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
PhD Christopher T Rentsch, MPH Nicholas J Devito, Brian Mackenna, Caroline E Morton, Prof Krishnan Bhaskaran, PhD Jeremy P Brown, MSc 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 Drysdale, Angel Y S Wong, Helen I Mcdonald, Jonathan Cockburn, Harriet Forbes, John Parry, Frank Hester, Sam Harper, Liam Smeeth, PhD Ian J Douglas, William G Dixon, Stephen J W Evans, Laurie Tomlinson, Ben Goldacre
The Lancet Rheumatology, doi:10.1016/s2665-9913(20)30378-7
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.
A Cumulative mortality (%)
Days since March 1, 2020 No hydroxychloroquine Hydroxychloroquine 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.
Declaration of interests BG has received research funding from the Laura and John Arnold Foundation, the National Health Service (NHS) National Institute for Health Research (NIHR), the NIHR School of Primary Care Research, the NIHR Oxford Biomedical Research Centre, the MohnWestlake Foundation, NIHR Applied Research Collaboration Oxford and Thames Valley, the Wellcome Trust, the Good Thinking Foundation, Health Data Research UK, the Health Foundation, and WHO; he also receives personal income from speaking and writing for lay audiences on the misuse of science. IJD reports grants from NIHR, and has received unrestricted research grants and holds shares in..
References
Bhaskaran, Smeeth, What is the difference between missing completely at random and missing at random?, Int J Epidemiol
Boulware, Pullen, Bangdiwala, A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid19, N Engl J Med
Cavalcanti, Zampieri, Rosa, Hydroxychloroquine with or without azithromycin in mildtomoderate Covid19, N Engl J Med,
doi:10.1056/NEJMoa2019014Choy, Taylor, Mcauliffe, Roberts, Sargeant, Variation in the use of biologics in the management of rheumatoid arthritis across the UK, Curr Med Res Opin
De Achaval, Suarezalmazor, Treatment adherence to diseasemodifying antirheumatic drugs in patients with rheumatoid arthritis and systemic lupus erythematosus, Int J Clin Rheumatol
Goldacre, Mackenna, The NHS deserves better use of hospital medicines data, BMJ
Griffith, Morris, Tudball, Collider bias undermines our understanding of COVID19 disease risk and severity, Nature Comms
Hernandez, Roman, Pasupuleti, Barboza, White, Hydroxychloroquine or chloroquine for treatment or prophylaxis of COVID19: a living systematic review, Ann Intern Med
Lauffenburger, Acri, Gross, Studies of medication adherence
Lee, Mackenzie, Mcdonald, Tong, An observational cohort study of hydroxychloroquine and azithromycin for COVID19: (Can't Get No) Satisfaction, Int J Infect Dis
Lee, Son, Peck, Can postexposure prophylaxis for COVID19 be considered as an outbreak response strategy in longterm care hospitals?, Int J Antimicrob Agents
Liu, Cao, Xu, Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARSCoV2 infection in vitro, Cell Discov
Magagnoli, Narendran, Pereira, Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID19, Med,
doi:10.1016/j.medj.2020.06.001Mahévas, Tran, Roumier, Clinical efficacy of hydroxychloroquine in patients with covid19 pneumonia who require oxygen: observational comparative study using routine care data, BMJ
Mitjà, Corbachomonné, Ubals, Hydroxychloroquine for early treatment of adults with mild Covid19: a randomized controlled trial, Clin Infect Dis,
doi:10.1093/cid/ciaa1009Pintilie, Analysing and interpreting competing risk data, Stat Med
Price, Hydroxychloroquine is not in short supply, Financial Times
Rosenberg, Dufort, Udo, Association of treatment with hydroxychloroquine or azithromycin with inhospital mortality in patients with COVID19 in New York State, JAMA
Skipper, Pastick, Engen, Hydroxychloroquine in nonhospitalized adults with early COVID19: a randomized trial, Ann Intern Med,
doi:10.7326/M204207Thomas, Edwards, Smeeth, Cooper, Hall, How accurate are diagnoses for rheumatoid arthritis and juvenile idiopathic arthritis in the general practice research database?, Arthritis Rheum
Vanderweele, Unmeasured confounding and hazard scales: sensitivity analysis for total, direct, and indirect effects, Eur J Epidemiol
Watson, Tarning, Hoglund, Concentrationdependent mortality of chloroquine in overdose, eLife
Who, Emergency use ICD codes for COVID19 disease outbreak
Who, Solidarity" clinical trial for COVID19 treatments
Williamson, Walker, Bhaskaran, OpenSAFELY: factors associated with COVID19 death in 17 million patients, Nature
Yao, Ye, Zhang, In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARSCoV2), Clin Infect Dis
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