Coronary Flow Reserve to Assess Cardiovascular Inflammation (CIRT-CFR)
Condition: Coronary Heart Disease; Metabolic Syndrome; Diabetes Mellitus
MeSH terms: Heart Diseases; Coronary Disease; Coronary Artery Disease; Myocardial Ischemia; Metabolic Syndrome; Inflammation
Study type: Interventional

Summary: 
      Coronary flow reserve (CFR, calculated as the ratio of hyperemic over rest myocardial blood
      flow) is emerging as a powerful quantitative prognostic imaging marker of clinical
      cardiovascular risk. CFR provides a robust and reproducible clinical measure of the
      integrated hemodynamic effects of epicardial coronary artery disease (CAD), diffuse
      atherosclerosis, and microvascular dysfunction on myocardial tissue perfusion. Inflammation
      is a key mediator of this constellation of abnormalities, affecting the entire coronary
      vasculature, but no clinical trial to date has shown that directly reducing inflammation
      lowers cardiovascular event rates. As such, the recently launched Cardiovascular Inflammation
      Reduction Trial (CIRT) provides a unique opportunity for mechanistic investigation of the
      impact of anti-inflammatory therapy on changes in CFR as a reflection of coronary vascular
      dysfunction, which may precede clinical outcomes, particularly in patients at high-risk of
      events. The investigators are ideally positioned to examine the impact of inflammation on
      CFR, having extensive experience in both the quantitation of CFR using clinically-integrated
      dynamic positron emission tomography (PET) and the ability to assess its association with
      cardiovascular outcomes. The central hypothesis of this ancillary proposal, CIRT-CFR, is that
      reducing systemic inflammation using low-dose methotrexate (LDM) will, compared to placebo,
      quantitatively improve myocardial blood flow and coronary flow reserve as measured by PET
      over one year, in stable CAD patients with type 2 diabetes or metabolic syndrome enrolled in
      CIRT. In so doing, improvement in coronary vasoreactivity, endothelial function, and tissue
      perfusion may have beneficial effects on myocardial mechanics, left ventricular deformation
      and function and, ultimately, symptoms and prognosis.
    

Detailed description: 
      Randomization and double-blind study treatment period to either placebo or LDM (1:1) of
      willing and eligible patients will occur at the end of the open label run-in phase per the
      parent CIRT protocol, and will be stratified by time since the qualifying event (< 6 or ≥ 6
      months from the date of MI or most recent angiogram), type of event (MI or multivessel CAD),
      presence of either type 2 DM or metabolic syndrome, and site, which will ensure balance in
      the proposed study. Patients willing to participate in CIRT will be asked to enroll into the
      sub-study and may sign the CIRT-CFR informed consent at any point between signing the parent
      CIRT informed consent and completing the parent CIRT randomization visit (Visit 4). After
      giving informed consent for the ancillary CIRT-CFR, patients will undergo the baseline PET
      scan along with echocardiography at any point between the parent CIRT post run-in visit
      (Visit 3) and up to 4 weeks after randomization (Visit 4).

      Imaging will be performed at the 3 imaging centers (BWH, OHI, and UAB). To minimize
      participant and site burden, only a baseline and single follow-up imaging time point will be
      pursued. Imaging tests (PET and echo) will be scheduled on the same day for patient
      convenience if possible, and no more than one week apart. "Baseline" study visit imaging will
      follow the open label run-in period of the parent trial to enhance long-term compliance and
      eliminate risk of radiation exposure for any individuals with immediate intolerance to the
      LDM study protocol. The imaging tests proposed are non-invasive, routinely performed, and
      historically well tolerated by patients.
    

Intervention name(s): PET scan; Echocardiogram
Intervention type(s): Radiation; Radiation
Intervention description(s): A cardiac PET scan will be performed at baseline (main CIRT trial randomization) and at 12-months.; An echocardiogram will be performed at baseline (main CIRT trial randomization) and at 12-months.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: The CIRT-CFR study is a sub-study based off the main CIRT trial.
Masking: Double (Participant, Investigator)
Primary purpose: Diagnostic