Methods:

ACTIV-4a (Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 Acute) is an international, adaptive, randomized clinical trial, designed to evaluate whether P2Y12 inhibition increases organ support-free days among patients hospitalized with COVID-19. This report includes results from the non–critically ill study cohort (enrollment of critically ill patients is still ongoing). Patients at 60 sites in the United States, Brazil, Italy, and Spain were enrolled from February–June 2021. To qualify, patients were required to meet any one of the following criteria: 1) D-dimer level ≥2-fold upper limit of normal, 2) 60-84 years of age, 3) <60 years of age with oxygen requirement >2 L/min, diabetes, hypertension, chronic kidney disease, cardiovascular disease, or body mass index ≥35 kg/m². A notable exclusion criterion was a clinical requirement for dual antiplatelet therapy. Participants were randomized to P2Y12 inhibitor + therapeutic anticoagulation with heparin, versus therapeutic anticoagulation only (standard of care). The preferred P2Y12 inhibitor was ticagrelor. P2Y12 inhibitor treatment was continued for 14 days or until hospital discharge, whichever occurred first. The composite primary outcome was organ support-free days (up to 21 days, with in-hospital death receiving a value of -1). The primary safety outcome was major bleeding by 28 days, as defined by the International Society of Thrombosis and Hemostasis.