Covid-19 living Data

Therapeutic anticoagulant vs Prophylactic anticoagulant (RCT)

Hospitalized patients

FOREST PLOTS -2022-04-29

Studies description

Trial NCT02735707, NCT04505774, NCT04359277, NCT04372589
Publication Goligher E, N Engl J Med (2021) (published paper)
Dates: 2020-04-21 to 2020-12-19
Funding: Mixed (Multiple funders, internationally, with multiple regional sponsors)
Conflict of interest: *

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Australia, Brazil, Canada, Ireland, Mexico, Netherlands, New Zealand, Saudi Arabia, UK, USA Follow-up duration (days): 90
Inclusion criteria	Adult hospitalized for Covid-19 infection confirmed by laboratory testing patients with severe Covid-19 Severe Covid-19 was defined as Covid-19 that led to receipt of ICU-level respiratory or cardiovascular organ support (oxygen through a highflow nasal cannula, noninvasive or invasive mechanical ventilation, extracorporeal life support, vasopressors, or inotropes) in an ICU receipt of ICU-level organ support, irrespective of hospital setting, was used to define ICU-level care (ACTIV-4a).
Exclusion criteria	admitted to the ICU with Covid-19 for more than 48 hours (REMAP-CAP) or to hospital for more than 72 hours (ACTIV-4a, ATTACC) prior to randomization at imminent risk of death without an ongoing commitment to full organ support at high risk of bleeding receiving dual antiplatelet therapy had a separate clinical indication for therapeutic anticoagulation history of heparin sensitivity including heparin-induced thrombocytopenia
Interventions
	Treatment Therap UFH Therapeutic anticoagulation according to local practice (IV unfractionated heparin or SC low molecular weight heparin) for up to 14 days or until hospital discharge or liberation from the need for supplemental oxygen, whichever comes first For UFH, suggested target for aPTT of 1.5 to 2.5 times the upper limit of normal or therapeutic anti-Xa levels Low molecular weight heparin dosed according to patient weight and creatinine clearance.
	Control Prophylactic AC Standard thromboprophylaxis according to local practice (enoxaparin, dalteparin, tinzaparin, fondaparinux, or heparin) for up to 14 days or until hospital discharge or liberation from the need for supplemental oxygen, whichever comes first
Participants
	Randomized participants : Therap UFH=591 Prophylactic AC=616
	Characteristics of participants N= 1207 Mean age : NR 772 males Severity : Mild: n=* / Moderate: n=* / Severe: n=773 Critical: n=315
Primary outcome
	In the register For the mpRCT, organ support-free days (OSFD). The endpoint is the number of days, out of the first 21 days after randomization, that a patient is alive and free of ICU-level organ support.
	In the report Organ support-free days (OSFDs), an ordinal scale composed of survival to hospital discharge and, in survivors, the number of days free of organ support to day 21
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published/pre-print article, the study registries, protocol, and statistical analysis plan were used in data extraction and risk of bias assessment. The article reports preliminary results for the severe/critical subgroup of patients in three international adaptive platform trials with harmonized protocols that evaluated the effect of an anticoagulation protocol using predominantly therapeutic dosing versus standard anticoagulation using predominantly prophylactic dosing. The three trials were REMAP-CAP (NCT02735707), ACTIV-4a (NCT04505774 and NCT04359277), and ATTACC (NCT04372589). The individual trial registries reflect each trial’s individual primary objectives, while the harmonized protocol reflects the objectives of this comparison. There were no major differences in population, procedures and intervention between the protocol and the published/pre-print article, and the outcomes reported are appropriate for a preliminary report. Recruitment of severe/critical patients was halted after interim analysis revealed futility. On 12th of August, 2021, this study was updated based on the published report.

Trial NCT02735707, NCT04505774, NCT04359277, NCT04372589
Publication Lawler PR, N Engl J Med (2021) (published paper)
Dates: 2020-04-21 to 2021-01-22
Funding: Mixed (Canadian Institutes of Health Research, LifeArc Foundation, Thistledown Foundation, Research Manitoba, Ontario Ministry of Health, Peter Munk Cardiac Centre, Cancercare Manitoba Foundation, Victoria General Hospital Foundation, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, National Institutes of Health (NIH), European Union, Australian National Health and Medical Research Council, Health Research Council of New Zealand, U.K. NIHR, NIHR Imperial Biomedical Research Centre, Health Research Board of Ireland, UPMC Learning While Doing Program, Breast Cancer Research Foundation, French Ministry of Health, the Minderoo Foundation, Amgen, Eisai, Global Coalition for Adaptive Research, Wellcome Trust.)
Conflict of interest: *

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Australia, Brazil, Canada, Mexico, Nepal, Netherlands, Spain, UK, USA. Follow-up duration (days): 90
Inclusion criteria	Adults hospitalized for Covid-19 (≥18 years in ACTIV-4a and ATTACC, not specified in REMAP-CAP) Suspected or confirmed SARS-CoV-2 infection with intent to test for COVID-19 in REMAP-CAP, confirmed SARS-CoV-2 infection in ACTIV-4a and ATTACC expected hospital LOS > 48 hours in REMAP-CAP, expected hospital LOS ≥ 72 hours in ACTIV-4a and ATTACC <48 hours from admission in REMAP-CAP, <72 hours in ACTIV-4a and ATTACC. If the patient is already hospitalized and the COVID-19 diagnosis is due to an outbreak or an incidental finding, then enrollment can occur within 72 hours of a clinical syndrome attributable to COVID-19 that requires continued hospitalization (e.g. new or worsening oxygen requirements or acute kidney injury) which is further anticipated to extend the hospital admission by an additional 72 hours from randomization patients with moderate Covid-19 Moderate disease severity was defined as hospitalization for Covid-19 without the need for ICU-level care (oxygen delivered by high-flow nasal cannula, noninvasive or invasive mechanical ventilation, or the use of vasopressors or inotropes)
Exclusion criteria	Discharge expected within 48 hours (REMAP-CAP) or 72 hours (ACTIV-4a and ATTACC) clinical indication for therapeutic anticoagulation high risk for bleeding required dual antiplatelet therapy history of heparin allergy including heparin-induced thrombocytopenia.
Interventions
	Treatment Therap UFH Therapeutic dose low molecular weight or unfractionated heparin administered according to local protocols used for the treatment of acute venous thromboembolism for up to 14 days or until recovery.
	Control Prophylactic AC Prophylactic dose low molecular weight or unfractionated heparin administered according to local practice.
Participants
	Randomized participants : Therap UFH=1190 Prophylactic AC=1054
	Characteristics of participants N= 2244 Mean age : NR 1310 males Severity : Mild: n=* / Moderate: n=* / Severe: n=98 Critical: n=0
Primary outcome
	In the register ATTACC/ACTIV-4 - The primary endpoint in the trial is days alive and free of organ support at day 21. This endpoint is defined as the number of days that a patient is alive and free of organ support through the first 21 days after trial entry. Organ support is defined as receipt of invasive or non-invasive mechanical ventilation, high flow nasal oxygen (>30 L/min), vasopressor therapy, or ECMO support. Death at any time (including beyond 21 days) during the index hospital stay is assigned the worst possible score of -1. REMAP-CAP - All-cause mortality [ Time Frame: Day 90 ] ; Days alive and not receiving organ support in ICU [ Time Frame: Day 21 ]
	In the report Organ support–free days, evaluated on an ordinal scale that combined in-hospital death and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published/pre-print article, the trial registries, protocol and statistical plan for the multi-platform RCT and supplementary appendices were used in data extraction and assessment of risk of bias. The study reports results from three adaptive randomized controlled trial protocols evaluating therapeutic-dose anticoagulation with heparin versus standard care anticoagulation in patients hospitalized for Covid-19 that were integrated into a single multi-platform RCT. Other than minor differences between the three merged studies, there were no major differences between the combined protocol and trial registries in populations, procedures, interventions or outcomes. Mortality was reported as in hospital mortality by day 90, while time to death was based on survival until hospital discharge. The trial was stopped when prespecified criteria for superiority were met for therapeutic-dose anticoagulation. On 12th of August, 2021, this study was updated based on the published report.

Trial RBR-949z6v
Publication Lemos ACB, Thromb Res (2020) (published paper)
Dates: 2020-04-01 to 2020-07-30
Funding: No specific funding (None)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Single center / Brazil Follow-up duration (days): 28
Inclusion criteria	Age over 18 years-old SARS-CoV-2 infection confirmed by RT-PCR presence of acute respiratory distress syndrome according to the Berlin definition severe clinical presentation with respiratory failure requiring mechanical ventilation D-dimer levels greater than 1000 μg/L prothrombin time/international normalized ratio (INR) < 1.5 activated partial thromboplastin time (aPTT)/ratio < 1.5 platelet count greater than 100,000/mm3.
Exclusion criteria	Age greater than 85 years creatinine clearance < 10 mL/min severe circulatory shock with a dose of norepinephrine higher than 1.0 μg/kg/min chronic renal failure in renal replacement therapy Child B and C chronic liver disease advanced diseases, such as active cancer, heart failure chronic obstructive pulmonary disease using home oxygen advanced dementia significant disability from stroke or severe head injury cardiorespiratory arrest pregnant women major surgery or severe trauma in the last 3 weeks stroke in the last 3 months active bleeding blood dyscrasia such as hemophilia Von Willebrand factor deficiency participation in another clinical investigation indication for therapeutic anticoagulation due to pulmonary embolism acute coronary syndrome.
Interventions
	Treatment Therap EX 1 mg/kg subcutaneously twice a day (maximum 140 mg twice a day) for 4-14 days
	Control Prophylactic AC heparin: 5000 IU subcutaneously 3 times a day (if weight < 120 kg) and 7500 IU 3 times a day (if weight > 120 kg) OR enoxaparin: 40 mg once daily (if weight < 120 kg) and 40 mg twice daily (if weight > 120 Kg) according to the doctor's judgment.
Participants
	Randomized participants : Therap EX=10 Prophylactic AC=10
	Characteristics of participants N= 20 Mean age : NR 16 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=0 Critical: n=20
Primary outcome
	In the register Evaluation of gas exchange between D0 / D4 /D7 /D14 evaluated through the PO2 / FIO2 ratio; days without mechanical ventilation (within 28 days of follow-up, how many days were out of mechanical ventilation, if the patient dies before 28 days of foll
	In the report Variation in gas exchange over time evaluated through the ratio of partial pressure of arterial oxygen (PaO2) to the fraction of inspired oxygen (FiO2) at baseline, 7, and 14 days after randomization
Documents avalaible	Protocol Yes. In language other than English Statistical plan NR Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published study report, the protocol (available in Portuguese) and trial registry were used in data extraction and assessment of risk of bias. The study differed from its original protocol in that there are only two arms in the reported trial whereas three were intended, but the authors are transparent about this, stating the reason for the abandonment of the third arm. The reported study achieved the sample size proposed in the protocol. Whereas the protocol stated that Enoxaparin may be extended up to 7-10 days at the discretion of the medical team, the published article reports maintaining treatment for up to 14 days. There were no substantive differences in outcomes between the registry or protocol and the published study report.

Trial NCT04394377
Publication ACTION - Lopes RD, Lancet (2021) (published paper)
Dates: 2020-06-24 to 2021-02-26
Funding: Mixed (Coalition COVID-19 Brazil, Bayer SA.)
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Brazil Follow-up duration (days): 60
Inclusion criteria	Hospitalised ≥ 18 years old confirmation of COVID-19 based on specific tests used in clinical practice (RT-PCR, antigen test, or IgM test) symptoms for up to 14 days before randomization elevated D-dimer concentration (above the upper limit of normal reference range per local laboratory).
Exclusion criteria	Indication for therapeutic anticoagulation during inclusion (e.g, diagnosis of VTE, AF, mechanical valve prosthesis) Platelets <50,000 /mm3 Use of ASA >100 mg Use of P2Y12 inhibitor (clopidogrel, prasugrel, ticagrelor) Chronic use of NSAIDs Sustained uncontrolled systolic BP ≥180 mm Hg or diastolic BP ≥100 mm Hg INR >1·5 Patients contraindicated to therapeutic anticoagulation (active bleeding, liver failure, blood dyscrasia or prohibitive haemorrhage risk as evaluated by the investigator) Patients with DIC History of haemorrhagic stroke or any intracranial bleeding at any time in the past or current intracranial neoplasm (benign or malignant), cerebral metastases, arteriovenous malformation, or aneurysm Active cancer (excluding non-melanoma skin cancer) defined as cancer not in remission or requiring active chemotherapy or adjunctive therapies such as immunotherapy or radiotherapy Hypersensitivity to rivaroxaban Use of strong inhibitors of cytochrome P450 (CYP) 3A4 and/or P-gp (e.g., protease inhibitors, ketoconazole, itraconazole) and/or use of P-gp and strong CYP3A4 inducers (including, but not limited to, rifampin/rifampicin, rifabutin, rifapentine, phenytoin, phenobarbital, carbamazepine, or St. John's Wort) Known HIV infection Creatinine clearance <30 mL/min Pregnancy or breastfeeding.
Interventions
	Treatment Therap AC Clinically stable patients: PO rivaroxaban, 20 mg once daily (15 mg once daily if reduced creatinine clearance). Clinically unstable patients: SC enoxaparin 1 mg/kg twice per day, or IV unfractionated heparin at a dose to achieve anti-Xa concentration or partial thromboplastin time targets. Unfractionated heparin preferred option for patients with renal dysfunction or disseminated intravascular coagulation. Treatment to day 30.
	Control Prophylactic AC Standard IV thromboembolism prophylaxis with enoxaparin or unfractionated heparin during hospitalisation and extended at the discretion of the treating physician.
Participants
	Randomized participants : Therap AC=311 Prophylactic AC=304
	Characteristics of participants N= 615 Mean age : NR 368 males Severity : Mild: n=155 / Moderate: n=369 / Severe: n=53 Critical: n=38
Primary outcome
	In the register Hierarchical composite endpoint composed of mortality, number of days alive, number of days in the hospital and number of days with oxygen therapy at the end of 30 days. [ Time Frame: In 30 days ]
	In the report Hierarchical composite of time to death, duration of hospitalisation, or duration of supplemental oxygen use through 30 days; Major or clinically relevant non-major bleeding
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the registry, published and unpublished protocols and statistical analysis plan, and supplementary appendices were used in data extraction and assessment of risk of bias. The WHO 8-point ordinal scale (on which data extracted were based) was not in the registry or first version of the study protocol, but was added in an approved amendment to the protocol within 2 weeks of start of recruitment. There were no differences between the protocol and the published article in populations, procedures or interventions. The study achieved its pre-specified target sample size.

Trial NCT04604327
Publication Marcos M, Thromb Haemost (2021) (published paper)
Dates: 2020-10-26 to 2021-05-30
Funding: Mixed (This trial was an investigator-initiated study. Laboratorios Farmacéuticos ROVI kindly provided the study drugs, but did not participate in any other step of the clinical trial process.)
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Spain Follow-up duration (days): 30
Inclusion criteria	Age 18 or older Hospitalization at the conventional ward due to mild or moderate (CURB65 90%) COVID-19 pneumonia. Maximum allowed time between hospitalization and randomization is 48 hours 3-4 points according to the WHO ordinal scale Confirmed COVID-19 diagnosis by PCR or other validated test Baseline D-Dimer >500 ng/mL Signed informed consent The patient, according to investigator’s opinion, is able to deal with all the requirements of the clinical trial
Exclusion criteria	Need of intensive care unit admission Moderate or severe adult respiratory distress syndrome Body weight <50Kg Creatinine clearance (Cockroft-Gault) <30ml/min Severe liver disease (elevation of hepatic enzymes 3 times above the upper limit of normal) Thrombocytopenia <75,000/mm3 History of coagulopathy or thrombocytopathy Active bleeding of increased bleeding risk due to impairment of haemostasis Recent (1 month) central nervous system o gastrointestinal bleeding Lesions of surgery involving central nervous system, eyes or inner ear in the last 2 months Presence of organic lesions with high bleeding risk (e.g. active peptic ulcer, hemorragic, stroke, brain aneurism or tumor) Planned surgery or interventional procedure requiring regional anesthesia Uncontrolled arterial hypertension Acute or subacute bacterial endocarditis Need of therapeutic anticoagulation for other reasons (e.g. atrial fibrillation, valvular prosthesis, venous thromboembolism) Need of antiplatelet therapy Simultaneous participation in another clinical trial (use of drugs against COVID-19 in the setting of local clinical management protocols is allowed) Previous history of heparin-induced thrombocytopenia Hypersensitivity or allergy to sodic bemiparin, heparin, compounds of porcine origin or any of the excipients
Interventions
	Treatment Therap AC 115 IU/Kg subcutaneously, adjusted to body weight (7,500 IU for patients between 50-70 Kg; 10,000 IU for patients weighing >70-100 Kg; 12,500 IU for patients who weighed >100 Kg) once a day for 10 days (extended at the discretion of the treating physician)
	Control Prophylactic AC 3,500 IU subcutaneously once a day for 10 days (extended at the discretion of the treating physician)
Participants
	Randomized NR Analyzed 65 participants Prophylactic AC=33 Therap AC=32
	Characteristics of participants N= 65 Mean age : NR 41 males Severity : Mild: n=27 / Moderate: n=38 / Severe: n=0 Critical: n=0
Primary outcome
	In the register Clinical deterioration [ Time Frame: 10 days ] Combined outcome that includes number of patients who suffer any of the following: Death, ICU admission, mechanical ventilatory support, progression to moderate or severe ARDS (according to Berlin criteria) or arterial or venous thrombosis.
	In the report Composite of death, ICU admission, need of mechanical ventilation support, development of moderate/severe acute respiratory distress syndrome and venous or arterial thrombosis within 10 days of enrollment
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	High
General comment	In addition to the published article, the study registry was used in data extraction and risk of bias assessment. Neither protocol nor statistical analysis plan was available. There is no change from the trial registration in the intervention and control treatments. he primary outcome in the article reflects the primary outcome in the registry. The secondary outcomes in the article were not included in the registry. Recruitment to the study was terminated after an interim analysis, conducted at 40% of target sample size, because of both slow recruitment and futility. As a result the trial did not achieve its target sample size (164 versus 65).

Trial 0112U001413 (Ukraine)
Publication Oliynyk O, Life (2021) (published paper)
Dates: 2020-07-01 to 2021-03-01
Funding: Public/non profit (Ministry of Science and Higher Education in Poland)
Conflict of interest: No

Methods
	RCT
	Location : Single center / Ukraine Follow-up duration (days): 28
Inclusion criteria	Confirmed SARS-CoV-2 infection (confirmed with a positive reverse transcription polymerase chain reaction (RT PCR) test) Presence of bilateral interstitial pneumonia on a computed tomography (CT) scan Respiratory failure with arterial partial pressure of oxygen (PaO2) < 60 mm Hg with room air D-dimer level > 3 mg/L Platelet count < 120 × 109/L Informed consent of the patient or their legal representative to participate in the study
Exclusion criteria	Respiratory failure requiring intubation prior to enrolment Hypersensitivity to enoxaparin sodium or unfractionated heparin History of heparin-induced type-II thrombocytopenia caused by the use of unfractionated heparin or low-molecular-weight heparin Clinically significant active bleeding Creatinine clearance (Cockcroft-Gault formula) < 30 mL/min Unstable arterial hypertension (systolic pressure > 180 mmHg or diastolic pressure > 110 mmHg) Pulmonary embolism (PE) confirmed by a CT pulmonary angiography Pregnancy or breastfeeding Participation in other clinical studies
Interventions
	Treatment Therap LMWH 100 IU/kg/day subcutaneously twice a day until D-dimer normalized Therap UFH Initial dose: 80 U/kg/h intravenously; Maintenance dose: 18 U/kg/h intravenously until the D-dimer values normalized
	Control Prophylactic AC 50 IU/kg/day subcutaneously once a day until D-dimer normalized
Participants
	Randomized participants : Prophylactic AC=42 Therap LMWH=42 Therap UFH=42
	Characteristics of participants N= 126 Mean age : NR 76 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=0 Critical: n=126
Primary outcome
	In the register NR
	In the report NR
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	Only the published article was used in data extraction and risk of bias assessment. The protocol, statistical analysis plan and study registry were not available. There is no information on whether the study achieved the target sample size or if the interventions, control treatments or outcomes were determined a-priori. Of note, 4 patients in the UFH (control) group were withdrawn from the study due to adverse events and provided with LMWH (treatment), but there was no information on which LMWH treatment arm they were moved to or which group they were analyzed in.

Trial *
Publication Rashidi F, Thromb Res (2021) (published paper)
Dates: 2020-09-01 to 2021-04-30
Funding: Not reported/unclear
Conflict of interest: No

Trial NCT04362085; NCT04444700
Publication RAPID - Sholzberg M, BMJ (2021) (published paper)
Dates: 2020-05-29 to 2021-04-12
Funding: Public/non profit (Task 54, Department of National Defence; St. Michael’s Hospital Foundation; St. Joseph’s Health Centre Foundation; 2020 TD Community Health Solutions Fund – COVID-19 Research Grant; Michael Garron Hospital; The Ottawa Hospital Foundation COVID-19 Emergency Response Fund; INVENT Kickstarter Award; Science Foundation Ireland, Enterprise Ireland, IDA Ireland COVID-19 Rapid Response Funding; SEAMO COVID-19 Innovation Fund; National Institute of General Medical Sciences, NIH; University of Vermont Medical Center Fund Grant; King Saud University)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Brazil, Canada, Ireland, Saudi Arabia, UAE, USA Follow-up duration (days): 28
Inclusion criteria	Patients moderately ill admitted to hospital wards for covid-19 with laboratory confirmed SARS-CoV-2 infection Increased D-dimer levels within the first five days of admission (D-dimer levels were required to be above the upper limit of normal of the local hospital) Not already mechanically ventilated, and not imminently requiring mechanical ventilation or critical care Presence of an oxygen saturation ≤93% on room air, or ≥2 times the upper limit of normal irrespective of oxygen saturation.
Exclusion criteria	Participants with substantial bleeding risks An absolute indication for or any contraindication to heparin anticoagulation based on care team judgment Pregnant Already experienced, or would imminently experience any component of the primary outcome (all cause death, non-invasive or invasive mechanical ventilation, or ICU admission).
Interventions
	Treatment Therapeutic Heparin Creatinine clearance ≥30 + BMI <40: - Enoxaparin 1 mg/kg SC every 12 hours OR 1.5 SC mg/kg every 24 hours; - Dalteparin 200 units/kg SC every 24 hours OR 100 IU/kg SC every 12 hours; - Tinzaparin 75 U/kg SC every 24 hours; - unfractionated heparin IV bolus, with continuous infusion to titrate to institution specific anti-Xa or aPTT values. Creatinine clearance ≥30 + BMI ≥40: - Enoxaparin 1 mg/kg every 12 hours; - Dalteparin 100 units/kg SC every 12 hours; - Tinzaparin 175 U/kg SC daily; - unfractionated heparin IV bolus, with continuous infusion to titrate to institution specific anti-Xa or aPTT values. Creatinine clearance <30: - UFH IV bolus, with continuous infusion to titrate to institution specific anti-Xa or aPTT values or LMWH per hospital protocol. Administered until hospital discharge, death, day 28 or study withdrawal.
	Control Prophylactic Heparin Creatinine clearance ≥30 + BMI <40: - Enoxaparin 40 mg SC every 24 hours; - Dalteparin 5000 units SC q24h; - Tinzaparin 4500 U SC every 24 hours; - Fondaparinux 2.5 mg SC every 24 hours; - Unfractionated Heparin 5000 units SC every 8-12 hours. Creatinine clearance ≥30 + BMI ≥40: - Enoxaparin 40 mg SC every 24 hours; - Dalteparin 5000 units SC every 12 hours; - Tinzaparin 9000 (+/- 1000) U SC every 24 hours; - Unfractionated Heparin 7000 units SC every 8 hours. Creatinine clearance <30 + BMI <40: - UFH 5000 units SC every 8-12 hours or LMWH per hospital protocol. Creatinine clearance <30 + BMI ≥40: - UFH 7500 units SC every 8 hours or LMWH per hospital protocol. Administered until hospital discharge, death, day 28 or study withdrawal.
Participants
	Randomized participants : Therapeutic Heparin=228 Prophylactic Heparin=237
	Characteristics of participants N= 465 Mean age : NR 264 males Severity : Mild: n=* / Moderate: n=* / Severe: n=* Critical: n=0
Primary outcome
	In the register Composite outcome of ICU admission (yes/no), non-invasive positive pressure ventilation (yes/no), invasive mechanical ventilation (yes/no), or all-cause death (yes/no) up to 28 days. [ Time Frame: up to 28 days ]
	In the report Composite of ICU admission, non-invasive (bilevel or continuous positive airway pressure) or invasive mechanical ventilation, or death up to 28 days
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the pre-print, study registries, protocol, supplementary appendix and data gained from contact with authors were used in data extraction and risk of bias assessment. There is no change from the trial registration in the intervention and control treatments. The registry primary outcome reflects the reported primary outcome. Quote: "RAPID had an adaptive design. The protocol prespecified that the sample size would be increased if the conditional power at 75% of the original sample size was between 60 and 80%.21 However, the conditional power was below 60%, therefore the sample size was not increased, thus RAPID remained underpowered." The study was updated on the November 24th, 2021 after the published article. The study was updated on the April 25th, 2022 after contact with the authors.

Trial NCT04401293
Publication Spyropoulos A, JAMA Intern Med (2021) (published paper)
Dates: 2020-05-08 to 2021-05-14
Funding: Public/non profit (Feinstein Institutes for Medical Research, the Broxmeyer Fellowship in Clinical Thrombosis, and grant R24AG064191 from the National Institute on Aging)
Conflict of interest: Yes

Methods
	RCT Blinding: single blinding
	Location : Multicenter / USA Follow-up duration (days): 30
Inclusion criteria	Hospitalized nonpregnant adults 18 years or older with COVID-19 diagnosed by nasal swab or serologic testing requirement for supplemental oxygen per investigator judgment and plasma D-dimer level greater than 4 times the upper limit of normal based on local laboratory criteria or a sepsis-induced coagulopathy score of 4 or greater
Exclusion criteria	Physician-determined need for full-dose anticoagulation or dual antiplatelet therapy bleeding within the past month active gastrointestinal or intracranial cancer bronchiectasis or pulmonary cavitation hepatic dysfunction with baseline international normalized ratio greater than 1.5 creatinine clearance (CrCl) less than 15 mL/min/1.73 m2 platelet count less than 25 000/μL a history of heparin-induced thrombocytopenia (HIT) within 100 days and hypersensitivity/intolerance to study drug or components
Interventions
	Treatment Therap AC 1 mg/kg subcutaneously twice daily if CrCl was 30 mL/min/1.73 m2 or greater or 0.5 mg/kg twice daily if CrCl was 15-29 mL/min/1.73 m2. Postdischarge anticoagulation allowed at the discretion of treating physicians.
	Control Intermediate dose Unfractionated heparin ≤ 22 500 IU subcutaneously daily; enoxaparin, 30 mg or 40 mg subcutaneously once or twice daily; dalteparin 2500 IU or 5000 IU subcutaneously daily. If CrCl fell below 15 mL/min/1.73 m2, enoxaparin was converted to treatment-dose intravenous UFH until CrCl >15 mL/min/1.73 m2. Postdischarge anticoagulation allowed at the discretion of treating physicians.
Participants
	Randomized participants : Therap AC=130 Intermediate dose=127
	Characteristics of participants N= 257 Mean age : NR 136 males Severity : Mild: n=* / Moderate: n=192 / Severe: n=39 Critical: n=13
Primary outcome
	In the register Composite outcome of arterial thromboembolic events, venous thromboembolic events and all-cause mortality at Day 30 ± 2 days. [ Time Frame: Day 30 ± 2 days ] Risk of arterial thromboembolic events (including myocardial infarction, stroke, systemic embolism), venous thromboembolism (including symptomatic deep vein thrombosis (DVT) of the upper or lower extremity, asymptomatic proximal DVT of the lower extremity, non-fatal pulmonary embolism (PE)), and all-cause mortality at Day 30 ± 2 days.
	In the report VTE (symptomatic upper or lower extremity deep vein thrombosis, asymptomatic lower extremity proximal deep vein thrombosis, symptomatic pulmonary embolism, splanchnic vein thrombosis, or cerebral sinus thrombosis), or ATE (myocardial infarction, ischemic stroke, peripheral or systemic ATE) or death from any cause within 30 ± 2 days after randomization
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: N
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the registry, published and full protocols with statistical analysis plan and supplementary appendices as well as data from contact with authors were used in data extraction and assessment of risk of bias. The primary and secondary outcomes in the article reflected those in the registry. The trial (n = 257) achieved its target sample size (n = 246). There is no change from the trial registration in the intervention and control treatments. The study was updated on the March 28th, 2022 with data from authors.

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Iran Follow-up duration (days): 30
Inclusion criteria	Adult patients positive SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) assay within 5 days of the index hospitalization without known diagnosis of thrombosis admitted to the ICU with PaO2/FiO2 (P/F) ratios <100 and D-dimer levels >3000 ng/mL.
Exclusion criteria	Hemodynamic instability Estimated life expectancy < 24 hours Pregnancy or breastfeeding Active bleeding and any contraindications for thrombolytic therapy and anticoagulation therapy Allergic reaction to study medications
Interventions
	Treatment tPA Initial dose: 25 mg infused over 2 hr, 25 mg for the next 22 h - followed by UFH until aPTT of 50–70/sec until hospital discharge Therap AC 5000 IU of UFH subcutaneously three times a day until hospital discharge
	Control Prophylactic AC Initial dose: 80 IU/kg UFH - maintenance dose: 18 mg/kg by continuous infusion until aPTT of 50–70/sec until hospital discharge
Participants
	Randomized participants : tPA=5 Therap AC=5 Prophylactic AC=5
	Characteristics of participants N= 15 Mean age : NR 11 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=5 Critical: n=10
Primary outcome
	In the register NR
	In the report P/F ratio improvement during the first 48-h of enrollment
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	Only the published article was used in data extraction and assessment of risk of bias. No registry, protocol or statistical analysis plan was available and so it is not clear whether the primary outcome reported reflected a pre-specified outcome or whether the study achieved a target sample size.