Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction

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Clinical Question

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

Bottom Line

The purpose of the study was to determine if the use of low dose colchicine, compared to placebo, is safe and effective for the prevention of future cardiovascular morbidity and mortality in patients with a recent myocardial infarction. The study showed that low dose colchicine can potentially be beneficial in preventing some types of cardiovascular events, such as stroke, or urgent hospitalization for angina leading to coronary revascularization, but shows no efficacy in prevention of mortality.

Major Points

Colchicine is a proinflammatory drug that is predominantly used for the treatment of gout, familial Mediterranian fever, and pericarditis. The mechanism of action of colchicine is through the inhibition of tubulin polymerization and microtubule generation and, possibly effects on cellular adhesion molecules, inflammatory chemokines, and the inflammasome. Through this, it has the ability to relieve inflammation.

A low dose colchicine trial was conducted in patients with stable coronary disease.The study did not have a placebo controlled trial. The authors of this journal took notes of the previous trial they studied and conducted a study which showed that the addition of colchicine could potentially lower cardiovascular events and for the possible safety of patients with a recent myocardial infarction. The randomized, double-blind, placebo-controlled, investigator-initiated trial consisted of 4,500 patients who recently had a myocardial infarction within 30 days, had completed any planned percutaneous revascularization procedures, and were treated according to national guidelines that included the intensive use of statins. The patients received either colchicine or placebo with a ratio of 1:1 with 2,500 patients in each group. The primary endpoints were a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization in a time-to-event analysis. The secondary end points consisted of the components of the primary efficacy endpoint; a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, or stroke; and total mortality in time to event analyses. A primary end-point event occurred in 5.5% of the patients in the colchicine group, as compared with 7.1% of those in the placebo group. The secondary efficacy endpoint consisting of a composite of death from cardiovascular causes, cardiac arrest, myocardial infarction, or stroke occurred in 4.7% of the patients in the colchicine group and in 5.5% of those in the placebo group. among patients with a recent myocardial infarction, colchicine at a dose of 0.5 mg daily led to a significantly lower percentage of patients with ischemic cardiovascular events than placebo.

The primary endpoint had a p-value of 0.89 which is not significant (<0.05). The most common adverse events observed were gastrointestinal. Diarrhea was reported in 9.7% of the patients in the colchicine group and in 8.9% of those in the placebo group, and nausea occurred in 1.8% and 1.0%, respectively. Infection as a serious adverse event was more frequent in the colchicine group than in the placebo group (in 2.2% vs. 1.6% of the patients), and pneumonia as a serious adverse event was also more frequent in the colchicine group (0.9% vs. 0.4%). Certain criticisms were obtained from the study. The duration of follow-up was relatively short at approximately 23 months. The risks and benefits of longer-term treatment with colchicine were not evaluated. Although the inclusion of 4745 patients was sufficient for the trial to show a significant benefit with regard to the primary composite efficacy endpoint, a larger trial could have allowed a better assessment of individual end points and subgroups and the risks associated with colchicine. Finally, the results apply only to patients who have recently had a myocardial infarction.

Guidelines

No guidelines relevant to the use of colchicine for the prevention of cardiovascular events.

Design

Trial type: randomized, double-blind, placebo-controlled, investigator-initiated trial N=4745 Experimental arm (n=2366) Standard (n=2379) Setting: Montreal Health Innovations Coordinating Center, Quebec, Canada Enrollment: 2015-2018 Mean follow-up: 22.6 months Analysis: intention-to-treat Primary 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 Adult patients who had a myocardial infarction within 30 days before enrollment Adult patients who had completed any planned percutaneous revascularization procedures Adult patients who were treated according to national guidelines that included the intensive use of statins

Exclusion Criteria Severe heart failure A left ventricular ejection fraction of less than 35% Stroke within the previous 3 months A type 2 index myocardial infarction Coronary-bypass surgery either within the previous 3 years or planned A history of noncutaneous cancer within the previous 3 years Inflammatory bowel disease or chronic diarrhea Neuromuscular disease or a nontransient creatine kinase level that was greater than three times the upper limit of the normal range (unless due to infarction) Clinically significant nontransient hematologic abnormalities Severe renal disease with a serum creatinine level that was greater than two times the upper limit of the normal range Severe hepatic disease Drug or alcohol abuse Current or planned long-term systemic glucocorticoid therapy A history of clinically significant sensitivity to colchicine

Baseline Characteristics 4745 total patients 2366 patients assigned to the colchicine group 2379 patients assigned to the placebo group Age: 60.6 years old Female sex: 472 (19.9%) White Race: 1350/ 1850 (73%) BMI: 28.3 Current Smoking: 708/2366 (29.9%) Hypertension: 1185 (50.1%) Diabetes: 462 (19.5%) History of myocardial infarction: 370 (15.6%) History of PCI: 392 (16.6%) History of CABG: 69 (2.9%) History of heart failure: 48 (2.0%) History of stroke or TIA: 55 (2.3%) Time from index MI to randomization: 13.4 days PCI for index myocardial infarction: 2192/ 2364 (92.7) Medication use: Aspirin: 2334 (98.6%) Other antiplatelet agent: 2310 (97.6%) Statin: 2339 (98.9%) Beta-blocker: 2116 (89.4%)

Interventions

Randomized, double-blind trial Quadruple masking (Participant, Care Provider, Investigator, Outcomes Assessor) Enrollment within 30 days after myocardial infarction Randomized in 1:1 fashion either to colchicine 0.5 mg once daily or placebo Patients were followed for a median of 22.6 months

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) Resuscitated cardiac event 5 (0.20%) vs 6 (0.3%); HR 0.83 (95% Cl 0.25-2/73) 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) Deep Venous thrombosis or pulmonary embolus 10 (0.4%) vs 7 (0.3%); HR 1.43 (95% Cl 0.54-3.75) Atrial fibrillation 36 (1.5%) vs 40 (1.7%); HR 0.93 (95% CI 0.59-1.46)

Subgroup Analysis The primary endpoint event rates per 100 patient-months 0.29% vs 0.42%; rate ratio 0.66 (95% CI 0.51- 0.86)

Adverse Events Any related adverse event: 372 (16.0%) Adverse events: Gastrointestinal event: 408 (17.5%) Diarrhea: 225 (9.7%) Nausea: 43 (1.8%) Flatulence: 15 (0.6%) Gastrointestinal hemorrhage: 7 (0.3%) Anemia: 14 (0.6%) Leukopenia: 2 (0.1%) Thrombocytopenia: 3 (0.1%) Serious adverse events: Any serious adverse event: 383 (16.4%) Gastrointestinal event: 46 (2.0%) Infection: 51 (2.2%) Pneumonia: 21 (0.9%) Septic Shock: 2 (0.1%) Hospitalization for heart failure: 25 (1.1%) Cancer: 43 (1.8%)

Criticisms

The duration of follow-up was relatively short at approximately 23 months The risks and benefits of longer-term treatment with colchicine were not evaluated Although the inclusion of 4745 patients was sufficient for the trial to show a significant benefit with regard to the primary composite efficacy endpoint, a larger trial could have allowed a better assessment of individual endpoints and subgroups and the risks associated with colchicine Results apply only to patients who have recently had a myocardial infarction

Funding

The trial was funded by the Government of Quebec, the Canadian Institutes of Health Research, and philanthropic foundations.

Further Reading

Tardif J-C, Newby LK. “Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction.” New England Journal of Medicine. 2019;381:2497-2505