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Research

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

BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m2980 (Published 30 July 2020) Cite this as: BMJ 2020;370:m2980

This article has a correction. Please see:

  1. Reed AC Siemieniuk, methodologist, internist12*,
  2. Jessica J Bartoszko, methodologist1*,
  3. Dena Zeraatkar, methodologist1*,
  4. Elena Kum, methodologist1*,
  5. Anila Qasim, research associate1,
  6. Juan Pablo Díaz Martinez, statistician1,
  7. Ariel Izcovich, methodologist, internist3,
  8. Bram Rochwerg, methodologist, critical care physician12,
  9. Francois Lamontagne, methodologist, critical care physician4,
  10. Mi Ah Han, methodologist5,
  11. Arnav Agarwal, methodologist, internist12,
  12. Thomas Agoritsas, methodologist, internist16,
  13. Maria Azab, student1,
  14. Gonzalo Bravo, methodologist1,
  15. Derek K Chu, methodologist, immunologist12,
  16. Rachel Couban, librarian7,
  17. Ellen Cusano, physician8,
  18. Tahira Devji, medical student9,
  19. Zaira Escamilla, methodologist1,
  20. Farid Foroutan, methodologist110,
  21. Ya Gao, methodologist1,
  22. Long Ge, methodologist11,
  23. Maryam Ghadimi, PhD student1,
  24. Diane Heels-Ansdell, statistician1,
  25. Kimia Honarmand, methodologist, critical care physician12,
  26. Liangying Hou, medical doctor candidate11,
  27. Sara Ibrahim, student1,
  28. Assem Khamis, data analyst13,
  29. Bonnie Lam, student1,
  30. Cristian Mansilla, methodologist1,
  31. Mark Loeb, infectious disease physician12,
  32. Anna Miroshnychenko, methodologist1,
  33. Maura Marcucci, methodologist, internist12,
  34. Shelley L McLeod, methodologist, assistant professor1415,
  35. Sharhzad Motaghi, methodologist1,
  36. Srinivas Murthy, pediatric critical care, infectious diseases physician16,
  37. Reem A Mustafa, associate professor, nephrologist117,
  38. Hector Pardo-Hernandez, methodologist1819,
  39. Gabriel Rada, methodologist2021,
  40. Yamna Rizwan, methodologist1,
  41. Pakeezah Saadat, methodologist22,
  42. Charlotte Switzer, methodologist1,
  43. Lehana Thabane, professor1,
  44. George Tomlinson, senior biostatistician23,
  45. Per O Vandvik, methodologist, internist2425,
  46. Robin WM Vernooij, methodologist2627,
  47. Andrés Viteri-García, methodologist2028,
  48. Ying Wang, methodologist, pharmacist1,
  49. Liang Yao, methodologist1,
  50. Yunli Zhao, methodologist1,
  51. Gordon H Guyatt, methodologist, internist12,
  52. Romina Brignardello-Petersen, methodologist1
  1. 1Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada
  2. 2Department of Medicine, McMaster University, Hamilton, ON, Canada
  3. 3Servicio de Clinica Médica del Hospital Alemán, Buenos Aires, Argentina
  4. 4Department of Medicine and Centre de recherche du CHU de Sherbrooke, Sherbrooke, Quebec, Canada
  5. 5Department of Preventive Medicine, College of Medicine, Chosun University, Gwangju, Republic of Korea
  6. 6Division of General Internal Medicine & Division of Clinical Epidemiology, University Hospitals of Geneva, Geneva, Switzerland
  7. 7Department of Anesthesia, McMaster University, Hamilton, ON, Canada
  8. 8Department of Medicine, University of Calgary, Calgary, AB, Canada
  9. 9Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
  10. 10Ted Rogers Center for Heart Research, Toronto General Hospital, Toronto, ON, Canada
  11. 11Evidence Based Social Science Research Center, School of Public Health, Lanzhou University, Lanzhou, Gansu, China
  12. 12Department of Medicine, Western University, London, ON, Canada
  13. 13Wolfson Palliative Care Research Centre, Hull York Medical School, Hull, UK
  14. 14Schwartz/Reisman Emergency Medicine Institute, Sinai Health, Toronto, ON, Canada
  15. 15Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada
  16. 16Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
  17. 17Department of Medicine, University of Kansas Medical Center, Kansas City, MO, USA
  18. 18Iberoamerican Cochrane Centre, Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona, Spain
  19. 19CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
  20. 20Epistemonikos Foundation, Santiago, Chile
  21. 21UC Evidence Center, Cochrane Chile Associated Center, Pontificia Universidad Católica de Chile, Santiago, Chile
  22. 22Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada
  23. 23Department of Medicine, University Health Network, Toronto, ON, Canada
  24. 24Department of Medicine, Lovisenberg Diaconal Hospital Trust, Oslo, Norway
  25. 25MAGIC Evidence Ecosystem Foundation, Oslo, Norway
  26. 26Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, Netherlands
  27. 27Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
  28. 28Centro de Investigación de Salud Pública y Epidemiología Clínica (CISPEC), Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
  29. *Joint first authors
  1. Correspondence to: R Siemieniuk reed.siemieniuk{at}medportal.ca
  • Accepted 23 July 2020
  • Final version accepted 21 June 2022

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.

Footnotes

  • Contributors: RACS, JJB, and DZ contributed equally to the systematic review and are joint first authors. RACS, JJB, DZ, and RB-P were the core team leading the systematic review. JJB, RC, SAF, MG, BL, RWMV, 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, SLM, QL, AS, AQ, LY, and FF collected the data. LG, AK, 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 CIHR-IRSC:057900132 and Coronavirus Rapid Research Funding Opportunity - OV2170359.

  • 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.

  • RACS affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

  • Dissemination to participants and related patient and public communities: The infographic and MAGICapp decision aids (available at www.magicapp.org/) were created to facilitate conversations between healthcare providers and patients or their surrogates. The MAGICapp decision aids were co-created with people who have lived experience of covid-19.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

Data availability statement

No additional data available.

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