The potential effects of methotrexate on cardiovascular outcomes in rheumatoid arthritis patients: a multi-institutional analysis

Abstract Introduction and Purpose The association between rheumatoid arthritis (RA) and increased risk of developing cardiovascular disease has been previously described. Recent studies have also shown that methotrexate may reduce the risk of cardiovascular events in patients with RA but have been limited by small sample size and/or demographic constraints. Methotrexate is a first-line drug treatment for RA and works by suppressing multiple anti-inflammatory and immune reactions, thereby reducing the inflammation that promotes progression of cardiovascular disease in these patients. The goal of this study is to evaluate the potential benefit of methotrexate use on cardiovascular outcomes in patients with RA on a larger scale by utilizing a large international medical record database. Methods The TriNetX Diamond network was used for this study. Two cohorts were generated for comparison by using International Classification of Disease 10 (ICD-10) codes. Both cohorts included adult patients with a diagnosis of rheumatoid arthritis (M06) and both were excluded from being treated with the following biologic therapies: etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. One cohort was on active treatment with methotrexate while the other was excluded from being on it. The cohorts were then balanced for age, gender, race, ethnicity, presence of known coronary artery disease (I20-I25) and history of prior cardiovascular diseases (Z86.7) by propensity score matching and use of the greedy nearest neighbor algorithm. This resulted in 471,054 patients in each arm. They were then compared for the outcomes of acute myocardial infarction, chronic ischemic heart disease, congestive heart failure, and death at 5 years. Results Untreated RA patients were 11% more likely to develop myocardial infarction (RR 1.11, 95% CI (1.09,1.14), P value <0.0001) and 14% more likely to develop chronic ischemic heart disease (RR 1.14, 95% CI (1.13,1.15), P value <0.0001). CHF incidence was 21% higher (RR 1.21, 95% CI (1.19,1.22), P value <0.0001) in the untreated group, but 5-year mortality in the two groups was comparable at around 8.2% (RR 0.98, 95% CI (0.97,0.997), P value 0.016). Conclusion This study confirms that methotrexate is associated with fewer cardiovascular events in RA patients, especially congestive heart failure. Although the use of methotrexate in patients with RA did not result in a mortality benefit, treatment may offer substantial improvements in patient morbidity and healthcare system cost. These benefits were seen in a sample of greater than 900,000 patients representing every adult demographic. These data reaffirm the previously described association between RA and cardiovascular disease and support the initiation of treatment with methotrexate for any adult patient with RA. Watchful waiting is associated with a higher incidence of adverse events in this population.