| Bias | Author's judgement | Support for judgement |
| Confounding |
Moderate |
Comment: The following review confounders (age, sex, ethnicity, comorbidities and severity) were controlled for (See Table 2). Review confounders site effects and insurance were not measured and not included in the final model. At baseline regarding site effects: "Treatments were protocol driven, uniform in all hospitals and established by a system-wide interdisciplinary COVID-19 Task Force." |
| Selection of participants into the study |
Serious |
Comment: One of the exclusion criterion states: "All patients evaluated were 18 years of age and older and were treated as inpatients for at least 48 hours unless they expired within the time period." The results state: "There was a total of 2,948 COVID-19 admissions, of these, 267 (9%) patients had not been discharged, 15 (0.5%) left against medical advice, and four (0.1%) were transferred to another healthcare facility; these patients were excluded from analysis as we could not ascertain their outcome. In addition, there were 121 (4.1%) readmissions, which were also excluded." It is unclear when the baseline is and whether baseline/start of follow up and start of treatment are approximately the same. There is a risk for immortal time bias. |
| Intervention classification |
Low |
Quote: "Hydroxychloroquine was dosed as 400 mg twice daily for 2 doses on day 1, followed by 200 mg twice daily on days 2-5. Azithromycin was dosed as 500mg once daily on day 1 followed by 250mg once daily for the next 4 days. The combination of hydroxychloroquine+azithromycin was reserved for selected patients with severe COVID-19 and with minimal cardiac risk factors. An electrocardiogram (ECK) based algorithm was utilized for hydroxychloroquine use. QTc>500ms was considered an elevated cardiac risk and consequently hydroxychloroquine was reserved for patients with severe disease with telemetry monitoring and serial QTc checks." "The data source for analysis of patient information was derived from electronic medical records in the Electronic Information System." Comment: Data were collected from electronic medical records. Treatment groups were classified using clearly defined criteria. |
| Deviation from intended intervention |
Serious |
Comment: Administration of two review co-interventions, steroids and tocilizumab, were reported. At baseline, steroids were not balanced across intervention groups - HCQ (78.9%), HCQ+AZM (74.3%), AZM (38.8%), SC (35.7%). This favors the any HCQ groups and would affect the outcome. Information on the administration of other review co-interventions of interest per arm is not reported. |
| Missing data |
Low |
Comment: 2541 included in cohort, 2541 analyzed. Risk assessed to be low for outcome: Time to death |
| Measurements of outcomes |
Low |
Comment: Time to death is an observer reported outcome whose assessment cannot be influenced by knowledge of the intervention assignment. Risk assessed to be low for outcome: Mortality/time to death. |
| Selection of the reported results |
Moderate |
Comment: The outcomes and analyses are clearly defined in the Methods section. There is no a-priori registered protocol or statistical analysis plan available. Risk assessed to be moderate for the outcome: Time to death. |