Does Low Dose Methotrexate Prevent Athersclerotic Events in Patients?

Mahshid Mir
By Mahshid Mir on

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).

“The observations in CANTOS, CIRT, and other trials highlight the importance of considering the mechanistic diversity of inflammatory pathways in atherosclerosis and of exploring approaches to their inhibition.” -Paul Ridker et al.

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.

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