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

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.

Figure 1

Study diagram End of follow-up was the date of death or 7 days before last date of the Office of National Statistics mortality data to account for reporting lag, or date of first hydroxychloroquine prescription on or after index date (for people without hydroxychloroquine use at index date), whichever came first. STP=Sustainability and Transformation Partnership. DMARD=disease-modifying antirheumatic drug. IMD=index of multiple deprivation. SLE=systemic lupus erythematosus.

Figure 2

Study profile SLE=systemic lupus erythematosus. *Including sex and index of multiple deprivation.

Figure 3

Cumulative mortality by hydroxychloroquine use among people with rheumatoid arthritis or systemic lupus erythematosus (A) Time to COVID-19 death in ONS data and (B) time to non-COVID-19 death in ONS data. Outcome counts were 70 of 547 deaths among hydroxychloroquine users for COVID-19 mortality and 234 of 2003 deaths among hydroxychloroquine users for non-COVID-19 mortality. ONS=Office for National Statistics.

Figure 4

Comparisons between hydroxychloroquine use and no hydroxychloroquine use among people with rheumatoid arthritis or systemic lupus erythematosus Outcome counts were 70 of 547 deaths among hydroxychloroquine users for COVID-19 mortality and 234 of 2003 deaths among hydroxychloroquine users for non-COVID-19 mortality. DAG=directed acyclic graph.