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AbstractObjectivesTo 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.

Background Low-dose (0.5 mg/day) colchicine improves cardiovascular outcomes in patients with stable coronary disease. Around 10–15% of these patients simultaneously use anticoagulant therapy, including vitamin-K antagonists (VKAs). In vitro studies and case reports have described a possible interaction between colchicine and VKAs leading to increased INR, but controlled studies are lacking. Objective The aim of this study was to investigate if there is a drug-drug interaction between low-dose colchicine and VKAs in patients with chronic coronary disease. Methods This study was a sub-analysis of the randomized low-dose colchicine for secondary prevention of cardiovascular disease 2 (LoDoCo2) trial. This placebo-controlled trial investigated efficacy of colchicine 0.5 mg once daily in patients with chronic coronary disease. For the current study, we included a selection of Dutch patients who concomitantly used a VKA. Following a 30 days open-label colchicine run-in phase, patients were randomized to colchicine or placebo. The primary outcome was the intra-patient difference in international normalized ratio (INR) during the first month after starting or stopping colchicine as compared to the preceding month. Secondary outcomes included changes in VKA daily dosage, assessed in the same pattern and before and after randomization, and time in therapeutic range (TTR), assessed before and after randomization to reflect long-term effects. INR measurements were part of routine clinical care. Results In total, 73 patients were included (35 colchicine and 38 in the placebo group). No significant intra-patient change in INR was observed after starting colchicine during the open-label run-in phase (mean INR: 2.60 before vs. 2.67 during run-in, difference 0.07, 95% CI − 0.13 to 0.26; p  = 0.50). Similarly, stopping colchicine treatment (i.e., randomization to placebo) did not significantly alter INR levels (mean INR: 2.70 during run-in vs. 2.81 after randomization, difference 0.11, 95% CI − 0.12 to 0.33; p  = 0.34). The change in mean VKA daily dosage was − 0.01 mg (95% CI − 0.03 to 0.01; p  = 0.35) when starting colchicine and − 0.01 mg (95% CI − 0.03 to 0.01; p  = 0.41) when switching to placebo. TTR in patients allocated to active treatment was 65.8% in the year prior to the start of colchicine and 73.4% in the year after randomization to colchicine (change in TTR 7.56%, 95% CI − 0.14 to 15.26%; p  = 0.05). Mean VKA dosage remained similar (change in VKA dosage of 0.01 mg; 95% CI − 0.11 to 0.13 mg; p  = 0.84). Conclusion No significant changes in INR, VKA dosage, or TTR in patients using VKAs after starting or stopping colchicine were observed. These results suggest that there is no need for additional INR monitoring beyond the standard of care when using low-dose colchicine, though further studies in larger populations would help to confirm this conclusion.

Patients with chronic coronary disease were randomly assigned to receive 0.5 mg of colchicine once daily or matching placebo. The incidence of the composite end point of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization was significantly lower with colchicine than with placebo.

Inflammation appears to play a role in atherosclerosis, raising the possibility that treatments that reduce inflammation could prevent cardiovascular events. In a randomized, placebo-controlled trial involving 4745 patients with recent myocardial infarction, low-dose colchicine (0.5 mg once daily) prevented ischemic cardiovascular events.

Inflammation is associated with adverse cardiovascular events. Data from recent trials suggest that colchicine reduces the risk of cardiovascular events. In this multicenter trial with a 2-by-2 factorial design, we randomly assigned patients who had myocardial infarction to receive either colchicine or placebo and either spironolactone or placebo. The results of the colchicine trial are reported here. The primary efficacy outcome was a composite of death from cardiovascular causes, recurrent myocardial infarction, stroke, or unplanned ischemia-driven coronary revascularization, evaluated in a time-to-event analysis. C-reactive protein was measured at 3 months in a subgroup of patients, and safety was also assessed. A total of 7062 patients at 104 centers in 14 countries underwent randomization; at the time of analysis, the vital status was unknown for 45 patients (0.6%), and this information was most likely missing at random. 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 over a median follow-up period of 3 years (hazard ratio, 0.99; 95% confidence interval [CI], 0.85 to 1.16; P = 0.93). The incidence of individual components of the primary outcome appeared to be similar in the two groups. The least-squares mean difference in C-reactive protein levels between the colchicine group and the placebo group at 3 months, adjusted according to the baseline values, was -1.28 mg per liter (95% CI, -1.81 to -0.75). Diarrhea occurred in a higher percentage of patients with colchicine than with placebo (10.2% vs. 6.6%; P<0.001), but the incidence of serious infections did not differ between groups. Among patients who had myocardial infarction, treatment with colchicine, when started soon after myocardial infarction and continued for a median of 3 years, did not reduce the incidence of the composite primary outcome (death from cardiovascular causes, recurrent myocardial infarction, stroke, or unplanned ischemia-driven coronary revascularization). (Funded by the Canadian Institutes of Health Research and others; CLEAR ClinicalTrials.gov number, NCT03048825.).

Anti-inflammatory therapy with long-term colchicine prevented vascular recurrence in coronary disease. Unlike coronary disease, which is typically caused by atherosclerosis, ischaemic stroke is caused by diverse mechanisms including atherosclerosis and small vessel disease or is frequently due to an unknown cause. We aimed to investigate the hypothesis that long-term colchicine would reduce recurrent events after ischaemic stroke. We did a randomised, parallel-group, open-label, blinded endpoint assessed trial comparing long-term colchicine (0·5 mg orally per day) plus guideline-based usual care with usual care only. Hospital-based patients with non-severe, non-cardioembolic ischaemic stroke or high-risk transient ischaemic attack were eligible. The primary endpoint was a composite of first fatal or non-fatal recurrent ischaemic stroke, myocardial infarction, cardiac arrest, or hospitalisation (defined as an admission to an inpatient unit or a visit to an emergency department that resulted in at least a 24 h stay [or a change in calendar date if the hospital admission or discharge times were not available]) for unstable angina. The p value for significance was 0·048 to adjust for two prespecified interim analyses conducted by the data monitoring committee, for which the steering committee and trial investigators remained blinded. The trial was registered at ClinicalTrials.gov (NCT02898610) and is completed. 3154 patients were randomly assigned between Dec 19, 2016, and Nov 21, 2022, with the last follow-up on Jan 31, 2024. The trial finished before the anticipated number of outcomes was accrued (367 outcomes planned) due to budget constraints attributable to the COVID-19 pandemic. Ten patients withdrew consent for analysis of their data, leaving 3144 patients in the intention-to-treat analysis: 1569 (colchicine and usual care) and 1575 (usual care alone). A primary endpoint occurred in 338 patients, 153 (9·8%) of 1569 patients allocated to colchicine and usual care and 185 (11·7%) of 1575 patients allocated to usual care alone (incidence rates 3·32 vs 3·92 per 100 person-years, hazard ratio 0·84; 95% CI 0·68–1·05, p=0·12). Although no between-group difference in C-reactive protein (CRP) was observed at baseline, patients treated with colchicine had lower CRP at 28 days and at 1, 2, and 3 years (p<0·05 for all timepoints). The rates of serious adverse events were similar in both groups. Although no statistically significant benefit was observed on the primary intention-to-treat analysis, the findings provide new evidence supporting the rationale for anti-inflammatory therapy in further randomised trials. Health Research Board Ireland, Deutsche Forschungsgemeinschaft (German Research Foundation), and Fonds Wetenschappelijk Onderzoek Vlaanderen (Research Foundation Flanders), Belgium.