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

Albert Prats-Uribe, Anthony G. Sena, Lana Yin Hui Lai, Waheed Ul Rahman Ahmed, Heba Alghoul, Osaid Alser, Thamir M. Alshammari, Carlos Areia, William Carter, Paula Casajust, Dalia Dawoud, Asieh Golozar, Jitendra Jonnagaddala, Paras P. Mehta, Mengchun Gong, Daniel R. Morales, Fredrik Nyberg, Jose D. Posada, Martina Recalde, Elena RoelKarishma Shah, Nigam H. Shah, Lisa M. Schilling, Vignesh Subbian, David Vizcaya, Lin Zhang, Ying Zhang, Hong Zhu, Li Liu, Jaehyeong Cho, Kristine E. Lynch, Michael E. Matheny, Seng Chan You, Peter R. Rijnbeek, George Hripcsak, Jennifer C.E. Lane, Edward Burn, Christian Reich, Marc A. Suchard, Talita Duarte-Salles, Kristin Kostka, Patrick B. Ryan*, Daniel Prieto-Alhambra

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Abstrakt

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.

OriginalsprogEngelsk
Artikelnummern1038
TidsskriftThe BMJ
Vol/bind373
ISSN0959-8146
DOI
StatusUdgivet - 11. maj 2021

Bibliografisk note

Funding Information:
Contributors: All authors designed the study, interpreted the results, and reviewed the manuscript. AGS designed and prepared the statistical package and set up the web app. AP-U, LYHL, AGS, and DP-A wrote the first draft of the manuscript. AP-U produced and designed the figures and tables. AP-U and AGS are joint first authors. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. AGS, GH, SCY, TDS, CR, KK, MG, PBR, JDP, KEL, and MM are the guarantors. Funding: The European Health Data and Evidence Network has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 806968. This initiative receives support from the European Union’s Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA). This research received partial support from the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, US National Institutes of Health (R01 LM00691), US Department of Veterans Affairs, Janssen Research and Development, and IQVIA. This work was also supported by the Bio Industrial Strategic Technology Development programme (20001234) funded by the Ministry of Trade, Industry, and Energy (MOTIE, Korea) and a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (grant No HI16C0992). This study was supported by the National Key Research and Development programme of China (project No 2018YFC0116901). Personal funding included Versus Arthritis (21605), Medical Research Council Doctoral Training Partnership (MRC-DTP) (MR/K501256/1) (JL); MRC-DTP (MR/K501256/1, MR/N013468/1) and Fundación Alfonso Martín Escudero (FAME) (APU); Innovation Fund Denmark (5153-00002B) and the Novo Nordisk Foundation (NNF14CC0001) (BSKH); VINCI (VA HSR RES 13-457) (SLD, MEM, KEL); and NIHR senior research fellowship (SRF-2018-11-ST2-004, DPA). The University of Oxford received funding related to this work from the Bill and Melinda Gates Foundation (investment ID INV-016201 and INV-019257). No funders had a direct role in this study. The views and opinions expressed are those of the authors and do not necessarily reflect those of the Clinician Scientist Award programme, NIHR, Department of Veterans Affairs or the US government, the Ministry of Science and Technology of China, and the UK National Health Service or Department of Health, England. The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.

Funding Information:
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. Ethical approval: All the data partners received institutional review board (IRB) approval or exemption. STARR-OMOP had approval from IRB panel #8 (RB-53248) registered to Leland Stanford Junior University under the Stanford Human Research Protection Program (HRPP). The use of Veterans Affairs data was reviewed by the Department of Veterans Affairs Central IRB and was determined to meet the criteria for exemption under Exemption Category 4(3) and approved the request for waiver of the Health Insurance Portability and Accountability Act of 1996 authorisation. The research was approved by the Columbia University IRB as an Observational Health Data Sciences and Informatics network study. The IRB number for use of HIRA data was AJIB-MED-EXP-20-065). The use of HM Hospitales data as approved by the Clinical Research Ethics Committee of the IDIAPJGol (project code: 20/070-PCV). The collection and usage of the data for clinical research in NFHCRD was approved by the IRB of Nanfang Hospital.

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