By Michael H. Crawford, MD, Editor

SYNOPSIS: An analysis of the COLCOT study of colchicine administration after myocardial infarction (MI) showed the benefit of this therapy for preventing subsequent cardiovascular events was greatest when therapy was initiated within three days after MI onset.

SOURCE: Bouabdallaoui N, Tardif J-C, Waters DD, et al. Time-to-treatment initiation of colchicine and cardiovascular outcomes after myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT). Eur Hear J 2020;41:4092-4099.

Myocardial infarction (MI) is associated with acute inflammation of the myocardium, which is involved in the detrimental remodeling process. Recent attempts to modulate inflammation in MI patients have produced modest success, including the use of colchicine, which is a potent but inexpensive anti-inflammatory agent.

In the original report on the Colchicine Cardiovascular Outcomes Trial (COLCOT), low-dose colchicine administered within 30 days after MI was shown to reduce subsequent ischemic cardiovascular (CV) events by 23% vs. placebo.1 However, many individual events were not affected, and absolute differences in events were small. Bouabdallaoui et al examined whether the timing of colchicine initiation played any role in the outcomes. COLCOT was an international, multicenter, randomized, double-blinded trial of colchicine 0.5 mg daily vs. placebo administered within 30 days of an MI and continued for three months. Exclusion criteria were severe heart failure, reduced left ventricular ejection fraction (< 35%), recent stroke, or other inflammatory diseases. All patients underwent guideline-directed management of their MI, including percutaneous coronary intervention (PCI) when indicated. The primary efficacy endpoint was a composite of CV death, cardiac arrest, MI, stroke, or urgent revascularization. The authors studied three periods for colchicine initiation: days 0-3 (in-hospital), days 4-7 (early post-discharge), and day 8-30 (late post-discharge). Of 4,745 patients enrolled, 4,661 patients were available for this analysis. The mean day of colchicine initiation was 14 days, with 26% at days 0-3, 15% at days 4-7, and 59% at days 8-30. Patients mostly were men (81%; mean age, 61 years), and 93% underwent PCI. Patients with therapy initiation at days 0-3 were younger, more often smokers, had less hypertension and diabetes, and more often were treated with PCI.

The primary endpoint occurred in 4.3% of the colchicine group initiated in the earliest period vs. 8.3% of the placebo group (HR, 0.52; 95% CI, 0.32-0.84; P = 0.007). The colchicine and placebo rates were 6% for both groups in the days 4-7 group and 5.7% and 7.1% after day 8 (P = NS). Also, many components of the primary endpoint were significantly lower in the colchicine patients treated early, including CV death (HR, 1.04), cardiac arrest (HR, 0.33), MI (HR, 0.58), stroke (HR, 0.21), and urgent revascularization (HR, 0.35). The authors concluded the early in-hospital initiation of low-dose colchicine after MI and continuing for 30 days results in fewer CV events over two years vs. placebo.

COMMENTARY

Myocardial necrosis activates complement, which mobilizes white blood cells. In turn, this amplifies the damage to the myocardium and extends detrimental remodeling after MI. Colchicine interferes with microtubule polymerization in white cells, which hinders their effectiveness. This results in less myocardial damage in experimental models of MI. Inflammation also plays an important role in the progression of atherosclerosis. If persistent, this would increase the risk of future vascular events. A recent study of the anti-inflammatory agent canakinumab showed a 15% reduction in CV events in patients with stable ischemic heart disease. The original analysis of the COLCOT study revealed a 23% reduction in composite CV events after MI, but little effect on individual events. This reanalysis of the COLCAT study by time of administration of colchicine exhibits a 48% reduction in CV events after MI when colchicine is administered within three days of MI onset. This makes sense if one considers the inflammatory response after MI begins almost immediately and is largely over in a week, to be replaced by fibroblast proliferation. Also of interest is the observation that stroke is much less likely, suggesting colchicine produces anti-inflammatory effects on the vasculature, too.

This could be the most provocative post-MI treatment study in quite a while. Colchicine is inexpensive; produces few side effects at this low, once-a-day dose; and only has to be given for 30 days to reap the benefits. Of course, this was a relatively small trial; the authors explored only three time frames. It would take a larger trial to parse the timing of administration more precisely. The real question is whether cardiologists should start administering colchicine to all early post-MI patients who are not contraindicated to it. Administering the drug may lower the incidence rate of post-MI pericarditis. For early adopters, this work may be enough, but I would like to see a confirmatory study.

REFERENCE

  1. Tardif J-C, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 2019;381:2497-2505.