TY - JOUR
T1 - Drug treatments for covid-19
T2 - living systematic review and network meta-analysis
AU - Siemieniuk, Reed Ac
AU - Bartoszko, Jessica J
AU - Ge, Long
AU - Zeraatkar, Dena
AU - Izcovich, Ariel
AU - Kum, Elena
AU - Pardo-Hernandez, Hector
AU - Rochwerg, Bram
AU - Lamontagne, Francois
AU - Han, Mi Ah
AU - Liu, Qin
AU - Agarwal, Arnav
AU - Agoritsas, Thomas
AU - Chu, Derek K
AU - Couban, Rachel
AU - Darzi, Andrea
AU - Devji, Tahira
AU - Fang, Bo
AU - Fang, Carmen
AU - Flottorp, Signe Agnes
AU - Foroutan, Farid
AU - Heels-Ansdell, Diane
AU - Honarmand, Kimia
AU - Hou, Liangying
AU - Hou, Xiaorong
AU - Ibrahim, Quazi
AU - Loeb, Mark
AU - Marcucci, Maura
AU - McLeod, Shelley L
AU - Motaghi, Sharhzad
AU - Murthy, Srinivas
AU - Mustafa, Reem A
AU - Neary, John D
AU - Qasim, Anila
AU - Rada, Gabriel
AU - Riaz, Irbaz Bin
AU - Sadeghirad, Behnam
AU - Sekercioglu, Nigar
AU - Sheng, Lulu
AU - Sreekanta, Ashwini
AU - Switzer, Charlotte
AU - Tendal, Britta
AU - Thabane, Lehana
AU - Tomlinson, George
AU - Turner, Tari
AU - Vandvik, Per O
AU - Vernooij, Robin Wm
AU - Viteri-García, Andrés
AU - Wang, Ying
AU - Yao, Liang
AU - Ye, Zhikang
AU - Guyatt, Gordon H
AU - Brignardello-Petersen, Romina
N1 - Funding Information:
Contributors: RACS, JJB, LG, and DZ contributed equally to the systematic review and are joint first authors. RACS, JJB, DZ, LG, and RB-P were the core team leading the systematic review. JJB, RC, SAF, RWMV, PA, SM, YW, ZY, IR, AD, TD, AI, AQ, CS, LY, FF, QL, XH, LS, BF, and AV-G identified and selected the studies. DZ, EK, NS, RWMV, AA, YW, KH, HP-H, MAH, CF, SLM, QL, AQ, LY, and FF collected the data. LG, BS, LH, QI, DH-A, GHG, GT, and LT analysed the data. RB-P, HPH, AI, RAM, TD, NS, and DC assessed the certainty of the evidence. SLM, FL, BR, TA, POV, GHG, MM, JDN, ML, TT, BT, FF, and GR provided advice at different stages. RACS, RB-P, and GHG drafted the manuscript. All authors approved the final version of the manuscript. RACS is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. Funder: This study was supported by the Canadian Institutes of Health Research (grant CIHR-IRSC:0579001321). Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from the Canadian Institutes of Health Research; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. Ethical approval: Not applicable. All the work was developed using published data. Data sharing: No additional data available.
Publisher Copyright:
©
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2020/7/30
Y1 - 2020/7/30
N2 - 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.
AB - 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.
KW - Adenosine Monophosphate/analogs & derivatives
KW - Alanine/analogs & derivatives
KW - Antiviral Agents/therapeutic use
KW - Betacoronavirus/isolation & purification
KW - Centers for Disease Control and Prevention, U.S./statistics & numerical data
KW - China/epidemiology
KW - Coronavirus Infections/diagnosis
KW - Databases, Factual/statistics & numerical data
KW - Drug Combinations
KW - Evidence-Based Medicine/methods
KW - Glucocorticoids/therapeutic use
KW - Humans
KW - Hydroxychloroquine/therapeutic use
KW - Lopinavir/therapeutic use
KW - Network Meta-Analysis
KW - Pandemics
KW - Pneumonia, Viral/diagnosis
KW - Randomized Controlled Trials as Topic
KW - Respiration, Artificial/statistics & numerical data
KW - Ritonavir/therapeutic use
KW - Severity of Illness Index
KW - Standard of Care
KW - Treatment Outcome
KW - United States/epidemiology
KW - COVID-19
KW - SARS-CoV-2
UR - http://www.scopus.com/inward/record.url?scp=85088885045&partnerID=8YFLogxK
U2 - 10.1136/bmj.m2980
DO - 10.1136/bmj.m2980
M3 - Review article
C2 - 32732190
SN - 1756-1833
VL - 370
JO - BMJ (Clinical research ed.)
JF - BMJ (Clinical research ed.)
M1 - m2980
ER -