systematic review and meta-analysis of randomized controlled trials (PRISMA-guided). Random-effects (DerSimonian–Laird) models pooled hazard ratios for efficacy and risk ratios for safety; heterogeneity assessed with I2; publication bias with funnel plots and Egger’s test. Minimum follow-up ≥12 months.

Level of Evidence

Level 1 (systematic review and meta-analysis of randomized controlled trials).

Follow up period

12–34 months across trials (median follow-up per trial 12–33.6 months).

Results

• Primary outcome (MACE): Colchicine reduced MACE (pooled HR 0.75, 95% CI 0.56–0.93).
  • NNT: Not estimable from pooled hazard ratios without absolute baseline risks; not reported in the meta-analysis.
• Secondary outcomes:
  • Myocardial infarction: HR 0.71 (95% CI 0.51–0.91).
  • Ischemic stroke: HR 0.63 (95% CI 0.34–0.92).
  • Urgent coronary revascularization: HR 0.67 (95% CI 0.41–0.93).
  • Cardiovascular mortality: No significant difference.
• Safety:
  • All-cause mortality: RR 1.01 (95% CI 0.80–1.28).
  • Non-cardiovascular mortality: RR 1.08 (95% CI 0.76–1.54).
  • Infections, pneumonia, hospitalizations for gastrointestinal events, and incident cancer: No significant differences.
• Sensitivity and subgroup analyses:
  • Pre-COVID subset showed a larger benefit (HR 0.70, 95% CI 0.60–0.81) with lower heterogeneity.
  • Excluding the stroke trial increased the magnitude of benefit and reduced heterogeneity.
  • No significant interaction by age, sex, or diabetes (limited power for women).
  • No evidence of publication bias.

Limitations

• Moderate-to-high heterogeneity across efficacy endpoints, partly due to differing populations (ACS, stable CAD, stroke), pandemic-era data collection, inflammation control, adherence/discontinuation, and endpoint definitions.
• CLEAR-SYNERGY conducted during COVID-19 with potential underreporting of nonfatal events and less hsCRP reduction, attenuating observed efficacy.
• Limited absolute event rate data in pooled report prevents NNT calculation.
• Subgroup analyses underpowered, especially for women; few studies preclude meta-regression.

Funding

None declared.

Citation

Samuel M, Berry C, Dubé M-P, Koenig W, López-Sendón J, Maggioni AP, Pinto FJ, Roubille F, Tardif J-C. Long-term trials of colchicine for secondary prevention of vascular events: a meta-analysis. European Heart Journal. 2025;00:1–12. doi:10.1093/eurheartj/ehaf174