"Inflammation and risk of atherothrombosis: Methotrexate versus placebo". The New England Journal of Medicine. Published on November 10, 2018.
Links to original sources: Wiki Journal Post Full Journal Article
Does low-dose methotrexate reduce cardiovascular events in patients with previous myocardial infarction or multivessel coronary disease who also have type 2 diabetes or the metabolic syndrome?
Low-dose methotrexate did not reduce levels of interleukin-1β, interleukin-6, or C-reactive protein and did not result in fewer cardiovascular events than placebo in patients with stable atherosclerosis and high cardiovascular risk.
The Cardiovascular Inflammation Reduction Trial (CIRT) aimed to evaluate whether inhibiting inflammation with low-dose methotrexate could reduce cardiovascular event rates. Methotrexate is widely used to treat inflammatory conditions, and observational studies suggested a potential for reduced cardiovascular events in patients receiving methotrexate. The trial included patients with previous myocardial infarction or multivessel coronary disease and type 2 diabetes or the metabolic syndrome.
Current guidelines do not recommend low-dose methotrexate for the reduction of cardiovascular events in patients with atherosclerosis and high cardiovascular risk.
- Multicenter, double-blind, parallel group, randomized, placebo-controlled trial - N=4,786 patients with previous myocardial infarction or multivessel coronary disease and either type 2 diabetes or the metabolic syndrome. - Interventions: Low-dose methotrexate (target dose of 15 to 20 mg weekly) or matching placebo. - Median follow-up: 2.3 years - Primary outcome: Composite of nonfatal myocardial infarction, nonfatal stroke, cardiovascular death, and hospitalization for unstable angina leading to urgent revascularization.
- Inclusion Criteria: Patients 18 years or older with a history of myocardial infarction or multivessel coronary disease, stable medical condition, and completed planned revascularization procedures, plus either type 2 diabetes or the metabolic syndrome. - Exclusion Criteria: History of chronic infection, tuberculosis, interstitial pneumonitis, pulmonary fibrosis, alcohol abuse, hepatic or renal dysfunction, class IV heart failure, women of childbearing potential, patients receiving oral glucocorticoids or other immunosuppressive agents. - Baseline Characteristics: Median age of 66 years, 19% women, 22% nonwhite or Hispanic.
Patients received low-dose methotrexate with doses increasing sequentially during the run-in phase. After successful run-in, patients were randomized to continue methotrexate or switch to placebo, both groups receiving daily folate supplementation.
- Primary Outcomes: The 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). - Secondary Outcomes: There were no significant differences in secondary cardiovascular endpoints between the groups. - Adverse Events: Methotrexate was associated with more non–basal-cell skin cancers, elevations in liver-enzyme levels, reductions in leukocyte counts and hematocrit levels compared to placebo.
The trial was terminated early due to futility and lack of evidence for a reduction in inflammation with methotrexate treatment.
Funded by the National Heart, Lung, and Blood Institute (NHLBI). The drug and matching placebo were purchased from Teva Pharmaceuticals, which donated costs for packaging and shipping.
The full article with supplementary material can be accessed on NEJM.org.