Drug treatments for covid-19: living systematic review and network meta-analysis
Authors: Siemieniuk Reed AC , Bartoszko Jessica J , Zeraatkar Dena , Kum Elena , Qasim Anila , Díaz Martinez Juan Pablo , Izcovich Ariel , Rochwerg Bram , Lamontagne Francois , Han Mi Ah , Agarwal Arnav , Agoritsas Thomas , Azab Maria , Bravo Gonzalo , Chu Derek K , Couban Rachel , Cusano Ellen , Devji Tahira , Escamilla Zaira , Foroutan Farid , Gao Ya , Ge Long , Ghadimi Maryam , Heels-Ansdell Diane , Honarmand Kimia , Hou Liangying , Ibrahim Sara , Khamis Assem , Lam Bonnie , Mansilla Cristian , Loeb Mark , Miroshnychenko Anna , Marcucci Maura , McLeod Shelley L , Motaghi Sharhzad , Murthy Srinivas , Mustafa Reem A , Pardo-Hernandez Hector , Rada Gabriel , Rizwan Yamna , Saadat Pakeezah , Switzer Charlotte , Thabane Lehana , Tomlinson George , Vandvik Per O , Vernooij Robin WM , Viteri-García Andrés , Wang Ying , Yao Liang , Zhao Yunli , Guyatt Gordon H , Brignardello-Petersen Romina 
Published: July 2020

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 3 December 2021 and six additional Chinese databases up to 20 February 2021. Studies identified as of 1 December 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
463 trials enrolling 166 581 patients were included; 267 (57.7%) trials and 89 814 (53.9%) patients are new from the previous iteration; 265 (57.2%) trials evaluating treatments with at least 100 patients or 20 events met the threshold for inclusion in the analyses. Compared with standard care, three drugs reduced mortality in patients with mostly severe disease with at least moderate certainty: systemic corticosteroids (risk difference 23 fewer per 1000 patients, 95% credible interval 40 fewer to 7 fewer, moderate certainty), interleukin-6 receptor antagonists when given with corticosteroids (23 fewer per 1000, 36 fewer to 7 fewer, moderate certainty), and Janus kinase inhibitors (44 fewer per 1000, 64 fewer to 20 fewer, high certainty). Compared with standard care, two drugs probably reduce hospital admission in patients with non-severe disease: nirmatrelvir/ritonavir (36 fewer per 1000, 41 fewer to 26 fewer, moderate certainty) and molnupiravir (19 fewer per 1000, 29 fewer to 5 fewer, moderate certainty). Remdesivir may reduce hospital admission (29 fewer per 1000, 40 fewer to 6 fewer, low certainty). Only molnupiravir had at least moderate quality evidence of a reduction in time to symptom resolution (3.3 days fewer, 4.8 fewer to 1.6 fewer, moderate certainty); several others showed a possible benefit. Several drugs may increase the risk of adverse effects leading to drug discontinuation; hydroxychloroquine probably increases the risk of mechanical ventilation (moderate certainty).

Conclusion
Corticosteroids, interleukin-6 receptor antagonists, and Janus kinase inhibitors probably reduce mortality and confer other important benefits in patients with severe covid-19. Molnupiravir and nirmatrelvir/ritonavir probably reduce admission to hospital in patients with non-severe covid-19.

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 fifth 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.