Effect of pre-exposure use of hydroxychloroquine on COVID-19 mortality: a population-based cohort study in patients with rheumatoid arthritis or systemic lupus erythematosus using the OpenSAFELY platform

Christopher T. Rentsch, Nicholas J. DeVito, Brian MacKenna, Caroline E. Morton, Krishnan Bhaskaran, Jeremy P. Brown, Anna Schultze, William J. Hulme, Richard Croker, Alex J. Walker, Elizabeth J. Williamson, Chris Bates, Seb Bacon, Amir Mehrkar, Helen J. Curtis, David Evans, Kevin Wing, Peter Inglesby, Rohini Mathur, Henry DrysdaleAngel Y.S. Wong, Helen I. McDonald, Jonathan Cockburn, Harriet Forbes, John Parry, Frank Hester, Sam Harper, Liam Smeeth, Ian J. Douglas, William G. Dixon, Stephen J.W. Evans, Laurie Tomlinson, Ben Goldacre

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Abstract

Background: Hydroxychloroquine has been shown to inhibit entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into epithelial cells in vitro, but clinical studies found no evidence of reduced mortality when treating patients with COVID-19. We aimed to evaluate the effectiveness of hydroxychloroquine for prevention of COVID-19 mortality, as opposed to treatment for the disease. Methods: We did a prespecified observational, population-based cohort study using national primary care data and linked death registrations in the OpenSAFELY platform, which covers approximately 40% of the general population in England, UK. We included all adults aged 18 years and older registered with a general practice for 1 year or more on March 1, 2020. We used Cox regression to estimate the association between ongoing routine hydroxychloroquine use before the COVID-19 outbreak in England (considered as March 1, 2020) compared with non-users of hydroxychloroquine and risk of COVID-19 mortality among people with rheumatoid arthritis or systemic lupus erythematosus. Model adjustment was informed by a directed acyclic graph. Findings: Between Sept 1, 2019, and March 1, 2020, of 194 637 people with rheumatoid arthritis or systemic lupus erythematosus, 30 569 (15·7%) received two or more prescriptions of hydroxychloroquine. Between March 1 and July 13, 2020, there were 547 COVID-19 deaths, 70 among hydroxychloroquine users. Estimated standardised cumulative COVID-19 mortality was 0·23% (95% CI 0·18 to 0·29) among users and 0·22% (0·20 to 0·25) among non-users; an absolute difference of 0·008% (−0·051 to 0·066). After accounting for age, sex, ethnicity, use of other immunosuppressive drugs, and geographical region, no association with COVID-19 mortality was observed (HR 1·03, 95% CI 0·80 to 1·33). We found no evidence of interactions with age or other immunosuppressive drugs. Quantitative bias analyses indicated that our observed associations were robust to missing information for additional biologic treatments for rheumatological disease. We observed similar associations with the negative control outcome of non-COVID-19 mortality. Interpretation: We found no evidence of a difference in COVID-19 mortality among people who received hydroxychloroquine for treatment of rheumatological disease before the COVID-19 outbreak in England. Therefore, completion of randomised trials investigating pre-exposure prophylactic use of hydroxychloroquine for prevention of severe outcomes from COVID-19 are warranted. Funding: Medical Research Council.

Original languageEnglish
Pages (from-to)e19-e27
JournalThe Lancet Rheumatology
Volume3
Issue number1
DOIs
Publication statusPublished - 5 Nov 2020
Externally publishedYes

Bibliographical note

Funding Information:
CTR, LS, IJD, WGD, SJWE, LT, and BG were responsible for conceptualisation. BM, CEM, CB, SB, DE, PI, JC, JP, FH, and SH were responsible for data curation. CTR, KB, and JPB were responsible for formal analysis. LS and BG were responsible for funding acquisition. CB, AM, JP, and BG were responsible for information governance. CTR, NJD, BM, CEM, KB, JPB, AS, WJH, LS, IJD, WGD, SJWE, LT, and BG were responsible for methodology. CTR, BM, CEM, KB, AS, AJW, CB, SB, AM, HJC, DE, KW, PI, RM, HD, HIM, JC, HF, JP, SH, IJD, WGD, SJWE, and LT were responsible for disease category conceptualisation and codelists. EJW, HJC, LS, and BG were responsible for ethics approval. CTR, BM, CEM, CB, SB, AM, HJC, LS, IJD, SW, LT, and BG were responsible for project administration. LS and BG were responsible for resources. BM, CEM, WJH, AJW, CB, SB, DE, PI, JC, FH, and SH were responsible for software. LS, IJD, WGD, SJWE, LT, BG were responsible for supervision. CTR and KB were responsible for visualisation. CTR, NJD, BM, IJD, SJWE, and LT were responsible for writing the first draft of the manuscript. CT, NJD, BM, CEM, KB, JPB, AS, WJH, RC, AJW, EJW, CB, SB, AM, HJC, DE, KW, PI, RM, HD, AYSW, HIM, JC, HF, JP, FH, SH, LS, IJD, WGD, SJWE, LT, and BG were responsible for writing (review and editing). CTR, CEM, AJW, CB, and JC were responsible for verification of the underlying data. CTR, LS, and BG were guarantors.

Funding Information:
We are very grateful for all the support received from the The Phoenix Partnership Technical Operations team throughout this work and for generous assistance from the information governance and database teams at NHS England and NHSX. This work was supported by the MRC MR/V015737/1. The Phoenix Partnership provided technical expertise and infrastructure within their data centre pro bono in the context of a national emergency. BG's work on better use of data in health care more broadly is currently funded in part by: NIHR Oxford Biomedical Research Centre, NIHR Applied Research Collaboration Oxford and Thames Valley, the Mohn-Westlake Foundation, NHS England, and the Health Foundation; all DataLab staff are supported by BG's grants on this work. KB holds a Sir Henry Dale fellowship jointly funded by Wellcome and the Royal Society (107731/Z/15/Z). HIM is funded by the NIHR Health Protection Research Unit in Immunisation, a partnership between Public Health England and London School of Hygiene & Tropical Medicine. AYSW holds a fellowship from the British Heart Foundation. EJW holds grants from MRC. RG holds grants from NIHR and MRC. RM holds a Sir Henry Wellcome Fellowship funded by the Wellcome Trust (201375/Z/16/Z). HF holds a UKRI fellowship. The views expressed are those of the authors and not necessarily those of the NIHR, NHS England, Public Health England, or the Department of Health and Social Care.

Publisher Copyright:
© 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology

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