Colchicine and the combination of rivaroxaban and aspirin in patients hospitalised with COVID-19 (ACT): an open-label, factorial, randomised, controlled trial

Background COVID-19 disease is accompanied by a dysregulated immune response and hypercoagulability. The AntiCoronavirus Therapies (ACT) inpatient trial aimed to evaluate anti-inflammatory therapy with colchicine and antithrombotic therapy with the combination of rivaroxaban and aspirin for prevention of disease progression in patients hospitalised with COVID-19. Methods The ACT inpatient, open-label, 2 x 2 factorial, randomised, controlled trial was done at 62 clinical centres in 11 countries. Patients aged at least 18 years with symptomatic, laboratory confirmed COVID-19 who were within 72 h of hospitalisation or worsening clinically if already hospitalised were randomly assigned (1:1) to receive colchicine 1 center dot 2 mg followed by 0 center dot 6 mg 2 h later and then 0 center dot 6 mg twice daily for 28 days versus usual care; and in a second (1:1) randomisation, to the combination of rivaroxaban 2 center dot 5 mg twice daily plus aspirin 100 mg once daily for 28 days versus usual care. Investigators and patients were not masked to treatment allocation. The primary outcome, assessed at 45 days in the intention-to-treat population, for the colchicine randomisation was the composite of the need for high-flow oxygen, mechanical ventilation, or death; and for the rivaroxaban plus aspirin randomisation was the composite of major thrombosis (myocardial infarction, stroke, acute limb ischaemia, or pulmonary embolism), the need for high-flow oxygen, mechanical ventilation, or death. The trial is registered at www.clinicaltrials.gov, NCT04324463 and is ongoing. Findings Between Oct 2, 2020, and Feb 10, 2022, at 62 sites in 11 countries, 2749 patients were randomly assigned to colchicine or control and the combination of rivaroxaban and aspirin or to the control. 2611 patients were included in the analysis of colchicine (n=1304) versus control (n=1307); 2119 patients were included in the analysis of rivaroxaban and aspirin (n=1063) versus control (n=1056). Follow-up was more than 98% complete. Overall, 368 (28 center dot 2%) of 1304 patients allocated to colchicine and 356 (27 center dot 2%) of 1307 allocated to control had a primary outcome (hazard ratio [HR] 1 center dot 04, 95% CI 0 center dot 90-1 center dot 21, p=0 center dot 58); and 281 (26 center dot 4%) of 1063 patients allocated to the combination of rivaroxaban and aspirin and 300 (28 center dot 4%) of 1056 allocated to control had a primary outcome (HR 0 center dot 92, 95% CI 0 center dot 78-1 center dot 09, p=0 center dot 32). Results were consistent in subgroups defined by vaccination status, disease severity at baseline, and timing of randomisation in relation to onset of symptoms. There was no increase in the number of patients who had at least one serious adverse event for colchicine versus control groups (87 [6 center dot 7%] of 1304 vs 90 [6 center dot 9%] of 1307) or with rivaroxaban and aspirin versus control groups (85 [8 center dot 0%] vs 91 [8 center dot 6%]). Among patients assigned to colchicine, 8 (0 center dot 61%) had adverse events that led to discontinuation of study drug, mostly gastrointestinal in nature. 17 (1 center dot 6%) patients assigned to the combination of rivaroxaban and aspirin had bleeding compared with seven (0 center dot 66%) of those allocated to control (p=0 center dot 042); the number of serious bleeding events was two (0 center dot 19%) versus six (0 center dot 57%), respectively (p=0 center dot 18). No patients assigned to rivaroxaban and aspirin had serious adverse events that led to discontinuation of study drug.