Data from the Phase III CLEAR SYNERGY trial indicates that long-term treatment with colchicine following acute myocardial infarction did not reduce major cardiovascular events compared to placebo, but it did increase the incidence of diarrhea. The study, published in The New England Journal of Medicine, enrolled 7,062 patients across 104 centers in 14 countries. These findings add to the mixed results from prior trials evaluating colchicine's role in cardiovascular disease.
The primary outcome, a composite of death from cardiovascular causes, recurrent myocardial infarction, stroke, or unplanned ischemia-driven coronary revascularization, was analyzed over a median follow-up of three years. The results showed that 9.1% of patients in the colchicine group experienced a primary outcome event, compared to 9.3% in the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.85 to 1.16; P=0.93). This indicates no statistically significant difference between the two groups.
Individual Components and Safety
Individual components of the primary outcome were similar across both cohorts. Cardiovascular death occurred in 3.3% of patients in the colchicine group and 3.2% in the placebo group (hazard ratio, 1.03; 95% CI, 0.80 to 1.34). Regarding safety, diarrhea was reported in 10.2% of patients receiving colchicine compared to 6.6% in the placebo group (P<0.001). The incidence of serious infections, however, was similar between the two groups.
Mechanism of Action and Prior Studies
Colchicine is known to inhibit neutrophil activity and the release of inflammatory chemokines, including interleukin-1 and interleukin-6. Previous studies have shown conflicting results regarding its cardiovascular effects. For example, a trial involving 4,745 patients showed beneficial cardiovascular effects when colchicine was initiated within 30 days after myocardial infarction. Another trial with 5,522 patients with stable coronary artery disease also suggested benefits. However, two recent trials involving patients with ischemic stroke showed no reduction in cardiovascular events with colchicine treatment.
Trial Design and Patient Population
CLEAR SYNERGY was a multicenter, two-by-two factorial design trial. Patients with myocardial infarction were randomly assigned to receive either colchicine or placebo and either spironolactone or placebo. The primary efficacy outcome was the composite of death from cardiovascular causes, recurrent myocardial infarction, stroke, or unplanned ischemia-driven coronary revascularization. C-reactive protein was measured at three months in a subgroup of patients.
C-Reactive Protein Levels
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). This indicates a reduction in inflammation in the colchicine group, although this did not translate into a significant reduction in cardiovascular events.
Implications and Future Directions
The study authors noted the divergence between the results of CLEAR SYNERGY and previous trials, suggesting that recent trials like CLEAR, CHANCE, and CONVINCE provide the most up-to-date evidence on the effects of colchicine in patients with vascular disease. They also addressed concerns raised by recent meta-analyses regarding a nominal excess in death from noncardiovascular causes with colchicine, finding a lower rate of such deaths in the colchicine group compared to the placebo group in their trial.
