HYPOTHESES

• Rosiglitazone in diabetic patients with previous coronary bypass surgery may prevent or slow the progression of atherosclerosis in SVGs and native coronary arteries.
• Rosiglitazone has favorable effects on adipose tissue distribution variables as well as on thrombosis, pro-inflammatory, and lipid profiles in diabetic patients after coronary bypass artery surgery.
• Rosiglitazone therapy influences favorably metabolism and clinical outcomes in diabetic patients after coronary artery bypass surgery.

OBJECTIVES

• PRIMARY To assess the efficacy of rosiglitazone to reduce atherosclerosis progression in vein grafts in diabetic patients after coronary bypass surgery by using IVUS imaging after a 12 mo follow-up.

• SECONDARY

  • To prospectively compare the secondary IVUS endpoints.
  • To prospectively compare the angiographic endpoints.
  • To prospectively compare the metabolic risk factor endpoints.
  • To prospectively compare the body composition and distribution endpoints.
  • To prospectively compare the clinical outcomes of rosiglitazone versus standard care using composite endpoints.

STUDY DESIGN

This is a prospective multicenter randomized placebo-controlled double-blind trial assessing the efficacy and safety of rosiglitazone in the prevention of atherosclerosis progression in vein grafts and native coronary arteries of diabetic patients. Stable diabetic patients with previous coronary bypass surgery (≥ 1 year ≤ 10 years) will be screened. After baseline evaluation, all eligible patients will undergo baseline coronary angiogram. IVUS will be performed in a segment length of at least 40 mm in a SVG suitable for IVUS analysis and in a segment length of at least 20 mm in the anastomosed native coronary artery corresponding to the SVG chosen. Following the IVUS procedure, patients will be randomized to either rosiglitazone treatment or to placebo in addition to their standard clinical care. Study drug will be titrated over an 8-week period up to a dose of 8 mg/day (or to maximum tolerated dose). The patients will receive the study drug or the placebo for 50-54 weeks in a double-blind manner. At the beginning and at 2, 4, 6, 8, 10 and 12 months of treatment, patients will be subjected to a set of morphological, physiological and metabolic evaluations. At the final visit (12 months), patients will also be submitted to IVUS and angiography.

Inclusion Criteria:

AT SCREENING:

1. Male or female, aged ≥ 40 years & ≤ 75 years.
2. Women of childbearing potential with contraceptive measure, or of non-childbearing potential or surgically sterile.
3. Type 2 diabetes mellitus.
4. Patients with no new medication for hyperglycemia and no change in dose of oral hypoglycemic medication within the last 3 mo prior to screening.
5. Diabetic patients with ischemic heart disease and CABG with at least one SVG (≥1 yr & ≤10 yrs).
6. Patient agrees to participate.
7. Patient legally capable of giving consent and understand what participation in study entails, potential risks and benefits, freedom to withdraw without any prejudice to subsequent medical arrangement or treatment, sign an ICF prior to any protocol specific procedure.

AT IVUS & ANGIOGRAPHY (VISIT 2):

Subject eligible if at least 1), 2) and 3) of the following criteria apply:

1. Patient with at least 1 patent SVG.

2. Segment length of at least 40 mm in SVG suitable for IVUS.

3. Reference of target (SVG) diameter ≥ 2.5 mm.

   If anastomosed native coronary artery or non grafted coronary artery can be evaluated, the following criteria must be met:

4. Reference of target anastomosed native coronary artery or non grafted coronary artery diameter≥ 2.5 mm.

5. Segment length of at least 20 mm in anastomosed native coronary artery corresponding to SVG chosen or, in case of impossibility of performing IVUS in the anastomosed coronary artery, a non grafted coronary artery (≥ 30 mm length segment) might be used for reference.

Exclusion Criteria:

AT SCREENING:

1. Clinically significant abnormality at screening tests & exams.
2. Type 1 diabetes or history of diabetic ketoacidosis.
3. Uncontrolled type 2 diabetes mellitus.
4. Recent MI or ACS (≤ 90 days).
5. History of hypersensitivity to thiazolidinediones (TZD) or compounds of similar chemical structures.
6. Last LVEF≤ 35%.
7. SBP>170mmHg or DBP>100mmHg at screening/baseline should be appropriately treated and under control prior to randomization.
8. Unstable or Canadian Cardiovascular Society class III and IV angina, acute heart failure or congestive heart failure (NYHA class III and IV).
9. History of hepatocellular reaction/severe oedema/other potentially fluid-related AE associated with use of any TZD or PPAR-γ agonist.
10. Hepatic disease.
11. Renal dysfunction.
12. Anemia.
13. TG ≥ 10 mmol/L.
14. History of PCI in all SVG(s).
15. Known occlusion(s) of all SVG(s).
16. Treatment involving TZD within 3 mo prior to screening.
17. Chronic use (≥ 6 mo) of insulin for glycemic control at any time in the past or administration of insulin any time within the last 12 mo.
18. Allergy to contrast agents.
19. Current intake of anorectic agents or have been taken off an anorectic agent or equivalent within 3 mo prior to screening.
20. Patients for whom oral or injectable corticosteroids are used on a regular or recurrent basis.
21. Recent history/suspicion of current drug abuse or alcohol abuse within last 6 mo.
22. Women breast feeding, pregnant, or planning to become pregnant during conduct of trial and for 30 days after study completion.
23. Other illness that precludes survival.
24. History of malignancy within the last 5 yrs.
25. Concurrent participation in other investigational device or drug studies and/or having received any experimental therapeutic agents within 30 days of the screening.
26. Use of any investigational drug for glycemic control within 3 mo of the screening.
27. Patient travelling out of town/country for periods exceeding 2 mo.
28. Medical condition which may interfere with intake and/or absorption of study medication.
29. Patients unwilling or unable to comply with procedures.
30. Recent major surgery within 90 days of the screening.

AT IVUS AND ANGIOGRAPHY (VISIT 2):

1. PCI was performed on the target segment(s) after CABG.
2. Target SVG and/or target native coronary artery show ≥ 50% angiographic lesion precluding IVUS.
3. Thrombus/thrombus aspect in target vessels.
4. Target vessel has been subjected to surgical endarterectomy.