Comparative Efficacy and Safety of Pharmacological Interventions for the Treatment of COVID-19: A Systematic Review and Network Meta-Analysis of Confounder-Adjusted 36813 Hospitalized Patients

Background: No evidence-based guideline exists for pharmacological management of COVID-19. Methods: We conducted a random-effects network meta-analysis of randomized controlled trials (RCTs) and baseline-adjusted observational studies to identify optimal pharmacological treatment of COVID-19. We searched PubMed, Google Scholar, MEDLINE, the Cochrane Library, medRxiv, SSRN, WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov from inception to May 2020. The primary outcomes were mortality, progression to severe course or admission to intensive care unit (ICU), time to viral clearance, QT prolongation, fatal cardiac complications, and non-cardiac serious adverse events. Effect size measures were odds ratios (OR) and mean differences (MD), with 95% confidence intervals (95% CI). The certainty of evidence was assessed using GRADE framework. This study is registered with PROSPERO, number CRD42020186527. Findings: 40 studies including a total of 114,371 hospitalized COVID-19 patients (36,813 confounder-adjusted patients) were included for analysis. Remdesivir and hydroxychloroquine demonstrated efficacy for non-ICU patients with COVID-19 as remdesivir reduced disease progression (OR 0·31, 95% CI 0·18 to 0·55, high certainty) while hydroxychloroquine reduced the time to viral clearance compared to standard care (MD -3·84 days, 95% CI -5·78 to -1·90, moderate certainty). However, the combination of hydroxychloroquine and azithromycin was shown to be associated with increased QT prolongation incidence and fatal cardiac complications in cardiac-impaired population (OR 1·85, 95% CI 1·05 to 3·26 and OR 8·08, 95% CI 1·37 to 47·65, respectively, low certainty), and thus hydroxychloroquine monotherapy is preferable to combination therapy. For ICU-based critically ill patients, high dose IVIG (low certainty) and tocilizumab (very low certainty) may reduce mortality while corticosteroids (moderate certainty) may increase mortality. Interpretation: individualized treatment strategies based on clinical setting and target outcome should be implemented. The gradient of evidence levels presented in this review may be used to assist decision-making of clinicians and policy makers. Funding Statement: None. Declaration of Interests: All authors have no potential or actual conflict of interest.