Colchicine

ObjectivesTo assess the efficacy and safety of colchicine versus placebo on reducing the risk of subsequent stroke after high risk non-cardioembolic ischaemic stroke or transient ischaemic attack within the first three months of symptom onset (CHANCE-3).DesignMulticentre, double blind, randomised, placebo controlled trial.Setting244 hospitals in China between 11 August 2022 and 13 April 2023.Participants8343 patients aged 40 years of age or older with a minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L were enrolled.InterventionsPatients were randomly assigned 1:1 within 24 h of symptom onset to receive colchicine (0.5 mg twice daily on days 1-3, followed by 0.5 mg daily thereafter) or placebo for 90 days.Main outcome measuresThe primary efficacy outcome was any new stroke within 90 days after randomisation. The primary safety outcome was any serious adverse event during the treatment period. All efficacy and safety analyses were by intention to treat.Results4176 patients were assigned to the colchicine group and 4167 were assigned to the placebo group. Stroke occurred within 90 days in 264 patients (6.3%) in the colchicine group and 270 patients (6.5%) in the placebo group (hazard ratio 0.98 (95% confidence interval 0.83 to 1.16); P=0.79). Any serious adverse event was observed in 91 (2.2%) patients in the colchicine group and 88 (2.1%) in the placebo group (P=0.83).ConclusionsThe study did not provide evidence that low-dose colchicine could reduce the risk of subsequent stroke within 90 days as compared with placebo among patients with acute non-cardioembolic minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L.Trial registrationClinicalTrials.gov, NCT05439356.

Cholesterol crystal- (CC-) induced endothelial cell inflammation and pyroptosis play an important role in the development of cardiovascular diseases, especially in atherosclerosis (AS). Increasing evidence suggests that cholesterol crystals are known to be a pivotal pathological marker of atherosclerotic plaque vulnerability. As a classical nonspecific anti-inflammatory drug, colchicine has been widely used in the treatment of acute gout. However, whether colchicine could alleviate CC-induced endothelial cell injury and the related mechanisms remains to be addressed. In this study, the protective effect of colchicine on human umbilical vein endothelial cells (HUVECs) was confirmed. Our results revealed that after cotreatment with colchicine and cholesterol crystals in endothelial cells, the uptake of cholesterol crystals was significantly decreased, the cell viability was obviously increased, and the release of lactate dehydrogenase (LDH) and the number of pyroptotic cells decreased significantly; then, the expression of NLRP3 inflammasome-related proteins and various inflammatory factors was also visibly suppressed; moreover, as a potent activator of NLRP3 inflammasome, the intracellular ROS level was clearly reduced, while mitochondrial membrane potential improved significantly. In addition, the expression levels of AMP-dependent kinase (AMPK) pathway-related proteins as well as various antioxidant enzymes were elevated notably in varying degrees. However, the above effects of colchicine were completely offset by the treatment of siRNA targeting AMPKα and Sirtuin1 (SIRT1). Therefore, we conclude that colchicine plays a crucial role in alleviating the intracellular inflammatory response and NLRP3 inflammation activation, attenuating the levels of cellular oxidative stress and pyroptosis in endothelial cells via regulating AMPK/SIRT1 signaling, which may be a concrete mechanism for the secondary prevention of cardiovascular diseases.

Background and aimsColchicine has emerged as a safe and inexpensive anti-inflammatory medication to target the residual risk of cardiovascular events in the secondary prevention of coronary artery disease. Two recently published randomized controlled trials (RCTs) investigating colchicine in the post-stroke and post-myocardial infarction (MI) populations warrant a re-evaluation of colchicine. New evidence was synthesized in a systematic review and meta-analysis to determine the long-term efficacy and safety of colchicine for the secondary prevention of vascular disease.MethodsRandomized controlled trials comparing the incidence of cardiovascular events between patients with clinically manifest vascular disease randomized to colchicine vs. placebo and ≥12-month follow-up were included. The primary efficacy endpoint is major adverse cardiovascular events (MACE) and includes cardiovascular mortality, MI, ischaemic stroke, and urgent coronary revascularization. The DerSimonian and Laird random effects model was used to calculate pooled effect estimates.ResultsSix RCTs, with a pooled sample size of 21 800 patients, were included (colchicine n = 10 871; placebo n = 10 929). Over a follow-up of 12-34 months, colchicine reduced the incidence of MACE compared with placebo [pooled hazard ratio .75, 95% confidence interval (CI) .56-.93]. The reduction in cardiovascular events among colchicine patients was driven by reductions in MIs, ischaemic strokes, and urgent coronary revascularizations (P .05 for all), including non-cardiovascular deaths (risk ratio 1.08, 95% CI .76-1.54).ConclusionsThis updated meta-analysis of RCTs demonstrated a substantial reduction in MACE, MI, ischaemic stroke, and recurrent coronary revascularization with colchicine compared with placebo. Therefore, the results support the use of colchicine to reduce recurrent cardiovascular events.

Chronic inflammation plays a key role in the development and progression of atherosclerotic cardiovascular disease (ASCVD) and its complications. Despite the use of blood pressure-, lipid-, and glucose-lowering therapies as well as antithrombotic agents, the lifetime residual cardiovascular (CV) risk in patients with ASCVD remains high. Because chronic inflammation remains an unaddressed risk factor, anti-inflammatory therapy has the potential to further lower residual CV risk in these patients. Low-dose colchicine (0.5 mg daily) has emerged as a promising low-cost oral anti-inflammatory therapy for this indication. In patients with chronic coronary syndrome (CCS), low-dose colchicine was well-tolerated and reduced the risk of myocardial infarction, stroke, coronary revascularization, and CV death. However, trials in patients with acute coronary syndrome (ACS) yielded conflicting results, and two trials in patients with ischemic stroke did not show a benefit. In patients with peripheral artery disease (PAD), preliminary observational data suggested a potential benefit, and a randomized trial is currently underway to examine its efficacy in reducing CV and limb events. The long-term safety data for low-dose colchicine in ASCVD are reassuring. Although pooled data from trials in ASCVD show a small (0.55%) absolute increase in the risk of hospitalization for gastrointestinal events, adverse signals were not observed for serious infection, cancer, or severe myotoxicity. In this article, we review the clinical studies of colchicine that examined its risk-benefit for the prevention of CV events in patients with ASCVD, discuss clinical and research implications, and highlight knowledge gaps.