Connors 2021.

Study characteristics
Methods	Prospective, multicentre, double‐blind, placebo‐controlled RCT
Participants	Number of participants: 657 Age: between 40 and 80 years Gender: female (388 participants) and male (269 participants) Inclusion criteria Ambulatory patients COVID‐19 positive in past 14 days Platelets > 100,000/mm3 eGFR > 30 mL/min Exclusion criteria Hospitalised Contraindication/other indication for anticoagulation Pregnancy Active cancer
Interventions	Intervention 1: apixaban 2.5 mg orally twice a day for 45 days Intervention 2: apixaban 5.0 mg orally twice a day for 45 days Intervention 3: aspirin 81 mg orally twice a day for 45 days Control: placebo orally twice a day for 45 days
Outcomes	Planned primary outcome Need for hospitalisation for cardiovascular/pulmonary events: composite endpoint of need for hospitalisation for cardiovascular/pulmonary events, symptomatic DVT, PE, arterial thromboembolism, myocardial infarction, ischaemic stroke, and all‐cause mortality for up to 45 days after initiation of assigned treatment Reported primary outcomes Composite of symptomatic DVT, PE, arterial thromboembolism, myocardial infarction, ischaemic stroke, hospitalisation for cardiovascular or pulmonary events, and all‐cause mortality for up to 45 days after treatment initiation Secondary outcomes Individual components of the primary study endpoint Mortality without antecedent hospitalisation Major bleeding Clinically relevant non‐major bleeding as defined by ISTH
Funding	Funded in part by NIH Agreement 1OT2HL156812‐01. Specifically, the ACTIV‐4B trial was supported by Other Transition Authorities from the NHLBI. Grantee institutions included the University of Pittsburgh; the University of Illinois Chicago; and the Brigham and Women’s Hospital. The trial drugs and matching placebo were donated by the Bristol Myers Squibb‐Pfizer Alliance.
Declaration of interest	Dr Connors reported receiving personal fees from Bristol Myers Squibb, Pfizer, Abbott, Alnylam, Takeda, Roche, and Sanofi, and that his institution has received research funding from CSL Behring. Dr Brooks reported receiving personal fees for data and safety monitoring board membership from Cerus Corporation. Dr Krishnan reported receiving grants from Sergey Brin Family Foundation Research in COVID. Dr Bledsoe reported receiving grants payable to his institution from the NIH for clinical trial work and receiving consulting fees from JAJ LLC. Dr Kirwan reported receiving grants from SOCAR Research SA. Dr Everett reported receiving consulting fees from Johnson & Johnson, Gilead, and Merck. Dr Hou reported receiving grants from Brigham and Women’s Hospital, NIH, Novartis, and CalciMedica. Dr Haight reported receiving grants and non‐financial support from OneFlorida. Dr Wilson reported receiving personal fees from Pfizer, Bristol Myers Squibb, Alexion, Janssen, and Paratek and receiving grants from Gilead. Dr Ridker reported receiving grants from Bristol Myers Squibb and Pfizer and serving as a consultant for work unrelated to this study for Corvidia, Novartis, Flame, Agepha, Inflazome, AstraZeneca, Janssen, Civi Biopharm, SOCAR, Novo Nordisk, Uptton, Omeicos, and Boehringer Ingelheim. No other authors reported disclosures.
Notes	Quote: "The trial drugs and matching placebo were donated by the Bristol Myers Squibb‐Pfizer Alliance." Quote: "The National Heart, Lung, and Blood Institute had no role in the collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication." Comment: information from the study article
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: 'Randomisation code lists were computer generated using permuted blocks with block size equal to 4 during the process of drug labelling and then implemented electronically through the central electronic data‐capture system.' Comment: information from the study article.
Allocation concealment (selection bias)	Low risk	Quote: 'Participants were randomised centrally in a 1:1:1:1 ratio to receive aspirin (81 mg once daily) with matching placebo, prophylactic‐dose apixaban (2.5 mg twice daily), apixaban at therapeutic dose (5 mg twice daily), or placebo twice daily.' Quote: 'After randomisation, drug was shipped directly to the participant’s home with subsequent follow‐up conducted by the RCC central study staff.' Comment: information from the study article.
Blinding of participants and personnel (performance bias)	Low risk	Quote: 'To try to ensure consistency across sites in the setting of an outpatient COVID‐19 trial, all post‐randomisation participant contact was conducted by weekly electronic links to REDCap surveys or by the Research Communication Center (RCC) at the University of Illinois Chicago with live telephone calls by call centre agents and research pharmacists in Chicago and Pittsburgh. Direct shipment of study drug to participants homes, end point and safety adjudication, and 24‐hour emergency and unblinding services were provided by investigators at the Brigham and Women’s Hospital in Boston.' Comment: information from the study article.
Blinding of outcome assessment (detection bias)	Low risk	Quote: 'Medical records were sent to the Clinical Endpoints Committee, who adjudicated events using standardized criteria. Both the medical monitors and the end points committee were unaware of randomised drug assignment.' Comment: information from the study article.
Incomplete outcome data (attrition bias) All outcomes	Low risk	The numbers of participants in each analysis population were similar between treatment groups. Also, the dropouts were reported and also similar between groups.
Selective reporting (reporting bias)	Low risk	The study protocol is available and all of the study's prespecified (primary and secondary) outcomes that are of interest in the review have been reported asprespecified.
Other bias	Low risk	We did not find other bias in the study.