Low-Dose Methotrexate Does Not Reduce Atherosclerotic Events in Stable Atherosclerosis
Low-dose methotrexate did not result in a reduced number of cardiovascular events among patients with stable atherosclerosis. Photo Credit: ISM/ATHENAIS
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For patients with stable atherosclerosis, use of low-dose methotrexate does not decrease cardiovascular (CV) events compared with placebo, according to study data presented at the 2018 American Heart Association Scientific Sessions, held November 10–12, 2018, in Chicago, Illinois.
The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS, ClinicalTrials.gov Identifier: NCT01327846) previously demonstrated that treatment with canakinumab, a monoclonal antibody that neutralizes interleukin-1β, resulted in fewer CV events compared with placebo. Therefore it was hypothesized that inhibition of inflammation with low-dose methotrexate could be an alternative approach to lower CV event rates in high-risk patients.
Study authors conducted the Cardiovascular Inflammation Reduction Trial (CIRT; NCT01594333), a randomized, double-blind, placebo-controlled study (N=4786) that evaluated patients aged ≥18 years with previous myocardial infarction or multivessel coronary disease who also had either type 2 diabetes or metabolic syndrome.
Participants were randomly assigned to receive either low-dose methotrexate (target dose of 15mg to 20mg weekly) or matching placebo. All participants received folate 1mg daily.
The primary endpoint was the first occurrence of a major adverse CV event (a composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death). Hospitalization for unstable angina that led to urgent revascularization was added to the primary endpoint towards the end of the trial.
The data showed low-dose methotrexate did not result in reduced levels of interleukin-1β, interleukin-6, or C-reactive protein vs placebo.
After a median follow-up of 2.3 years, the original primary endpoint occurred in 170 patients in the methotrexate group and in 167 patients in the placebo group (incidence rate [IR] 3.46 vs 3.43 per 100 person-years; hazard ratio [HR] 1.01; 95% CI, 0.82–1.25).
The final primary endpoint occurred in 201 patients in the methotrexate group and in 207 in the placebo group (IR 4.13 vs 4.31 per 100 person-years; HR 0.96; 95% CI, 0.79–1.16).
CV death occurred in 48 patients in the methotrexate group and 43 in the placebo group (IR 0.92 vs 0.80 per 100 person-years; HR 1.14, 95% CI, 0.76–1.72).
Modest elevations in liver enzyme levels, reductions in leukocyte counts and hematocrit levels, as well as an increased incidence of non-basal-cell skin cancers were seen more often with methotrexate than with placebo.
The study authors concluded that low-dose methotrexate did not result in a reduced number of cardiovascular events among patients with stable atherosclerosis.
“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. Understanding these differences is likely to be crucial for future studies targeting inflammation in atherosclerosis,” added study author Paul M. Ridker, MD, from the Center for Cardiovascular Disease Prevention at Brigham and Women's Hospital, Boston, Massachusetts, whose comments were published in The New England Journal of Medicine where the results were co-published.
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- Ridker RM, Everett B, Pradhan A, et al. The cardiovascular inflammation reduction trial (CIRT): Low dose methotrexate for the prevention of atherosclerotic events. Presented at: AHA 2018. November 10-12, 2018; Chicago, Illinois. Session LBS.02 - Late Breaking Clinical Trial: Novel Approaches to CV Prevention.
- Ridker PM, Everett BM, Pradhan A. Low-dose methotrexate for the prevention of atherosclerotic events [published online November 10, 2018]. NEJM. doi:10.1056/NEJMao1809798