COLCOT

Purpose: To study the long-term effect of colchicine’s anti-inflammatory effects in reducing ischemic CV events in patients with a recent MI.

Trial Design: Phase 3. 167 sites. N=4745. Randomized 1:1, double-blinded, placebo-controlled trial.  Patients with MI within prior 30 days received low-dose colchicine, 0.5 mg/day, or placebo.  Follow-up 1 month, 3 months, and every 3 months after up to 3.5 years. Median follow-up 22.6 months.

Primary Endpoints: Time to composite of CV death, resuscitated cardiac arrest, MI, stroke, or urgent angina hospitalization with revascularization.

Results: Low-dose colchicine, along with standard medical care,  compared to placebo reduced the risk of ischemic CV events in patients with a recent MI.

Key Findings

Among patients with recent myocardial infarction on guideline directed medical therapies followed for a median of 23 months, colchicine 0.5 mg daily compared to placebo reduced the risk of both initial and total cardiovascular events (CV death, resuscitated cardiac arrest, acute MI, stroke, or urgent hospitalization for angina requiring coronary revascularization), by 23% and 34%. Overall rates of adverse events were low with colchicine, with a small increase in pneumonia compared to placebo (0.9 vs. 0.4%; P=.03); there was no significant difference in rates of diarrhea (9.7% vs. 8.9%; P=.35).

Impression

In the COLCOT trial of patients with recent myocardial infarction treated with guideline directed therapies, colchicine conferred a significant risk reduction for ischemic cardiovascular events, as compared to placebo. The risk reduction was primarily driven by reductions in angina and stroke, but there was no significant difference in cardiovascular death or myocardial infarction.

Study Groups:

Colchicine (N = 2366) versus placebo (N = 2379)

Primary Endpoint

Time from randomization to the first event of CV death, resuscitated cardiac arrest, acute MI, stroke, or urgent hospitalization for angina requiring coronary revascularization

• 131 (5.5%) vs. 170 (7.1%); Hazard Ratio 0.77 (95% CI 0.61-0.96); P=.02

Secondary Endpoints:

• Cardiovascular death: 20 (0.8%) vs. 24 (1.0%); HR 0.84 (0.46-1.52)
• Resuscitated cardiac arrest: 5 (0.2%) vs. 6 (0.3%); HR 0.83 (0.25-2.73)
• Myocardial infarction: 89 (3.8%) vs. 98 (4.1%); HR 0.91 (0.68-1.21)
• Stroke: 5 (0.2%) vs. 19 (0.8%); HR 0.26 (0.10-0.70)
• Urgent hospitalization for angina leading to revascularization: 25 (1.1%) vs. 50 (2.1%); HR 0.50 (0.31-0.81)
• Secondary composite endpoint (cardiovascular death, resuscitated cardiac arrest, myocardial infarction, and stroke): 111 (4.7%) vs. 130 (5.5%); HR 0.85 (0.66-1.10)
• All-cause death: 43 (1.8%) vs. 44 (1.8%); HR 0.98 (0.64-1.49)
• Deep venous thrombosis or pulmonary embolus: 10 (0.4%) vs. 7 (0.3%); HR 1.43 (0.54-3.75)
• Atrial fibrillation: 36 (1.5) vs. 40 (1.7); HR 0.93 (0.59-1.46)

Recommended

• COLCOT Abstract
• Jean-Claude Tardif's presentation slides (PDF)
• Discussant slides (PDF)
• NEJM: Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction

Related Science

• Imazio M, Bobbio M, Cecchi E, et al. Colchicine in addition to conventional therapy for acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial. Circulation 2005;112:2012-2016.
• Ridker PM, Howard CP, Walter V et al. Effects of Interleukin-1b2; Inhibition With Canakinumab on Hemoglobin A1c, Lipids, C-Reactive Protein, Interleukin-6, and Fibrinogen. Circulation 2012;126:2739-2748.
• Weber C, Hundelshausen P. CANTOS Trial Validates the Inflammatory Pathogenesis of Atherosclerosis. Circulation research 2017;121:1119-1121.

Trial Design — Randomized, double blind, placebo-controlled, multinational trial with parallel assignment to either colchicine (0.5 mg once daily) or placebo tablet; 167 sites total; subjects followed until 301 primary CV events occurred for adequate power (80%).

Trial Population — Adult (>18 years) men & women who suffered MI within the last 30 days and completed any planned percutaneous revascularization procedures. Follow-up visits at 1 and 3 months post-randomization and every ≈3 months thereafter. Patients received standard medical care including intensive use of statins.

Key inclusion criteria

• Adult men & women >18 years of age
• Prior MI within the preceding 30 days
• On treatment with guideline directed medical therapy and having completed any indicated percutaneous coronary interventions
• Female patients not of childbearing potential or on adequate contraception, not breast feeding or considering becoming pregnant during the study or after, for 6 months after last dose
• In good health & willing to comply with study protocol

Key exclusion criteria

• NYHA Class III-IV heart failure, recent stroke, or any poorly controlled medical condition potentially placing the patient at risk by participating in the study, per the investigator’s assessment
• Type II MI as the index event
• Prior coronary artery bypass graft surgery within 3 years or planned CABG for the future
• Cancer/lymphoproliferative disease
• Inflammatory bowel disease
• Pre-existing neuromuscular disease with significant and persistent muscle injury (CPK)
• Hematologic, hepatic, and renal impairment per laboratory studies
• Hepatic cirrhosis or other chronic active or severe hepatic dysfunction
• Clinically significant drug or alcohol abuse
• Chronic systemic steroid therapy (oral/intravenous)
• Patients taking colchicine at the time of the study for another indication
• History of allergic reaction/sensitivity to colchicine
• Any recent investigational drug therapy within 30 days or 5 half-lives

Primary Endpoints

• Time from randomization to the first event of CV death, resuscitated cardiac arrest, acute MI, stroke, or urgent hospitalization for angina requiring coronary revascularization

Secondary Endpoints

• Cardiovascular death
• Resuscitated cardiac arrest
• Myocardial infarction
• Stroke
• Urgent hospitalization for angina requiring coronary revascularization
• Secondary composite endpoint (cardiovascular death, resuscitated cardiac arrest, myocardial infarction, and stroke)
• All-cause death

Exploratory Endpoints

• Deep venous thrombosis or pulmonary embolus
• Atrial fibrillation
• Heart failure hospitalization
• Coronary revascularization
• Change in high-sensitivity C-reactive protein from baseline to 6 months
• Change in white blood cell count from baseline to 12 months

Sponsor(s)/Collaborator(s): Montreal Heart Institute, Montreal, Quebec, Canada