Effect of Extended-Release Niacin on Saphenous Vein Graft Atherosclerosis

This is a phase II, single-center, double-blind trial that will randomize 138 prior CABG
patients with an intermediate SVG lesion (30%-60% angiographic diameter stenosis) on
clinically-indicated coronary angiography, and HDL-C<60 mg/dL to ER-niacin at a dose of
1500-2000 mg daily or matching placebo (containing 50 mg of niacin that can cause flushing
but has no lipid lowering effect) for 12 months. All patients will receive a statin with
goal LDL-C <70 mg/dL. Coronary angiography, intravascular ultrasonography (IVUS), and
intravascular near-infrared intracoronary spectroscopy (NIRS), and optical coherence
tomography (OCT) of the intermediate SVG lesion will be performed at enrollment and after 12
months in each patient, along with exercise stress testing at 1 month and 12 months, B-mode
carotid ultrasound imaging at enrollment and after 6 and 12 months, reactive hyperemia
peripheral arterial tonometry (RH-PAT) at enrollment and after 6 and 12 months, and with
peripheral blood sampling performed at enrollment and at 1, 3, 6, 9 and 12 months, to
determine whether compared to placebo, administration of ER-niacin will result in:

1. Reduction of the percent atheroma volume (PAV) of the intermediate SVG lesion at
12-month follow-up IVUS imaging (primary endpoint)

2. Reduction of total and normalized total intermediate SVG lesion atheroma volume,
reduction of atheroma volume in the most diseased 10-mm subsegment of the target
intermediate lesion, reduction of atheroma volume in the subsegment of the target
intermediate lesion with lipid core plaque by NIRS, reduction of lipid core burden
index as assessed by near-infrared intracoronary spectroscopy, increase in fibrous cap
thickness and reduction in the prevalence and number of microchannels, in the presence
and extent of necrotic lipid pool, plaque rupture, calcification, and thrombus, as
assessed by optical coherence tomography, and reduction of angiographic intermediate
SVG target lesion failure at 12-month follow-up SVG imaging (secondary endpoints)

3. Increased exercise capacity and reduction in ischemia, as assessed by exercise stress
testing between 1 and 12 months (secondary endpoint)

4. Less increase in mean carotid intima-media thickness at 6 and 12 months (secondary
endpoint)

5. Greater increase in natural logarithmic scaled reactive hyperemia index (L_RHI) at 6
and 12 months (secondary endpoint)

6. Greater increase in EPC-CFU/mL of peripheral blood from baseline to 1, 3, 6, and 12
months post enrollment (secondary endpoint)

7. Reduction of major adverse cardiac events (defined as the composite of death, acute
coronary syndrome, or coronary revascularization) during follow-up (secondary endpoint)

Inclusion Criteria:

1. Age 18 years or greater

2. Willing and able to give informed consent. The patients must be able to comply with
study procedures and follow-up.

3. Undergoing clinically-indicated coronary and SVG angiography

4. Have an intermediate SVG lesion (defined as a lesion 30-60% angiographic diameter
stenosis) without previous percutaneous intervention, amenable to examination with
IVUS. The lesion should have no thrombus or ulceration and should not be considered
responsible for the patient's clinical presentation and referral for graft
angiography.

Exclusion Criteria:

1. Known allergy to niacin

2. History of statin-induced myopathy

3. Positive pregnancy test or breast-feeding

4. Coexisting conditions that limit life expectancy to less than 12 months or that could
affect a patient's compliance with the protocol

5. Uncontrolled fasting triglyceride levels ( 500 mg/dL)

6. Fasting LDL-C >200 mg/dL

7. Fasting HDL-C >60 mg/dL

8. Poorly controlled diabetes (glycosylated hemoglobin levels 10%)

9. Current active liver disease or hepatic dysfunction

10. AST or ALT > 2x the upper limit of normal

11. Uncontrolled hypothyroidism (Thyroid Stimulating Hormone >1.5 x upper limit of normal
[ULN])

12. Unexplained creatine kinase elevations (>3 x ULN)

13. Recent history of acute gout

14. Serum creatinine > 2.5 mg/dL

15. HIV (due to potential anti-retroviral drug-interactions with niacin)

16. Use of high-dose, antioxidant vitamins (vitamins C, E, or beta-carotene) that may
interfere with the HDL-raising effect of niacin

17. Severe peripheral arterial disease limiting vascular access

18. Referral for cardiac catheterization by a physician who is an investigator in the
present study.

19. Symptoms consistent with moderate or greater severity of congestive heart failure
(New York Heart Association - NYHA class III or IV) or whose most recent
determination of left ventricular ejection fraction is <25%

20. Uncontrolled hypertension, defined as either a resting diastolic blood pressure of
≥100 mmHg or a resting systolic blood pressure of ≥200 mmHg

21. History of allergic reaction to iodine-based contrast agents

22. Significant medical or psychological condition that, in the opinion of the
investigator, may compromise the patient's safety or successful participation in the
study