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: WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, up to 1 March 2021 and six additional Chinese databases up to 20 February 2021. Studies identified as of 12 February 2021 were included in the analysis.

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 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: 196 trials enrolling 76 767 patients were included; 111 (56.6%) trials and 35 098 (45.72%) patients are new from the previous iteration; 113 (57.7%) trials evaluating treatments with at least 100 patients or 20 events met the threshold for inclusion in the analyses. Compared with standard care, corticosteroids probably reduce death (risk difference 20 fewer per 1000 patients, 95% credible interval 36 fewer to 3 fewer, moderate certainty), mechanical ventilation (25 fewer per 1000, 44 fewer to 1 fewer, moderate certainty), and increase the number of days free from mechanical ventilation (2.6 more, 0.3 more to 5.0 more, moderate certainty). Interleukin-6 inhibitors probably reduce mechanical ventilation (30 fewer per 1000, 46 fewer to 10 fewer, moderate certainty) and may reduce length of hospital stay (4.3 days fewer, 8.1 fewer to 0.5 fewer, low certainty), but whether or not they reduce mortality is uncertain (15 fewer per 1000, 30 fewer to 6 more, low certainty). Janus kinase inhibitors may reduce mortality (50 fewer per 1000, 84 fewer to no difference, low certainty), mechanical ventilation (46 fewer per 1000, 74 fewer to 5 fewer, low certainty), and duration of mechanical ventilation (3.8 days fewer, 7.5 fewer to 0.1 fewer, moderate certainty). The impact of remdesivir on mortality and most other outcomes is uncertain. The effects of ivermectin were rated as very low certainty for all critical outcomes, including mortality. In patients with non-severe disease, colchicine may reduce mortality (78 fewer per 1000, 110 fewer to 9 fewer, low certainty) and mechanical ventilation (57 fewer per 1000, 90 fewer to 3 more, low certainty). Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to reduce risk of death or have an effect on any other patient-important outcome. The certainty in effects for all other interventions was low or very low.

Conclusion: Corticosteroids and interleukin-6 inhibitors probably confer important benefits in patients with severe covid-19. Janus kinase inhibitors appear to have promising benefits, but certainty is low. Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to have any important benefits. Whether or not remdesivir, ivermectin, and other drugs confer any patient-important benefit remains uncertain.

Systematic review registration: This review was not registered. The protocol is publicly available in the supplementary material.

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. This is the fourth version of the original article published on 30 July 2020 (BMJ 2020;370:m2980), and previous versions can be found as data supplements. When citing this paper please consider adding the version number and date of access for clarity.

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
  • COVID-19
  • 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
  • SARS-CoV-2
  • 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 drug treatment