Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction

Trial Reference

Tardif JC, Kouz S, Waters DD, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019 Nov 16. doi: 10.1056/NEJMoa1912388. [Epub ahead of print]

Abstract | Full Text

Expert Comment

Pablo Avanzas, Hospital Universitario Central Asturias

Comment:

Inflammation is widely believed to play a central role in the pathogenesis of atherosclerosis and acute coronary events. Although treatments with proven benefits for secondary prevention of coronary artery disease (e.g., statins and aspirin) appear to have salutary effects on inflammation, the identification of an effective treatment specifically targeting inflammation has been elusive. Colchicine is an orally administered, potent anti-inflammatory medication that is indicated for the treatment of gout and pericarditis.

The authors performed a randomized, double-blind trial involving patients recruited within 30 days after a myocardial infarction. The patients were randomly assigned to receive either low-dose colchicine (0.5 mg once daily) or placebo. The primary efficacy end point was a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization. The components of the primary end point and safety were also assessed. A total of 4745 patients were enrolled; 2366 patients were assigned to the colchicine group, and 2379 to the placebo group. Patients were followed for a median of 22.6 months.

The risk of the primary composite end point (death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization) was lower in the colchicine group than in the placebo group (hazard ratio, 0.77; 95% confidence interval [CI], 0.61 to 0.96; P = 0.02), but this result was driven predominantly by lower risks of angina and stroke. A significant effect on death from cardiovascular causes or myocardial infarction was not shown. Overall, the incidence of adverse events or serious adverse events was similar in the two groups; however, some known gastrointestinal side effects of colchicine, including nausea, were more frequent in the colchicine group, as were pneumonias.

Some points to consider:

  • Although vital status was known in 99.5% of the patients in COLCOT, 1.9% of the patients were lost to follow-up and 0.6% withdrew consent. Furthermore, nearly 19% of the patients in both treatment groups stopped receiving colchicine or placebo prematurely.
  • This high percentage of patients discontinuing the trial regimen, combined with unknown end-point status for 2.5% of the patients, could have obscured the true cardiovascular treatment effect or adverse-event profile.
  • Although the inclusion of 4745 patients was sufficient for the trial to show a significant benefit with regard to the primary composite efficacy end point, a larger trial could have allowed a better assessment of individual end points and subgroups and the risks associated with colchicine.
  • 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.
  • An interesting observation in this trial was the lower risk of stroke in the colchicine group than in the placebo group. Whether this reflects a unique mechanistic effect of colchicine in the cerebrovasculature or is simply the play of chance is a question for further investigation.

The final question to be answered is whether the modest benefit driven by a soft end point of hospitalization for angina and revascularization does support the routine use of colchicine for secondary prevention (without a better understanding of the absence of effect on death or myocardial infarction).

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