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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
  1. Reed AC Siemieniuk, methodologist, internist1 *,
  2. Jessica J Bartoszko, methodologist1 *,
  3. Long Ge, methodologist2 *,
  4. Dena Zeraatkar, methodologist1 *,
  5. Ariel Izcovich, methodologist, internist3,
  6. Hector Pardo-Hernandez, methodologist45,
  7. Bram Rochwerg, methodologist, critical care physician16,
  8. Francois Lamontagne, methodologist, critical care physician7,
  9. Mi Ah Han, methodologist8,
  10. Elena Kum, methodologist1,
  11. Qin Liu, professor910,
  12. Arnav Agarwal, methodologist, internist111,
  13. Thomas Agoritsas, methodologist, internist112,
  14. Paul Alexander, methodologist, assistant professor1,
  15. Derek K Chu, methodologist, immunologist16,
  16. Rachel Couban, librarian13,
  17. Andrea Darzi, methodologist1,
  18. Tahira Devji, methodologist1,
  19. Bo Fang, methodologist910,
  20. Carmen Fang, registered nurse14,
  21. Signe Agnes Flottorp, senior researcher1516,
  22. Farid Foroutan, methodologist117,
  23. Diane Heels-Ansdell, statistician1,
  24. Kimia Honarmand, methodologist, critical care physician3,
  25. Liangying Hou, medical doctor candidate2,
  26. Xiaorong Hou, librarian18,
  27. Quazi Ibrahim, statistician1,
  28. Mark Loeb, methodologist, infectious disease physician16,
  29. Maura Marcucci, methodologist, internist16,
  30. Shelley L McLeod, methodologist, assistant professor1920,
  31. Sharhzad Motaghi, methodologist1,
  32. Srinivas Murthy, clinical associate professor, pediatric critical care, infectious diseases physician21,
  33. Reem A Mustafa, associate professor, nephrologist122,
  34. John D Neary, methodologist, internist3,
  35. Anila Qasim, research associate1,
  36. Gabriel Rada, methodologist2324,
  37. Irbaz Bin Riaz, methodologist, internist25,
  38. Behnam Sadeghirad, assistant professor113,
  39. Nigar Sekercioglu, assistant professor1,
  40. Lulu Sheng, methodologist910,
  41. Charlotte Switzer, methodologist1,
  42. Britta Tendal, methodologist26,
  43. Lehana Thabane, professor1,
  44. George Tomlinson, senior biostatistician27,
  45. Tari Turner, senior research fellow26,
  46. Per O Vandvik, methodologist, internist14,
  47. Robin WM Vernooij, methodologist2829,
  48. Andrés Viteri-García, methodologist2330,
  49. Ying Wang, methodologist, pharmacist1,
  50. Liang Yao, methodologist1,
  51. Zhikang Ye, methodologist, pharmacist1,
  52. Gordon H Guyatt, methodologist, internist16,
  53. 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. 2Evidence Based Social Science Research Center, School of Public Health, Lanzhou University, Lanzhou, Gansu, China
  3. 3Servicio de Clinica Médica del Hospital Alemán, Buenos Aires, Argentina
  4. 4Iberoamerican Cochrane Centre, Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona, Spain
  5. 5CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
  6. 6Department of Medicine, McMaster University, Hamilton, ON, Canada
  7. 7Department of Medicine and Centre de recherche du CHU de Sherbrooke, Sherbrooke, Quebec, Canada
  8. 8Department of Preventive Medicine, College of Medicine, Chosun University, Gwangju, Republic of Korea
  9. 9Cochrane China Network Affiliate, Chongqing Medical University, Chongqing, China
  10. 10School of Public Health and Management, Chongqing Medical University, Chongqing, China
  11. 11Department of Medicine, University of Toronto, Toronto, ON, Canada
  12. 12Division of General Internal Medicine & Division of Clinical Epidemiology, University Hospitals of Geneva, Geneva, Switzerland
  13. 13Department of Anesthesia, McMaster University, Hamilton, ON, Canada
  14. 14William Osler Health Network, Toronto, ON, Canada
  15. 15Norwegian Institute of Public Health, Oslo, Norway
  16. 16Institute of Health and Society, University of Oslo, Oslo, Norway
  17. 17Ted Rogers Center for Heart Research, Toronto General Hospital, ON, Canada
  18. 18College of Medical Informatics, Chongqing Medical University, Chongqing, China
  19. 19Schwartz/Reisman Emergency Medicine Institute, Sinai Health, Toronto, ON, Canada
  20. 20Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada
  21. 21Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
  22. 22Department of Medicine, University of Kansas Medical Center, Kansas City, MO, USA
  23. 23Epistemonikos Foundation, Santiago, Chile
  24. 24UC Evidence Center, Cochrane Chile Associated Center, Pontificia Universidad Católica de Chile, Santiago, Chile
  25. 25Hematology and Oncology, Mayo Clinic Rochester, Rochester, MN, USA
  26. 26School of Public Health and Preventative Medicine, Monash University, Melbourne, Australia
  27. 27Department of Medicine, University Health Network, Toronto, ON, Canada
  28. 28Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, Netherlands
  29. 29Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
  30. 30Centro de Investigación de Salud Pública y Epidemiología Clínica (CISPEC), Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
  31. *Joint first authors
  1. Correspondence to: R Siemieniuk reed.siemieniuk{at}medportal.ca
  • Accepted 23 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 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.

Footnotes

  • 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.

  • 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.

  • 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.

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