Systematic Review/Meta-analysis
Colchicine for Secondary Prevention of Cardiovascular Disease: A Systematic Review and Meta-analysis of Randomized Controlled Trials

https://doi.org/10.1016/j.cjca.2020.10.006Get rights and content

Abstract

Background

Reduction of inflammation with colchicine has emerged as a therapeutic option for secondary prevention of cardiovascular disease (CVD) in patients with coronary artery disease (CAD). Our objective was to consolidate evidence from randomized controlled trials (RCTs) evaluating the efficacy and safety of low-dose colchicine for secondary prevention of CVD among patients with CAD on standard medical therapy.

Methods

RCTs comparing the incidence of cardiovascular (CV) events between patients with clinically manifest CAD randomized to colchicine vs placebo (or no colchicine) were included. The primary composite efficacy endpoint included CV mortality, myocardial infarction (MI), ischemic stroke, and urgent coronary revascularization. The DerSimonian and Laird random-effects model was used to calculate pooled hazard ratios (HRs) and 95% confidence intervals (CIs).

Results

Four RCTs, with a pooled sample size of 11,594 patients, were included (colchicine n = 5774; placebo/no colchicine n = 5820). Included RCTs studied populations with stable CAD (N = 2) and acute coronary syndrome (N = 2). Compared with placebo or no colchicine, colchicine was associated with a statistically significant reduction in the incidence of the primary composite endpoint (pooled HR, 0.68; 95% CI, 0.54-0.81; I2 = 37.7%). The reduction in CV events among patients randomized to colchicine was driven by statistically significant reductions in MIs, ischemic strokes, and urgent coronary revascularizations (P < 0.05 for all) and was relatively consistent among subgroups. The incidence of safety outcomes did not differ between groups (P > 0.05).

Conclusions

In secondary prevention of CV events, the addition of low-dose colchicine to standard medical therapy reduces the incidence of major CV events—except CV mortality—when compared with standard medical therapy alone.

Résumé

Contexte

L’emploi de la colchicine pour réduire l’inflammation s’est révélé être une option thérapeutique dans le cadre de la prévention secondaire des maladies cardiovasculaires (MCV) chez les patients atteints d’une coronaropathie. Notre objectif était de rassembler les données probantes issues d’essais contrôlés avec répartition aléatoire évaluant l’efficacité et l’innocuité de l’administration de colchicine à faible dose pour la prévention secondaire des MCV chez les patients atteints d’une coronaropathie recevant un traitement standard.

Méthodologie

Notre étude comprenait les essais contrôlés avec répartition aléatoire comparant l’incidence des événements cardiovasculaires (CV) chez des patients atteints d’une coronaropathie cliniquement observable et répartis aléatoirement pour recevoir de la colchicine ou un placebo (ou un traitement sans colchicine). Le critère d’évaluation principal de l’efficacité regroupait la mortalité d’origine CV, l’infarctus du myocarde (IM), l’accident vasculaire cérébral (AVC) ischémique et la revascularisation coronaire d’urgence. Le modèle à effets aléatoires DerSimonian-Laird a été utilisé pour calculer les rapports des risques instantanés (RRI) groupés et les intervalles de confiance (IC) à 95 %.

Résultats

Quatre essais contrôlés avec répartition aléatoire, réunissant au total 11 594 patients, ont été inclus (colchicine : n = 5774; placebo/traitement sans colchicine : n = 5820). Deux de ces essais incluaient des patients atteints de coronaropathie stable (n = 2), et les deux autres, des patients présentant un syndrome coronarien aigu (n = 2). Comparativement au placebo ou au traitement sans colchicine, la colchicine a entraîné une réduction statistiquement significative de l’incidence des événements du critère d’évaluation principal composé (RRI groupés : 0,68; IC à 95 % : de 0,54 à 0,81; I2 : 37,7 %). La réduction des événements CV chez les patients répartis aléatoirement pour recevoir de la colchicine était due à des réductions statistiquement significatives des IM, des AVC ischémiques et des revascularisations coronaires d’urgence (p < 0,05 dans tous les cas) et était relativement constante dans tous les sous-groupes. L’incidence des problèmes d’innocuité était la même dans les deux groupes (p > 0,05).

Conclusions

Chez les patients en prévention secondaire des événements CV, l’ajout de colchicine à faible dose au traitement standard réduit l’incidence des événements CV majeurs – sauf la mortalité d’origine CV – comparativement au traitement standard seul.

Section snippets

Data sources

Medline (PUBMED), EMBASE, and Cochrane central were searched to identify RCTs comparing colchicine with placebo or no colchicine for secondary prevention of CVD (inception to September 1, 2020). To maximized sensitivity, citation chasing was performed in Google Scholar, Scopus, and Web of Science. Secondary prevention was defined as prevention of events in patients with clinically manifest or established CAD. Query terms included colchicine, coronary artery disease, acute coronary syndrome,

Literature search results and risk of bias

The search strategy identified 79 studies. After the first- and second-level screening processes, 4 RCTs were retained in the current meta-analysis. The characteristics of included RCTs are listed in Table 1. The LoDoCo and LoDoCo2 trials assessed the efficacy of colchicine in patients with stable CAD (defined as clinically stable for ≥6 months).11,12 In comparison, COLCOT was conducted in patients who had recent MIs (≤ 30 days), and the COPS trial enrolled patients with ACS.10,13

The pooled

Discussion

In this contemporary meta-analysis of RCTs comparing colchicine to placebo (or no colchicine) for secondary prevention of CVD, we found that (1) treatment with colchicine was associated with a 32% reduction in the incidence of major CV events; (2) significantly fewer MIs, ischemic strokes, and urgent coronary revascularizations were the primary drivers for the overall decrease in CV events; (3) the protective treatment effect of colchicine was relatively consistent among most subgroups studied;

Conclusions

In patients with CAD, the addition of low-dose colchicine to standard medical therapy consistently and significantly reduces the incidence of major CV events compared with standard medical therapy alone. With the exception of CV mortality, significant reductions were observed for components of the primary outcome including MIs, ischemic strokes, and urgent coronary revascularizations.

Funding Sources

COLCOT was supported by the Government of Québec, the Canadian Institutes of Health Research, and philanthropic funds, with the funds administered by the Montréal Heart Institute. Dr Samuel is supported by a postdoctoral fellowship training award from Fonds de recherche du Québec-Santé (FRQS).

Disclosures

Dr Tardif has received grant support from Amarin, Esperion, Ionis Pharmaceuticals, and RegenXBio; grant support and honoraria from AstraZeneca, Pfizer, Sanofi, and Servier; grant support and honoraria from—and minor equity interest in—DalCor Pharmaceuticals. He holds a pending patent (US20170233812A1) on genetic markers for predicting responsiveness to therapy with a high-density lipoprotein (HDL)-raising or HDL mimicking agent and pending patents (62/935,751 and 62/935,865) on methods for

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