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
Authors: Prats-Uribe Albert , Sena Anthony G. , Hui Lai Lana Yin , Ahmed Waheed-Ul-Rahman , Alghoul Heba , Alser Osaid , Alshammari Thamir M , Areia Carlos , Carter William , Casajust Paula , Dawoud Dalia , Golozar Asieh , Jonnagaddala Jitendra , Mehta Paras P. , Gong Mengchun , Morales Daniel R. , Nyberg Fredrik , Posada Jose D. , Recalde Martina , Roel Elena , Shah Karishma , H. Shah Nigam , Schilling Lisa M. , Subbian Vignesh , Vizcaya David , Williams Andrew , Zhang Lin , Zhang Ying , Zhu Hong , Liu Li , Rijnbeek Peter , Hripcsak George , Lane Jennifer CE , Burn Edward , Reich Christian , Suchard Marc A. , Duarte-Salles Talita , Kostka Kristin , Ryan Patrick , Prieto-Alhambra Daniel 
Published: September 2020

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)