Barco 2022.

Study characteristics
Methods	Prospective, 2‐armed, open‐label, parallel‐group, multicentre RCT
Participants	Number of participants: 472 Age: ≥ 50 years Gender: male (255 participants) and female (217 participants) Inclusion criteria Patients aged 50 years or older with a positive test for SARS‐CoV‐2 in the past 5 days and eligible for ambulatory treatment Presence of respiratory symptoms (i.e. cough, sore throat, or shortness of breath) or body temperature > 37.5 °C. Ability of the patient to travel to the study centre by private transportation, performed either by accompanying person from same household or by the patient him/herself Ability to comply with standard hygiene requirements at the time of in‐hospital visit, including a face mask and hand disinfectant Ability to walk from car to study centre or reach it using a wheelchair transport with the help of an accompanying person from the same household also complying with standard hygiene requirements Ability to self‐administer prefilled enoxaparin injections after instructions received at the study centre, or availability of a person living with the patient to administer enoxaparin Exclusion criteria Any acute or chronic condition posing an indication for anticoagulant treatment, e.g. atrial fibrillation, prior VTE, acute confirmed symptomatic VTE, acute coronary syndrome Anticoagulant thromboprophylaxis deemed necessary in view of the patient's history, comorbidity, or predisposing strong risk factors for thrombosis: Any of the following events occurring in the prior 30 days: fracture of lower limb, hospitalisation for heart failure, hip/knee replacement, major trauma, spinal cord injury, stroke Previous VTE Histologically confirmed malignancy that was diagnosed or treated (surgery, chemotherapy, radiotherapy) in the past 6 months, or is recurrent, metastatic, or inoperable Any clinically relevant bleeding (defined as bleeding requiring hospitalisation, transfusion, surgical intervention, invasive procedures, occurring in a critical anatomical site, or causing disability) within 30 days prior to randomisation or sign of acute bleeding Intracerebral bleeding at any time in the past or signs/symptoms consistent with acute intracranial haemorrhage Haemoglobin < 8 g/dL and platelet count < 50 x 109 cells/L confirmed by recent laboratory test (< 90 days) Patients with any known coagulopathy or bleeding diathesis, including known significant liver disease associated with coagulopathy Severe renal insufficiency (baseline creatinine clearance < 30 mL/min calculated using the Cockcroft‐Gault formula) confirmed by recent laboratory test (< 90 days) Contraindications to enoxaparin therapy, including prior heparin‐induced thrombocytopenia and known hypersensitivity Current use of dual antiplatelet therapy Participation in other interventional studies over the past 30 days Non‐compliance or inability to adhere to treatment or lack of a family environment or support system for home treatment
Interventions	Intervention: enoxaparin 40 mg/0.4mL syringe daily sc for 14 days Control: standard of care (no thromboprophylaxis)
Outcomes	Planned and reported primary outcomes Hospitalisations (time frame: 30 days) All‐cause death (time frame: 30 days) Planned and reported secondary outcomes Number of cardiovascular events (time frame: within 14 days, 30 days, and 90 days of randomisation) including DVT (including catheter‐associated), PE, myocardial infarction/myocarditis, arterial ischaemia including mesenteric and extremities, acute splanchnic vein thrombosis, or ischaemic stroke Any hospitalisations (time frame: within 14 days, 30 days, and 90 days of randomisation) All‐cause death (time frame: within 14 days, 30 days, and 90 days of randomisation) Net clinical benefit (time frame: within 14 days, 30 days, and 90 days of randomisation) measured by number of cardiovascular events, and major bleeding Disseminated intravascular coagulation (time frame: within 14 days, 30 days, and 90 days of randomisation) ISTH criteria, in‐hospital diagnosis
Funding	National Research Programme COVID‐19, University Hospital Zurich, University of Zurich, Dr‐Ing Georg Pollert, Johanna Dürmüller‐Bol Foundation
Declaration of interest	SB reports institutional research grants from Concept Medical, Bard, Bentley, Boston Scientific, INARI, Sanofi, and Bayer; and personal fees from Concept Medical, Bayer, Boston Scientific, and INARI. BG reports non‐financial support and funding for an accredited continuing medical education programme from Axonlab and Thermo Fisher Scientific; personal fees and funding for an accredited continuing medical education programme from Alnylam, Pfizer, and Sanofi; funding for an accredited continuing medical education programme from Bayer, Bristol Myers Squibb, Daiichi‐Sankyo, Takeda, Octapharma, SOBI, Janssen, Novo Nordisk, Mitsubishi Pfizer, Tanabe Pharma, outside the submitted work. SVK reports grants or contracts from Bayer AG; consulting fees from Bayer, Daiichi‐Sankyo, and Boston Scientific; and payment or honoraria from Bayer, INARI Medical, MSD, Pfizer, and Bristol Myers Squibb. SS reports research grants from Edwards Lifesciences to the institution, research grants from Medtronic to the institution, research grants from Boston Scientific to the institution, research grants from Abbott to the institution, personal fees from Boston Scientific, Teleflex, BTG ‐Boston Scientific outside the submitted work. HRE reports speaker honoraria from Daiichi‐Sankyo and Bayer. DS reports employment by Sanofi‐Aventis Switzerland. DD reports research support from German Research Foundation, CytoSorbents, Haemonetic; consulting and speaker's fees from Bayer Healthcare, Daiichi‐Sankyo, LEO Pharma, AstraZeneca, Boston Scientific, and BMS‐Pfizer. NK reports institutional research grants from Concept Medical, Bard, Bentley, Boston Scientific, INARI, Sanofi, and Bayer; and personal fees from Concept Medical, Bayer, Boston Scientific, and INARI
Notes	Quote: "The funder of the study had no role in study design, data collection, management, data analysis, data interpretation, or writing of the report." Comment: information from study article
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The randomisation sequence was computer‐generated and integrated into the electronic data capture software RedCAP (Vanderbild University, version 9.1.24)." Comment: information from the study article
Allocation concealment (selection bias)	Low risk	Quote: "Eligible participants underwent block‐stratified randomisation (by age group 50 – 70 vs > 70 years and by study centre) in a 1:1 ratio to receive either enoxaparin or standard of care (no thromboprophylaxis). " Quote: ''Participants and study personnel were aware of treatment allocation, but not of the allocation sequence." Comment: information from the study article
Blinding of participants and personnel (performance bias)	High risk	Quote: 'Participants and study personnel were aware of treatment allocation, but not of the allocation sequence.' Comment: information from the study article
Blinding of outcome assessment (detection bias)	Unclear risk	Quote: 'An independent data and safety monitoring board (DSMB) composed of a vascular medicine specialist, a respiratory physician, and a clinical biostatistician monitored the trial.' Quote: 'At the beginning of the study, the sponsor planned independent monitoring of the trial in collaboration with the deputed division of the Clinical Trial Centre of the University Hospital Zurich. Monitoring was done remotely during the lockdown periods, or by visiting study sites thereafter, and consisted of a site initiation visit followed by regular visits based on the number of patients enrolled.' Comment: information from the study article
Incomplete outcome data (attrition bias) All outcomes	Low risk	Between Aug 15, 2020 and Jan, 14, 2022, from 3319 participants prescreened, 475 with acute symptomatic COVID‐19 scheduled for an ambulatory treatment were enrolled in the trial and randomly assigned to receive prophylactic‐dose enoxaparin versus standard of care (no anticoagulation). Quote: 'The final intention‐to‐treat population consisted of 472 patients: 234 received enoxaparin and 238 no thromboprophylaxis.' Comment: information from the study article
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 as prespecified
Other bias	Low risk	We did not find other bias in the study.