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
Number of vaccinated participants: NR
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
available

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.