Sadeghipour 2021.

Study characteristics
Methods	Study design: multicentre, open‐label with blinded outcomes adjudication, investigator‐sponsored, 2‐armed, 2 × 2 factorial design, phase IV, parallel‐assignment RCT Type of publication: peer‐reviewed publication Setting and dates: hospital, 29 July 2020‐19 November 2020 Country: Iran Language: English Number of centres: 10
Participants	600 participants randomised (experimental (higher dose anticoagulation) = 299; comparator (prophylactic anticoagulation) = 299), 562 participants analysed (experimental = 276; comparator = 286), 38 participants were lost to follow‐up (experimental/comparator): withdrew consent and declined to contribute data (15/13), duplicate entry (1/1), did not meet eligibility criteria (1/0), did not receive at least 1 dose of the assigned treatment (4/0) Mean age (years) ± SD: 61.23 ± 14.68 (experimental); 59.66 ± 17.88 (comparator) Gender (male/female): 162/114 (experimental), 163/123 (comparator) Severity of condition (experimental/comparator): systolic blood pressure < 100 mmHg at the time of randomisation 25/33, vasopressor agent support within 72 h of enrolment 63/64, FiO2 > 50% at the time of randomisation 112/122, acute physiology and chronic health evaluation II score at the time of randomisation 8/8 Acute respiratory support (experimental/comparator): nasal cannula 10/14, face mask 33/27, reservoir mask 76/96, high‐flow nasal cannula 9/6, non‐invasive positive pressure ventilation 93/85, invasive positive‐pressure ventilation (endotracheal intubation) 55/58 Comorbidities (experimental/comparator): hypertension 131/118, diabetes 82/73, hyperlipidaemia 75/68, coronary artery disease 45/33, obstructive airway disease 23/16, heart failure 7/6, ischaemic cerebrovascular accidents 6/11, hemorrhagic stroke 0/0, VTE 0/0 Confounding factors: surgery (NR), cancer (NR) BMI (kg/m²), mean ± SD: 26.73 ± 3.50 (experimental), 26.86 ± 3.57 (comparator) Anticoagulation before randomisation (experimental/comparator): prophylactic anticoagulation NR, therapeutic anticoagulation 0/0 Baseline medication (experimental/comparator): aspirin 91/81, platelet ADP P2Y12 receptor inhibitors 7/6 Inclusion criteria for anticoagulation hypothesis Adult patients (≥ 18 years), with PCR‐confirmed COVID‐19 admitted to ICU within 7 days of initial hospitalisation, who do not have another firm indication for anticoagulation (such as mechanical valve, high‐risk atrial fibrillation, VTE, or left ventricle thrombus, who are not enrolled in another blinded randomised trial, and are willing to participate in the study and provide informed consent Estimated survival of at least 24 h at the discretion of enrolling physician Exclusion criteria for anticoagulation hypothesis Weight < 40 kg Overt bleeding at the day of enrolment Known major bleeding within 30 days (according to the Bleeding Academic Research Consortium (BARC) definition) Platelet count < 50,000/μL Pregnancy (as confirmed by Beta HCG testing among female patients < 50 years) Patients on ECMO History of heparin‐induced thrombocytopenia or immune thrombocytopenia Ischemic stroke within the past 2 weeks Craniotomy/major neurosurgery within the past 3 months Major head or spinal trauma in the past 30 days Known brain metastases or vascular malformations (aneurysm) Presence of an epidural, spinal or pericardial catheter Major surgery other than neurosurgery within 14 days prior to enrolment Coexistence of severe obesity (weight > 120 kg or BMI > 35 kg/m² along with severe renal insufficiency defined as CrCl < 30 mL/s) Allergic reaction to study medications Lack or withdrawal of informed consent
Interventions	Experimental: intermediate‐dose anticoagulation (enoxaparin, 1 mg/kg daily), with modification according to body weight and CrCl Comparator: standard prophylactic anticoagulation (enoxaparin, 40 mg daily), with modification according to body weight and CrCl Concomitant therapy (experimental/comparator): antiviral therapy 226/217, remdesivir 168/170, favipiravir 52/43, lopinavir/ritonavir 3/3, atazanavir/ritonavir 27/19, corticosteroid use 262/262, renin‐angiotensin‐aldosterone system inhibitors 78/74, tocilizumab 34/40
Outcomes	Primary (specified) Composite of adjudicated acute VTE, arterial thrombosis, treatment with ECMO, or all‐cause mortality Primary (collected) Composite of adjudicated acute VTE, arterial thrombosis, treatment with ECMO, or all‐cause mortality Secondary (specified) Rate of all‐cause mortality Rate of objectively‐confirmed VTE Ventilator‐free days Rate of major bleeding Rate of clinically‐relevant non‐major bleeding Rate of severe thrombocytopenia Rate of rise in liver enzymes Clinically‐diagnosed myopathy Objectively‐confirmed arterial thrombosis. Imaging‐confirmed acute arterial thrombosis (by ultrasonography, CT, MRI, or invasive angiography) Secondary (collected) All‐cause mortality Adjudicated VTE Ventilator‐free days Objectively clinically diagnosed type I acute myocardial infarction Objectively clinically diagnosed stroke Objectively clinically diagnosed acute peripheral arterial thrombosis ICU length of stay Patients discharged from the ICU Incident atrial fibrillation New in‐hospital kidney replacement therapy Major bleeding Clinically relevant non‐major bleeding Composite of major and non‐major bleeding Thrombocytopenia Time points reported: at 30 and 90 days after the start of the intervention
Notes	Sponsor/funding: quote "The study was funded by the Rajaie Cardiovascular Medical and Research Center. Some study authors, including the lead author, are affiliated with the Rajaie Cardiovascular Medical and Research Center. Enoxaparin was provided through Alborz Darou, Pooyesh Darou, and Caspian Pharmaceuticals companies, and atorvastatin and matching placebo was provided by Sobhan Darou. None of these companies were study sponsors. Neither the founder, nor the companies who donated the study drugs (Alborz Darou, Pooyesh Darou and Caspian Pharmaceuticals) had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication." COIs: the major study authors declared financial relationship with the industry. Trial registration number: NCT04486508
Item	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Yes	Quote "Randomization was done using an electronic web‐based system with permuted blocks of 4 and allocation sequence concealment."
Allocation concealment (selection bias)	Yes	Quote "For the first hypothesis, allocation sequence concealment and blinded endpoint adjudication."
Blinding of participants and personnel (performance bias)	No	Quote "an open‐label randomised clinical trial with blinded outcome adjudication."
Blinding of outcome assessment (detection bias)	Yes	Quote "an open‐label randomised clinical trial with blinded outcome adjudication."
Incomplete outcome data (attrition bias)	Yes	The losses were balanced between the groups (experimental = 24 (8%); comparator = 14 (4%))
Selective reporting (reporting bias)	Yes	All prespecified outcomes were reported.
Other bias	Yes	We do not suspect any other bias related to this study.