Combined hydroxychloroquine, azithromycin use increases card
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The combination of hydroxychloroquine and azithromycin significantly increased risk for heart failure and cardiovascular mortality among patients with rheumatoid arthritis, according to data published in The Lancet Rheumatology. To analyze the safety of hydroxychloroquine, both as monotherapy and in combination with azithromycin, as part of routine care for rheumatoid arthritis, Lane and colleagues conducted a multinational, retrospective study of new-user cohort trials. The researchers compared adult patients with RA who initiated hydroxychloroquine with those who began treatment with sulfasalazine over a period of 30 days. In addition, self-controlled case series, including all patients treated with hydroxychloroquine regardless of RA status or indication, were used to further determine safety in larger populations.

The researchers also separately examined severe adverse events linked to combination therapy with hydroxychloroquine and azithromycin, compared with hydroxychloroquine plus amoxicillin. Analyzed data included 14 sources of claims data and electronic medical records from Germany, Japan, the Netherlands, Spain, the United Kingdom and the United States. Lane and colleagues used propensity score stratification and calibration, with negative control outcomes, to address confounding. They then employed Cox models to estimate calibrated hazard ratios according to drug use. Estimates were pooled when the I2 value was less than 0.4.

In all, the researchers included 956,374 patients treated with hydroxychloroquine, 310,350 patients treated with sulfasalazine, 323,122 treated with hydroxychloroquine plus azithromycin, and 351,956 participants who received hydroxychloroquine plus amoxicillin. According to the researchers, there was no excess risk for severe adverse events over a period of 30 days among patients who initiated hydroxychloroquine, compared with those who started sulfasalazine. This finding was later confirmed by self-controlled case series. However, long-term hydroxychloroquine use was associated with increased cardiovascular mortality (calibrated HR = 1.65; 95% CI, 1.12-2.44).

Meanwhile, adding azithromycin to a regimen of hydroxychloroquine was associated with an increased risk for not only 30-day cardiovascular mortality but also chest pain or angina and heart failure. “In this large-scale, international, real-world data network study, hydroxychloroquine appears to be largely safe for short-term use in patients with rheumatoid arthritis compared with sulfasalazine, but when used in combination with azithromycin, this therapy carries a relative risk of 2.19 for cardiovascular death compared with hydroxychloroquine combined with amoxicillin,” Lane and colleagues wrote.