Cardiovascular Inflammation Reduction Trial (CIRT)

• Rate of recurrent major cardiovascular events [ Time Frame: Up to six years ] [ Designated as safety issue: No ]
  Investigate whether low-dose methotrexate (LDM) will reduce rates of recurrent myocardial infarction, stroke, and cardiovascular death among stable post-myocardial infarction patients with type 2 diabetes or metabolic syndrome.
  
  

• Rate of all-cause mortality [ Time Frame: Up to six years ] [ Designated as safety issue: No ]
  
• Rate of the primary endpoint plus coronary revascularization [ Time Frame: Up to six years ] [ Designated as safety issue: No ]
  
• Rate of hospitalization for congestive heart failure [ Time Frame: Up to six years ] [ Designated as safety issue: No ]
  
• Rate of primary endpoint plus all-cause mortality plus coronary revascularization plus congestive heart failure [ Time Frame: Up to six years ] [ Designated as safety issue: No ]
  
• Rate of new onset type 2 diabetes among those with metabolic syndrome but not diabetes at study entry [ Time Frame: Up to six years ] [ Designated as safety issue: No ]
  

• Rate of the primary endpoint plus unstable angina requiring unplanned coronary revascularization [ Time Frame: Up to six years ] [ Designated as safety issue: No ]
  
• Rate of coronary revascularization [ Time Frame: Up to six years ] [ Designated as safety issue: No ]
  
• Rate of peripheral artery disease [ Time Frame: Up to six years ] [ Designated as safety issue: No ]
  
• Rate of symptomatic deep vein thrombosis or pulmonary embolism, including those considered to be provoked and those considered to be idiopathic [ Time Frame: Up to six years ] [ Designated as safety issue: No ]
  
• Rate of clinically significant aortic stenosis [ Time Frame: Up to six years ] [ Designated as safety issue: No ]
  
• Rate of atrial fibrillation [ Time Frame: Up to six years ] [ Designated as safety issue: No ]
  

While inflammation contributes crucially to atherothrombosis, it is unknown whether inhibition of inflammation per se will lower vascular event rates. The primary aim of the 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 stable post-myocardial infarction patients with type 2 diabetes or metabolic syndrome, conditions associated with an enhanced pro-inflammatory response. CIRT is a randomized, double-blind, placebo-controlled, multi-center, event-driven trial that will randomize 7,000 men and women from the United States and Canada. Following a five- to six-week open-label run-in (maximum 8 weeks), eligible participants who have suffered documented myocardial infarction in the past five years will be randomly allocated over a three to four year period to usual care plus placebo or usual care plus LDM. The target methotrexate dose among those allocated to active therapy is 15 to 20 mg po per week, a dose within the range of that commonly used for the treatment of rheumatoid arthritis. All study participants will additionally receive 1.0 mg oral folate to be taken daily six days per week. LDM complications will be minimized through education programs for all investigators and coordinators, through enhanced communication with study participants, by limiting enrollment to those with no evidence of malignancy, hepatitis, renal dysfunction, chronic infection, pulmonary disease, or other risk factors for toxicity; by conducting an initial 5- to 6-week active-therapy run-in (maximum 8 weeks) designed to eliminate individuals who are either intolerant of or unable to adhere to treatment before randomization; and through regular monitoring of liver function and hematologic indices using a centralized methodology designed to ensure participant safety, allow for dose adjustments 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 is the rate of recurrent myocardial infarction, stroke, or cardiovascular death. Secondary and tertiary endpoints include all-cause mortality, coronary revascularization, incident congestive heart failure, incident peripheral artery disease, incident venous thrombosis, clinically significant aortic stenosis, incident atrial fibrillation, incident diabetes among those with metabolic syndrome but not diabetes at study entry, and hemoglobin A1c (HbA1c) control among those with diabetes at study entry. The trial is event driven such that in the absence of extreme effects, the trial will conclude after accrual of at least 530 primary endpoints, an effect estimated to provide 90 percent power to detect a 25 percent relative risk reduction. The potential clinical impact of CIRT 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.