Background/Purpose: Rheumatoid arthritis (RA) is a known risk factor for cardiovascular (CV) events. While most RA patients use conventional disease-modifying antirheumatic drugs (DMARDs) such as methotrexate (MTX) and hydroxychloroquine (HCQ) as the 1^st line DMARD, little is known about the comparative cardiovascular safety of these DMARDs. The objective of this study was to compare the incidence rate of CV events in RA patients initiating MTX versus HCQ as their 1^st line therapy.

Methods: We conducted a cohort study of RA patients who initiated MTX or HCQ using Medicare claims data (Parts A/B/D 2008-2016) linked with the National Death Index. All patients were required to be ≥65 years old and have ≥365 days of continuous insurance enrollment and no prior use of any DMARDs at the cohort entry (i.e. MTX or HCQ initiation date). Patients with a hospitalization for myocardial infarction (MI), unstable angina, stroke, transient ischemic attack, or heart failure (HF), or a procedure for coronary revascularization within 60 days prior to the cohort entry were excluded. The primary outcome was a composite endpoint of major adverse CV event (MACE) including MI, stroke, or CV mortality. Secondary outcomes included a modified definition of MACE (MI, stroke, or all-cause mortality), individual components of MACE, and hospitalized HF. To control for 59 baseline covariates, we used 1:1 propensity score (PS) matching. For the primary as-treated analysis, Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of the primary and secondary outcomes.

Results: We included a total of 22,923 PS-matched pairs of MTX and HCQ initiators with a mean (standard deviation) age of 74 (7) years and 80% female. Even before PS matching, baseline characteristics were similar between the two groups except 6% higher steroids use among MTX initiators. After PS matching, all the patient characteristics were well balanced (Table 1). Over a median of 212 days (interquartile range 105-529 days) on treatment, 660 MACE occurred in MTX initiators and 610 in HCQ initiators. The incidence rate (per 1,000 person-years) of MACE was 23.38 (95% CI 21.63-25.23) in the MTX group and 24.32 (95% CI 22.43-26.33) in the HCQ group (Table 2). The HR for MACE associated with MTX versus HCQ initiation was 0.96 (95% CI 0.86-1.08). The two groups had no different risk for the modified MACE (HR 0.95, 95% CI 0.88-1.03), CV mortality (HR 0.86, 95% CI 0.72-1.02), and all-cause mortality (HR 0.91, 95% CI 0.82-1.00). However, comparing MTX with HCQ initiators, we observed an increased risk of stroke (HR 1.33, 95% CI 1.08-1.63), but a decreased risk of MI (HR 0.80, 95% CI 0.67-0.95) and hospitalized HF (HR 0.60, 95% CI 0.51-0.71) (Table 2).

Conclusion: In this large observational study of 45,846 older RA patients enrolled in Medicare, we found no difference in the risk of MACE between patients who newly received MTX versus HCQ. However, results from the secondary analyses were different with respect to individual endpoints – a greater stroke risk but a lower risk of MI and hospitalized HF in MTX than HCQ initiators.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cardiovascular-risk-in-rheumatoid-arthritis-patients-treated-with-methotrexate-versus-hydroxychloroquine/