Article Text

Original research
Adverse effects of remdesivir, hydroxychloroquine and lopinavir/ritonavir when used for COVID-19: systematic review and meta-analysis of randomised trials
  1. Ariel Izcovich1,
  2. Reed Alexander Siemieniuk2,
  3. Jessica Julia Bartoszko2,
  4. Long Ge3,
  5. Dena Zeraatkar2,
  6. Elena Kum2,
  7. Anila Qasim2,
  8. Assem M Khamis4,
  9. Bram Rochwerg2,
  10. Thomas Agoritsas2,5,
  11. Derek K Chu2,6,
  12. Shelley L McLeod7,8,
  13. Reem A Mustafa2,9,
  14. Per Vandvik10,
  15. Romina Brignardello-Petersen2
  1. 1Department of Internal Medicine, Hospital Alemán de Buenos Aires, Buenos Aires, Argentina
  2. 2Department of Health Research Methods, Evidence, and Impact (HEI), McMaster University, Hamilton, Ontario, Canada
  3. 3Evidence Based Social Science Research Center, School of Public Health, Lanzhou University, Lanzhou, China
  4. 4Hull York Medical School, University of Hull, York, UK
  5. 5Division of General Internal Medicine & Division of Epidemiology, University Hospitals of Geneva, Geneva, Switzerland
  6. 6Department of Medicine, McMaster University, Hamilton, Ontario, Canada
  7. 7Schwartz/Reisman Emergency Medicine Institute, Sinai Health System, Toronto, Ontario, Canada
  8. 8Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada
  9. 9Department of Medicine, University of Kansas Medical Center, Kansas City, Missouri, USA
  10. 10MAGIC Evidence Ecosystem Foundation, Oslo, Norway
  1. Correspondence to Dr Ariel Izcovich; ariel.izcovich{at}gmail.com

Abstract

Background To summarise specific adverse effects of remdesivir, hydroxychloroquine and lopinavir/ritonavir in patients with COVID-19.

Methods We searched 32 databases through 27 October 2020. We included randomised trials comparing any of the drugs of interest to placebo or standard care, or against each other. We conducted fixed-effects pairwise meta-analysis and assessed the certainty of evidence using the grading of recommendations assessment, development and evaluation approach.

Results We included 16 randomised trials which enrolled 8152 patients. For most interventions and outcomes the certainty of the evidence was very low to low except for gastrointestinal adverse effects from hydroxychloroquine, which was moderate certainty. Compared with standard care or placebo, low certainty evidence suggests that remdesivir may not have an important effect on acute kidney injury (risk difference (RD) 8 fewer per 1000, 95% CI 27 fewer to 21 more) or cognitive dysfunction/delirium (RD 3 more per 1000, 95% CI 12 fewer to 19 more). Low certainty evidence suggests that hydroxychloroquine may increase the risk of cardiac toxicity (RD 10 more per 1000, 95% CI 0 more to 30 more) and cognitive dysfunction/delirium (RD 33 more per 1000, 95% CI 18 fewer to 84 more), whereas moderate certainty evidence suggests hydroxychloroquine probably increases the risk of diarrhoea (RD 106 more per 1000, 95% CI 48 more to 175 more) and nausea and/or vomiting (RD 62 more per 1000, 95% CI 23 more to 110 more) compared with standard care or placebo. Low certainty evidence suggests lopinavir/ritonavir may increase the risk of diarrhoea (RD 168 more per 1000, 95% CI 58 more to 330 more) and nausea and/or vomiting (RD 160 more per 1000, 95% CI 100 more to 210 more) compared with standard care or placebo.

Discussion Hydroxychloroquine probably increases the risk of diarrhoea and nausea and/or vomiting and may increase the risk of cardiac toxicity and cognitive dysfunction/delirium. Lopinavir/ritonavir may increase the risk of diarrhoea and nausea and/or vomiting. Remdesivir may have no important effect on risk of acute kidney injury or cognitive dysfunction/delirium. These findings provide important information to support the development of evidence-based management strategies for patients with COVID-19.

  • infectious diseases
  • COVID-19
  • adverse events

Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information. No additional data available.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information. No additional data available.

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Footnotes

  • Twitter @izcovichA, @ThomasAgoritsas, @SMcLeod_SREMI

  • Contributors AI, RAS, JJB, LG and DZ contributed equally to the systematic review and are joint first authors. RAS, JJB, DZ, LG and RB-P were the core team leading the systematic review. JJB, AI and AMK identified and selected the studies. DZ, EK, AMK and AQ collected the data. LG and AQ analysed the data. RB-P, AI and RAS assessed the certainty of the evidence. SLM, BR, TA, PV, DKC and RAM provided advice at different stages. AI, RAS and RB-P drafted the manuscript. All authors approved the final version of the manuscript. AI is the guarantor. The corresponding author attested 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: VR4-172738).

  • Competing interests None declared.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.