Colchicine Among Patients with Acute Coronary Syndrome: A Meta-Analysis of Randomized Trials

Abstract

Introduction

Prior trials evaluating the benefit of colchicine in patients with acute coronary syndrome (ACS) have yielded mixed results. Hence, we conducted a meta-analysis of randomized controlled trials (RCTs) to evaluate the role of colchicine after ACS.

Methods

We performed an electronic search of MEDLINE, Embase, and Cochrane databases through November 2024 for studies comparing colchicine with placebo after ACS. Our study’s primary outcome was major adverse cardiac events (MACE).

Results

Our final analysis included five RCTs with 12,979 patients with a mean follow-up of 26.6 months. The weighted mean age was 59.8 years. Colchicine was associated with a modest reduction of MACE with marginal significance and high heterogeneity (7.3% vs. 8.3%; relative risk [RR] 0.73; 95% confidence interval [CI] 0.54–0.99; I² = 68%) compared with placebo. This benefit was inconsistent after excluding the study with higher heterogeneity. There was no significant difference between colchicine and placebo in all-cause mortality (3.4% vs. 3.5%; RR 1.04; 95% CI 0.71–1.53; I² = 43%), cardiac mortality (2.2% vs. 2.2%; RR 1.02; 95% CI 0.81–1.29; I² = 0), myocardial infarction (MI) (3.1% vs. 3.6%; RR 0.82; 95% CI 0.61–1.11; I² = 35%), ischemia-driven repeat revascularization (4.3% vs. 4.6%; RR 0.75; 95% CI 0.37–1.50; I² = 54%), and stroke (0.9% vs. 1.1%; RR 0.51; 95% CI 0.18–1.44; I² = 68%). Colchicine had a higher risk of gastrointestinal (GI) side effects (11.7% vs. 8.6%; RR 1.36; 95% CI 1.07–1.71; I² = 67%) compared with placebo.

Conclusions

Among patients with ACS, colchicine may modestly reduce the incidence of MACE compared with placebo, but this effect is not robust after excluding the study with a higher risk of bias. In addition, no significant benefits were observed for the main individual outcomes of MACE, including all-cause mortality, cardiac mortality, MI, ischemia-driven repeat revascularization and stroke. Yet, colchicine was associated with a higher risk of GI side effects.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40119-025-00440-6.

Key Summary Points

Why carry out this study?

Prior trials evaluating the benefit of colchicine in patients with acute coronary syndrome (ACS) have yielded mixed results.

This meta-analysis evaluated the efficacy and safety of colchicine in patients with ACS.

What was learned from the study?

Colchicine may be associated with a modest reduction in the incidence of major adverse cardiac events (MACE) with no benefit of individual outcomes in patients with ACS compared with placebo.

The benefits of colchicine in ACS are questionable. Current evidence does not support routine use of colchicine after ACS.

Introduction

Despite advances in secondary prevention therapies, patients with acute coronary syndrome (ACS) are at high risk for recurrent cardiovascular events [1]. Inflammation plays a crucial role in the pathogenesis of ACS [1]. Colchicine exerts an anti-inflammatory effect, as it may reduce inflammatory cytokines and limit the infarct size [1, 2]. However, prior studies have shown mixed results regarding the benefits of colchicine among patients with ACS. Therefore, we conducted a meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of colchicine in patients with ACS. Specifically, we aimed to determine whether colchicine reduces the incidence of major adverse cardiac events (MACE) compared with placebo and to assess its impact on individual cardiovascular outcomes, mortality, and safety endpoints. By synthesizing the totality of current evidence, this study seeks to clarify the potential role of colchicine in the management of ACS.

Methods

An electronic search of MEDLINE, Embase, and Cochrane databases through November 2024 for studies evaluating the role of colchicine versus placebo after ACS. We used the following search terms “ACS” OR “Acute Coronary Syndrome” OR “NSTEMI” OR “STEMI” OR “unstable angina” AND “Colchicine”. The study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [3].

Two investigators obtained the study features, characteristics, and outcomes. Any discrepancy between investigators was resolved by consensus. We included RCTs comparing colchicine with control in patients with ACS. Studies with a follow-up of less than 30 days were excluded.

The primary study outcome was MACE, as defined by the individual trials (Supplementary Table 1). Secondary outcomes included all-cause mortality, cardiac mortality, non-cardiovascular mortality, myocardial infarction (MI), ischemia-driven repeat revascularization, and stroke. Safety outcomes included all-adverse events, serious adverse events, and gastrointestinal (GI) side effects. The quality of the included studies was assessed using the Cochrane Risk Assessment Tool [4]. We used a random effects model to pool data utilizing the Mantel–Haenszel method. Outcomes were reported as risk ratios (RR) for categorical variables and mean differences (MD) for continuous variables. Subgroup analysis, including studies with similar MACE definitions, was performed. Publication bias was assessed using funnel plots. We used RevMan 5.4 software to analyze the data.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Results

The study selection process was outlined in Fig. 1. The final analysis included five RCTs with a total of 12,979 patients: 6474 patients in the colchicine group and 6505 patients in the placebo group [1, 2, 5–7]. The mean follow-up was 26.6 months. The weighted mean age was 59.8 years, and the proportion of women was 20.1%. The dose of colchicine was 0.5 mg daily in the COLCOT, COLOCT, and Akrami et al. [2, 5, 7]. While CLEAR SYNERGY initially dosed colchicine using weight-based dosing (daily for < 70 kg and twice daily for > 70 kg), the dose was then reduced to daily during the trial due to an increased rate of drug discontinuation. The Australian COPS used colchicine 0.5 mg twice daily for the first month, and the dose was then reduced to 0.5 mg daily [1]. All included trials were placebo-controlled. Regarding risk of bias, Akrami et al. had a high risk of selective reporting bias [5]. For all other criteria, all studies were considered to have a low risk of bias (Supplementary Table 2). There was no evidence of publication bias (Supplementary Fig. 1).

Fig. 1.

Study flow diagram

Colchicine was associated with a slight reduction in MACE with marginal significance and high heterogeneity compared with placebo (7.3% vs. 8.3%; RR 0.73; 95% confidence interval [CI] 0.54–0.99; p = 0.04, I² = 68%) (Fig. 2). However, sensitivity analysis excluding the study with a higher risk of bias showed no difference in MACE between colchicine and placebo (RR 0.87; 95% CI 0.72–1.05; p = 0.14) with reduced degree of heterogeneity (I² = 35%). In addition, subgroup analysis including studies with similar MACE definitions showed no difference in MACE between both groups (RR 0.87; 95% CI 0.70–1.07; p = 0.19, I² = 52) (Supplementary Fig. 2). There were no differences in all-cause mortality (3.4% vs. 3.5%; RR 1.04; 95% CI 0.71–1.53; p = 0.83, I² = 43%), cardiac mortality (2.2% vs. 2.2%; RR 1.02; 95% CI 0.81–1.29; p = 0.85, I² = 0%), non-cardiovascular mortality (1.2% vs. 1.4%; RR 0.99; 95% CI 0.50–1.99; p = 0.98, I² = 62%), MI (3.1% vs. 3.6%; RR 0.82; 95% CI 0.61–1.11; P = 0.21, I² = 35%), ischemia-driven repeat revascularization (4.3% vs. 4.6%; RR 0.75; 95% CI 0.37–1.50; p = 0.42, I² = 54%), stroke (0.9% vs. 1.1%; RR 0.51; 95% CI 0.18–1.44; p = 0.20, I² = 68%), C-reactive protein (CRP) levels (MD − 0.67; 95% CI − 1.44 to 0.10; p = 0.09, I² = 100%), all-adverse events (25.3% vs. 25.2%; RR 1.01; 95% CI 0.95–1.07; p = 0.86. I² = 0%), and serious adverse events (10.5% vs. 11.3%; RR 0.93; 95% CI 0.84–1.03; p = 0.19, I² = 0%) between both groups. Compared with placebo, colchicine had a higher risk of GI side effects (11.7% vs. 8.6%; RR 1.36; 95% CI 1.07–1.71; p = 0.01, I² = 67%) (Fig. 2).

Fig. 2.

Forest plot for major adverse cardiac events (MACE) (A), all-cause mortality (B), cardiac mortality (C), myocardial infarction (D), and gastrointestinal side effects (E) among colchicine versus placebo groups. M–H Mantel–Haenszel, CI confidence interval

Discussion

This meta-analysis included the totality of RCTs comparing clinical outcomes of colchicine versus placebo in patients with ACS. Our analysis demonstrated that colchicine may reduce the primary outcome of MACE compared with placebo. However, this outcome was limited by marginal statistical significance and high heterogeneity. In addition, excluding the study with a higher risk of bias (Akrami et al.) and a subgroup analysis including studies with similar MACE definitions showed no difference in MACE between colchicine and placebo which raises uncertainty regarding the true benefit of colchicine in the reduction of MACE. Although the study by Akrami et al. was included in the overall pooled analysis to provide a comprehensive synthesis of the available RCT evidence, it substantially influenced the overall results, as the observed modest benefit appears to be largely driven by this single high-risk trial.

Furthermore, colchicine did not reduce individual outcomes of MACE, including all-cause mortality, cardiac mortality, MI, ischemia-driven repeat revascularization, and stroke. The marginal reduction of MACE could be attributed to increased statistical power from pooling individual outcomes. However, inconsistent MACE definitions across trials led to high heterogeneity. Sensitivity analysis excluding the study with a higher risk of bias showed no reduction in MACE, with a marked reduction of heterogeneity (I² = 35%). Additionally, there were no differences in CRP levels, all-adverse events or serious adverse events between both groups. However, colchicine was associated with a higher risk of GI side effects. Although colchicine is an anti-inflammatory drug, the lack of CRP reduction in our study suggests limited anti-inflammatory efficacy in ACS, which may explain the absence of clear clinical benefits. These findings call into question the benefits of routine use of colchicine after ACS.

Prior meta-analyses have shown mixed results regarding the role of colchicine in patients with coronary artery disease (CAD). A previous meta-analysis by Ullah et al., which included patients with stable CAD and ACS, showed that colchicine reduced the risk of MACE, ACS, ischemic stroke, and the need for revascularization [8]. Another meta-analysis by Ma et al. which included acute and chronic CAD, demonstrated a reduction in MACE, stroke, MI, and risk of revascularization but showed no reduction in cardiovascular death or all-cause mortality [9]. A meta-analysis by Razavi et al. that involved patients with ACS demonstrated that colchicine did not show difference in the incidence of MI or the composite endpoint of MI or all-cause mortality but showed a reduction in the incidence of stroke [10]. Our meta-analysis included recent RCTs of 12,979 patients and focused solely on patients with ACS. Our study demonstrated that colchicine may be associated with only a marginal reduction in MACE, with no benefit in individual outcomes.

This meta-analysis has few limitations. First, there was a high degree of heterogeneity among the included trials, particularly in the primary outcome, which may have influenced the pooled estimates showing a modest and marginally significant reduction in MACE in the primary analysis. So, we conducted a sensitivity analysis excluding the study with a higher risk of bias, which mitigated the heterogeneity and eliminated the statistical significance of the association. Second, the analysis was based on study-level data rather than patient-level data, which limited the ability to perform more granular analyses. Third, publication bias, although not detected in the funnel plot inspection, cannot be completely ruled out, given the limited number of studies available. Finally, the adherence and drug discontinuation rates have varied among the included studies, which may have affected the treatment efficacy and safety outcomes.

Conclusions

Colchicine may be associated with a modest reduction in the incidence of MACE in patients with ACS compared with placebo. However, this finding appears to be driven by a study with a higher risk of bias (Akrami et al.) and is not robust, as the benefit disappears after excluding this study in sensitivity analysis. Furthermore, colchicine did not show a reduction in individual outcomes of MACE, including all-cause mortality, cardiac mortality, non-cardiovascular mortality, MI, ischemia-driven repeat revascularization, or stroke, nor all-adverse events or serious adverse events. Moreover, colchicine was associated with a higher risk of GI side effects compared with placebo. The high heterogeneity and lack of benefit after sensitivity analysis underscore the uncertainty of routine use of colchicine in ACS. Overall, the current evidence does not support the routine use of colchicine after ACS.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

All authors [Mohamed Hamed, Sheref A. Mohamed, Mohamed Abdelazeem, Eric Lieberman, Abdelrahman Ali, Dharam J. Kumbhani, Anthony Bavry, Hani Jneid, Islam Y. Elgendy, and Ayman Elbadawi] contributed to the study conception and design, material preparation, data collection, statistical analysis, writing the article, critical revision of the article and final approval of the article.

Funding

No funding or sponsorship was received for this study or publication of this article.

Data Availability

All data generated or analyzed during this study are included in this published article/as supplementary information files.

Declarations

Conflict of Interest

Mohamed Hamed, Sheref A. Mohamed, Mohamed Abdelazeem, Eric Lieberman, Abdelrahman Ali, Dharam J. Kumbhani, Hani Jneid, Islam Y. Elgendy, and Ayman Elbadawi have nothing to disclose. Anthony Bavry is an Editor in Chief of Cardiology and Therapy. Anthony Bavry was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.