Methotrexate has no role in the secondary prevention of atherothrombotic events in patients with a history of myocardial infarction or coronary artery disease.

Results from the Cardiovascular Inflammation Reduction Trial (CIRT) of low-dose methotrexate versus placebo in almost 5,000 patients found no impact on laboratory measures of inflammation or clinical end points.

Patients also had additional risk factors such as type 2 diabetes or the metabolic syndrome. All received 1mg folate daily.

Treatment with methotrexate (15-20mg weekly) did not reduce levels of C-reactive protein (CRP), interleukin-1β or interleukin-6 compared to placebo.

And after a median follow-up of 2.3 years, the incidence rate of the primary end-point (non-fatal MI, nonfatal stroke, CV death or hospitalisation for unstable angina) was 4.13 with methotrexate and 4.31 with placebo.

Cardiovascular deaths occurred in 49 patients in the methotrexate groups and 43 in the control group. Rates of serious adverse events were also similar on both groups.

There was also no observed effect of methotrexate in sub-groups of patients based on type of index event, time since index event, metabolic status or baseline CRP.

The trial was predicated on evidence from the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) that the monoclonal antibody selectively targeting interleukin-1β inhibits inflammation and lowers the rate of cardiovascular events.

And observational studies in patients with rheumatoid and psoriatic arthritis have also suggested that low dose methotrexate reduced cardiovascular events.

The CIRT authors said the mechanism for methotrexate’s efficacy in rheumatoid arthritis was probably related to adenosine-mediated anti-inflammatory effects.

“Thus, although abundant data indicate that inflammation contributes critically to atherothrombosis, an important provisional hypothesis deriving from these two contemporary trials is that reducing the risk of cardiovascular events may depend on the pathway targeted.”