While inflammation contributes crucially to atherothrombosis and patients with elevated levels of the inflammatory biomarker hsCRP have increased vascular risk, it is unknown whether inhibition of inflammation per se will lower vascular event rates. The primary aim of the proposed Cardiovascular Inflammation Reduction Trial (CIRT) is to directly test the inflammatory hypothesis of atherothrombosis by evaluating whether or not low-dose methotrexate (LDM) will reduce rates of recurrent myocardial infarction, stroke, and cardiovascular death among patients with stable cardiovascular disease who are at increased risk indicated by persistent elevations of hsCRP. The investigators propose to conduct a randomized, double-blind, placebo-controlled, multi-center trial among 7,000 men and women with prior myocardial infarction and hsCRP>2mg/L and <20mg/L. Eligible participants will be randomly allocated over a three to four year period to usual care plus placebo or usual care plus LDM (initial dose 10 mg po per week with a safety-based titration to 15 mg po per week after 4 months based on evidence of safety and tolerability). Study participants will additionally receive 1 mg daily oral folate. Although widely considered safe in contemporary practice settings, LDM complications will further be minimized by mandatory bi-annual education programs for all investigators and coordinators, through weekly telephone communication with all study participants, by limiting enrollment to those with no evidence of malignancy, hepatitis, renal dysfunction, chronic infection, or other methotrexate risk factors, by conducting an initial 4-week active-therapy run-in designed to eliminate individuals intolerant to treatment before randomization, and through monthly monitoring of liver function and hematologic indices using a centralized methodology designed to ensure participant safety, allow for dose reductions while maintaining the study blind, and provide an efficient method to address issues of compliance and follow- up on a cost-effective centralized basis. The primary trial endpoint will include non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, with additional monitoring for all-cause mortality. Secondary endpoints include diabetes, venous thrombosis, and atrial fibrillation, all of which have an inflammatory basis. The study team assembled has extensive experience in the design, initiation, conduct, and analysis of large-scale randomized trials and in the clinical use of LDM. Our external rheumatology consultants all feel the dose of LDM is safe for this post-MI population and that LDM is free of the confounding effects on lipids, glucose, and thrombosis that significantly limit other agents including hydroxychloroquine. The potential clinical impact of this trial is broad as it has sufficient power to directly address core issues in the inflammatory hypothesis of atherothrombosis, and thus, if successful, will open major new directions for cardiovascular treatment. (End of Abstract) PUBLIC HEALTH RELEVANCE: