Increased Cardiovascular Risks with Hydroxychloroquine vs Methotrexate in RA

Human heart attack, computer illustration.
Researchers evaluated the cardiovascular safety of hydroxychloroquine vs methotrexate among patients with rheumatoid arthritis.

Compared with methotrexate (MTX), treatment with hydroxychloroquine (HCQ) is not associated with an increased risk for sudden cardiac arrest or ventricular arrhythmia (SCA or VA) in older adult patients with rheumatoid arthritis (RA) who were disease-modifying antirheumatic drug (DMARD)-naive. Within a subgroup of individuals with a history of heart failure (HF), however, initiation of HCQ vs MTX appears to be associated with an increased risk for a major adverse cardiovascular event (MACE), cardiovascular mortality, all-cause mortality, and myocardial infarction (MI). These study findings were published in Journal of the American College of Cardiology.

Researchers conducted an active-comparator, incident-user cohort study that used data from patients enrolled in Medicare Fee-for-Service Part A (inpatient coverage), Part B (outpatient coverage), and Part D (prescription benefits). The 2 primary study outcomes were (1) SCA or VA and (2) 3-point MACE (ie, a hospitalization for acute MI, ischemic or hemorrhagic stroke, or cardiovascular mortality). Secondary study outcomes included cardiovascular mortality, all-cause mortality, MI, stroke, and hospitalization for HF.

The study population comprised individuals who were DMARD-naive with RA aged at least 65 years and had initiated HCQ or MTX between January 1, 2008, and December 31, 2016. Cohort entry was defined as “the day of the first filled prescription of the exposure drugs,” with no use of either HCQ or MTX in the past year among participants with at least 1 year of continuous enrollment prior to study entry.

Results of the study showed that HCQ treatment was not associated with the risk for SCA/VA (hazard ratio [HR], 1.03; 95% CI, 0.79-1.35) or MACE (HR, 1.07; 95% CI, 0.97-1.18) compared with MTX treatment. In participants with a history of HF, HCQ initiators experienced a higher risk for MACE (HR, 1.30; 95% CI, 1.08-1.56), cardiovascular mortality (HR, 1.34; 95% CI, 1.25-2.42), and hospitalization for HF (HR, 1.29; 95% CI, 1.07-1.54) vs MTX initiators.

Cardiovascular risks did not differ among patients without a history of HF, except for an increased risk for hospitalization for HF among those who initiated HCQ (HR, 1.57; 95% CI, 1.30-1.90).

Limitations of the study included the fact that the severity or disease activity of RA was not measured in claims; therefore, confounding by indication might exist because of different prescription recommendations. The results with respect to SCA/VA did not take drug interactions into consideration.

The study authors concluded that the findings from the current study show that clinicians should be more cautious in prescribing HCQ to older adult patients with baseline HF or those at high risk for the development of HF, paying particular attention to cardiac manifestations.

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


D’Andrea E, Desai RJ, He M, et al. Cardiovascular risks of hydroxychloroquine vs methotrexate in patients with rheumatoid arthritis. J Am Coll Cardiol. 2022;80(1):36-46. doi:10.1016/j.jacc.2022.04.039