Anti-Inflammatory Therapy May Not Prevent Atherosclerotic Events Low-Dose Methotrexate for the Prevention of Atherosclerotic Events

A randomized double-blinded trial called Cardiovascular Inflammation Reduction Trial (CIRT) recently published in the New England Journal of Medicine by Ridker, M.D. and his colleges at  the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, Boston illustrated that that low-dose methotrexate did not reduce atherosclerotic events or any markers of inflammation such as interleukin-1β, interleukin-6, or C-reactive protein.

It has been speculated that inflammation plays a crucial role in atherothrombosis. In a previous study, called the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), interleukin1β inhibition with canakinumab, a monoclonal agent against interleukin-1β, conferred a significant decrease in recurrent risk of myocardial infarction. Therefore, this provided evidence in favor of the opinion that the inhibition of inflammation could prevent atherosclerotic events. The CIRT trial, thus, sought to test this hypothesis with the use of an alternative approach to inflammatory inhibition such as low-dose methotrexate and aimed to observe if it would provide similar benefits.

 

In the CIRT trial, 4786 patients with previous cardiac events were placed under double-blind of low-dose methotrexate (at a target dose of 15 to 20 mg weekly) or matching placebo and were assessed for the secondary prevention of atherothrombotic events. Nonfatal myocardial infarction or stroke, cardiovascular death and urgent revascularization with hospitalization were all considered as the primary endpoint. However, unlike the CANTOS trial, low-dose methotrexate did not result in lower interleukin-1β, interleukin-6, or C-reactive protein levels, neither did it lower the incidence of the primary endpoint as compared to placebo. The investigators reported that the final primary endpoint occurred in 201 patients in the methotrexate group and in 207 in the placebo group (incidence rate, 4.13 vs. 4.31 per 100 person-years; hazard ratio, 0.96; 95% confidence interval [CI], 0.79 to 1.16). The original primary endpoint occurred in 170 patients in the methotrexate group and in 167 in the placebo group (incidence rate, 3.46 vs. 3.43 per 100 person-years; hazard ratio, 1.01; 95% CI, 0.82 to 1.25). Furthermore, it was found that methotrexate was also associated with several adverse events such as elevations in liver-enzyme levels, reductions in leukocyte counts and hematocrit levels, including a higher incidence of a higher incidence of non–basal-cell skin cancers in comparison with placebo.

In an editorial comment by Karol E. Watson M.D. from the NEJM JOURNAL WATCH , it was stated that “The CIRT trial did not reduce markers of inflammation, therefore it neither confirmed nor refuted the inflammatory hypothesis of atherosclerosis. The authors note that a significant difference between CIRT and CANTOS was that CANTOS, by design, included patients with higher baseline inflammatory risk as evidenced by a persistently elevated high-sensitivity C-reactive protein level (median, 4.2 mg/L in CANTOS vs. 1.6 mg/L in CIRT).” Thus discerning that anti-inflammatory therapy may not have any impact if there is not a lot of inflammation, to begin with, or if the anti-inflammatory agent chosen does not effectively decrease inflammation.”