Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE (ACTIV4A) is a randomized, open label, adaptive platform trial that compares the effectiveness of several antithrombotic strategies for the prevention of adverse outcomes in COVID-19 positive inpatients. Investigators assessed outcomes such as the number of days that a patient is alive and free of organ support through the first 21 days after study enrollment, all-cause mortality, morbidity and hospitalization status, acute kidney injury, major bleeding, and heparin induced thrombocytopenia (HIT). A total of 2,545 patients were consented across sites in the United States, Brazil, Italy, and Spain.

To be eligible for the study, patients needed to be at least 18 years of age, hospitalized for COVID-19 (confirmed with a positive microbiological test prior to randomization or within 24 hours of randomization), enrolled within 72 hours of hospital admittance or 72 hours of positive COVID test, and expected to remain hospitalized for over 72 hours. Randomization criteria for specific treatment arms are detailed in the study protocol.

Treatment arms included:

• Therapeutic Dose Anticoagulation: Patients received an increased dose of heparin above standard of care. This arm was discontinued for severe patients in December 2020 and for moderate patients in January 2021.
• Prophylactic Dose Anticoagulation: Patients received a standard of care dose of heparin. This arm was discontinued for all patients in January 2021.
• Therapeutic Dose Anticoagulation + P2Y12 inhibitor: Patients received an increased dose of heparin above standard of care with an added P2Y12 inhibitor. This arm included patients with moderate illness only and ended in June 2021.
• Prophylactic Dose Anticoagulation + P2Y12 inhibitor: Patients received a standard of care dose of heparin with an added P2Y12 inhibitor. This arm enrolled only patients with severe illness and ended in June 2022.
• Standard of Care + Crizanlizumab: Patients with severe or moderate illness received standard of care treatment plus crizanlizumab infusion. This arm ended in September 2022.
• Standard of Care + SGLT2 inhibitor: Patients with severe or moderate illness received standard of care treatment plus SGLT2 inhibitor. This arm ended in March 2023.