Cardiovascular Risks of Hydroxychloroquine vs Methotrexate in Patients With Rheumatoid Arthritis

Background: Hydroxychloroquine is often used as a first-line treatment of rheumatoid arthritis despite limited evidence on its cardiovascular risk.

Objectives: We conducted a cardiovascular safety evaluation comparing hydroxychloroquine to methotrexate among patients with rheumatoid arthritis.

Methods: Using Medicare data (2008-2016), we identified 54,462 propensity score-matched patients with rheumatoid arthritis, aged ≥65 years, who initiated hydroxychloroquine or methotrexate. Primary outcomes were sudden cardiac arrest or ventricular arrythmia (SCA/VA) and major adverse cardiovascular event (MACE). Secondary outcomes were cardiovascular mortality, all-cause mortality, myocardial infarction, stroke, and hospitalized heart failure (HF). We also examined treatment effect modification by history of HF.

Results: Hydroxychloroquine was not associated with risk of SCA/VA (HR: 1.03; 95% CI: 0.79-1.35) or MACE (HR: 1.07; 95% CI: 0.97-1.18) compared with methotrexate. In patients with history of HF, hydroxychloroquine initiators had a higher risk of MACE (HR: 1.30; 95% CI: 1.08-1.56), cardiovascular mortality (HR: 1.34; 95% CI: 1.06-1.70), all-cause mortality (HR: 1.22; 95% CI: 1.04-1.43), myocardial infarction (HR: 1.74; 95% CI: 1.25-2.42), and hospitalized HF (HR: 1.29; 95% CI: 1.07-1.54) compared to methotrexate initiators. Cardiovascular risks were not different in patients without history of HF except for an increased hospitalized HF risk (HR: 1.57; 95% CI: 1.30-1.90) among hydroxychloroquine initiators.

Conclusions: In older patients with rheumatoid arthritis, hydroxychloroquine and methotrexate showed similar SCA/VA and MACE risks; however, hydroxychloroquine initiators with history of HF had higher risks of MACE, cardiovascular mortality, all-cause mortality, and myocardial infarction. An increased hospitalized HF risk was observed among hydroxychloroquine initiators regardless of an HF history.