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

Abstract

Objective: To 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. Design: Systematic review and network meta-analysis Data Sources: PubMed, Google Scholar, MEDLINE, the Cochrane Library, medRxiv, SSRN, WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov up to June 9th, 2020. Study Selection: Published and unpublished randomized controlled trials (RCTs) and baseline-adjusted observational studies which met our predefined eligibility criteria. Main Outcome Measures: The 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. Results: 49 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). Conclusion: Anti-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; remaining 80% are of low or very low certainty and warrant further studies to establish firm conclusions. Systematic Review Registration: PROSPERO 2020: CRD42020186527.

Frequency of Long QT in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine: A Meta-analysis

“…Our findings can be compared with those of four related types of studies, namely: similar systematic reviews in SARS-CoV-2 infection, studies with HCQ used for short periods against malaria, studies of HCQ used chronically for rheumatologic diseases, and studies with other drugs that cause LQT. Currently, three meta-analytic studies on cardiotoxicity of antimalarials used in SARS-CoV-2 infection have been published [39] , [40] , [41] and the differences with the present study (which reports lower risk frequencies) may be due to the fact that our study had the largest numbers of subjects and we only included studies with HCQ. Indeed, studies with CQ [ 42 , 43 ] were purposefully excluded after Borba et al’s study [43] was prematurely discontinued due to high mortality associated with high doses of CQ.…”

Treatment Response to Hydroxychloroquine and Antibiotics for mild to moderate COVID-19: a retrospective cohort study from South Korea

“…Azithromycin and/or cefixime were prescribed in addition to HQ in our study cohort for management of pneumonia and bacterial co-infection as per recommendations from the Korean Society of Infectious Disease(15) and other literature (16-20). Combination of HQ and azithromycin has gained attention for its potential synergistic therapeutic effect on managing COVID-19 as both drugs were proposed to act as competitive inhibitors of SARS-CoV-2 attachment to the host-cell membrane (21); on the other hand, the potential cardiotoxicity after taking HQ and azithromycin raised concern from many clinicians as multiple studies presented accumulating evidence of higher risk for serious adverse events such as torsades de pointes and ventricular arrhythmia in those who were prescribed the combination therapy (22-24). Our study did not include heart rhythm monitoring for patients and is thus unable to add to the safety aspect of the discussion.…”

A Systematic Review and Network Meta-Analysis for COVID-19 Treatments

“…Interventions composed of more than one drug were treated as separate nodes with each corresponding to one drug. In addition, interval estimates could be imprecise for treatments tested with small sample size 8, 19 . Therefore, for each clinical outcome, we excluded the treatments appearing in only one trial with fewer than 100 patients to alleviate potential risk caused by inadequate information.…”

“…The pandemic of novel coronavirus disease 2019 (COVID- 19), first identified at the end of 2019 in Wuhan, China, has become a global threat to public health. By December 20, 2020, over 76.4 million confirmed cases including 1.69 million deaths have been reported.…”