Colchicine after Myocardial Infarction

Article Citation

Tardif J, et al. “Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction”. The New England Journal of Medicine. 2019. 381:2497-2505.

Clinical Question

In patients with a recent myocardial infarction, is the use of low-dose colchicine, compared to the standard of care, safe and effective for the prevention of future cardiovascular morbidity and mortality?

Bottom Line

In patients with recent myocardial infarction, the use of low-dose colchicine significantly reduced the risk of ischemic cardiovascular events, and was associated with minimal risk of side effects.

Major Points

Atherosclerosis is a disease in which the walls of arteries collect fats, cholesterol and other sticky substances which will lead to inflammation. This is concerning because it will lead to narrowing of the arteries and a decrease in oxygenated blood to organs. In some studies, anti-inflammatory medications have been shown to have benefits in prevention of atherosclerosis-related CV events. However, some agents appear to be more effective than others (Canakinumab)1 being associated with fatal infections while some have shown no significant benefit (methotrexate).2 Colchicine is an inexpensive, orally administered anti-inflammatory medication used for gout and pericarditis. Preliminary studies (LoDoCo)3 have indicated potential efficacy in prevention of CV events in patients with stable coronary disease, but further evidence was needed to evaluate long term safety and efficacy in patients with a history of recent MI. Among 4745 patients, 2366 patients were assigned to the colchicine group (low dose: 0.5mg once daily), and 2379 to the placebo group in a randomized double-blind trial to determine its effects. The patient population was selected from those who experienced a myocardial infarction within the last 30 days and followed for a median of 22.6 months.

The colchicine group experienced significantly fewer ischemic cardiovascular events. Comparably, 5.5% of the patients in the colchicine group experienced CV related events, while 7.1% of those in the placebo group experienced these same CV events (hazard ratio, 0.77; 95% confidence interval [CI], 0.61 to 0.96; P=0.02). 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).

However, there were several limitations to the study. The median follow-up was only 22.6 months, which is short compared to other trials.1,3 The long-term effects of colchicine on safety and efficacy can therefore not be extrapolated. Another limitation for this study was the small sample sizes for the subgroup analyses, including those for high-sensitivity C-reactive protein (CRP) and white-cell counts. These small sample sizes could lead to bias or error during analyses.

Guidelines

As of March 2020, no guidelines have been published that reflect the results of this trial.

Design

• Randomized, double-blind, placebo-controlled, investigator-initiated trial
• N= 4,745 patients who had a myocardial infarction in past 30 days
• Colchicine 0.5 mg (n=2,366)
• Placebo (n=2,379)
• Setting: 167 centers in 12 countries
• Enrollment: 2015-2018
• Analysis: Intention-to-treat
• Median follow-up: 22.6 months
• Primary efficacy outcome: Composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization

Population

Inclusion Criteria

• ≥18 years old
• Myocardial infarction within 30 days before enrollment
• Completed planned percutaneous revascularization procedures
• Treated according to national guidelines that included intensive use of statins

Exclusion Criteria

• Severe heart failure
• Left ventricular ejection fraction less than 35%
• Stroke within previous three months
• Type 2 index myocardial infarction
• Coronary-bypass surgery either within the previous three years or planned
• History of non-cutaneous cancer within previous three years
• Inflammatory bowel disease or chronic diarrhea
• Neuromuscular disease or nontransient creatinine kinase level greater than three times the ULN of the normal range (unless due to infarction)
• Clinically significant nontransient hematologic abnormalities
• Severe renal disease with serum creatinine level greater than two times the ULN of the normal range
• Severe hepatic disease
• Drug or alcohol abuse
• Current or planned long-term systemic glucocorticoid therapy
• History of clinically significant sensitivity to colchicine

Baseline Characteristics

• Age: 60.6 years
• Female: 19.2%
• White: 72.6%
• BMI: 28.3 kg/m2
• Current smoking: 29.9%
• Hypertension: 51.1%
• Diabetes: 20.2%
• History of myocardial infarction: 16.2%
• History of PCI: 16.9%
• History of CABG: 3.2%
• History of heart failure: 1.9%
• History of stroke or TIA: 2.6%
• Time from index myocardial infarction to randomization: 13.5 days
• PCI for index myocardial infarction: 93%

The number of patients was notably greater in the placebo group for hypertension and history of myocardial infarction. The percentage of female patients was notably greater in the intervention group.

Baseline Medications

• Aspirin: 98.8%
• Other antiplatelet agent: 97.9%
• Statin: 99%
• Beta-blocker: 88.9%

There were no notable differences between groups for baseline medications.

Interventions

Randomization to:

• Colchicine 0.5mg by mouth daily (randomized 1:1 within 30 days of MI) or placebo
• Evaluation occurred at months 1, 3, and every 3 months after

Outcomes

All comparisons are colchicine 0.5mg therapy vs. placebo.

Primary Outcomes

• Composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization (efficacy)

5.5% vs. 7.1% (HR 0.77; CI 0.61-0.96; P=0.02; NNT=63)

Secondary Outcomes

• Composite of death from cardiovascular causes, cardiac arrest, myocardial infarction, or stroke

4.7% vs. 5.5% (HR 0.85; CI 0.66-1.10; NNT=125)

Additional Analyses

• Death 1.8% vs. 1.8% (HR 0.98; CI 0.64-1.49)
• Deep vein thrombosis or pulmonary embolus 0.4% vs. 0.3% (HR 1.43; CI 0.54-3.75; NNT=1,000)
• Atrial fibrillation 1.5% vs. 1.7% (HR 0.93; CI 0.59-1.46; NNT=500)

Subgroup Analysis

• High-sensitivity C-reactive protein (CRP) (n=207) -70.0% vs. -66.6% (CI -28.4 to 13.4)
• White-cell count percent change from baseline (n=1972) -18.8% vs. -19.0% (CI -2.2 to 2.7)

Adverse Events

• Any related adverse event 16.0% vs. 15.8% (P=0.89; NNH=500)
• Diarrhea 9.7% vs 8.9% (P=0.35; NNH=125)
• Nausea 1.8% vs. 1.0% (P=0.02; NNH=125)
• Pneumonia 0.9% vs. 0.4% (P=0.03; NNH=200)

Criticisms

The median follow-up with patients was relatively short (22.6 months). Therefore, the long-term safety profile and efficacy was not completely assessed. CRP and white-cell counts, both at baseline and during the trial, were measured in only a small subgroup of patients. Analyses conducted with these values could be subject to bias or error.

Funding

The Government of Quebec, Canadian Institutes of Health Research, and other philanthropic foundations with funding administered by the Montreal Heart Institute

Further Reading

• Ridker PM, et al. "Anti Inflammatory Therapy with Canakinumab for Atherosclerotic Disease". The New England Journal of Medicine. 2017. 377(12):1119-1131.
• Ridker PM, et al. “Low-Dose Methotrexate for the Prevention of Atherosclerotic Events”. New England Journal of Medicine 2019. 380(8):752–762.
• Nidorf SM, et al. "Low-dose colchicine for secondary prevention of cardiovascular disease". Journal of the American College of Cardiology. 2013. 61(4):404-410.