Heterogeneity and temporal variation in the management of COVID-19: a multinational drug utilization study including 71,921 hospitalized patients from China, South Korea, Spain, and the United States of America

  1. Albert Prats-Uribe
  2. Anthony G. Sena
  3. Lana Yin Hui Lai
  4. Waheed-Ul-Rahman Ahmed
  5. Heba Alghoul
  6. Osaid Alser
  7. Thamir M Alshammari
  8. Carlos Areia
  9. William Carter
  10. Paula Casajust
  11. Dalia Dawoud
  12. Asieh Golozar
  13. Jitendra Jonnagaddala
  14. Paras P. Mehta
  15. Mengchun Gong
  16. Daniel R. Morales
  17. Fredrik Nyberg
  18. Jose D. Posada
  19. Martina Recalde
  20. Elena Roel
  21. Karishma Shah
  22. Nigam H. Shah
  23. Lisa M. Schilling
  24. Vignesh Subbian
  25. David Vizcaya
  26. Andrew Williams
  27. Lin Zhang
  28. Ying Zhang
  29. Hong Zhu
  30. Li Liu
  31. Peter Rijnbeek
  32. George Hripcsak
  33. Jennifer CE Lane
  34. Edward Burn
  35. Christian Reich
  36. Marc A. Suchard
  37. Talita Duarte-Salles
  38. Kristin Kostka
  39. Patrick Ryan
  40. Daniel Prieto-Alhambra

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Abstract

Objectives

A plethora of medicines have been repurposed or used as adjunctive therapies for COVID-19. We characterized the utilization of medicines as prescribed in routine practice amongst patients hospitalized for COVID-19 in South Korea, China, Spain, and the USA.

Design

International network cohort

Setting

Hospital electronic health records from Columbia University Irving Medical Centre (NYC, USA), Stanford (CA, USA), Tufts (MA, USA), Premier (USA), Optum EHR (USA), department of veterans affairs (USA), NFHCRD (Honghu, China) and HM Hospitals (Spain); and nationwide claims from HIRA (South Korea)

Participants

patients hospitalized for COVID-19 from January to June 2020

Main outcome measures

Prescription/dispensation of any medicine on or 30 days after hospital admission date

Analyses

Number and percentage of users overall and over time

Results

71,921 people were included: 304 from China, 2,089 from Spain, 7,599 from South Korea, and 61,929 from the USA. A total of 3,455 medicines were identified. Common repurposed medicines included hydroxychloroquine (<2% in NFHCRD to 85.4% in HM), azithromycin (4.9% in NFHCRD to 56.5% in HM), lopinavir/ritonavir (<3% in all US but 34.9% in HIRA and 56.5% in HM), and umifenovir (0% in all except 78.3% in NFHCRD). Adjunctive medicines were used with great variability, with the ten most used treatments being (in descending order): bemiparin, enoxaparin, heparin, ceftriaxone, aspirin, vitamin D, famotidine, vitamin C, dexamethasone, and metformin. Hydroxychloroquine and azithromycin increased rapidly in use in March-April but declined steeply in May-June.

Conclusions

Multiple medicines were used in the first months of COVID-19 pandemic, with substantial geographic and temporal variation. Hydroxychloroquine, azithromycin, lopinavir-ritonavir, and umifenovir (in China only) were the most prescribed repurposed medicines. 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.

What is already known in this topic

  • Drug repurposing is a common approach in the clinical management of novel diseases and conditions for which there are no available pharmacotherapies

  • Hydroxychloroquine was widely used in the management of COVID-19 patients during the early phases of the pandemic

  • Recent NIH (and other) guidelines recommend the use of concomitant therapies including immune-based, antithrombotic, antibiotic and other treatments

What this study adds

  • This study demonstrates great variability and extensive drug repurposing and utilization in the management of COVID-19 patients.

  • A wide range of adjunctive treatments has been used, including antithrombotics, antibiotics, H2 receptor antagonists, and systemic corticosteroids.

  • Emerging clinical data on the safety and efficacy of hydroxychloroquine and azithromycin impacted their rise and rapid decline in use internationally

  • Conversely, the use of corticosteroids grew only in more recent months, with little use in the early stages of the pandemic (January to April)

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  1. ScreenIT

    SciScore for 10.1101/2020.09.15.20195545: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: Thank you for sharing your code and data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Study limitations: Our study was based on routinely collected real world (EHR and claims) data, where misclassification of disease and therapies may be present. We only included patients who had a clinical COVID-19 diagnosis or a positive PCR test at the time of hospitalization; therefore, patients without a coded diagnosis would have been excluded even if they were suspected of having the disease. There may also be an underreporting of COVID-19 cases in clinical settings where testing resources were scarce, especially during the peak of the outbreak. In addition, medical conditions may be underreported as the absence of a medical code for the disease is interpreted as an absence of the disease itself. Exposure misclassification is also possible; participating data sources varied in their capture of drugs, from hospital billing records, prescription orders, or dispensing data. Medication use estimates on the date of hospitalization is particularly sensitive to misclassification and may conflate baseline concomitant drug history with immediate treatment upon admission. Another limitation was the inability to assess the prescribing pattern of remdesivir as data was not available in our study. The lack of information on the dose and duration of medications was another limitation as these are important information that would have added value to the understanding of prescribing trends, especially among those in high-risk groups or those who are more susceptible to medication-relat...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  2. Version published to 10.1101/2020.09.15.20195545v3 on medRxiv
  3. Version published to 10.1101/2020.09.15.20195545v2 on medRxiv
  4. Version published to 10.1101/2020.09.15.20195545v1 on medRxiv