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., Olivier F. Bertrand, M.D., Ph.D., Rafael Diaz, M.D., Aldo P. Maggioni, M.D., Fausto J. Pinto, M.D., Ph.D., Reda Ibrahim, M.D., Habib Gamra, M.D., Ghassan S. Kiwan, M.D., Colin Berry, M.D., Ph.D., José López-Sendón, M.D., Petr Ostadal, M.D., Ph.D., Wolfgang Koenig, M.D., Denis Angoulvant, M.D., Jean C. Grégoire, M.D., Marc-André Lavoie, M.D., Marie-Pierre Dubé, Ph.D., David Rhainds, Ph.D., Mylène Provencher, Ph.D., Lucie Blondeau, M.Sc., Andreas Orfanos, M.B., B.Ch., Philippe L. L’Allier, M.D., Marie-Claude Guertin, Ph.D., François Roubille, M.D., Ph.D.
Journal Name: The New England Journal of Medicine
Year: 2019
Volume: 381
Issue: 26
Type of Study: Randomized, double-blind, placebo-controlled trial
Quick Reference Summary
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 a myocardial infarction (5.5% vs. 7.1%; hazard ratio, 0.77; 95% CI, 0.61 to 0.96; P=0.02).
The reduction was primarily driven by fewer strokes and urgent hospitalizations for angina, with a slight increase in serious pneumonia events in the colchicine group.
Core Clinical Question
In patients who have 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 worldwide, often resulting from atherosclerosis and its complications.
- Inflammation plays a crucial role in the pathogenesis and progression of atherosclerosis.
Prior Data on the Topic:
- The Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) showed that inhibiting interleukin-1β with canakinumab reduced cardiovascular events by 15% but increased fatal infections.
- The Cardiovascular Inflammation Reduction Trial (CIRT) found that methotrexate did not impact cardiovascular outcomes or inflammatory markers.
Current Standard of Care:
- Intensive use of statins, aspirin, and antiplatelet agents following MI.
- Percutaneous coronary intervention is commonly performed.
Knowledge Gaps Addressed by Study:
- Need for an effective, widely available anti-inflammatory treatment to reduce atherosclerotic events post-MI.
- Limited data on the long-term safety and efficacy of colchicine in the post-MI population.
Study Rationale:
- Colchicine, a potent anti-inflammatory agent, showed promise in the LoDoCo trial for stable coronary disease but lacked placebo-controlled, large-scale evidence in the acute post-MI setting.
Methods Summary
Study Design:
Randomized, double-blind, placebo-controlled, investigator-initiated trial.
Setting and Time Period:
Conducted across 167 centers in 12 countries from December 2015 to July 2019.
Population Characteristics:
- 4,745 adult patients within 30 days post-MI.
- Mean age: 60.6 years; 19.2% female; 20.2% with diabetes.
- 93.0% underwent percutaneous coronary intervention.
Inclusion/Exclusion Criteria:
- Included adults post-MI treated with guideline-directed medical therapy.
- Excluded those with severe heart failure, recent stroke, certain cancers, inflammatory diseases, severe renal/hepatic disease, among others.
Intervention Details:
Colchicine group received 0.5 mg orally once daily.
Control/Comparison Group Details:
Placebo group received matching placebo once daily.
Primary and Secondary Outcomes:
- Primary Efficacy Endpoint: Composite of death from cardiovascular causes, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization.
- Secondary Endpoints: Components of the primary endpoint, composite of death from cardiovascular causes, cardiac arrest, MI, stroke, and total mortality.
Statistical Analysis Approach:
- Time-to-event analysis using log-rank test and Cox proportional-hazards model.
- Interim analysis with Lan–DeMets procedure.
- Intention-to-treat principle.
Sample Size Calculations:
Approximately 4,500 patients or 301 primary events for 80% power to detect a 27% risk reduction.
Ethics and Funding Information:
- Approved by institutional review boards of participating centers.
- Funded by the Government of Quebec, Canadian Institutes of Health Research, and philanthropic foundations.
- Trial medication provided by Pharmascience without their involvement in trial design or manuscript preparation.
Detailed Results
Participant Flow and Demographics:
- Enrollment: 4,745 patients randomized; 2,366 colchicine, 2,379 placebo.
- Follow-up: Median of 22.6 months.
- Baseline Characteristics: Mean age 60.6 years; 19.2% women; 20.2% diabetes; 93.0% underwent PCI.
- Discontinuation: ~18.5% in both groups discontinued trial regimen.
Primary Outcome Results:
- Primary Endpoint Occurrence:
- Colchicine: 5.5%
- Placebo: 7.1%
- Hazard Ratio: 0.77; 95% CI: 0.61 to 0.96; P=0.02
Component Outcomes:
Outcome | Colchicine Group | Placebo Group | Difference (95% CI) | P-value |
---|---|---|---|---|
Death from cardiovascular causes | - | - | Hazard Ratio 0.84 (0.46-1.52) | - |
Resuscitated cardiac arrest | - | - | Hazard Ratio 0.83 (0.25-2.73) | - |
Myocardial infarction | - | - | Hazard Ratio 0.91 (0.68-1.21) | - |
Stroke | - | - | Hazard Ratio 0.26 (0.10-0.70) | - |
Urgent hospitalization for angina leading to revascularization | - | - | Hazard Ratio 0.50 (0.31-0.81) | - |
Secondary Outcome Results:
- Composite of death from cardiovascular causes, cardiac arrest, MI, or stroke:
- Colchicine: 4.7%
- Placebo: 5.5%
- Hazard Ratio: 0.85; 95% CI: 0.66 to 1.10
Subgroup Analyses:
Efficacy results consistent across prespecified subgroups (detailed in Table S3).
Biomarkers of Inflammation:
- C-reactive Protein (CRP):
- Median baseline: 4.28 mg/L
- 6-month change: -70.0% (colchicine) vs. -66.6% (placebo); 95% CI: −28.6 to 13.4
- White-Cell Counts:
- 12-month change: −18.8% (colchicine) vs. −19.0% (placebo); 95% CI: −2.2 to 2.7
Adverse Events/Safety Data:
- Related Adverse Events:
- Colchicine: 16.0%
- Placebo: 15.8%
- Serious Adverse Events:
- Colchicine: 16.4%
- Placebo: 17.2%
- Gastrointestinal Events:
- Diarrhea: 9.7% (colchicine) vs. 8.9% (placebo); P=0.35
- Nausea: 1.8% vs. 1.0%; P=0.02
- Infections:
- Serious pneumonia: 0.9% (colchicine) vs. 0.4% (placebo); P=0.03
Authors' Conclusions
Primary Conclusions:
Low-dose colchicine (0.5 mg daily) significantly reduced the risk of ischemic cardiovascular events in patients with a recent myocardial infarction compared to placebo.
Interpretation of Results:
- The reduction in primary endpoints was mainly due to fewer strokes and urgent hospitalizations for angina leading to revascularization.
- The anti-inflammatory effects of colchicine may contribute to its cardiovascular benefits.
Clinical Implications:
- Colchicine can be considered as an adjunctive therapy post-MI to reduce ischemic events.
- Benefits were observed on top of standard therapies, including statins and antiplatelet agents.
Future Research Recommendations:
- Long-term studies to evaluate the sustained efficacy and safety of colchicine.
- Larger trials to assess individual endpoints and specific subgroups in greater detail.
Literature Review
Not applicable as the article does not provide a detailed literature comparison beyond the background and discussion provided.
Critical Analysis
A. Strengths:
- Large Sample Size: Included 4,745 patients, providing adequate power to detect differences in primary outcomes.
- Randomized, Double-Blind, Placebo-Controlled Design: Minimizes bias and ensures the reliability of results.
- High Adherence to Standard Care: 98-99% received aspirin, antiplatelet agents, and statins, reflecting real-world practice.
- Independent Adjudication of Endpoints: Ensures objective assessment of outcomes.
B. Limitations:
- Follow-Up Duration: Median follow-up of 22.6 months may be insufficient to assess long-term safety and efficacy.
- Subgroup Data Limitations: Inflammatory biomarkers were measured in small, non-random subgroups, limiting interpretability.
- Generalizability: Results apply only to patients who have recently experienced an MI and met specific inclusion criteria.
- Adverse Events: Increased serious pneumonia in the colchicine group, though overall serious adverse events were similar.
C. Literature Context
Not applicable as detailed in the prompt instructions.
Clinical Application
How Findings Change Current Practice:
- Incorporation of low-dose colchicine as an adjunctive therapy post-MI may reduce the incidence of ischemic cardiovascular events.
Specific Patient Populations or Scenarios:
- Particularly beneficial for patients with recent MI who are already on standard therapies including statins and antiplatelet agents.
Implementation Considerations:
- Monitoring for gastrointestinal symptoms and infections, especially pneumonia, is necessary.
Integration with Existing Evidence:
- Aligns with the anti-inflammatory approach to reducing atherosclerotic events, complementing therapies like statins.
How To Use This Info In Practice
Practitioners should consider adding low-dose colchicine (0.5 mg daily) to the treatment regimen of patients who have recently experienced a myocardial infarction to reduce the risk of subsequent ischemic events, while monitoring for potential adverse effects.
Notes for Clarity
- Statistical Significance: Primary endpoint reduction was statistically significant (P=0.02).
- Confidence Intervals: Provided for all hazard ratios to indicate the precision of estimates.
- Conflicts of Interest: Not explicitly stated; however, trial medication was provided by Pharmascience, which did not influence study design or manuscript preparation.
- Areas of Uncertainty: Long-term effects and safety of colchicine beyond the median follow-up of 22.6 months.
- Funding Sources: Government of Quebec, Canadian Institutes of Health Research, philanthropic foundations.
- Post-Hoc Analyses: Not reported; all analyses were prespecified except the CRP substudy which was optional.
Disclaimer:
The medical literature summaries provided are for informational and educational purposes only. They are not all-inclusive and may not cover all aspects of the topic discussed. These summaries should not be considered a substitute for reviewing the original primary sources, which remain the authoritative reference. Additionally, this information does not constitute medical advice, diagnosis, or treatment. Always consult a qualified healthcare professional for specific medical questions or concerns. Use of this information is at your own discretion and risk.
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