Cardiovascular Inflammation Reduction Trial - Inflammation Imaging Study

The NHLBI funded (Ridker 5U01HL101422) Cardiovascular Inflammation Reduction Trial (CIRT)
provides a unique opportunity to investigate whether a commonly used anti-inflammatory agent
used in rheumatoid arthritis (low dose methotrexate (LDM)) can reduce CVD morbidity and
mortality among patients with stable coronary artery disease. CIRT, is a randomized,
double-blind, placebo-controlled, multi-center trial among 7,000 men and women with prior
myocardial infarction or angiographically demonstrated multivessel coronary artery disease.
Eligible participants will be randomly allocated over a three to four year period to usual
care plus placebo or usual care plus LDM (average dose of 15-20 mg po/weekly. CIRT proposes
that the reduction in CVD events with methotrexate derives from its effect on vascular
inflammation, thus it is crucial to incorporate a measure of vascular inflammation imaging
for confirmation of the primary mechanism of action underlying CIRT. As such, the direct
evaluation of arterial inflammation would enhance the scientific value of the CIRT trial.

The inclusion of the proposed vascular inflammation imaging substudy has widespread
implications that will allow this imaging modality to serve as a surrogate measure of
disease, and thereby provide an opportunity for stratification in individuals at risk for CVD
and evaluation of other interventions with presumed anti-inflammatory effects.

Inclusion Criteria:

- Age > 18 years at screening

- Documented MI in the past or past evidence of multivessel coronary artery disease by
angiography must have completed any planned coronary revascularization procedures
associated with the qualifying event, and must be clinically stable for at least 60 d
before screening; the qualifying prior MI must be documented either by hospital
records or by evidence on current electrocardiogram of Q waves in 2 contiguous leads
and/or an imaging test demonstrating wall motion abnormality or scar; the qualifying
documentation of multivessel coronary disease must include angiographic evidence of
atherosclerosis in at least 2 major epicardial vessels defined either as the presence
of a stent, a coronary bypass graft, or an angiographic lesion of 60% or greater. Left
main coronary artery disease that has been revascularized with a stent or bypass graft
will qualify as multivessel disease, as will the presence of a 50% or greater isolated
left main stenosis.

- History of type 2 diabetes or metabolic syndrome at the time of study enrollment

- Willing to participate as evidence by signing the study informed consent

Exclusion Criteria:

1. Prior history of chronic infectious disease, including tuberculosis, severe fungal
disease, or known HIV positive

2. Chronic hepatitis B or C infection

3. Interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis. Chest x-ray evidence
in the past 12 months of interstitial pneumonitis, bronchiectasis, or pulmonary
fibrosis.

4. Prior history of non basal cell malignancy or myeloproliferative or
lymphoproliferative disease within the past 5 years

5. White blood cell count <3,500/mm3, hematocrit <32%, or platelet count <75000/mm3

6. Liver transaminase levels (AST/ALT) greater than the upper limit of normal or albumin
less than the lower limit of normal

7. Creatinine clearance (CrCl) <40 mL/min as estimated by the Cockcroft-Gault equation

8. History of alcohol abuse or unwillingness to limit alcohol consumption to <4 drinks
per week

9. Women of child bearing potential, even if currently using contraception, and women
intending to breastfeed

10. Men who plan to father children during the study period or who are unwilling to use
contraception

11. Requirement for use of drugs that alter folate metabolism
(trimethoprim/sulfamethoxazoyl) or reduce tubular excretion (probenecid) or known
allergies to antibiotics making avoidance of trimethoprim impossible

12. Current indication for methotrexate therapy

13. Chronic use of oral steroid therapy or other immunosuppressive or biologic response
modifiers

14. Known chronic pericardial effusion, pleural effusion, or ascites

15. New York Heart Association class IV congestive heart failure

16. Life expectancy of <3 years

The study population for the ancillary study will be the same as the main trial with the
following additional exclusion criteria

1. Subjects with a history of multiple imaging studies associated with radiation exposure

2. Insulin-dependent diabetics

3. If subject is Type 2 diabetic, hemoglobin A1c greater than 8% as determined by patient
medical record review in the one year prior to the date of consent to this study.

4. BMI greater than 37 kg/m2 or weight greater than 350 pounds