Colchicine Fails to Reduce Cardiovascular Events After Myocardial Infarction, Increases Diarrhea Risk

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Data from the Phase III CLEAR SYNERGY trial (NCT03048825) show that long-term treatment with colchicine for acute myocardial infarction did not reduce major cardiovascular events compared to placebo but was associated with increased incidence of diarrhea.^1,2 The study, published by The New England Journal of Medicine, found that patients administered colchicine soon after experiencing myocardial infarction and who continued on treatment for a median of three years did not achieve a reduction in the incidence of the trial’s composite primary outcomes—death from cardiovascular causes, recurrent myocardial infarction, stroke, or unplanned ischemia-driven coronary revascularization.

According to the authors, these findings highlight the mixed results from prior trials evaluating colchicine's role in cardiovascular disease.

“Colchicine inhibits the actions of neutrophils and the release of inflammatory chemokines, including interleukin-1 and interleukin-6,” the authors of the current study wrote. “A trial involving 4745 patients in which treatment with colchicine was initiated within 30 days after myocardial infarction and a trial involving 5522 patients with stable coronary artery disease showed beneficial cardiovascular effects of colchicine; however, two recent trials involving patients with ischemic stroke showed no reductions in cardiovascular events with colchicine treatment, although in one trial the treatment duration was only 3 months.”¹

Colchicine primarily has an anti-inflammatory effect and is FDA-approved for the treatment and prevention of gout and acute gout attacks, as well as for the treatment of familial Mediterranean fever. The drug has also been used off-label to treat conditions such as hepatic cirrhosis, primary biliary cirrhosis, and pseudogout.³

A 2022 study suggested that colchicine improved survival rates for patients hospitalized with worsening heart failure. The authors of that study reviewed data from more than 1,000 patients who were hospitalized for worsening heart failure at the University of Virginia Medical Center between March 2011 and February 2020. They found that patients who were administered colchicine for a gout flare had a survival rate of 97.9% compared with a survival rate of 93.5% for patients who did not receive colchicine.⁴

CLEAR SYNERGY was a multicenter trial with a two-by-two factorial design. Investigators enrolled 7062 patients with myocardial infarction across 104 centers in 14 countries, who were randomly assigned to receive either colchicine or placebo and either spironolactone or placebo.

The trial’s primary efficacy outcome was composite of death from cardiovascular causes, recurrent myocardial infarction, stroke, or unplanned ischemia-driven coronary revascularization, which was analyzed via time-to-event evaluation. Investigators also assessed safety and C-reactive protein, which was measured at three months in a subgroup of patients.

When the analysis was conducted, 45 patients had an unknown vital status, which investigators said was most likely missing at random. Over a median follow-up of three years, the results showed a primary outcome event in 322 of 3528 patients (9.1%) randomly assigned to the colchicine cohort compared with 327 of 3534 patients (9.3%) in the placebo cohort (hazard ratio, 0.99; 95% confidence interval [CI], 0.85 to 1.16; P=0.93).

The investigators found that the incidence rates of the individual components for the primary outcome was apparently similar across both cohorts. Death attributed to cardiovascular causes were observed in 3.3% of patients in the colchicine cohort compared with 3.2% in the placebo cohort (hazard ratio, 1.03; 95% CI, 0.80 to 1.34).

At three months, the least-squares mean difference in C-reactive protein levels between patients administered colchicine and the placebo group, adjusted according to baseline values, was −1.28 mg per liter (95% CI, −1.81 to −0.75). In terms of adverse events, diarrhea was reported by 10.2% of patients in the colchicine cohort compared with 6.6% in the placebo cohort (P<0.001); however, incidence of serious infections was similar between the two cohorts.

“The reasons for the divergence between the results of our trial and those of previous trials of colchicine in patients with cardiovascular diseases are not immediately evident; however, three of the latest trials, CLEAR, CHANCE, and CONVINCE, provide what is likely to be the most recent evidence to date of the effects of colchicine in patients with vascular disease,” the study authors concluded. “Recent meta-analyses have shown a nominal excess in death from noncardiovascular causes with colchicine. We found the opposite: a lower rate of death from noncardiovascular causes in the colchicine group than in the placebo group. COLCOT showed an excess of pneumonia among patients who received colchicine, whereas the LODOCO 2 trial did not show any increase in serious infection. We also found no excess in serious infection with colchicine as compared with placebo.”¹

References

1. Jolly S., et al. Colchicine in Acute Myocardial Infarction. N Engl J Med. Published November 17, 2024. DOI: 10.1056/NEJMoa2405922.

2. Colchicine and Spironolactone in Patients with MI /​ SYNERGY Stent Registry (CLEAR SYNERGY). ClinicalTrials.gov. Updated October 15, 2024. Accessed November 19, 2024.

3. Sadiq NM, Robinson KJ, Terrell JM. Colchicine. StatPearls [Internet]. Updated May 29, 2023; 2024 Jan-. Accessed November 19, 2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK431102/

4. Gout medicine improves survival for heart failure patients, study finds. EurekAlert, News release. May 19, 2022. Accessed November 19, 2024. https://www.eurekalert.org/news-releases/953315