COLCOT 2019

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Clinical Question

In patients with previous myocardial infarction, does the addition of colchicine in comparison to the standard secondary prevention treatments alone reduce the risk of future cardiovascular events?

Bottom Line

In adult patients with previous myocardial infarction, taking low-dose colchicine daily as a part of the patient’s secondary prevention regimen, compared to a placebo, leads to a lowered risk of future cardiovascular events.

Major Points

  • Inflammation has been found to play a huge role in artherosclerotic heart disease. Colchicine, an orally administered anti-inflammatory medication, is indicated for gout and pericarditis. Results from LoDoCo, a small randomized control trial without placebo, showed that colchicine may be effective in reducing cardiovascular events.(1)
  • The COLCOT study randomized 4745 adult patients who suffered a myocardial infarction within 30 days of initiating the trial. 2366 patients were assigned to the colchicine group and 2379 patients were assigned to the placebo group. The primary outcome was a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke or urgent hospitalization for angina leading to coronary revascularization. After a median follow-up time of 22.6 months, the primary endpoint occurred in 5.5% (n = 131) of patients from the colchicine group in comparison to 7.1% (n = 170) of patients from the placebo group (CI = 0.61-0.96, p=0.02).
  • Based on these results, the trial effectively demonstrated the use of colchicine to prevent future cardiovascular events, while maintaining an overall safe side effect profile. Some criticisms of this trial include a short follow-up period, potential funding bias through grant support, and its lack of application to patients without past myocardial infarctions.

Guidelines

Guidelines do not comment for or against the use of colchicine as secondary prevention to myocardial infarctions at this time.^3

Design

  • Randomized, double-blinded, placebo-controlled, investigator initiated trial
  • N= 4745
    • Colchicine 0.5 mg daily (n = 2366)
    • Placebo (n = 2379)
  • Setting: 167 centers in 12 countries
  • Enrollment: December 2015 - August 2018
  • Median follow-up: 22.6 months
  • Analysis: Intention-to-treat
  • Primary Outcome: Composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke or urgent hospitalization for angina leading to coronary revascularization.

Population

  • Demographics
    • Placebo
      • Age - 60.5 ± 10.6
      • Sex - female 18.4%
      • Race - white 72.1%
    • Colchicine
      • Age - 60.6 ± 10.7
      • Sex - female 19.9%
      • Race - white 73.0%

Inclusion Criteria

  • ≥18/adult patients
  • Documented MI within 30 days before entering enrollment
  • Completed percutaneous revascularization procedures
  • Treated for secondary prevention according to national guidelines that included the use of statins.

Exclusion Criteria

  • If patient has severe heart failure
  • Left ventricular ejection fraction of less than 35%
  • Stroke within the previous 3 months
  • History of non-cutaneous cancer within the previous 3 years
  • Inflammatory bowel disease or chronic diarrhea
  • Neuromuscular disease or non transient creatine kinase level that was greater than 3x the upper limit range (unless due to infarction)
  • Clinically significant nontransient hematologic abnormalities
  • Severe renal disease with a SCr level that was greater than 2x the upper limit of the normal range
  • Severe hepatic disease
  • Drug or alcohol abuse
  • Current or planned long-term systemic glucocorticoid therapy
  • History of clinically significant sensitivity to colchicine

Baseline Characteristics

  • There were no significant differences between the placebo group and the colchicine group.
  • Comorbidities - placebo group
    • BMI - 28.4%
    • Smoker - 29.8%
    • HTN - 52%
    • Diabetes - 20.9%
    • History of MI - 16.7%
    • History of PCI - 17.1%
    • History of CABG - 3.4%
    • History of HF - 1.8%
    • History of TIA - 2.8%
  • Comorbidities - colchicine group
    • BMI - 28.2%
    • Smoker - 29.9%
    • HTN - 50.1%
    • Diabetes - 19.5%
    • History of MI - 15.6%
    • History of PCI - 16.6%
    • History of CABG - 2.9%
    • History of HF - 2.0%
    • History of TIA - 2.3%
  • 98-99% of the patients in both groups were on aspirin, other antiplatelet agents, and statins prior to the start of this study.
    • Medication Use - placebo group
      • Aspirin- 98.9%
      • Other antiplatelet agent- 98.2%
      • Statin- 99.1%
      • Beta-Blocker- 88.3%
      • Medication use - colchicine group
      • Aspirin- 98.6%
      • Other antiplatelet agent- 97.6%
      • Statin- 98.9%
      • Beta-Blocker- 80.4%


Interventions

  • Patients were assigned in a 1:1 ratio to receive either colchicine (0.5 mg once daily) or placebo.
  • Patients were evaluated at 1 month and 3 months after randomization and continued to be evaluated every 3 months after.

Outcomes

Comparisons of outcomes are colchicine vs. placebo.

Primary Outcomes

Death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization

  • 131(5.5%) vs. 170(7.1%); HR= 0.77 (95% CI - 0.61-0.96); p=0.02
  • NNT = 63

Secondary Outcomes

Stroke

  • 5(0.2%) vs. 19(0.8%); HR=0.26 (95% CI - 0.10-0.70)
  • NNT = 167

Urgent Hospitalization for Angina Leading to Revascularization

  • 25(1.1%) vs. 50(2.1%); HR=0.50 (95% CI - 0.31-0.81)
  • NNT = 100

Adverse Events

Any related adverse events

  • These events were judged by the investigator to be related to colchicine or placebo, that were not serious and did not require medical attention.
    • 372(16.0%) vs. 371 (15.8%); p=0.89
      • Nausea
        • 43 (1.8%) vs. 24 (1.0%); p=0.02
        • NNH = 125
      • Flatulence
        • 15 (0.6%) vs. 5 (0.2%); p=0.02
        • NNH = 250

Any related serious adverse events

  • Serious adverse events were judged by the investigator to be related to colchicine or placebo, which required medical attention.
    • 383 (16.4%) vs. 404 (17.2%); p=0.47
      • Pneumonia
        • 21 (0.9%) vs. 9 (0.4%); p=0.03
        • NNH = 200

Criticisms

  • Internal Criticisms
    • The trial had a fairly short follow-up period (23 months) meaning that an analysis of long-term risks and benefits associated with colchicine therapy could not be completed.
    • The sample size was able to demonstrate a statistically significant effect for the primary endpoint, but a more widespread trial could have demonstrated significance for minor or non-composite endpoints.
    • The findings of the trial are not applicable to healthy patients who have not suffered a recent myocardial infarction.
  • External Criticisms
    • The major criticisms of this trial were the lack of stronger outcomes, weak indicators for stroke, and the presence of unmeasured factors that would limit colchicine’s use long-term.^2

Funding

This study was funded by the Government of Quebec, the Canadian Institutes of Health Research, and the Montreal Health Institute.

Further Reading

1. Nidorf SM, et al. “Low-Dose Colchicine for Secondary Prevention of Cardiovascular Disease” [Internet]. American College of Cardiology Foundation. 2013 Jan 29 [cited 17 April 2020].

2. Cox, C. “COLCOT Renews Hope for Anti-Inflammatory in Secondary Prevention: Colchicine” [Internet]. Philadelphia: TCTMD; 16 Nov 2019 [cited 17 April 2020].

3. Smith S, et al. “ACC/AHA Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and Other Atherosclerotic Vascular Disease”. Circulation. 2011 Nov 3; 124(22): 2458-2473.

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