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: "Randomization code lists were computer generated using permuted
blocks with block size equal to 4 during the process of drug labeling and then implemented electronically through the central electronic data-capture system"
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance |
| Deviations from intervention |
Some concerns |
Quote: "double-blind, placebo-controlled trial" (report); "Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)" (registry)
Comment: Blinded study (participants and personnel/carers) HOSPITALIZATION OR DEATH, MORTALITY, AE, SAE Our analysis for the outcome 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 outcome: Hospitalization or death. Mortality (D28). Mortality (D60 or more). Time to death. Adverse events. Serious adverse events. TIME TO DEATH Participants were analyzed according to their randomized groups for the outcome. Of note, this outcome was reported (via contact with authors) for the apixaban therapeutic dose vs placebo. 21 vs 27 participants were excluded from the analysis post-randomization because they did not initiate therapy as randomized. This method was considered inappropriate to estimate the effect of assignment to intervention for this outcome. There was probably no substantial impact of failure to analyze participants according to their randomized groups. Risk assessed to be some concerns for the outcome: Time to death. |
| Missing outcome data |
Some concerns |
Comment: 657 participants randomized; 558 participants analyzed (Mortality D60 or more). 657 participants analyzed (Mortality D28, Hospitalization or death, Adverse events. serious adverse events)
Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: blood draw not obtained, laboratory criteria not met, or other (9 vs 15 vs 11 vs 5), admitted for pneumonia (6 vs 4 vs 3 vs 8), trial termination- no drug shipped or no drug started (3 vs 6 vs 3 vs 7), withdrew (2 vs 5 vs 3 vs 6), no follow-up contact (0 vs 0 vs 0 vs 1). Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome (similar reasons and proportion of missingness among arms). Risk assessed to be some concerns for the outcomes: Mortality (D60 or more). Mortality D28. Hospitalization or death. Adverse events. Serious adverse events. TIME TO DEATH (Apixaban therapeutic dose vs placebo) Comment: 328 participants randomized, 279 participants analyzed Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: did not initiate therapy as randomized (21 vs 27) which is accounted for in domain 2. no follow-up contact (0 vs 1) which is missing data but a very small proportion Hence, overall, missingness could not depend on the true value of the outcome. Risk assessed to be low for the outcome: Time to death. |
| Measurement of the outcome |
Low |
Quote: "blinded adjudication of outcomes"
Comment: Method of measuring the outcome probably appropriate. Measurement or ascertainment of outcome probably does not differ between groups. Blinded study (outcome assessor). Risk assessed to be low for the outcomes: Hospitalization or death. Mortality (D28). Mortality (D60 or more). Time to death. Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan were available but retrospective (dated June 2021 and May 2021 respectively). The prospective registry was also available (dated August 3rd, 2020) and utilized.
MORTALITY D60 Outcome pre-specified (as part of composite primary outcome). 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 outcome: Mortality (D60 or more). HOSPITALIZATION OR DEATH, MORTALITY D28, TIME TO DEATH, AE, SAE Outcome data acquired from direct contact with authors. Analysis performed by the COVID-NMA. Risk assessed to be low for the outcome: Hospitalization or death. Mortality (D28). Time to death. Adverse events. Serious adverse events |
| Overall risk of bias |
Some concerns |