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

BMJ. 2020 Jul 30;370:m2980. doi: 10.1136/bmj.m2980.

Abstract

Objective: To compare the effects of treatments for coronavirus disease 2019 (covid-19).

Design: Living systematic review and network meta-analysis.

Data sources: US 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 selection: Randomised 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.

Methods: After 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.

Results: 23 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.

Conclusion: Glucocorticoids 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 registration: This review was not registered. The protocol is included as a supplement.

Readers' note: This 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Adenosine Monophosphate / analogs & derivatives
  • Adenosine Monophosphate / therapeutic use
  • Alanine / analogs & derivatives
  • Alanine / therapeutic use
  • Antiviral Agents / therapeutic use*
  • Betacoronavirus / isolation & purification*
  • Betacoronavirus / pathogenicity
  • Centers for Disease Control and Prevention, U.S. / statistics & numerical data
  • China / epidemiology
  • Coronavirus Infections / diagnosis
  • Coronavirus Infections / drug therapy
  • Coronavirus Infections / mortality
  • Coronavirus Infections / therapy*
  • Coronavirus Infections / virology
  • Databases, Factual / statistics & numerical data
  • Drug Combinations
  • Evidence-Based Medicine / methods
  • Evidence-Based Medicine / statistics & numerical data
  • Glucocorticoids / therapeutic use
  • Humans
  • Hydroxychloroquine / therapeutic use
  • Lopinavir / therapeutic use
  • Network Meta-Analysis
  • Pandemics
  • Pneumonia, Viral / diagnosis
  • Pneumonia, Viral / mortality
  • Pneumonia, Viral / therapy*
  • Pneumonia, Viral / virology
  • Randomized Controlled Trials as Topic
  • Respiration, Artificial / statistics & numerical data*
  • Ritonavir / therapeutic use
  • Severity of Illness Index
  • Standard of Care
  • Treatment Outcome
  • United States / epidemiology

Substances

  • Antiviral Agents
  • Drug Combinations
  • Glucocorticoids
  • lopinavir-ritonavir drug combination
  • Lopinavir
  • remdesivir
  • Adenosine Monophosphate
  • Hydroxychloroquine
  • Ritonavir
  • Alanine

Supplementary concepts

  • COVID-19
  • COVID-19 drug treatment
  • severe acute respiratory syndrome coronavirus 2