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Comparative Efficacy And Safety Of Pharmacological Interventions For The Treatment Of COVID-19: A Systematic Review And Network Meta-analysis Of Confounder-adjusted 20212 Hospitalized Patients

Min Seo Kim, Min Ho An, Won Jun Kim, Tae-Ho Hwang

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ABSTRACTObjectiveTo evaluate the comparative efficacy and safety of pharmacological interventions used in treating COVID-19 and form a basis for an evidence-based guideline of COVID-19 management by evaluating the level of evidence behind each treatment regimen in different clinical settings.DesignSystematic review and network meta-analysisData SourcesPubMed, Google Scholar, MEDLINE, the Cochrane Library, medRxiv, SSRN, WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov up to June 9th, 2020.Study SelectionPublished and unpublished randomized controlled trials (RCTs) and baseline-adjusted observational studies which met our predefined eligibility criteria.Main Outcome MeasuresThe outcomes of interest were mortality, progression to severe disease (severe pneumonia or admission to intensive care unit (ICU)), time to viral clearance, QT prolongation, fatal cardiac complications, and non-cardiac serious adverse events. The level of evidence behind each outcome was also measured using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework.Results49 studies with a total of 20212 confounder-adjusted patients were included for analysis. The risk of progression to severe pneumonia or ICU admission was significantly reduced with tocilizumab (GRADE low), anakinra (GRADE very low), and remdesivir (GRADE high) compared to standard care. Tocilizumab was shown to reduce mortality rate for both moderate-severe patients in the non-ICU setting at admission (Odds ratio (OR) 0.31, 95% confidence interval (CI) 0.18 to 0.54, GRADE low) and critically ill patients in the ICU setting (OR 0.67, 95% CI 0.50 to 0.91, GRADE low). High dose IVIG reduced death rate (GRADE low) while corticosteroids increased mortality for critically ill patients (GRADE moderate). Convalescent plasma and hydroxychloroquine were shown to promote viral clearance (OR 11.39, 95% CI 3.91 to 33.18, GRADE low and OR 6.08, 95% CI 2.74 to 13.48, GRADE moderate, respectively) while not altering mortality or progression to the severe courses. The combination of hydroxychloroquine and azithromycin was shown to be associated with increased QT prolongation incidence (OR 1,85, 95% CI 1.05 to 3.26, GRADE low) and fatal cardiac complications in cardiac-impaired populations (OR 2.26, 95% CI 1.26 to 4.05, GRADE low). High-dose (>600mg/day) hydroxychloroquine monotherapy was significantly associated with increased non-cardiac serious adverse events (GRADE moderate).ConclusionAnti-inflammatory agents (tocilizumab, anakinra, and IVIG) and remdesivir may safely and effectively improve outcomes of hospitalized COVID-19 patients. Widely used hydroxychloroquine provides marginal clinical benefit in improving viral clearance rates whilst posing both cardiac and non-cardiac safety risks, especially in the vulnerable population. Only 20% of current evidence on pharmacological management of COVID-19 is on moderate and high evidence certainty and can be considered in practice and policy; remaining 80% are of low or very low certainty and warrant further studies to establish firm conclusions.Systematic Review RegistrationPROSPERO 2020: CRD42020186527.Summary BoxSection 1: What is already known on this topic-Numerous clinical trials and observational studies have investigated various pharmacological agents as potential treatment for COVID-19.-Results from numerous studies are heterogeneous and sometimes even contradictory to one another, making it difficult for clinicians to determine which treatments are truly effective.-Level of evidence behind each outcome from diverse studies remains unknown.Section 2: What this study adds-Anti-inflammatory agents (tocilizumab, anakinra, and IVIG) and remdesivir may safely and effectively improve clinical outcomes of COVID-19.-Widely used hydroxychloroquine provides marginal clinical benefit in improving viral clearance rates whilst posing both cardiac and non-cardiac safety risks.-Only 20% of current evidence on pharmacological management of COVID-19 is on moderate/high evidence certainty and can be considered in practice and policy; remaining 80% are of low or very low certainty and warrant further studies to establish firm conclusions.