Use of repurposed and adjuvant drugs in hospital patients with covid-19: multinational network cohort study

doi:10.1136/bmj.n1038

. 2021 May 11:373:n1038.

doi: 10.1136/bmj.n1038.

Use of repurposed and adjuvant drugs in hospital patients with covid-19: multinational network cohort study

Albert Prats-Uribe¹, Anthony G Sena^{2

3}, Lana Yin Hui Lai⁴, Waheed-Ul-Rahman Ahmed^{5

6}, Heba Alghoul⁷, Osaid Alser⁸, Thamir M Alshammari⁹, Carlos Areia¹⁰, William Carter¹¹, Paula Casajust¹², Dalia Dawoud^{13

14}, Asieh Golozar^{15

16}, Jitendra Jonnagaddala¹⁷, Paras P Mehta¹⁸, Mengchun Gong¹⁹, Daniel R Morales^{20

21}, Fredrik Nyberg²², Jose D Posada²³, Martina Recalde^{24

25}, Elena Roel^{24

25}, Karishma Shah⁵, Nigam H Shah²³, Lisa M Schilling¹¹, Vignesh Subbian²⁶, David Vizcaya²⁷, Lin Zhang^{28

29}, Ying Zhang¹⁹, Hong Zhu³⁰, Li Liu³⁰, Jaehyeong Cho³¹, Kristine E Lynch³², Michael E Matheny^{33

34}, Seng Chan You³⁵, Peter R Rijnbeek³, George Hripcsak³⁶, Jennifer Ce Lane⁵, Edward Burn^{1

24}, Christian Reich³⁷, Marc A Suchard³⁸, Talita Duarte-Salles²⁴, Kristin Kostka^{37

39}, Patrick B Ryan^{40

41}, Daniel Prieto-Alhambra¹

Affiliations

¹ Pharmaco- and Device Epidemiology, Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
² Janssen Research and Development, Titusville, NJ, USA.
³ Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, Netherlands.
⁴ Division of Cancer Sciences, School of Medical Sciences, University of Manchester, Manchester, UK.
⁵ Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
⁶ College of Medicine and Health, University of Exeter, Exeter, UK.
⁷ Faculty of Medicine, Islamic University of Gaza, Gaza City, Palestine.
⁸ Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁹ College of Pharmacy, Riyadh Elm University, Riyadh, Saudi Arabia.
¹⁰ Critical Care Research Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
¹¹ University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹² Real-World Evidence, Trial Form Support, Barcelona, Spain.
¹³ Faculty of Pharmacy, Cairo University, Cairo, Egypt.
¹⁴ National Institute for Health and Care Excellence, London, UK.
¹⁵ Regeneron Pharmaceuticals, Tarrytown, NY, US.
¹⁶ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁷ School of Population Health, UNSW Sydney, Sydney, Australia.
¹⁸ College of Medicine, University of Arizona, Tucson, AZ, USA.
¹⁹ DHC Technologies, Beijing, China.
²⁰ Division of Population Health and Genomics, University of Dundee, Dundee, UK.
²¹ Department of Public Health, University of Southern Denmark, Odense, Denmark.
²² School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
²³ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
²⁴ Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain.
²⁵ Universitat Autònoma de Barcelona, Barcelona, Spain.
²⁶ College of Engineering, University of Arizona Tucson, AZ, USA.
²⁷ Bayer Pharmaceuticals, Sant Joan Despí, Spain.
²⁸ School of Population Medicine and Public Health, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
²⁹ School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia.
³⁰ Nanfang University, Southern Medical University, Guangzhou, China.
³¹ Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, South Korea.
³² VA Informatics and Computing Infrastructure, VA Salt Lake City Healthcare System, Salt Lake City, Utah, USA; Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
³³ VA Informatics and Computing Infrastructure, Tennessee Valley Healthcare System, VA Medical Center, Nashville, TN, USA.
³⁴ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
³⁵ Department of Preventive Medicine and Public Health, Yonsei University College of Medicine, Seoul, South Korea.
³⁶ Department of Biomedical Informatics, Columbia University, New York, NY, USA.
³⁷ IQVIA, Cambridge, MA, USA.
³⁸ Department of Biostatistics, UCLA Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA.
³⁹ OHDSI Center at The Roux Institute, Northeastern University, Portland, ME, USA.
⁴⁰ Janssen Research and Development, Titusville, NJ, USA ryan@ohdsi.org.
⁴¹ Columbia University Irving Medical Center, New York, NY, USA.

PMID: 33975825
PMCID: PMC8111167
DOI: 10.1136/bmj.n1038

Free PMC article

Use of repurposed and adjuvant drugs in hospital patients with covid-19: multinational network cohort study

Albert Prats-Uribe et al. BMJ. 2021.

Free PMC article

. 2021 May 11:373:n1038.

doi: 10.1136/bmj.n1038.

Authors

Affiliations

¹ Pharmaco- and Device Epidemiology, Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
² Janssen Research and Development, Titusville, NJ, USA.
³ Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, Netherlands.
⁴ Division of Cancer Sciences, School of Medical Sciences, University of Manchester, Manchester, UK.
⁵ Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
⁶ College of Medicine and Health, University of Exeter, Exeter, UK.
⁷ Faculty of Medicine, Islamic University of Gaza, Gaza City, Palestine.
⁸ Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁹ College of Pharmacy, Riyadh Elm University, Riyadh, Saudi Arabia.
¹⁰ Critical Care Research Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
¹¹ University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹² Real-World Evidence, Trial Form Support, Barcelona, Spain.
¹³ Faculty of Pharmacy, Cairo University, Cairo, Egypt.
¹⁴ National Institute for Health and Care Excellence, London, UK.
¹⁵ Regeneron Pharmaceuticals, Tarrytown, NY, US.
¹⁶ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁷ School of Population Health, UNSW Sydney, Sydney, Australia.
¹⁸ College of Medicine, University of Arizona, Tucson, AZ, USA.
¹⁹ DHC Technologies, Beijing, China.
²⁰ Division of Population Health and Genomics, University of Dundee, Dundee, UK.
²¹ Department of Public Health, University of Southern Denmark, Odense, Denmark.
²² School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
²³ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
²⁴ Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain.
²⁵ Universitat Autònoma de Barcelona, Barcelona, Spain.
²⁶ College of Engineering, University of Arizona Tucson, AZ, USA.
²⁷ Bayer Pharmaceuticals, Sant Joan Despí, Spain.
²⁸ School of Population Medicine and Public Health, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
²⁹ School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia.
³⁰ Nanfang University, Southern Medical University, Guangzhou, China.
³¹ Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, South Korea.
³² VA Informatics and Computing Infrastructure, VA Salt Lake City Healthcare System, Salt Lake City, Utah, USA; Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
³³ VA Informatics and Computing Infrastructure, Tennessee Valley Healthcare System, VA Medical Center, Nashville, TN, USA.
³⁴ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
³⁵ Department of Preventive Medicine and Public Health, Yonsei University College of Medicine, Seoul, South Korea.
³⁶ Department of Biomedical Informatics, Columbia University, New York, NY, USA.
³⁷ IQVIA, Cambridge, MA, USA.
³⁸ Department of Biostatistics, UCLA Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA.
³⁹ OHDSI Center at The Roux Institute, Northeastern University, Portland, ME, USA.
⁴⁰ Janssen Research and Development, Titusville, NJ, USA ryan@ohdsi.org.
⁴¹ Columbia University Irving Medical Center, New York, NY, USA.

PMID: 33975825
PMCID: PMC8111167
DOI: 10.1136/bmj.n1038

Erratum in

Correction for vol. 373, p.
[No authors listed] [No authors listed] BMJ. 2021 May 21;373:n1277. doi: 10.1136/bmj.n1277. BMJ. 2021. PMID: 34020967 Free PMC article.

Abstract

Objective: To investigate the use of repurposed and adjuvant drugs in patients admitted to hospital with covid-19 across three continents.

Design: Multinational network cohort study.

Setting: Hospital electronic health records from the United States, Spain, and China, and nationwide claims data from South Korea.

Participants: 303 264 patients admitted to hospital with covid-19 from January 2020 to December 2020.

Main outcome measures: Prescriptions or dispensations of any drug on or 30 days after the date of hospital admission for covid-19.

Results: Of the 303 264 patients included, 290 131 were from the US, 7599 from South Korea, 5230 from Spain, and 304 from China. 3455 drugs were identified. Common repurposed drugs were hydroxychloroquine (used in from <5 (<2%) patients in China to 2165 (85.1%) in Spain), azithromycin (from 15 (4.9%) in China to 1473 (57.9%) in Spain), combined lopinavir and ritonavir (from 156 (<2%) in the VA-OMOP US to 2,652 (34.9%) in South Korea and 1285 (50.5%) in Spain), and umifenovir (0% in the US, South Korea, and Spain and 238 (78.3%) in China). Use of adjunctive drugs varied greatly, with the five most used treatments being enoxaparin, fluoroquinolones, ceftriaxone, vitamin D, and corticosteroids. Hydroxychloroquine use increased rapidly from March to April 2020 but declined steeply in May to June and remained low for the rest of the year. The use of dexamethasone and corticosteroids increased steadily during 2020.

Conclusions: Multiple drugs were used in the first few months of the covid-19 pandemic, with substantial geographical and temporal variation. Hydroxychloroquine, azithromycin, lopinavir-ritonavir, and umifenovir (in China only) were the most prescribed repurposed drugs. Antithrombotics, antibiotics, H2 receptor antagonists, and corticosteroids were often used as adjunctive treatments. Research is needed on the comparative risk and benefit of these treatments in the management of covid-19.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from Bill & Melinda Gates Foundation for the submitted work; AP-U reports grants from Fundacion Alfonso Martin Escudero and the Medical Research Council, outside the submitted work; AGS reports personal fees from Janssen Research and Development, during the conduct of the study and personal fees from Janssen Research and Development, outside the submitted work; W-U-RA reports funding from the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Aziz Foundation, Wolfson Foundation, and the Royal College Surgeons of England; AG reports personal fees from Regeneron Pharmaceuticals and full time employment at Regeneron Pharmaceuticals, outside the submitted work; DRM reports funding support from the Wellcome Trust, NIHR, Scottish Chief Scientist Office, and Tenovus Scotland for research unrelated to this work; FN was an employee of AstraZeneca until 2019, before the conduct of this study, owns some AstraZeneca shares, and has other relationships or activities that could appear to have influenced the submitted work; VS reports funding from the US National Science Foundation, Agency for Healthcare Research and Quality through the University of Utah, and Arizona Board of Regents; DV reports personal fees from Bayer, outside the submitted work, and full time employment at Bayer; JC reports grants from the Korean Ministry of Health and Welfare and the Korean Ministry of Trade, Industry, and Energy, during the conduct of the study; SCY reports grants from the Korean Ministry of Health and Welfare and the Korean Ministry of Trade, Industry, and Energy, during the conduct of the study; PRR reports grants from Innovative Medicines Initiative and Janssen Research and Development, during the conduct of the study; GH reports grants from the US National Institutes of Health (NIH) National Library of Medicine, during the conduct of the study; grants from Janssen Research, outside the submitted work; CR is an employee of IQVIA; MAS reports grants from the US National Science Foundation, US NIH, and IQVIA, personal fees from Janssen Research and Development, during the conduct of the study; KK is an employee of IQVIA; PR is an employee of Janssen Research and Development and shareholder of Johnson & Johnson; DP-A reports grants and other from Amgen; grants, non-financial support, and other from UCB Biopharma; and grants from Les Laboratoires Servier, outside the submitted work; and Janssen, on behalf of the Innovative Medicines Initiative (IMI) funded European Health Data and Evidence Network (EHDEN) and European Medical Information Framework (EMIF) consortiums, and Synapse Management Partners have supported training programmes organised by DP-A’s department and are open for external participants.

Figures

**Fig 2**
Percentage of any use (one day or more) of all drugs (rainbow plot) on days 0 to 30 after hospital admission in patients with a positive test result for or diagnosis of covid-19. CUIMC=Columbia University Irving Medical Center; HIRA=Health Insurance Review and Assessment; OMOP=Observational Medical Outcomes Partnership; Optum-EHR=Optum deidentified electronic health record dataset; STARR=STAnford medicine Research data Repository; TRDW=Tufts Research Data Warehouse; VA=Veterans Affairs

**Fig 3**
Percentage of any use (one day or more) of selected drugs on days 0 to 30 after hospital admission in patients with a positive test result for or diagnosis of covid-19. CUIMC=Columbia University Irving Medical Center; HIRA=Health Insurance Review and Assessment; OMOP=Observational Medical Outcomes Partnership; Optum-EHR=Optum deidentified electronic health record dataset; STARR=STAnford medicine Research data Repository; TRDW=Tufts Research Data Warehouse; VA=Veterans Affairs

**Fig 4**
Time trends in hydroxychloroquine use on days 0 to 30 after hospital admission in patients with a positive test result for or diagnosis of covid-19 by month. CUIMC=Columbia University Irving Medical Center; HIRA=Health Insurance Review and Assessment; OMOP=Observational Medical Outcomes Partnership; Optum-EHR=Optum deidentified electronic health record dataset; STARR=STAnford medicine Research data Repository; VA=Veterans Affairs

**Fig 5**
Time trends in remdesivir use on days 0 to 30 after hospital admission in patients with a positive test result for or diagnosis of covid-19 by month. ACTT-1=Adaptive COVID-19 Treatment Trial 1; CUIMC=Columbia University Irving Medical Center

**Fig 6**
Time trends combined lopinavir and ritonavir use on days 0 to 30 after hospital admission in patients with a positive test result for or diagnosis of covid-19 by month. CUIMC=Columbia University Irving Medical Center; HIRA=Health Insurance Review and Assessment; OMOP=Observational Medical Outcomes Partnership; Optum-EHR=Optum deidentified electronic health record dataset; VA=Veterans Affairs

**Fig 7**
Time trends in dexamethasone use on days 0 to 30 after hospital admission in patients with a positive test result for or diagnosis of covid-19 by month. CUIMC=Columbia University Irving Medical Center; HIRA=Health Insurance Review and Assessment; OMOP=Observational Medical Outcomes Partnership; Optum-EHR=Optum deidentified electronic health record dataset; STARR=STAnford medicine Research data Repository; VA=Veterans Affairs

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References

1. Johns Hopkins University. COVID-19 Dashboard by the Center for Systems Science and Engineering at Johns Hopkins University. 2020. https://coronavirus.jhu.edu/map.html.
1. Wang M, Cao R, Zhang L, et al. . Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020;30:269-71. 10.1038/s41422-020-0282-0. - DOI - PMC - PubMed
1. US Food & Drug Administration (FDA). Coronavirus (COVID-19) update: FDA evokes emergency use authorization for chloroquine and hydroxychloroquine. 2020. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19....
1. Horby P, Mafham M, Linsell L, et al. RECOVERY Collaborative Group . Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med 2020;383:2030-40. 10.1056/NEJMoa2022926. - DOI - PMC - PubMed
1. Pan H, Peto R, Henao-Restrepo AM, et al. WHO Solidarity Trial Consortium . Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med 2021;384:497-511. 10.1056/NEJMoa2023184. - DOI - PMC - PubMed

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[1] Johns Hopkins University. COVID-19 Dashboard by the Center for Systems Science and Engineering at Johns Hopkins University. 2020. https://coronavirus.jhu.edu/map.html.

[2] Johns Hopkins University. COVID-19 Dashboard by the Center for Systems Science and Engineering at Johns Hopkins University. 2020. https://coronavirus.jhu.edu/map.html.

[3] Wang M, Cao R, Zhang L, et al. . Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020;30:269-71. 10.1038/s41422-020-0282-0. - DOI - PMC - PubMed

[4] Wang M, Cao R, Zhang L, et al. . Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020;30:269-71. 10.1038/s41422-020-0282-0. - DOI - PMC - PubMed

[5] US Food & Drug Administration (FDA). Coronavirus (COVID-19) update: FDA evokes emergency use authorization for chloroquine and hydroxychloroquine. 2020. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19....

[6] US Food & Drug Administration (FDA). Coronavirus (COVID-19) update: FDA evokes emergency use authorization for chloroquine and hydroxychloroquine. 2020. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19....

[7] Horby P, Mafham M, Linsell L, et al. RECOVERY Collaborative Group . Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med 2020;383:2030-40. 10.1056/NEJMoa2022926. - DOI - PMC - PubMed

[8] Horby P, Mafham M, Linsell L, et al. RECOVERY Collaborative Group . Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med 2020;383:2030-40. 10.1056/NEJMoa2022926. - DOI - PMC - PubMed

[9] Pan H, Peto R, Henao-Restrepo AM, et al. WHO Solidarity Trial Consortium . Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med 2021;384:497-511. 10.1056/NEJMoa2023184. - DOI - PMC - PubMed

[10] Pan H, Peto R, Henao-Restrepo AM, et al. WHO Solidarity Trial Consortium . Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med 2021;384:497-511. 10.1056/NEJMoa2023184. - DOI - PMC - PubMed

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Use of repurposed and adjuvant drugs in hospital patients with covid-19: multinational network cohort study

Affiliations

Use of repurposed and adjuvant drugs in hospital patients with covid-19: multinational network cohort study

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Abstract

Conflict of interest statement

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