low dose colchicine in coronary heart disease (CHD)

Last edited 08/2023 and last reviewed 08/2023

Colchicine in patients with Coronary Heart Disease

There have been two significant trials investigating the use of low dose colchicine in patients with proven coronary heart disease (1,2). These two trials - LoDoCo2 trial and COLCOT trial - have contributed to the growing evidence that colchicine on top of standard medical therapy can reduce CV events in patients with chronic (LoDoCo2) and acute coronary syndromes (COLCOT).

COLCOT - Colchicine Cardiovascular Outcomes Trial

Background:

  • experimental and clinical evidence support the role of inflammation in atherosclerosis and its complications. Colchicine is an orally administered, potent antiinflammatory medication that is indicated for the treatment of gout and pericarditis

Methodology:

  • a randomized, double-blind trial involving patients recruited within 30 days after a myocardial infarction
    • patients were randomly assigned to receive either low-dose colchicine (0.5 mg once daily) or placebo
    • primary efficacy end point was a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization. The components of the primary end point and safety were also assessed.

Results:

  • total of 4745 patients were enrolled; 2366 patients were assigned to the colchicine group, and 2379 to the placebo group
    • patients were followed for a median of 22.6 months
    • primary end point occurred in 5.5% of the patients in the colchicine group, as compared with 7.1% of those in the placebo group (hazard ratio, 0.77; 95% confidence interval [CI], 0.61 to 0.96; P=0.02)
      • hazard ratios were 0.84 (95% CI, 0.46 to 1.52) for death from cardiovascular causes, 0.83 (95% CI, 0.25 to 2.73) for resuscitated cardiac arrest, 0.91 (95% CI, 0.68 to 1.21) for myocardial infarction, 0.26 (95% CI, 0.10 to 0.70) for stroke, and 0.50 (95% CI, 0.31 to 0.81) for urgent hospitalization for angina leading to coronary revascularization

    • diarrhoea was reported in 9.7% of the patients in the colchicine group and in 8.9% of those in the placebo group (P= 0.35)
    • pneumonia was reported as a serious adverse event in 0.9% of the patients in the colchicine group and in 0.4% of those in the placebo group (P= 0.03).

The study authors concluded that "among patients with a recent myocardial infarction, colchicine at a dose of 0.5 mg daily led to a significantly lower risk of ischemic cardiovascular events than placebo."

  • data showed that colchicine 0.5 mg/day significantly lowered the risk of first and total ischemic CV events by 23% and 34% respectively, compared to placebo, in patients with a recent MI. Rates of adverse events were low

Note that a limitation of the study is its relative short duration, of approximately 23 months. Risks and benefits of longer-term treatment with colchicine were therefore not evaluated

Sub-analysis of COLCOT data (2) - early initiation after an MI:

  • given that myocardial infarction is associated an excessive inflammatory burst, could the timing of use of colchicine (an anti-inflammatory agent) have an effect on outcomes
  • subanalysis of COLCOT assessed whether time-to-treatment initiation (TTI) of colchicine therapy had a clinical impact on CV outcomes in patients with an MI
  • primary efficacy endpoint was a composite of CV death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina requiring coronary revascularization
  • was a 48% risk reduction for the primary composite endpoint in patients treated between day 0 and 3 with colchicine compared to patients receiving placebo (4.3% vs. 8.3%, respectively, HR 0.52, 95% CI: 0.32-0.84, P=0.007)
  • study authors concluded that "Early initiation of low-dose colchicine after MI greatly reduced the risk of ischaemic CV events compared with placebo. These results support in-hospital initiation of adjunctive anti-inflammatory therapy with colchicine for post-MI prevention"
Colchicine in the prevention of CV events:

The subsequent study evaluating the use of colchicine in the prevention of CV events was the LoDoCo2 trial.

LoDoCo2 - low dose colchicine 2 trial

LoDoCo2 trial was an investigator-initiated, double-blind, placebo-controlled, event-driven trial that aimed to determine whether colchicine 0.5mg once daily prevents CV events in patients with chronic coronary disease.

A total of 6528 patients (aged 35-82 years) with proven coronary disease enrolled in the 30-day open label run-in of colchicine 0.5 mg daily

  • patients were clinically stable for >= 6 months, and no advanced renal disease, heart failure or severe heart disease. 91.3% of patients tolerated the open label therapy
  • a total of 5522 patients who were tolerant, clinically stable and willing to proceed were randomized to receive colchicine 0.5 mg once daily (n=2762, mean age was 65.8 years, 83.5% were male) or placebo (n=2760, mean age was 65.9 years, 85.9% were male) on a background of lipid lowering and antithrombotic therapy. Median follow-up was 29 months (12-64 months).

A total of 5522 patients (aged 35-82 years) with proven coronary disease were randomized to receive colchicine 0.5 mg once daily (n=2762, mean age was 65.8 years, 83.5% were male) or placebo (n=2760, mean age was 65.9 years, 85.9% were male) on a background of lipid lowering and antithrombotic therapy. Patients were clinically stable for >= 6 months, had no advanced renal disease, heart failure or severe heart disease, and were tolerant to colchicine during a 30-day open label run-in phase. Median follow-up was 29 months (12-64 months).

The primary endpoint was a composite of CV death, myocardial infarction (MI), ischemic stroke, or ischemia-driven coronary revascularization.

Main results
  • Colchicine reduced the risk for the primary composite endpoint by 31%, compared to placebo (HR 0.69, 95%CI 0.57-0.83, P<0.001). The effects of colchicine were seen to occur early and continued to accrue over time.
  • effect of colchicine extended to the first 5 of 8 ranked secondary endpoints including 1) the composite of CV death, MI or ischemic stroke (HR 0.72, 95%CI 0.57-0.92, P=0.007), 2) the composite of MI or ischemia-driven coronary revascularization (HR 0.67, 95%CI 0.55-0.83, P<0.001), 3) CV death or MI (HR 0.71, 95%CI 0.55-0.92, P=0.010), 4) ischemia-driven coronary revascularization (HR 0.75, 95%CI 0.60-0.94, P=0.012), and 5) MI (HR 0.70, 95%CI 0.53-0.93, P=0.014). No significant effects with colchicine, compared to placebo, were found for the following individual secondary end points: ischemic stroke, all-cause mortality and CV death.
  • effect of colchicine was also consistent across a number of prespecified sub-groups, including men and women, those who were older and younger than 65 years, and those with and without a history of hypertension.
  • no statistically significant differences in serious adverse events between the two treatment groups.
Study authors concluded that:
  • low-dose colchicine (0.5 mg once daily) reduced the risk of the primary composite endpoint (CV death, MI, ischemic stroke, or ischemia-driven coronary revascularization) and key secondary endpoints in patients with chronic coronary disease. Colchicine appeared safe with no statistically significant differences in serious adverse events compared to placebo

A systematic review and meta-analysis of randomized trials was performed to assess the overall effect of colchicine on MACE and individual end points in patients with acute or chronic coronary disease (4)

  • meta-analysis of 5 trials evaluating the effect of low-dose colchicine showed that colchicine reduced MACE and individual CV endpoints compared to placebo or no colchicine in patients with acute and chronic coronary disease when added to contemporary treatment

The US Food and Drug Administration (FDA) has approved colchicine to reduce the risk of myocardial infarction (MI), stroke, coronary revascularization, and cardiovascular (CV) death in adult patients with established atherosclerotic disease or with multiple risk factors for CV disease (5)

  • colchicine 0.5 mg once daily is the dose approved by the FDA

Reference:

Related pages:

colchicine