Review
Systematic Review and Meta-Analysis of Methotrexate Use and Risk of Cardiovascular Disease

https://doi.org/10.1016/j.amjcard.2011.06.054Get rights and content

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.

Section snippets

Methods

The Meta-Analysis of Observational Studies in Epidemiology guidelines6 were used as a reference for all stages of design, implementation, and reporting of this systematic review and meta-analysis.

We searched for all clinical trials or observational studies (prospective or retrospective or case-control studies) in which adults received methotrexate, the duration of follow-up was ≥3 months, and reported effect estimates on occurrence of “hard” CVD events (myocardial infarction [MI], coronary

Results

The 10 identified investigations included 8 prospective and 2 retrospective cohort studies in America (n = 6) and Europe (n = 4) and included 66,334 subjects in whom 6,235 CVD events were identified10, 13, 14, 15, 16, 17, 18, 19, 20, 21 (Table 1). We did not identify any randomized controlled trials that assigned methotrexate and assessed the occurrence of “hard” CVD events. One study19 provided 2 separate estimates for patients receiving methotrexate with RA and polyarthritis as the underlying

Discussion

In this meta-analysis of observational studies, methotrexate use among patients with systemic inflammation (mainly RA) was associated with 21% lower CVD risk, with little evidence of between-study heterogeneity. Similar inverse associations were observed for MI and stroke separately.

In general, findings in each of the sensitivity analyses performed were consistent and similar to the overall pooled estimate. For a few sources of heterogeneity, which in fact reflect potentially important study

Acknowledgment

We thank Vokko P. van Halm for providing additional unpublished data.

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    This study was supported by Grant RC2 HL101816 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland, and Grant R01 HL080644 from the National Institutes of Health, Bethesda, Maryland.

    Dr. Ridker is listed as a coinventor on patents held by Brigham and Women's Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease.

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