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Research

Prophylaxis against covid-19: living systematic review and network meta-analysis

BMJ 2021; 373 doi: https://doi.org/10.1136/bmj.n949 (Published 26 April 2021) Cite this as: BMJ 2021;373:n949

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A living WHO guideline on drugs to prevent covid-19
  1. Jessica J Bartoszko, methodologist1*,
  2. Reed AC Siemieniuk, methodologist, internist1*,
  3. Elena Kum, methodologist1*,
  4. Anila Qasim, methodologist1*,
  5. Dena Zeraatkar, methodologist1*,
  6. Juan Pablo Diaz Martinez, statistician1,
  7. Maria Azab, methodologist1,
  8. Sara Ibrahim, methodologist1,
  9. Ariel Izcovich, methodologist, internist2,
  10. Gonzalo Bravo Soto, methodologist1,
  11. Yetiani Roldan, methodologist1,
  12. Arnav Agarwal, methodologist, internist13,
  13. Thomas Agoritsas, methodologist, internist14,
  14. Derek K Chu, methodologist, immunologist15,
  15. Rachel Couban, librarian6,
  16. Tahira Devji, methodologist1,
  17. Farid Foroutan, methodologist1,
  18. Maryam Ghadimi, methodologist1,
  19. Kimia Honarmand, methodologist, critical care physician7,
  20. Assem Khamis, data analyst8,
  21. Francois Lamontagne, methodologist, critical care physician9,
  22. Mark Loeb, methodologist, infectious disease physician15,
  23. Shelley L McLeod, methodologist, assistant professor1011,
  24. Sharhzad Motaghi, methodologist1,
  25. Srinivas Murthy, clinical associate professor, pediatric critical care, infectious diseases physician12,
  26. Reem A Mustafa, methodologist, nephrologist113,
  27. Bram Rochwerg, methodologist, critical care physician15,
  28. Charlotte Switzer, methodologist1,
  29. Lehana Thabane, professor1,
  30. Per O Vandvik, methodologist, internist14,
  31. Robin WM Vernooij, methodologist1516,
  32. Ying Wang, methodologist, pharmacist1,
  33. Liang Yao, methodologist1,
  34. Gordon H Guyatt, methodologist, internist15,
  35. 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. 2Servicio de Clinica Médica del Hospital Alemán, Buenos Aires, Argentina
  3. 3Department of Medicine, University of Toronto, Toronto, ON, Canada
  4. 4Division of General Internal Medicine & Division of Clinical Epidemiology, University Hospitals of Geneva, Geneva, Switzerland
  5. 5Department of Medicine, McMaster University, Hamilton, ON, Canada
  6. 6Department of Anesthesia, McMaster University, Hamilton, ON, Canada
  7. 7Department of Medicine, Western University, London, ON, Canada
  8. 8Wolfson Palliative Care Research Centre, Hull York Medical School, Hull, UK
  9. 9Department of Medicine and Centre de recherche du CHU de Sherbrooke, Sherbrooke, Quebec, Canada
  10. 10Schwartz/Reisman Emergency Medicine Institute, Sinai Health, Toronto, ON, Canada
  11. 11Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada
  12. 12Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
  13. 13Department of Medicine, University of Kansas Medical Center, Kansas City, MO, USA
  14. 14Institute of Health and Society, University of Oslo, Oslo, Norway
  15. 15Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, Netherlands
  16. 16Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
  17. *Joint first authors
  1. Corresponding author:
    Reed AC Siemieniuk McMaster University Medical Centre 1280 Main Street West 2C Area Hamilton, Ontario, Canada L8S 4K1 (reed.siemieniuk{at}medportal.ca; https://orcid.org/0000-0002-3725-3031; Twitter: @RSiemieniuk)

Abstract

Updates This is the second version (first update) of the living systematic review, replacing the previous version (available as a data supplement). When citing this paper please consider adding the version number and date of access for clarity.

Objective To determine and compare the effects of drug prophylaxis on severe acute respiratory syndrome coronavirus virus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (covid-19).

Design Living systematic review and network meta-analysis (NMA).

Data sources WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature to 4 March 2022.

Study selection Randomised trials in which people at risk of covid-19 were allocated to prophylaxis or no prophylaxis (standard care or placebo). Pairs of reviewers independently screened potentially eligible articles.

Methods After duplicate data abstraction, we conducted random-effects bayesian network meta-analysis. We assessed risk of bias of the included studies using a modification of the Cochrane risk of bias 2.0 tool and assessed the certainty of the evidence using the grading of recommendations assessment, development and evaluation (GRADE) approach.

Results The second iteration of this living NMA includes 32 randomised trials which enrolled 25 147 participants and addressed 21 different prophylactic drugs; adding 21 trials (66%), 18 162 participants (75%) and 16 (76%) prophylactic drugs. Of the 16 prophylactic drugs analysed, none provided convincing evidence of a reduction in the risk of laboratory confirmed SARS-CoV-2 infection. For admission to hospital and mortality outcomes, no prophylactic drug proved different than standard care or placebo. Hydroxychloroquine and vitamin C combined with zinc probably increase the risk of adverse effects leading to drug discontinuation—risk difference for hydroxychloroquine (RD) 6 more per 1000 (95% credible interval (CrI) 2 more to 10 more); for vitamin C combined with zinc, RD 69 more per 1000 (47 more to 90 more), moderate certainty evidence.

Conclusion Much of the evidence remains very low certainty and we therefore anticipate future studies evaluating drugs for prophylaxis may change the results for SARS-CoV-2 infection, admission to hospital and mortality outcomes. Both hydroxychloroquine and vitamin C combined with zinc probably increase adverse effects.

Systematic review registration This review was not registered. The protocol established a priori is included as a supplement.

Funding This study was supported by the Canadian Institutes of Health Research (grant CIHR-IRSC:0579001321).

Footnotes

  • Contributors: RACS, JJB, AQ, EK, and DZ contributed equally to the systematic review and are joint first authors. RACS, JJB, DZ, EK, AQ, JPMD, MA, SI and RB-P were the core team leading the systematic review. JJB, SI, RC, RWMV, SM, YW, CS, LY and MG identified and selected the studies. DZ, EK, MA, GBS, RWMV, AA, YW, KH, SLM, AQ, YR and LY collected the data. JPMD, AQ, AI, AK, GHG, and LT analysed the data. RB-P, AI, FF, RAM, TD, and DC assessed the certainty of the evidence. SLM, FL, BR, POV, GHG, SM, ML and TA provided advice at different stages. JJB, 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.

  • Funding: 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: ML reports personal fees and non-financial support from Sanofi, grants and personal fees from Seqirus, personal fees from Pfizer, personal fees from Medicago, outside the submitted work; and Co-investigator on ACT randomised trial of covid-19 therapy. All other authors report 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.

Data availability statement

No additional data available.

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