Weekly Journal Scan: no CLEAR evidence of cardiovascular benefits of colchicine after acute myocardial infarction

This comment refers to ‘Colchicine in acute myocardial infarction’ presented at the American Heart Association Scientific Sessions, Chicago, IL, 17 November 2024, and simultaneously published in the New England Journal of Medicine, https://doi.org/10.1056/NEJMoa2405922.

Key points

• CLEAR-OASIS 9¹ was an investigator-initiated, multicentre, randomized, placebo-controlled trial (RCT), with a 2 × 2 factorial design, investigating the long-term cardiovascular (CV) effects of colchicine and spironolactone in patients with acute ST-segment elevation or large non–ST-segment elevation myocardial infarction (STEMI or NSTEMI, respectively) undergoing percutaneous coronary intervention (PCI).

• Between February 2018 and November 2022, the study recruited 7062 participants from 14 countries, who were randomized to colchicine (0.5 mg daily) or placebo, with additional randomization to spironolactone (25 mg daily) or placebo, as soon as possible after the index PCI. The results of the colchicine trial are discussed here. The primary efficacy outcome was a composite of CV death, recurrent MI, stroke, or unplanned ischaemia-driven coronary revascularization, evaluated in a time-to-event analysis. C-reactive protein (CRP) levels and safety were also assessed.

• The trial was initially designed to detect a 25% relative risk reduction in the primary outcome, using a Cox proportional hazard model stratified by STEMI vs. NSTEMI and spironolactone vs. placebo, based on an estimated 15% event rate at 3 years in the placebo group. Following a blinded interim analysis in April 2020 that identified a lower-than-expected event rate (∼9% over 3 years), the sample size was increased from 4000 to 7000 patients to maintain 80% power, and it was estimated that 546 primary outcome events would be needed to detect a 25% relative risk reduction. Initially, the trial employed a weight-based colchicine dosing regimen for the first 90 days, with patients weighing ≥ 70 kg receiving 0.5 mg twice daily and those weighing < 70 kg receiving 0.5 mg once daily. Following a blinded interim analysis in September 2020, which highlighted higher-than-expected discontinuation rates, the colchicine dosing regimen was revised to 0.5 mg once daily for the remaining treatment period.

• The mean age of patients was 61 years, with 20% women and 92% White. Key comorbidities included diabetes mellitus in one-fifth of participants, prior MI, and previous PCI in one-tenth. Overall, 95% of patients presented with STEMI, received treatment with at least one drug-eluting stent, and were discharged on statins and dual antiplatelet therapy. The median time from symptom onset to the first dose of the trial product was 28 h.

• The median follow-up period was 3 years; 26% of participants in both the colchicine and placebo groups discontinued the trial regimen during the study. A primary outcome event occurred in 322 of 3528 patients (9.1%) in the colchicine group and 327 of 3534 patients (9.3%) in the placebo group [hazard ratio (HR), 0.99; 95% confidence interval (CI), 0.85–1.16; P = .93]. The incidence of individual components of the primary outcome was similar in the two groups. The results of on-treatment analysis were consistent with those of the intention-to-treat analysis. Pre-specified subgroup analysis revealed no benefit of colchicine in any patient group.

• The least-squares mean level of CRP at 3 months, adjusted according to the baseline values, was 30% lower in the colchicine group than in the placebo group. Diarrhoea occurred in a higher percentage of colchicine-treated patients than in the placebo arm (10.2% vs. 6.6%; P < .001), potentially affecting adherence. However, the incidence of serious infections and drug discontinuation was similar in the two groups.

Comment

Over the past 10 years, a number of RCTs have addressed the concept of targeting a deleterious flare of excessive inflammation in the early phase after acute MI. Targeting different pathways and implementing various treatment regimens, these trials have met with inconsistent success.²

The CLEAR trial is the largest study to date addressing residual inflammatory risk very early post-STEMI, starting colchicine as soon as possible after the revascularization procedure.¹

Colchicine is an old drug with a narrow therapeutic window, used for decades in the treatment of acute gout and, more recently, in the management of acute and recurrent pericarditis. It exerts anti-inflammatory effects by disrupting microtubule polymerization; this inhibits neutrophil recruitment and activation, suppresses the NLRP3 inflammasome, and reduces the release of pro-inflammatory cytokines.³

Two earlier trials, the COLCOT trial,⁴ involving 4745 patients in which treatment with colchicine (0.5 mg daily) was initiated within 30 days (mean of 13.5 days) after MI, and the LoDoCo2 trial,⁵ involving 5522 patients with stable chronic coronary syndrome (CCS), demonstrated a 23% and 31% reduction in major adverse cardiovascular events (MACEs), respectively. Based on these findings, the US Food and Drug Administration, but not the European Medicines Agency, approved colchicine for reducing CV events in high-risk patients and those with atherosclerotic CV disease. The European Society of Cardiology recently included colchicine with a Class IIa recommendation in the CCS treatment guidelines for MACE prevention.⁶

Despite its robust design, adequate sample size, and 649 first primary outcome events minimizing the risk of chance findings, along with a median follow-up of 3 years providing insights into both immediate and long-term effects, the CLEAR trial found no statistically significant reduction in MACE with colchicine. Moreover, the lower limit of the 95% CI can exclude a 20%–30% relative risk reduction suggested by the COLCOT and LoDoCo2 trials.^4,5 The Kaplan–Meier curves of the CLEAR trial indicate that—after the initial phase likely influenced by peri-procedural events—the occurrence of MACE proceeded linearly and similarly in both groups over time. These findings contradict the favourable results of earlier colchicine trials.^4,5 The reasons for this divergence remain unclear. However, it should be emphasized that Phase 3 trials of colchicine for CV prevention were initiated without Phase 2 studies in the target patient population to assess the relationship between the drug dosing regimen and changes in relevant markers of the inflammatory response.

To support the evaluation of colchicine’s biological effects, CRP levels were measured in approximately one-third of the CLEAR patients in both treatment groups. Although CRP levels were reduced in the colchicine group, they remained elevated after treatment (3.0 mg/L vs. 4.3 mg/L in the colchicine and placebo groups, respectively, at 3 months). C-reactive protein was also measured in a small group of COLCOT participants showing a larger (>65%) reduction over the first 6 months after MI, in both colchicine- and placebo-treated patients.⁴ This finding raises the question of the mechanism(s) underlying the apparent benefit of colchicine in COLCOT participants. A proteomic analysis of the LoDoCo2 trial in 174 patients who underwent blood sampling at baseline and at the end of the 30-day run-in treatment period showed that colchicine reduces inflammasome activation and neutrophil degranulation in CCS.⁷ The absence of a placebo group in this 30-day run-in study represents a limitation of the analysis.

It should be emphasized that in COLCOT—the trial most comparable to CLEAR—there were only 301 primary outcome events (less than half the number of events in CLEAR), and the observed benefit was largely driven by urgent hospitalizations for angina leading to revascularization.⁴ While differences in population characteristics between COLCOT (conducted in Canada) and this international study may have contributed to the apparent discrepancy, no treatment-by-region interaction was observed in CLEAR.

Additional factors may have contributed to the negative results of CLEAR, including the challenges posed by conducting the trial during the COVID-19 pandemic. Moreover, colchicine use was linked to a significantly higher incidence of diarrhoea (10.2% vs. 6.6%), which likely affected patient adherence. The unexpectedly high discontinuation rate prompted a protocol adjustment, reducing the initially higher colchicine dose. Nevertheless, on-treatment analyses yielded results consistent with the primary analysis. Importantly, a previously reported signal for increased non-CV mortality associated with colchicine was not observed in this trial, providing some reassurance on its safety.⁸

Two additional recent trials—CHANCE-3,⁹ the largest RCT evaluating the efficacy and safety of acute colchicine use for preventing early recurrent stroke in over 8000 Chinese patients, and the open-label CONVINCE trial,¹⁰ which compared long-term colchicine therapy added to usual care (initiated between 72 h and 28 days after ischaemic stroke or TIA) vs. usual care alone—did not support the hypothesis that low-dose colchicine may reduce the risk of non-cardioembolic stroke.

The convincingly negative results of these studies do not exclude inflammation as a contributor to residual risk following MI. The heterogeneous and dynamic inflammatory response in acute MI, where certain pathways facilitate myocardial healing and scar formation, while excessive activation of others accelerates atherosclerosis, promotes adverse remodelling, and increases the risk of recurrent events, underscores the need for more targeted anti-inflammatory strategies, such as selective cytokine inhibition or combination therapies.^2,11 The ARTEMIS trial (NCT05021835), involving approximately 10 000 patients, is testing whether the interleukin-6 inhibitor ziltivekimab can reduce recurrent events in this setting. Meanwhile, the negative results of the CLEAR trial seriously question the evidence supporting the use of colchicine in patients with atherosclerotic CV disease.

Declarations

Disclosure of Interest

G.L. reports personal fees from Astra Zeneca, Boehringer Ingelheim, Novo Nordisk, Daiichi Sankyo, Sanofi, and Novartis and reports grant support (to the Institution) for investigator-initiated research from the American Heart Association, the Italian Ministry of University and Research, and the Italian Ministry of Health (grant: ‘Ricerca Corrente’). C.P. reports personal fees from AbbVie, Eli Lilly, and Tremeau and past grant support (to the Institution) for investigator-initiated research from AIFA (Italian Drug Agency), Bayer, Cancer Research UK, and European Commission; he chaired the Scientific Advisory Board of the International Aspirin Foundation.