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
Therapeutic heparin 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 anticoagulant ( / ) | |
| Participants | |
| Randomized 1207 participants (n1=591 / n2= 616) | |
| Characteristics of participants N=1207 Mean age : 61.1 772 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 available |
Protocol Yes. In English Statistical plan Yes Data-sharing stated 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 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. |