Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction

Article Identification

Article Title: Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction

Authors: Jean-Claude Tardif, M.D., Simon Kouz, M.D., David D. Waters, M.D., et al.

Journal Name: The New England Journal of Medicine

Year: 2019

Volume: 381

Issue: 26

Type of Study: Randomized, double-blind, placebo-controlled trial

ClinicalTrials.gov number: NCT02551094

Quick Reference Summary

Finding: Low-dose colchicine (0.5 mg daily) reduced the primary composite endpoint of ischemic cardiovascular events by 23% compared to placebo among patients who had recently experienced an MI (5.5% vs. 7.1%; HR, 0.77; 95% CI, 0.61 to 0.96; P=0.02).

Key Drivers: Reduction mainly due to fewer strokes and urgent hospitalizations for angina.

Safety Note: Slight increase in serious pneumonia events in the colchicine group.

Core Clinical Question

Question: In patients who recently experienced a myocardial infarction, does low-dose colchicine (0.5 mg daily) compared to placebo reduce the risk of ischemic cardiovascular events without significantly increasing adverse effects?

Background

Disease Overview:

• Myocardial infarction (MI) is a leading cause of morbidity and mortality, often related to atherosclerosis.
• Inflammation is a key contributor to atherosclerotic plaque progression and instability.

Prior Data on the Topic:

• CANTOS: IL-1β inhibition reduced CV events but at the cost of more fatal infections.
• CIRT: Methotrexate did not improve cardiovascular outcomes or reduce inflammatory markers.

Current Standard of Care:

• Post-MI patients typically receive statins, aspirin, dual antiplatelet therapy, and undergo PCI as indicated.

Knowledge Gaps Addressed by Study:

• Need for a safe, widely available anti-inflammatory option to further reduce ischemic events post-MI.

Study Rationale:

• Colchicine, a potent anti-inflammatory, showed promise in stable coronary disease. The COLCOT trial provides robust evidence in the recent post-MI setting.

Methods Summary

Study Design:

Randomized, double-blind, placebo-controlled trial.

Setting and Time Period:

167 centers in 12 countries, December 2015 to July 2019.

Population Characteristics:

• 4,745 patients within 30 days post-MI.
• Mean age: 60.6 years; 19.2% female; ~20% diabetes; 93% underwent PCI.

Inclusion/Exclusion Criteria:

• Included adults post-MI on guideline-directed medical therapy.
• Excluded severe comorbidities that could confound outcomes or tolerability.

Intervention:

Colchicine 0.5 mg daily.

Control:

Matching placebo once daily.

Primary Endpoint:

• Composite of CV death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina requiring revascularization.

Statistical Analysis:

• Cox proportional-hazards model, intention-to-treat basis.
• Powered to detect a 27% risk reduction.

Detailed Results

Primary Outcome:

• 5.5% (colchicine) vs. 7.1% (placebo), HR 0.77 (0.61–0.96), P=0.02.

Component Outcomes:

Outcome	Hazard Ratio (95% CI)
Stroke	0.26 (0.10-0.70)
Urgent hospitalization for angina leading to revascularization	0.50 (0.31-0.81)

Inflammatory Biomarkers:

• CRP reduction slightly greater in colchicine group, though not dramatically different.

Adverse Events:

• Slight increase in serious pneumonia: 0.9% (colchicine) vs. 0.4% (placebo).
• GI events (e.g., nausea, diarrhea) slightly more common with colchicine.

Authors' Conclusions

Primary Conclusions:

Low-dose colchicine significantly reduced ischemic cardiovascular events in patients with a recent MI.

Interpretation:

• Benefit attributed to anti-inflammatory effects.
• Primarily fewer strokes and less urgent angina hospitalization.

Clinical Implications:

• Colchicine as an adjunct post-MI therapy on top of standard care.

Future Research:

• Long-term safety and efficacy data needed.
• Exploration of effects in varied patient subgroups.

Literature Review

The COLCOT trial builds upon prior work in anti-inflammatory strategies for coronary disease. While CANTOS demonstrated benefits using canakinumab but with increased infection risk, and CIRT showed no benefit with methotrexate, COLCOT provides evidence that a low-cost, widely available drug like colchicine can improve outcomes with fewer severe safety concerns. This aligns with the evolving understanding of inflammation's pivotal role in atherosclerosis and highlights colchicine as a practical anti-inflammatory adjunct.

Critical Analysis

A. Strengths:

• Large sample size (4,745 patients).
• Randomized, double-blind, placebo-controlled design.
• High adherence to standard therapies, reflecting real-world practice.
• Independent adjudication of endpoints to reduce bias.

B. Limitations:

• Follow-up (~22.6 months) may not capture very long-term effects.
• CRP and other inflammatory markers measured in smaller subgroups.
• Generalizability limited to similar post-MI populations.
• Increased pneumonia risk needs attention.

C. Literature Context:

COLCOT adds to the literature by demonstrating that inflammation-targeting therapies can reduce ischemic events. Unlike canakinumab (CANTOS), colchicine is inexpensive and did not substantially increase fatal infections. Unlike methotrexate (CIRT), colchicine yielded positive results. Thus, COLCOT supports a new, practical anti-inflammatory approach in post-MI management.

Clinical Application

How Findings Change Practice:

• Colchicine can be considered as an adjunct to standard post-MI therapy to reduce ischemic events.

Patient Populations:

• Patients recently post-MI already receiving statins and antiplatelets may benefit most.

Implementation Considerations:

• Monitor for GI side effects and rare pneumonia cases.

Integration with Existing Evidence:

• Supports the anti-inflammatory hypothesis in coronary disease management.

How to Use This Info in Practice

Clinicians may consider adding low-dose colchicine (0.5 mg daily) to the regimen of patients who recently experienced an MI, alongside standard therapies, to reduce future ischemic events. Careful patient education and monitoring for potential adverse effects, particularly GI upset and pneumonia, are essential.

Notes for Clarity

• Statistical Significance: Primary endpoint reduction was significant (P=0.02).
• Confidence Intervals: Provided for hazard ratios to assess precision.
• Long-Term Effects: Uncertain beyond ~2 years of follow-up.
• Funding Sources: Government of Quebec, Canadian Institutes of Health Research, and philanthropic foundations. Trial medication provided by Pharmascience.