- Several randomized trials have shown reductions in MACE with colchicine in the treatment of coronary artery disease.
- The CLEAR SYNERGY (OASIS 9) trial showed that in patients with acute MI undergoing PCI, daily treatment with colchicine did not reduce MACE at 5 years compared with placebo.
Patients experiencing myocardial infarction (MI) remain at high risk of future major adverse cardiovascular events (MACE). While low-dose colchicine and spironolactone have been shown to decrease post-MI MACE, more data are required to confirm their safety and efficacy in an unselected post-MI population. Two prior studies, COLCOT and LoDoCo2 , showed a significant 23% and 31% reduction in cardiovascular events with colchicine in patients with acute myocardial infarction and stable coronary artery disease, respectively.
The CLEAR SYNERGY trial (ClinicalTrials.gov Identifier: NCT03048825) is a 2 × 2 factorial randomized controlled trial of low-dose colchicine 0.5 mg daily versus placebo and spironolactone 25 mg daily versus placebo in 7,062 post-MI participants who were within 72 hours of the index percutaneous coronary intervention (PCI). Patients were eligible if they had STEMI or large NSTEMI. Participants, healthcare providers, research personnel were blinded, and outcome adjudicators were also blinded to treatment allocation. The primary outcome for colchicine is the first occurrence of the composite of cardiovascular death, recurrent MI, stroke, or unplanned ischemia-driven revascularization. The coprimary outcomes for spironolactone are (1) the composite of the total numbers of cardiovascular death or new or worsening heart failure and (2) the first occurrence of the composite of cardiovascular death, new or worsening heart failure, recurrent MI or stroke. The trial was designed with 80% power to detect a 25% relative risk reduction in the primary outcome (9% estimated control event rate) as assessed using a Cox proportional hazards model, stratified by STEMI vs. NSTEMI and spironolactone vs. placebo. The main results were presented by Dr. Sanjit S. Jolly at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2024), Washington, DC, October 29, 2024.
A total of 7,062 participants were randomized within 72 hours of PCI to either colchicine or placebo at 104 sites in 14 countries between 2018 and 2022. Patient characteristics were similar between both groups, with a mean age was 60.6 years, almost one out of five had diabetes and 9% had prior MI. Following initial randomization, both groups were randomized again to receive spironolactone or placebo. At a median follow-up of three years, the composite of cardiovascular death, recurrent MI, stroke, or ischemia-driven revascularization was not significantly different between the colchicine and placebo groups (9.1 vs. 9.3%, respectively) [HR 0.99 (95% confidence interval 0.85-1.16), p = 0.93]. No significant differences were seen in any of the individual components of the composite endpoint. There was a significant reduction in C-reactive protein with colchicine therapy. Adverse events were similar between both groups, with the exception of diarrhea, which was more common following colchicine (10.2%) than with placebo (6.6%).
Sanjit S. Jolly, MD, MSc concluded that “As the largest trial to date on this subject (649 outcome events), with significantly more events than previous studies, colchicine did not provide a significant benefit and its role in long-term post MI use is uncertain.”
d’Entremont MA, Lee SF, Mian R, Kedev S, Montalescot G, Cornel JH, Stankovic G, Moreno R, Storey RF, Henry TD, Skuriat E, Tyrwhitt J, Mehta SR, Devereaux PJ, Eikelboom J, Cairns JA, Pitt B, Jolly SS. Design and rationale of the CLEAR SYNERGY (OASIS 9) trial: A 2×2 factorial randomized controlled trial of colchicine versus placebo and spironolactone vs placebo in patients with myocardial infarction. Am Heart J. 2024 Sep;275:173-182. doi: 10.1016/j.ahj.2024.06.007. Epub 2024 Jun 25.