Colchicine and the combination of rivaroxaban and aspirin in patients hospitalised with COVID-19 (ACT): an open-label, factorial, randomised, controlled trial
Prof John W Eikelboom, Sanjit S Jolly, Emilie P Belley-Cote, Prof Richard P Whitlock, Sumathy Rangarajan, MD, S Rangarajan MSc Lizhen Xu, PhD Laura Heenan, Prof S I Shrikant I Bangdiwala, Maria Luz Diaz, MD Rafael Diaz, Afzalhussein Yusufali, Sanjib Kumar Sharma, Wadea M Tarhuni, Mohamed Hassany, Alvaro Avezum, William Harper, Sean Wasserman, Aysha Almas, Oxana Drapkina, Camilo Felix, Renato D Lopes, Otavio Berwanger, Patricio Lopez-Jaramillo, Sonia S Anand, Jackie Bosch, Shurjeel Choudhri, Michael E Farkouh, Mark Loeb, Salim Yusuf
The Lancet Respiratory Medicine, doi:10.1016/s2213-2600(22)00298-3
Background COVID-19 disease is accompanied by a dysregulated immune response and hypercoagulability. The Anti-Coronavirus 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 × 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•2 mg followed by 0•6 mg 2 h later and then 0•6 mg twice daily for 28 days versus usual care; and in a second (1:1) randomisation, to the combination of rivaroxaban 2•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•2%) of 1304 patients allocated to colchicine and 356 (27•2%) of 1307 allocated to control had a primary outcome (hazard ratio [HR] 1•04, 95% CI 0•90-1•21, p=0•58); and 281 (26•4%) of 1063 patients allocated to the combination of rivaroxaban and aspirin and 300 (28•4%) of 1056 allocated to control had a primary outcome (HR 0•92, 95% CI 0•78-1•09, p=0•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•7%] of 1304 vs 90 [6•9%] of 1307) or with rivaroxaban and aspirin versus control groups (85 [8•0%] vs 91 [8•6%] ). Among patients assigned to colchicine, 8 (0•61%) had adverse events that led to discontinuation of study drug, mostly gastrointestinal in nature. 17 (1•6%) patients assigned to the combination of rivaroxaban and aspirin had..
Declaration of interests JWE reports grant or in-kind support from AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Janssen, Sanofi-Aventis and honoraria from Astra-Zeneca, Bayer, Boehringer-Ingelheim, Bristol-Myer-Squibb, Daiichi-Sankyo, Eli-Lilly, Glaxo-Smith-Kline, Merck, Pfizer, Janssen, Sanofi-Aventis, Servier. SSJ reports grant support from Boston Scientific, honoraria from Medtronic, Penumbra. EPB-C reports grant support from Bayer, Roche, BMS-Pfizer. RPW reports grant support from Bayer, Roche, BMS-Pfizer, grant and honorarium from Boehringer-Ingelheim, and consultancy fees from Atricure and Phasebio. MLD reports grant support from the Population Health Research Institute (PHRI) to manage the ACT study in Argentina. RD reports grant support from PHRI to manage the ACT study in Argentina. AA reports institutional grant support from Bayer and EMS, and lecture fees from Bayer and Sanofi-Aventis. SW reports grant support from NIH, honoraria from Pfizer, and safety monitoring committee of an AIDS Clinical Trial Group. RDL reports institutional grant support from Bristol Myers Squibb, Glaxo Smith Kline, Medtronic, Pfizer, and Sanofi, consulting fees from Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, Sanofi, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Merck, and Portola, honoraria from Pfizer and meeting travel support from IQVIA. OB reports grant support from Astra Zeneca, Bayer, Amgen, Novartis, Servier, Pfizer. SSA..
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