COLCOT

Published

Tardif J, et al. "Efficacy and safety of low-dose colchicine after myocardial infarction". The New England Journal of Medicine. 2019. 381(26):2497-2505.
PubMed • Full text • PDF

Clinical Question

In patients with myocardial infarction (MI) in the last 30 days, does colchicine reduce the risk of recurrent cardiovascular events versus placebo?

Bottom Line

In patients with MI in the last 30 days, colchicine was associated with a 1.6% absolute reduction in the primary composite endpoint of death from cardiovascular causes, resuscitated cardiac arrest, recurrent MI, stroke, or urgent hospitalization for angina leading to coronary revascularization at median 22.6 months.

Major Points

Recent evidence has confirmed a critical role for inflammation in the process of atherosclerotic heart disease. The recent CANTOS study was the first large cardiovascular outcomes trial to demonstrate a role for immunomodulation in reducing cardiovascular events. In CANTOS, treatment with the IL-1B inhibitor canakinumab resulted in a 15% lower risk of cardiovascular events when compared to placebo in individuals with established atherosclerotic heart disease. However, uptake of canakinumab has been limited due to a slightly higher incidence of severe infections, presumably related to potent immunosuppression. Shortly after CANTOS, the CIRT trial showed no detectable benefit with the weaker immune modulator methotrexate in individuals with established cardiovascular disease. As a result, identification of an effective immunosuppressant with a safer adverse effect profile with the potential to reduce cardiovascular events in individuals with residual inflammatory risk represents a major unmet need.

Colchicine is an inexpensive, orally administered, potent anti-inflammatory medication with a long history of use for indications such as gouty arthritis and pericarditis. The adverse effect profile of colchicine is thus relatively well-understood, with diarrhea representing its only major side effect. Results from a small, uncontrolled trial of colchicine in individuals with stable coronary disease suggested a possible benefit for reducing cardiovascular events. These findings, however, merited confirmation with a larger, randomized controlled trial.

The 2019 Colchicine Cardiovascular Outcomes Trial (COLCOT) randomized 4745 patients presenting with myocardial infarction (within 30 days) to colchicine or placebo and assessed for a primary endpoint of adverse cardiovascular events (composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization). At median 22.6 months, colchicine was associated with a 1.6% absolute reduction in the primary endpoint. There were fairly symmetric reductions in each component of the primary endpoint, although the benefit for stroke (74% relative risk reduction) was most marked. Diarrhea (9.7% vs 8.9%) and pneumonia (0.9% vs 0.4%) were slightly more common with colchicine than with placebo.

COLCOT is the first trial to provide strong evidence for the role of antiinflammatory agents to reduce recurrent event risk in the acute post-MI period. Importantly, colchicine was not only effective, but had a favorable side-effect profile. The role of colchicine in stable CAD was explored in the 2020 LoDoCo2 trial.

Guidelines

As of November 2019, no guidelines have been published that reflect the results of this trial.

Design

• Multicenter, double-blind, three-arm, randomized, controlled trial
• N=4745
  • Colchicine 0.5MG daily (N=2366)
  • Placebo (N=2379)
• Setting: 167 sites in 12 countries
• Enrollment: December 2015 - August 2018
• Median follow-up: 22.3 months
• Analysis: Intention-to-treat
• Primary Outcome: death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization

Population

Inclusion Criteria

• Age ≥ 18 years
• Documented acute myocardial infarction within last 30 days
• Treatment according to national guidelines (including anti-platelet therapy, statin, renin-angiotensin-aldosterone inhibitor, beta blocker, as indicated)
• Completed any planned percutaneous revascularization for index MI
• Female is either not of childbearing potential or is on durable contraception
• Judged to be in good general health by the principal investigator
• Willing and able to comply with study protocol

Exclusion Criteria

• Poorly controlled medical condition (e.g., NYHA III-IV heart failure, LVEF ≤ 35%, stroke within last 3 months) in the setting of which participation would pose undue risk to the patient
• Prior coronary artery bypass within the past 3 years, or planned
• Cardiogenic shock or hemodynamic instability
• History of cancer or lymphoproliferative disease within the past 3 years
• Inflammatory bowel disease or chronic diarrhea
• Pre-existent progressive neuromuscular disease or CPK level > 3x ULN (unless due to MI, which is allowed)
• Significant anemia, lymphopenia, thrombocytopenia, transammonitis, bilirubin elevation, or kidney injury
• Cirrhosis, chronic active hepatitis, or severe hepatic disease
• Pregnant, breastfeeding, or planning to become pregnant
• Clinically significant drug or alcohol abuse in the past year
• Using or planning to use chronic systemic steroids
• Currently taking colchicine for a chronic condition
• History of allergy or sensitivity to colchicine
• Considered by the investigator to be inappropriate for the study for any reason

Baseline Characteristics

From the placebo group.

• Demographics: Age 60.5 years, female 18.4%, white 72.1%,
• Comorbidities: BMI 28.4, smoking 29.8%, HTN 52.0%, DM 20.9%, prior MI 16.7%, prior PCI 17.1%, prior CABG 3.4%, heart failure 1.8%, stroke/TIA 2.8%
• Index MI: time from event to randomization 13.5 days, index PCI 93.3%
• Medications: aspirin 98.9%, other antiplatelet 98.2%, statin 99.1%, beta blocker 88.3%

Interventions

• Patients randomized 1:1 to colchicine 0.5MG daily or placebo
• Randomization occurred within 30 days of index acute myocardial infarction
• Any planned revascularization for index MI must have been completed prior to enrollment
• Clinical evaluations occurred at 1 month and 3 months after randomization and every 3 months thereafter
• Potential trial endpoint events were adjudicated by an independent clinical endpoint committee composed of experienced cardiologists and neurologists blinded to study group assignments

Outcomes

Comparisons are colchicine versus placebo

Primary Outcome

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

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

Secondary Outcomes

Death from cardiovascular causes

20 (0.8%) vs 24 (1.0%); HR 0.84 (95% CI 0.46-1.52)

Myocardial infarction

89 (3.8%) vs 98 (4.1%); HR 0.91 (95% CI 0.68-1.21)

Stroke

5 (0.2%) vs 19 (0.8%); HR 0.26 (95% CI 0.10-0.70)

Urgent hospitalization for angina leading to revascularization

25 (1.1%) vs 50 (2.1%); HR 0.50 (95% CI 0.31-0.81)

All-cause death

43 (1.8%) vs 44 (1.8%); HR 0.98 (95% CI 0.64-1.49)

Atrial fibrillation

36 (1.5%) vs 40 (1.7%); HR 0.93 (95% CI 0.59-1.46)

Adverse Events

Any related adverse event

372 (16.0%) vs. 371 (15.8%); p=0.89

GI adverse event

408 (17.5%) vs. 414 (17.6%); p=0.90

Diarrhea

225 (9.7%) vs. 208 (8.9%); p=0.35

Pneumonia

21 (0.9%) vs. 9 (0.4%); p=0.03

Criticisms

• Median follow-up of 23 months precludes the ability to draw firm conclusions regarding the long-term safety and efficacy of colchicine
• Findings apply only to the acute post-MI period
• Small numbers of individuals had inflammatory biomarker testing (e.g., CRP, WBC) at baseline and follow-up. As a result, confirmation of the proposed mechanism of benefit of colchicine (reduction in inflammatory mediators) was not achieved by this study
• Since there was no correction for multiple testing, p-values were not reported for non-primary outcome events. As a result, these findings (e.g., marked reduction in stroke rates with colchicine) must be considered hypothesis-generating

Funding

• Study supported by the Government of Quebec, the Canadian Institutes of Health Research, and philanthropic foundations, with the funds administered by the Montreal Heart Institute.