The combination of hydroxychloroquine and azithromycin was associated with significant cardiovascular risks, including mortality, in the largest ever safety study comparing hydroxychloroquine treatment with hydroxychloroquine and azithromycin treatment for rheumatoid arthritis (RA) patients.
In this multinational retrospective study, published in Lancet Rheumatology, new user cohort studies in adult RA patients initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up over 30 days, with 16 severe adverse events studied.
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, over a 20-year period spanning six nations (Germany, Japan, Netherlands, Spain, United Kingdom, United States).
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]).
The addition of azithromycin appeared to be associated with increased 30-day cardiovascular mortality risk (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]), compared with hydroxychloroquine combined with amoxicillin.
There was a higher prevalence of acute respiratory disease among azithromycin versus amoxicillin users (62.5% vs 50.7%).