| Study characteristics |
| Methods |
Study design: international multiplatform, adaptive, open‐label, 2‐armed, phase IV, parallel‐assignment RCT Type of publication: 2 preliminary reports by COVID‐19 severity, preprint and 2 published articles Setting and dates: hospital, 21 April 2020‐19 December 2020 (critically ill participants) and 22 January 2021 (moderate‐severity participants) Country: UK, USA, Canada, Brazil, Ireland, Netherlands, Australia, Nepal, Saudi Arabia, and Mexico Language: English Number of centres: 129 listed |
| Participants |
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13,377 participants were assessed for eligibility (3450 randomised)
critically ill: 1205 randomised (1074 analysed, 10.8% lost), experimental (therapeutic anticoagulation = 590 (529 analysed, 10 withdrew consent, 4 outcome not available, 47 SARS‐CoV‐2 not confirmed (10.3% lost)), comparator (prophylactic anticoagulation) = 615 (545 analysed, 15 withdrew consent, 11 outcome not available, 44 SARS‐CoV‐2 not confirmed (11.3% lost)) moderate‐severity: 2245 randomised (2219 analysed, 1.1% lost), experimental (therapeutic anticoagulation = 1190 (1171 analysed, 9 withdrew consent, 1 outcome not available, 9 SARS‐CoV‐2 not confirmed (1.5% lost)), comparator (prophylactic anticoagulation) = 1055 (1048 analysed, 2 withdrew consent, 2 outcome not available, 3 SARS‐CoV‐2 not confirmed (0.6% lost))
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Mean age (years) ± SD:
critically ill: 60.2 ± 13.1 (experimental), 61.6 ± 12.5 (comparator) moderate‐severity: 59.0 ± 14.1 (experimental), 58.8 ± 13.9 (comparator)
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Gender (male/female):
critically ill: 383/149 (experimental), 379/178 (comparator) moderate‐severity: 713/468 (experimental), 597/453 (comparator)
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Severity of condition (experimental/comparator):
critically ill: no oxygen/supplemental oxygen (1.5%/1.3%), high‐flow nasal oxygen (32.3%/33.8%), non‐invasive ventilation (40.2%/35.9%), invasive mechanical ventilation (25.9%/29.1%), vasopressors/inotropes (16.7%/18.2%) moderate‐severity: no oxygen/supplemental oxygen (13.2%/11.7%), low‐flow nasal cannula/face mask (66.8%/66.3), high‐flow nasal cannula (2.1%/2.7), non‐invasive mechanical ventilation (1.8%/2.3%), unspecified (16.1%/17.1%)
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Comorbidities (experimental/comparator):
critically ill: diabetes mellitus (type 1 or 2) 168 (32.1%)/182(33.3%), severe cardiovascular disease 36 (7.3%)/34 (6.6%), chronic kidney disease 56 (11.2%)/40 (8%), chronic respiratory diseased 121(24.1%)/125 (24.2%), chronic liver disease 6(1.2%)/2 (0.4%) moderate‐severity: hypertension 546 (53.4%)/447 (50.1%), diabetes mellitus 352 (29.8%)/311(29.6%), severe cardiovascular disease 123(10.6%)/123 (10.6%), chronic kidney disease 83 (7.1%)/69 (6.7%), chronic respiratory disease 249(22%)/212(21.5%), immunosuppressive disease 105 (9.2%)/103 (10.2%)
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BMI (kg/m²), mean ± SD:
critically ill: 31.06 ± 6.69 (experimental), 30.4 ± 6.09 (comparator) moderate‐severity: 30.26 ± 6.23 (experimental), 30.63 ± 6.08 (comparator)
Anticoagulation before randomisation (experimental/comparator): not described -
Baseline medication (experimental/comparator):
critically ill: antiplatelet agent 36 (7.4%)/42 (8.1%), remdesivir 149 (30.5%)/161 (31.1%), corticosteroids 387 (79.3%)/410 (79.3%), tocilizumab 9 (1.8%)/9 (1.7%) moderate‐severity: antiplatelet agent 148 (13.0%)/111 (11.0%), remdesivir 428 (36.3%)/383 (36.5%), corticosteroids 479 (60.6%)/415 (63.3%), tocilizumab 6 (0.5%)/7 (0.7%)
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D‐dimer (experimental/comparator):
Inclusion criteria
Adults Expected hospital length of stay > 48 h (REMAP‐CAP) or 72 h (ACTIV‐4a, ATTACC) Confirmed or suspected with intent to test for COVID‐19. Only participants with confirmed infection were included in the mpRCT primary analysis
Exclusion criteria
Admitted to the ICU with COVID‐19 for > 48 h (REMAP‐CAP) or to hospital for > 72 h (ACTIV‐4a, ATTACC) prior to randomisation At imminent risk of death without an ongoing commitment to full organ support At high risk of bleeding Receiving dual antiplatelet therapy Separate clinical indication for therapeutic anticoagulation History of heparin sensitivity including heparin‐induced thrombocytopenia
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| Interventions |
Experimental: therapeutic‐dose LMWH or UFH was administered according to local protocols used for the treatment of acute VTE for up to 14 days or until recovery (defined as hospital discharge, or liberation from supplemental oxygen for ≥ 24 h)
REMAP‐CAP: for UFH, suggested target for aPTT of 1.5‐2.5 times the ULN or therapeutic anti‐Xa levels; LMWH dosed according to patient weight ACTIV‐4a: for UFH, suggested target of anti‐Xa of 0.3‐0.7 IU/mL or aPTT 1.5‐2.5 times the ULN; LMWH dosed according to patient weight and CrCl ATTACC: for UFH, suggested target of aPTT 1.5‐2.5 times the ULN or therapeutic anti‐Xa levels; LMWH dosed according to patient weight and CrCl according to local practice and policy
Comparator: pharmacological thromboprophylaxis was administered according to local practice or with guidance from the trial protocol on maximum dosing, which included either standard low‐dose thromboprophylaxis or enhanced intermediate‐dose thromboprophylaxis
REMAP‐CAP: dose of chosen agent should not be sufficient to result in therapeutic anticoagulation ACTIV‐4a: dose of agent specified to be consistent with guidelines for low‐dose thromboprophylaxis ATTACC: dose of chosen agent should not be more than half of the approved therapeutic dose for the treatment of VTE
Concomitant therapy: NR |
| Outcomes |
Primary (specified)
REMAP‐CAP: all‐cause mortality (day 90); and days alive and not receiving organ support in ICU (day 21) ACTIV‐4a: days alive and not receiving organ support in ICU (day 21) ATTACC: mortality and days alive and not receiving organ support in ICU (day 21) as a unique outcome
Primary (collected)
Secondary (specified)
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REMAP‐CAP
ICU mortality (time frame: day 90) ICU length of stay (time frame: day 90) Hospital length of stay (time frame: day 90) Ventilator‐free days (time frame: day 28) Organ failure‐free days (time frame: day 28) All‐cause mortality (time frame: 6 months) Health‐related quality of life assessment (time frame: 6 months) Proportion of intubated patients who receive a tracheostomy (time frame: day 28) Destination at time of hospital discharge (time frame: free text day 90). Characterised as home, rehabilitation hospital, nursing home or long‐term care facility, or another acute hospital Readmission to the index ICU during the index hospitalisation (time frame: day 90) WHO 8‐point ordinal scale outcome (time frame: hospital discharge
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ACTIV‐4a
Key platform secondary thrombotic endpoint (time frame: 28 days from study enrolment). Composite endpoint of death, PE, systemic arterial thromboembolism, myocardial infarction, or ischaemic stroke at hospital discharge or 28 days, whichever occurs first Other platform secondary endpoints of morbidity and hospitalisation (time frame: 28 days from study enrolment). Acute kidney injury defined by KDIGO criteria, individual endpoints comprising the key secondary endpoint, death during hospitalisation, 28‐day ventilator‐free days, 28‐day vasopressor‐free days, 28‐day renal replacement‐free days, WHO clinical scale, 28‐day hospital ‐free days, 28‐day organ support‐free days All cause mortality (time frame: 90 days from enrolment). Any mortality of patients enrolled within 90 days Primary safety endpoint of major bleeding (time frame: 28 days from study enrolment). Major bleeding (as defined by the ISTH) Secondary safety endpoint of HIT (time frame: 28 days from study enrolment). Confirmed HIT
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ATTACC
Arterial and venous thrombotic conditions (time frame: 28 days and 90 days). A composite endpoint of death, DVT, PE, systemic arterial thromboembolism, myocardial infarction, or ischaemic stroke collected during hospitalisation or at 28 days and 90 days after enrolment (whichever is earlier) Intubation and mortality (time frame: 30 days). Ordered categorical endpoint with 3 possible outcomes based on the worst status of each patient through day 30 following randomisation: no invasive mechanical ventilation, invasive mechanical ventilation, or death All‐cause mortality (time frame: 28 days and 90 days) Intubation (time frame: 30 days). Invasive mechanical ventilation Hospital‐free days (time frame: 28 days). Days alive outside of the hospital through 28 days following randomisation Ventilator‐free days (time frame: 28 days). Days alive not on a ventilator assessed at 28 days following randomisation Myocardial infarction (time frame: 28 days and 90 days) Ischaemic stroke (time frame: 28 days and 90 days) VTE (time frame: 28 days and 90 days). Symptomatic proximal VTE (DVT or PE) Vasopressor‐free days (time frame: 28 days). Days alive not on a vasopressor assessed at 28 days following randomisation Renal replacement‐free days (time frame: 28 days). Days alive not on renal replacement assessed at 28 days following randomisation Hospital re‐admission (time frame: 28 days). Hospital re‐admission within 28 days Acute kidney injury (time frame: duration of study). As defined by KDIGO criteria Systemic arterial thrombosis or embolism (time frame: 28 days and 90 days) ECMO support (time frame: duration of study). Use of ECMO support Mechanical circuit thrombosis (time frame: duration of study). Dialysis or ECMO WHO ordinal scale (time frame: 28 days). Peak scale over 28 days, scale at 14 days, and proportion with improvement by at least 2 categories compared to enrolment, at 28 days Major bleeding (time frame: intervention period (maximum 14 days)). As defined by ISTH HIT (time frame: intervention period (maximum 14 days)). Laboratory‐confirmed
Secondary (collected)
Survival to hospital discharge Survival without organ support through 28 days Survival without intubation through 28 days Survival to hospital discharge without major thrombosis Freedom from major bleeding Major thrombotic event or death in hospital Composite secondary thrombosis Major bleeding PE Myocardial infarction Ischemic cerebrovascular event Systemic arterial thromboembolism
Time points reported: at 21, 28, or 90 (days after the start of the intervention |
| Notes |
Protocol available: 3 international adaptive platform trials harmonised their protocols ('randomised, embedded, multifactorial adaptive platform trial for community‐acquired pneumonia' (REMAP‐CAP, NCT02735707), 'accelerating COVID‐19 therapeutic interventions and vaccines‐4 antithrombotics inpatient platform trial' (ACTIV‐4a, NCT04505774 and PROTECT, NCT04359277), and 'antithrombotic therapy to ameliorate complications of COVID‐19' (ATTACC; NCT04372589). The PROTECT (NCT04359277) study was terminated (the PROTECT study was transitioned to ACTIV4 ACUTE anticoagulation inpatient study) -
Sponsor/funding
REMAP‐CAP: supported by the European Union — through FP7‐HEALTH‐2013‐INNOVATION: the Platform for European Preparedness Against (Re‐)emerging Epidemics (PREPARE) consortium (602525), and Horizon 2020 research and innovation program: the Rapid European Covid‐19 Emergency Research response (RECOVER) consortium (101003589) — and by the Australian National Health and Medical Research Council (APP1101719), the Health Research Council of New Zealand (16/631), a Canadian Institutes of Health Research Strategy for Patient‐Oriented Research Innovative Clinical Trials Program Grant (158584), the U.K. NIHR and the NIHR Imperial Biomedical Research Centre, the Health Research Board of Ireland (CTN 2014‐012), the UPMC Learning While Doing Program, the Breast Cancer Research Foundation, the French Ministry of Health (PHRC‐20‐0147), the Minderoo Foundation, Amgen, Eisai, the Global Coalition for Adaptive Research, and the Wellcome Trust Innovations Project (215522). Dr. Gordon is funded by an NIHR Research Professorship (RP‐2015‐06‐18), and Dr. Shankar‐Hari by an NIHR Clinician Scientist Fellowship (CS‐2016‐16‐011). ATTACC: The ATTACC platform was supported by grants from the Canadian Institutes of Health Research, LifeArc Foundation, Thistledown Foundation, Research Manitoba, Ontario Ministry of Health, and the Peter Munk Cardiac Centre. ACTIV‐4a: The ACTIV‐4a platform was sponsored by the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD and administered through OTA‐20‐011.
COIs: the major study authors declared a financial relationship with the industry. Quote "An Adjudicator is free of conflict of interest. One of adjudicators will also be the CEC Chairperson." |
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| Item |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Yes |
Quote: "Randomization was performed using central web‐based systems."
Quote: "ACTIV‐4a randomised all participants in a 1:1 ratio. The other two platforms specified response‐adaptive randomisation; randomisation probabilities were updated in the severe patient group within REMAP‐CAP and ATTACC during the interim period between the mpRCT interim data cut and the halt of enrolment" |
| Allocation concealment (selection bias) |
Yes |
Quote: "Randomization was performed using central web‐based systems."
Quote "The ATTACC and REMAP‐CAP designs specified the possibility for response‐adaptive randomisation, whereby blinded randomisation allocation ratios could be modified during the trial based on adaptive analyses to favor allocation of participants to the treatment arm demonstrating greater benefit." |
| Blinding of participants and personnel (performance bias) |
No |
Quote "One limitation of our trial is the open‐label design" |
| Blinding of outcome assessment (detection bias) |
No |
Not all outcomes were assessed in a blinding approach
Quote "The open label strategy may also introduce systematic bias in the ascertainment of thrombotic events."
Quote "All reported bleeding and thrombotic events were adjudicated in a blinded fashion by clinical endpoints committees using consensus definitions" |
| Incomplete outcome data (attrition bias) |
No |
There was an acceptable loss rate (critically ill: 1205 randomised, 1074 analysed, 10.8% lost; moderate‐severity: 2245 randomised, 2219 analysed, 1.1% lost). However, there was a high and imbalanced cross‐over rate (experimental/comparator): critically ill 92 (22.3%)/23 (5.3%), moderate‐severity 213 (20.4%)/8 (0.9%). Supplemental data |
| Selective reporting (reporting bias) |
No |
The trial protocol also planned to assess other outcomes of interest for this review. However, the available manuscript did not report 'quality of life' and reported 'hospitalisation time', 'necessity of additional respiratory support', 'thrombocytopenia', and 'DVT' only for moderate‐severity participants. The study authors planned to report data at 90 days of follow‐up but there are no available data at this time point. |
| Other bias |
No |
Although study authors declare that they harmonised their protocols into a "prospectively multiplatform uniformisation", they combined results from 3 different trials registries, with different centres of randomisation and documentation. It was reflected in an imbalance of losses to follow‐up (moderate‐severity: experimental = 19 losses (1.5%), comparator = 7 losses (0.6%))
Quote "may be imbalanced due to response adaptive randomisation"
There was a factorial randomisation for antiplatelet agent intervention in one of the considered trials (REMAP‐CAP).
Quote "A subset of participants enrolled in REMAP‐CAP were also randomised in the antiplatelet agent domain and in other domains of that trial."
There is a possibility of additional heterogeneity in overall results when combining these 3 trials as a unique trial
Although the trial authors merged their platforms, there was a change in the primary outcome specified in the registered protocols compared to the unique reported primary outcome. |
