Colchicine Post-MI: Close but No Cigar

Because inflammation plays a role in atherosclerosis, anti-inflammatory drugs hold promise for improving outcomes.

Two recently published trials have sparked interest in using the old (1500 BC-old) anti-inflammatory drug colchicine to reduce cardiac events after myocardial infarction (MI).

Before reviewing the data, first consider that the bar for making a (clinically) significant difference after MI is high.

MI care is already quite good. Few therapies approach the benefit of rapid percutaneous coronary intervention for an acutely closed coronary artery. Then there are statins, which deliver a consistent 25% reduction in future cardiac events. In fact, outcomes have improved so much that even routine use of β-blockers is now questioned.

Another problem is polypharmacy. After a first MI, a typical patient leaves the hospital on at least 4, maybe 5, new drugs. People can swallow only so many pills.

Should colchicine be one of those pills?

COLCOT Trial

In the COLCOT trial, low-dose colchicine (0.5 mg daily) was tested against placebo in about 4700 patients after a recent MI. The primary endpoint, a composite of cardiovascular (CV) death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization, occurred in 5.5% of the colchicine arm vs 7.1% of the placebo arm.

The 1.6–percentage point absolute risk reduction translated to a hazard ratio of 0.77 (95% CI, 0.61 - 0.96; P =.02)

This is a statistically significant result, but I am not sure it is clinically significant?

The largest driver of the primary endpoint was revascularization. Harder outcomes, such as CV death and MI, did not differ significantly. Stroke rates were lower in the colchicine arm, but the small number of strokes makes it hard to tell whether this was due to chance. Overall death rates were nearly identical.

LoDoCo2 Trial

In LoDoCo2, the same low dose of colchicine was tested against placebo in slightly more than 5500 post-MI patients from centers in Australia and the Netherlands. The primary end point, a composite of CV death, MI, ischemic stroke, or ischemia-driven coronary revascularization, occurred in 6.8% of the colchicine arm vs 9.6% of the placebo arm.

The 2.8–percentage point absolute risk reduction translated to a hazard ratio of 0.69 (95% CI, 0.57 - 0.83).

These data are much stronger. Three of the components of the endpoint (CV death, MI, and revascularization) were significantly reduced in the colchicine arm. Too few strokes occurred to show any differences.

Although these results look compelling, LoDoCo2 had important caveats.

Higher Death Rates in the Colchicine Arm

Despite the decrease in cardiac events, including fewer CV deaths, there were 13 more overall deaths in the colchicine arm (73 vs 60).

Death due to noncardiac causes occurred in 18 more patients in the colchicine arm, for a hazard ratio of 1.51 (95% CI, 0.99 - 2.31). Technically, this is not significant, but the vast majority of the CI spans a higher risk for noncardiac death. The authors write that this could be due to chance but also add that it is "of potential concern."

Does Geography Matter?

Patients enrolled in Australia had a massive 49% reduction in the primary endpoint, whereas those in the Netherlands had a nonsignificant 8% reduction.

I've written many times that subgroups may vary by chance alone, and this too may be noise rather than signal. That said, clinical trials pool data to produce an average effect. Widely disparate outcomes based on geography at least raise the possibility that the average effect may not apply to all patients.

This does not negate the trial's finding, but it is hard to simply ignore.

Careful Patient Selection and Real-world Use of Colchicine

LoDoCo2 had a run-in period during which more than 1000 patients were not randomly assigned, mostly because of side effects. Then, 10% of patients in each arm of the trial stopped taking their drug.

The trial excluded patients with moderately severe renal impairment, frailty, a life expectancy of less than 5 years, moderate or severe valvular disease, or severe heart failure.

Only 15% of trial participants were women. Will female patients have the same benefit to risk calculation? It's hard to say with such small numbers.

Nearly all clinical trials carefully select patients. But LoDoCo2 was quite particular in enrolling sturdy male patients—which is something to consider when using this evidence.

Conclusion

I worry about the harm-benefit tradeoffs with colchicine after MI.

The message from other trials of inflammation-blocking drugs in CVD, such as CANTOS and CIRT, was that the drugs may work only in patients with higher levels of inflammation. This might also be true for colchicine, but inflammatory markers were not collected in LoDoCo2 and were measured in only 200 patients in COLCOT.

Although the rate of adverse events for patients taking colchicine or placebo did not differ in either trial, colchicine use outside the confines of a clinical trial may be trickier. Colchicine can precipitate acute kidney injury, especially when used with other nephrotoxic drugs. It also interacts with most macrolide antibiotics and many cardiac drugs.

When you look into the nuances of these trials, the degree of benefit from colchicine looks a lot less certain. The higher death rate in LoDoCo2 really worries me. Isn't the point of reducing cardiac events to prolong life?

When the harm-benefit calculus is uncertain and there is no urgency to act, I favor the precautionary principle. I would not recommend use of colchicine in patients after MI.

You may disagree. I'd welcome your counterarguments.

John Mandrola practices cardiac electrophysiology in Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence.

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