Note: The risk of bias by domain corresponds to the highest risk of bias among outcomes by domain.
The overall risk of bias corresponds to the overall highest risk of bias assessed among outcomes.
| Bias | Author's judgement | Support for judgement |
| Randomization |
Low |
Quote: "We used web-based central randomization with a computer-generated random sequence with variable block sizes stratified by site and age (≤65 versus >65 years) to assign patients in a 1:1 ratio to therapeutic or prophylactic heparin."
Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Low |
Quote: "parallel, pragmatic, adaptive multi-center, open-label randomized controlled trial"
Unblinded study (participants and personnel/carers). Deviations from intended intervention arising because of the study context: The comparison was therapeutic-dose anticoagulation versus usual care/prophylactic anticoagulation during hospitalization. Both arms received anticoagulation, but the majority of the intervention group received therapeutic dose anticoagulation while the majority of the control group received prophylactic dose anticoagulation. No participant cross-over. Administration of co-interventions of interest, antivirals, corticosteroids, biologics and anticoagulants were reported and balanced between groups. Our analysis is an intention-to-treat analysis. This method was considered appropriate to estimate the effect of assignment to intervention. Risk assessed to be low for the outcomes: Mortality (D28). Time to death. WHO score 7 and above (D28). Clinical improvement (D28). Adverse events. Serious adverse events. |
| Missing outcome data |
Low |
Comment: 465 participants randomized; 465 participants analyzed
Of note, 4 vs 7 participants were lost to follow-up Data available for nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality (D28). Time to death. WHO score 7 and above (D28). Clinical improvement (D28). Adverse events. Serious adverse events. |
| Measurement of the outcome |
Some concerns |
Quote: "the trial had an open-label design, but all relevant outcomes were blindly adjudicated by an independent clinical events committee."
Comment: Method of measuring the outcome probably appropriate. Measurement or ascertainment of outcome probably does not differ between groups. Unblinded study (outcome assessor). An independent event-adjudication committee, which consisted of clinicians who were unaware of the treatment assignments, adjudicated the components of the primary outcome, bleeding and thrombotic events. MORTALITY. TIME TO DEATH. Observer-reported outcome not involving judgement. Risk assessed to be low for the outcomes: Mortality (D28). Time to death. WHO SCORE 7 AND ABOVE For this outcome, we consider that the assessment cannot possibly be influenced by knowledge of intervention assignment. Risk assessed to be low for the outcomes: WHO score 7 and above (D28). CLINICAL IMPROVEMENT Clinical improvement (defined as hospital discharge) requires clinical judgement and could be affected by knowledge of intervention receipt, but it not considered likely to in the context of a pandemic. Risk assessed to be some concerns for the outcomes: Clinical improvement (D28). ADVERSE and SERIOUS ADVERSE EVENTS The authors reported on adverse events and serious adverse events that may contain both clinically- and laboratory-detected events, which can be influenced by knowledge of the intervention assignment, but is not likely in the context of the pandemic. Risk assessed to be some concerns for the outcomes: Adverse events. Serious adverse events |
| Selection of the reported results |
Some concerns |
Comment: The retrospective protocol (dated October 13th, 2020) and a retrospective registry (dated June 22nd, 2020) were available. A prospective registry (dated April 23rd, 2020) was also available and consulted.
MORTALITY Outcome pre-specified. Results were not selected from multiple outcome measurements or analyses of the data. Trial analyzed as pre-specified. Risk assessed to be low for the outcomes: Mortality (D28). Time to death. WHO SCORE 7 AND ABOVE Outcome not pre-specified. No information on whether the result was selected from multiple outcome measurements or analyses of the data. Trial not analyzed as pre-specified. Risk assessed to be some concerns for the outcome: WHO score 7 and above (D28). CLINICAL IMPROVEMENT, ADVERSE EVENTS, SERIOUS ADVERSE EVENTS Outcome data acquired from direct contact with authors. Analysis performed by the COVID-NMA. Risk assessed to be low for the outcome: Clinical improvement (D28). Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |