Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease

Abstract

Inflammation predicts risk for cardiovascular disease (CVD) events, but the relation of drugs that directly target inflammation with CVD risk is not established. Methotrexate is a disease-modifying antirheumatic drug broadly used for the treatment of chronic inflammatory disorders. A systematic review and meta-analysis of evidence of relations of methotrexate with CVD occurrence were performed. Cohorts, case-control studies, and randomized trials were included if they reported associations between methotrexate and CVD risk. Inclusions and exclusions were independently adjudicated, and all data were extracted in duplicate. Pooled effects were calculated using inverse variance-weighted meta-analysis. Of 694 identified publications, 10 observational studies in which methotrexate was administered in patients with rheumatoid arthritis, psoriasis, or polyarthritis met the inclusion criteria. Methotrexate was associated with a 21% lower risk for total CVD (n = 10 studies, 95% confidence interval [CI] 0.73 to 0.87, p <0.001) and an 18% lower risk for myocardial infarction (n = 5, 95% CI 0.71 to 0.96, p = 0.01), without evidence for statistical between-study heterogeneity (p = 0.30 and p = 0.33, respectively). Among prespecified sources of heterogeneity explored, stronger associations were observed in studies that adjusted for underlying disease severity (relative risk 0.64, 95% CI 0.43 to 0.96, p <0.01) and for other concomitant medication (relative risk 0.73, 95% CI 0.63 to 0.84, p <0.001). Publication bias was potentially evident (funnel plot, Begg's test, p = 0.06); excluding studies with extreme risk estimates did not, however, alter results (relative risk 0.81, 95% CI 0.74 to 0.89). In conclusion, methotrexate use is associated with a lower risk for CVD in patients with chronic inflammation. These findings suggest that a direct treatment of inflammation may reduce CVD risk.

Figure 1

Screening and selection process of studies of methotrexate use and cardiovascular disease risk.

Figure 2

Risk of cardiovascular disease associated with methotrexate use, including 8 prospective and 2 retrospective cohort studies, 66,334 participants and 6,235 events. Random effects meta-analysis was used to calculate the overall pooled relative risk (RR), in the presence of statistical between-study heterogeneity (p>0.1). Solid diamonds and lines are study-specific RRs and 95% CI, respectively; the size of each box is weighted by the inverse-variance of each study. Dashed line and open diamond are pooled RR and 95% CI, respectively, combining each study-specific RR. * Assessed other RA medication vs. methotrexate as the reference group. The RR of methotrexate vs. other RA medication was calculated by pooling the inverse RRs of all other RA medication, using fixed effects meta-analysis. Abbreviations: CI, Confidence interval; CVD, Cardiovascular disease; IHD; Ischemic heart disease; MI, Myocardial infarction; RA, Rheumatoid arthritis; RR, Relative risk.

Figure 3

Risk of cardiovascular disease associated with methotrexate use, among studies that adjusted for underlying disease severity (top; 5 cohort studies and 1 retrospective study, 7,760 participants and 509 events), and among studies that adjusted for other medication used for underlying disease (bottom; 3 cohort studies and 1 retrospective study, 12,051 participants and 1,043 events). Fixed effects meta-analysis was used to calculate the overall pooled relative risk (RR), in the absence of statistical between-study heterogeneity (p>0.1). Solid diamonds and lines are study-specific RRs and 95% CI, respectively; the size of each box is weighted by the inverse-variance of each study. Dashed line and open diamond are pooled RR and 95% CI, respectively, combining each study-specific RR. * Assessed other RA medication vs. methotrexate as the reference group. The RR of methotrexate vs. other RA medication was calculated by pooling the inverse RRs of all other RA medication, using fixed effects meta-analysis. Abbreviations: CI, Confidence interval; CVD, Cardiovascular disease; RR, Relative risk.