Does Low Dose Methotrexate Prevent Athersclerotic Events in Patients?

A randomized clinical trial that was conducted by Paul M Ridker et al. and published in NEJM showed that there was no meaningful association between low dose methotrexate (MTX) administration and a decrease in cardiovascular events. Additionally, MTX usage was associated with adverse effects.

It has been shown in previous studies that inflammation plays a critical role in the development of atherosclerosis. Anti-inflammatory drugs like canakinumab, an interleukin -1beta inhibitor has been shown to be effective in decreasing cardiovascular death without any change in lipid profile or blood pressure, especially when it was associated with a decrease in CRP and IL-6 levels. This issues raised the question in the investigators’ minds whether other anti-inflammatory drugs that decrease CRP and IL-6 could be effective in the reduction of cardiovascular death or not. Endpoints were categorized as either primary endpoints (first occurrence of a major adverse cardiovascular event, hospitalization for unstable angina that led to urgent coronary revascularization) or secondary endpoints (death from any cause, a composite of major adverse cardiovascular events plus any coronary revascularization, hospitalization for congestive heart failure, and a composite of major adverse cardiovascular events plus coronary revascularization, hospitalization for congestive heart failure, or death from any cause).

A randomized, double-blinded, placebo-controlled study was designed. They included 4786 patients with multivessel coronary artery disease (39% percent of participants) or myocardial infarction (61% of participants) in the study. The patients were given oral methotrexate once weekly with a sequential increase in dosage from 5 mg to 10 mg to 15 mg. Out of patients who completed the trial, the investigators randomized patients to either continue MTX 15 mg weekly (2391 patients) or continue placebo (2395 patients) for 4 months, and then continued MTX 20 mg weekly. The study was terminated due to futility. Results of the study after 8 months treatment showed that the MTX was associated with abnormal liver function test development and a decrease in white blood cells, hematocrit, and hemoglobin level. Also, it was shown in this study that MTX did not decrease CRP, IL-1beta, or interleukin-6 levels. The median follow- up duration in patients was 2.3 years. There was no association between methotrexate use and any of the predefined endpoints. MTX also was associated with a higher incidence of non–basal-cell skin cancers.