Treatment With Hydroxychloroquine Plus Azithromycin Linked to Cardiovascular Mortality in Rheumatoid Arthritis

Hydroxychloroquine prescription
Researchers assessed the safety of hydroxychloroquine alone and in combination with azithromycin to determine the risk associated with its use in routine care in rheumatoid arthritis.

While the short-term risks of hydroxychloroquine treatment were minimal, long-term use was associated with excess cardiovascular mortality in rheumatoid arthritis (RA), according to study results published in Lancet Rheumatology. Researchers noted that combining hydroxychloroquine with azithromycin further increased risk for heart failure and cardiovascular mortality, even in the short term.

Hydroxychloroquine is frequently used as a first-line treatment agent in patients with autoimmune conditions, including RA. The potential efficacy of hydroxychloroquine as an antiviral agent against coronavirus disease 2019 (COVID-19) has led to widespread publicity, much of which focuses heavily on its side effects. The present study assessed the safety profile of hydroxychloroquine alone and in combination with azithromycin in patients with RA.

The multinational, retrospective cohort study enrolled adult patients with RA who were new users of hydroxychloroquine or sulfasalazine. Health records and claims data were obtained from 14 databases in Germany, Japan, the Netherlands, Spain, the United Kingdom, and the United States. The study period was from 2000 to 2020.

Study participants were followed up for the development of 16 severe adverse events of interest over the short (30 days) and long term (>30 days). Patients being initiated with hydroxychloroquine were compared with those being initiated with sulfasalazine. A self-controlled case series was also conducted to assess the safety of hydroxychloroquine in the general population, including patients without RA. Case series participants were identified from the same 14 databases. Finally, severe adverse events were assessed in patients receiving hydroxychloroquine plus azithromycin vs those receiving hydroxychloroquine plus amoxicillin. Propensity score matching and calibration were performed in all patient-to-patient comparisons to minimize confounding. Cox proportional hazard models were used to estimate the hazard ratios (HRs) for severe adverse outcomes among patients receiving hydroxychloroquine vs comparator drugs.

The study cohort included 956,374 patients receiving hydroxychloroquine, 310,350 receiving sulfasalazine, 323,122 receiving hydroxychloroquine plus azithromycin, and 351,956 receiving hydroxychloroquine plus amoxicillin. No excess risk for any of the 16 adverse events was observed with hydroxychloroquine vs sulfasalazine over 30 days of follow-up. The same trends were observed in the self-controlled case series. However, longer use of hydroxychloroquine vs sulfasalazine was associated with increased cardiovascular mortality (HR, 1.65; 95% CI, 1.12-2.44).

Compared to hydroxychloroquine plus amoxicillin, hydroxychloroquine plus azithromycin was associated with significantly increased risk for cardiovascular mortality (HR, 2.19; 95% CI, 1.22-3.95), chest pain or angina (HR, 1.15; 95% CI, 1.05-1.26), and heart failure (HR, 1.22; 95% CI, 1.02-1.45) in the short term.

While hydroxychloroquine presented no significantly increased risk for severe adverse events with short-term use, long-term use was associated with excess cardiovascular mortality. The addition of azithromycin appeared to increase the risk for 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,” the researchers concluded.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Lane JCE, Weaver J, Kostka K, et al. Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study. Published online August 21, 2020. Lancet Rheumatol. doi:10.1016/S2665-9913(20)30276-9