Cardiovascular Inflammation Reduction Trial (CIRT):
A randomized, double-blind, placebo-controlled, event-driven trial of weekly
low-dose methotrexate (LDM) in the prevention of cardiovascular events among stable coronary artery disease patients with type 2 diabetes or metabolic syndrome
RATIONALE: Because there has been a great deal of evidence that inflammation plays a major role in atherothrombotic events, we would like to test whether low doses of methotrexate (an antimetabolite that reduces inflammatory biomarkers) will decrease myocardial infarction, stroke, or cardiovascular dealth among patients with a recent history of coronary artery disease and either type 2 diabetes or metabolic syndome. INTERVENTION: First, all consented subjects will be given study drug, low-dose methotrexate (LDM), for a maximum of 8 weeks to see if they can safely tolerate the drug. Second, the subjects will be randomized into either study target dose of 15 to 20 mg po weekly or placebo. Safety and efficacy outcomes will be assessed.PRIMARY AIM: To determine in a randomized, double-blind, placebo-controlled setting whether LDM given at a target dose of 15 to 20 mg po weekly will reduce rates of myocardial infarction, stroke, or cardiovascular death among patients with a prior history of coronary artery disease and either type 2 diabetes or metabolic syndrome.STUDY POPULATION: CIRT will randomize 7,000 men and women, age 18 years and over, who have any past history of myocardial infarction or have multivessel coronary artery disease defined by angiography, have completed any planned coronary revascularization procedures associated with the qualifying event, have been on a stable secondary prevention regimen for a minimum of 60 days, and have either a clinical diagnosis of type 2 diabetes or metabolic syndrome.METHODOLOGY: CIRT is a randomized, double-blind, placebo-controlled, multi-center, event-driven trial. Following a five- to six-week open-label run-in (maximum 8 weeks), eligible participants who have either suffered documented myocardial infarction or have angiographically demonstrated multivessel coronary artery disease will be randomly allocated over a three to four year period to usual care plus placebo or usual care plus LDM. STATISTICS: The randomized design and large sample size of CIRT should provide balanced distributions of baseline characteristics between the two treatment groups; Initial analyses will form part of the routine monitoring of the trial and will be regularly reported to the DSMB. For continuous and ordinal variables, including age and baseline levels of risk factors including lipid levels, blood pressure, and body mass index, comparisons will use the Wilcoxon rank-sum test.