Safety of hydroxychloroquine, alone and in combination with azithromycin, in light of rapid wide-spread use for COVID-19: a multinational, network cohort and self-controlled case series study
Authors: C.E.Lane Jennifer , Weaver James , Kostka Kristin , Duarte-Salles Talita , Abrahao Maria Tereza F. , Alghoul Heba , Alser Osaid , Alshammari Thamir M , Biedermann Patricia , Burn Edward , Casajust Paula , Conover Mitch , Culhane Aedin C. , Davydov Alexander , DuVall Scott L. , Dymshyts Dmitry , Fernandez-Bertolin Sergio , Fišter Kristina , Hardin Jill , Hester Laura , Hripcsak George , Kent Seamus , Khosla Sajan , Kolovos Spyros , Lambert Christophe G. , van der Lei Johan , Londhe Ajit A. , Lynch Kristine E. , Makadia Rupa , Margulis Andrea V. , Matheny Michael E. , Mehta Paras , Morales Daniel R. , Morgan-Stewart Henry , Mosseveld Mees , Newby Danielle , Nyberg Fredrik , Ostropolets Anna , Park Rae Woong , Prats-Uribe Albert , Rao Gowtham A. , Reich Christian , Reps Jenna , Rijnbeek Peter , Kumaran Sathappan Selva Muthu , Schuemie Martijn , Seager Sarah , Sena Anthony , Shoaibi Azza , Spotnitz Matthew , Suchard Marc A. , Swerdel Joel , Torre Carmen O. , Vizcaya David , Wen Haini , de Wilde Marcel , You Seng Chan , Zhang Lin , Zhuk Oleg , Ryan Patrick , Prieto-Alhambra Daniel 
Published: April 2020

Background

Hydroxychloroquine has recently received Emergency Use Authorization by the FDA and is currently prescribed in combination with azithromycin for COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin.

Methods

New user cohort studies were conducted including 16 severe adverse events (SAEs). Rheumatoid arthritis patients aged 18+ and initiating hydroxychloroquine were compared to those initiating sulfasalazine and followed up over 30 days. Self-controlled case series (SCCS) were conducted to further establish safety in wider populations. Separately, SAEs associated with hydroxychloroquine- azithromycin (compared to hydroxychloroquine-amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, Netherlands, Spain, UK, and USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (CalHRs) according to drug use. Estimates were pooled where I2<40%.

Results

Overall, 956,374 and 310,350 users of hydroxychloroquine and sulfasalazine, and 323,122 and 351,956 users of hydroxychloroquine-azithromycin and hydroxychloroquine-amoxicillin were included. No excess risk of SAEs was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. SCCS confirmed these findings. However, when azithromycin was added to hydroxychloroquine, we observed an increased risk of 30-day cardiovascular mortality (CalHR2.19 [1.22- 3.94]), chest pain/angina (CalHR 1.15 [95% CI 1.05-1.26]), and heart failure (CalHR 1.22 [95% CI 1.02- 1.45])

Conclusions

Short-term hydroxychloroquine treatment is safe, but addition of azithromycin may induce heart failure and cardiovascular mortality, potentially due to synergistic effects on QT length. We call for caution if such combination is to be used in the management of Covid-19.

Trial registration number

Registered with EU PAS; Reference number EUPAS34497 (http://www.encepp.eu/encepp/viewResource.htm?id=34498). The full study protocol and analysis source code can be found at https://github.com/ohdsi-studies/Covid19EstimationHydroxychloroquine.

Funding sources

This research received partial support from the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) and Senior Research Fellowship (DPA), US National Institutes of Health, Janssen Research & Development, IQVIA, and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea [grant number: HI16C0992]. Personal funding included Versus Arthritis [21605] (JL), MRC-DTP [MR/K501256/1] (JL), MRC and FAME (APU). The European Health Data & Evidence Network has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 806968. The JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. No funders had a direct role in this study. The views and opinions expressed are those of the authors and do not necessarily reflect those of the Clinician Scientist Award programme, NIHR, NHS or the Department of Health, England.