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

Abstract

<h4>Objectives</h4> 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. <h4>Design</h4> International network cohort <h4>Setting</h4> 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) <h4>Participants</h4> patients hospitalized for COVID-19 from January to June 2020 <h4>Main outcome measures</h4> Prescription/dispensation of any medicine on or 30 days after hospital admission date <h4>Analyses</h4> Number and percentage of users overall and over time <h4>Results</h4> 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. <h4>Conclusions</h4> 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. <h4>What is already known in this topic</h4> 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 <h4>What this study adds</h4> 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)