Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study

Abstract

Summary Background Hydroxychloroquine, a drug commonly used in the treatment of rheumatoid arthritis, has received much negative publicity for adverse events associated with its authorisation for emergency use to treat patients with COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin, to determine the risk associated with its use in routine care in patients with rheumatoid arthritis. Methods In this multinational, retrospective study, new user cohort studies in patients with rheumatoid arthritis aged 18 years or older and initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up over 30 days, with 16 severe adverse events studied. Self-controlled case series were done to further establish safety in wider populations, and included all users of hydroxychloroquine regardless of rheumatoid arthritis status or indication. Separately, severe adverse events associated with hydroxychloroquine plus azithromycin (compared with hydroxychloroquine plus amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, the Netherlands, Spain, the UK, and the USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (HRs) according to drug use. Estimates were pooled where the I 2 value was less than 0·4. Findings The study included 956 374 users of hydroxychloroquine, 310 350 users of sulfasalazine, 323 122 users of hydroxychloroquine plus azithromycin, and 351 956 users of hydroxychloroquine plus amoxicillin. No excess risk of severe adverse events was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. Self-controlled case series confirmed these findings. However, long-term use of hydroxychloroquine appeared to be associated with increased cardiovascular mortality (calibrated HR 1·65 [95% CI 1·12–2·44]). Addition of azithromycin appeared to be associated with an increased risk of 30-day cardiovascular mortality (calibrated HR 2·19 [95% CI 1·22–3·95]), chest pain or angina (1·15 [1·05–1·26]), and heart failure (1·22 [1·02–1·45]). Interpretation Hydroxychloroquine treatment appears to have no increased risk in the short term among patients with rheumatoid arthritis, but in the long term it appears to be associated with excess cardiovascular mortality. The addition of azithromycin increases the risk of heart failure and cardiovascular mortality even in the short term. We call for careful consideration of the benefit–risk trade-off when counselling those on hydroxychloroquine treatment. Funding National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, NIHR Senior Research Fellowship programme, US National Institutes of Health, US Depar...

Revisiting the cardiovascular risk of hydroxychloroquine in RA

“…Although consistent with the described risk of heart rhythm disorders in patients with COVID-19 during treatment with a combination of hydroxychloroquine and azithromycin 2 , the results of the study by Lane et al 3 are subject to certain limitations. First of all, the statistical models used were based on data from a variety of databases with heterogeneous populations and different levels of exhaustiveness in data collection, the comparability of which was partially improved by the use of a propensity score.…”

“…Monotherapy with hydroxychloroquine is not recommended for patients with RA; however, it is sometimes used in combination with methotrexate, as data suggest hydroxychloroquine might potentiate the effects of methotrexate 6 . Although some studies have suggested a vascular protective angina and heart failure increased slightly but significantly (HR 1.15; 95% CI 1.05-1.26 for chest pain or angina and HR 1.22; 95% CI 1.02-1.45 for heart failure), as did the risk of cardiovascular mortality (HR 2.19; 95% CI 1.22-3.95) compared with treatment with hydroxychloroquine and amoxicillin 3 .…”

“…The potential antiviral activity of hydroxy chloroquine, which is enhanced when used in combination with azithromycin, has led to renewed interest in this molecule 1 , and the field of rheumatology has found itself at the frontline of the debate as rheumatologists are the foremost prescribers of this drug. Concerns raised about the cardiovascular safety of hydroxychloroquine during trials of the drug for COVID-19 2 have led researchers to revisit the cardiovascular risks associated with hydroxychloroquine use for other indications, including a large study by Lane et al 3 on hydroxychloroquine use by patients with rheumatoid arthritis (RA).…”

“…Moreover, in the 2019 update to the EULAR recommendations for the management of RA 6 , hydroxychloroquine does not have exactly the same indication as sulfasalazine, and its use is mainly reserved for patients with mild RA, calling into question the choice of sulfasalazine as a reference treatment by Lane et al Instead, it might have been preferable to compare patients treated with methotrexate alone or in combination with hydroxychloroquine to those treated with hydroxychloroquine in order to homogenize the study population and avoid the bias associated with adverse events of the reference treatment. In addition, it was quite unexpected that Lane et al 3 noted an increase in cardiovascular mortality without a concurrent increase in heart failure or role for hydroxychloroquine in the context of inflammatory diseases 7 , long-term hydroxychloroquine administration can induce severe cardiac disorders 8 . Hydroxychloroquine provokes sodium and calcium channel blockade, which leads to membrane-stabilizing effects, resulting in conduction disturbances with atrioventricular block, QRS interval widening and QT interval prolongation 8 .…”

“…In patients with RA, there is little robust data about the safety of hydroxychloroquine 9 . For this reason, Lane et al 3 studied the effects of hydroxychloroquine use in patients with RA, alone and in combination with azithromycin, in a large-scale (n = 956,374 hydroxychloroquine users), international, multicentre, retrospective study. They found that hydroxychloroquine alone, at doses of ~400 mg/day over a 30-day period, had no more adverse effects than sulfasalazine treatment.…”