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: "Participants were randomly assigned 1:1 to a strategy of
discontinuation of ACEI or ARB therapy or continuation
of therapy. If participants were randomly assigned
to a discontinuation strategy, a substitution with an
alternative substance class was at the discretion of the
treating physician. We used blocked randomisation with
a block size of 8. Allocation information was delivered to
participating centres by means of a secure web-based
system." (publication); ...allocation sequence was concealed.", "The allocation of each patient to the corresponding treatment group was finally distributed without interference of the primary investigators through an electronic system"(from contact with authors).
Allocation sequence random.Allocation concealed |
Deviations from intervention |
Some concerns |
Quote: "open label"
Comment: Unblinded study (participants and personnel/carers) Deviations from intended intervention arising because of the study context: 17 patients (16%) in the discontinuation group and 21 (21%) patients in the continuation group crossed over during the study period for medical reasons. 6 patients in the discontinuation group and 1 patient in the continuation group had a medically unjustified cross-overs. Result sensitivity analysis of patients cross-over without medical reasons: "sensitivity analyses with censoring of these patients at the time of crossover showed no effect on outcomes". No information on administration of co-interventions of interest: corticosteroids, biologics. Antivirals were reported. This deviation was not balanced and could affect the outcome. Nevertheless, this domain was rated as some concern as it is impossible to distinguish deviation because of trial context and deviation because of intervention effect. Data for the outcome were analyzed using intention-to-treat analysis. This method was considered appropriate to estimate the effect of assignment to intervention. Risk assessed to be some concerns for the outcome: Mortality (D28). Time to death. Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28). Time to WHO score 7 and above. Adverse events. Serious adverse events. |
Missing outcome data |
Some concerns |
Comment: 216 participants randomized; 204 participants analyzed.
Data not available for all or nearly all participants randomized. Reasons: withdrew consent (6 vs 2), lost to follow up (1 vs 4) however "30-day analyses were also not affected when patients who withdrew consent or were lost to follow-up were excluded", hence there is evidence that the result is not biased by these exclusions. Furthermore, participants never received intervention per protocol (4 vs 4), no evidence of SARS-CoV-2 infection (1 vs 3). No evidence that the result is not biased. Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome (same reasons for missing data and similar proportion between arms) Risk assessed to be some concerns for the outcomes: Mortality (D28). Time to death. Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28). Time to WHO score 7 and above. Adverse events. Serious adverse events. |
Measurement of the outcome |
Some concerns |
Comment: Method of measuring the outcome probably appropriate.
Measurement or ascertainment of outcome probably does not differ between groups. Unblinded study (outcome assessor) MORTALITY, TIME TO DEATH, WHO SCORE 7 AND ABOVE, TIME TO WHO SCORE 7 AND ABOVE, ADVERSE EVENTS, SERIOUS ADVERSE EVENTs Observer-reported outcome not involving judgement. Risk assessed to be low for the outcome: Mortality (D28).Time to death. WHO score 7 and above (D28). Time to WHO score 7 and above. CLINICAL IMPROVEMENT, TIME TO CLINICAL IMPROVEMENT, ADVERSE EVENTS, SERIOUS ADDVERSE EVENTS Requires clinical judgement and could be affected by knowledge of intervention receipt, but it not considered likely to in the context of a pandemic. Clinical improvement (D28). Time to clinical improvement. Adverse events. Serious adverse events. |
Selection of the reported results |
Some concerns |
Comment: The prospective protocol (dated April 6th, 2020) and registry (dated April 16th, 2020) were available.
MORTALITY No timepoint for mortality was given in the protocol No information on whether the result was selected from multiple outcome measurements or analyses of the data. Trial probably not analyzed as pre-specified. Risk assessed to be some concerns for the outcome: Mortality (D28). TIME TO DEATH, CLINICAL IMRPOVEMENT, TIME TO CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE, TIME TO WHO SCORE 7 AND ABOVE, ADVERSE EVENTS, SERIOUS ADVERSE EVENTS Outcome data acquired from contact with authors. Results were probably not selected from multiple outcome measurements or analyses of the data. Trial analyzed as pre-specified. Risk assessed to be low for the outcomes: Time to death. Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28). Time to WHO score 7 and above. Adverse events. Serious adverse events. |
Overall risk of bias |
Some concerns |