The effect of colchicine on coagulation in patients with chronic coronary disease who use vitamin K antagonists

Abstract

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.