Drug treatments for covid-19: living systematic review and network meta-analysis

Abstract

ObjectiveTo compare the effects of treatments for coronavirus disease 2019 (covid-19).DesignLiving systematic review and network meta-analysis.Data sourcesUS Centers for Disease Control and Prevention COVID-19 Research Articles Downloadable Database, which includes 25 electronic databases and six additional Chinese databases to 20 July 2020.Study selectionRandomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles.MethodsAfter duplicate data abstraction, a bayesian random effects network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance.Results23 randomised controlled trials were included in the analysis performed on 26 June 2020. The certainty of the evidence for most comparisons was very low because of risk of bias (lack of blinding) and serious imprecision. Glucocorticoids were the only intervention with evidence for a reduction in death compared with standard care (risk difference 37 fewer per 1000 patients, 95% credible interval 63 fewer to 11 fewer, moderate certainty) and mechanical ventilation (31 fewer per 1000 patients, 47 fewer to 9 fewer, moderate certainty). These estimates are based on direct evidence; network estimates for glucocorticoids compared with standard care were less precise because of network heterogeneity. Three drugs might reduce symptom duration compared with standard care: hydroxychloroquine (mean difference −4.5 days, low certainty), remdesivir (−2.6 days, moderate certainty), and lopinavir-ritonavir (−1.2 days, low certainty). Hydroxychloroquine might increase the risk of adverse events compared with the other interventions, and remdesivir probably does not substantially increase the risk of adverse effects leading to drug discontinuation. No other interventions included enough patients to meaningfully interpret adverse effects leading to drug discontinuation.ConclusionGlucocorticoids probably reduce mortality and mechanical ventilation in patients with covid-19 compared with standard care. The effectiveness of most interventions is uncertain because most of the randomised controlled trials so far have been small and have important study limitations.Systematic review registrationThis review was not registered. The protocol is included as a supplement.Readers’ noteThis article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.

Remdesivir for severe covid-19: a clinical practice guideline

“…We included data from both trials in the network meta-analysis10 to generate pooled estimates of effect (see main infographic for summary of findings). For outcomes in which the networks were too sparse to generate trustworthy effect estimates (need for and duration of mechanical ventilation, time to clinical improvement), we generated pooled estimates based on direct pairwise meta-analysis.…”

“…The largest ongoing trials examining remdesivir include WHO SOLIDARITY, DISCOVERY (NCT04315948), and SIMPLE (NCT04292899). The living network meta-analysis associated with this guideline10 will incorporate new data as the evidence base increases and allow for analysis of many different interventions within the same analytic model.…”

“…The covid-19 pandemic—which can also be characterised as an infodemic, given the explosion of research combined with misinformation and hoaxes—has demonstrated a need for trustworthy, accessible, and regularly updated guidance9 to place emerging findings into context and give clear recommendations for clinical practice. This guideline is based on a living network meta-analysis tracking the development of evidence from randomised controlled trials 10. This living review will continuously search for and rapidly incorporate new evidence into the network meta-analysis.…”

A living WHO guideline on drugs for covid-19

“…To create recommendations, the panel relied on evidence synthesised in a living network meta-analysis led by MAGIC,3 on a prospective meta-analysis of RCTs evaluating corticosteroids for critically ill COVID-19 patients commissioned by the WHO,6 as well as systematic reviews of the safety of similar regimens of systemic corticosteroids in distinct but relevant patient populations 78. While the investigators responsible for meta-analyses rate the certainty of the evidence, this is re-assessed independently by the guideline panel.…”

“…An overview of registered and ongoing trials is available from the Infectious Diseases Data Observatory (see table of ongoing trials for corticosteroids in appendix 1 on bmj.com) 2. The living network meta-analysis associated with this guideline will incorporate new trial data as the evidence base increases and allow for analysis of comparative effectiveness of multiple covid-19 treatments 3. This network meta-analysis and other related publications are included in box 1.…”