Clinical trial NCT01221402: Effect of Extended-Release Niacin on Saphenous Vein Graft Atherosclerosis
Official title: Effect of Extended-Release Niacin on Saphenous Vein Graft Atherosclerosis: The Atherosclerosis Lesion Progression Intervention Using Niacin Extended Release in Saphenous Vein Grafts (ALPINE-SVG) Pilot Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Aortocoronary Saphenous Vein Bypass Graft Atherosclerosis
Intermediate Saphenous Vein Graft Lesions
Lead sponsor: North Texas Veterans Healthcare System
Sponsor class: FED
Collaborators: name: National Institutes of Health (NIH)
name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2010-10-15
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Original plan was to enroll 138 subjects, but trial was terminated early and total randomized was 38.
Primary purpose: TREATMENT

Brief summary: Intermediate saphenous vein graft (SVG) lesions are common, have high rates of progression to severe lesions or occlusion, and are associated with high incidence of adverse clinical outcomes.

The ALPINE-SVG trial is a randomized-controlled trial of extended-release niacin vs. placebo in patients with intermediate saphenous vein graft lesions. The main hypothesis of the study is that compared to placebo, niacin administration will result in reduction in percent atheroma volume at 12-month follow-up angiography.

Detailed description: 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)

Eligibility criteria: 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

Primary outcomes:
measure: change in percent atheroma volume at 12 months intravascular ultrasonography
timeFrame: 12 months
Secondary outcomes:
measure: change in total and normalized total intermediate SVG lesion atheroma volume
timeFrame: 12 months
measure: reduction of atheroma volume in the most diseased 10-mm subsegment of the target intermediate lesion
timeFrame: 12 months
measure: reduction of atheroma volume in the subsegment of the target intermediate lesion with lipid core plaque by near-infrared spectroscopy
timeFrame: 12 months
measure: lipid core burden index as assessed by near-infrared intracoronary spectroscopy
timeFrame: 12 months
measure: 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
timeFrame: 12 months
measure: angiographic intermediate SVG target lesion failure
timeFrame: 12 month
measure: exercise capacity and ischemia, as assessed by exercise stress testing
timeFrame: 12 months
measure: carotid intima-media thickness
timeFrame: 6 and 12 months
measure: reactive hyperemia index
timeFrame: 12 months
measure: EPC-CFU/mL of peripheral blood
timeFrame: 12 months
measure: major adverse cardiac events (defined as the composite of death, acute coronary syndrome, or coronary revascularization)
timeFrame: 12 months
Other outcomes:
Locations:
city: Dallas
country: United States
facility: VA North Texas Healthcare System
state: Texas
Study officials:
affiliation: North Texas Veterans Healthcare System
name: Emmanouil S Brilakis, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kotsia AP, Rangan BV, Christopoulos G, Coleman A, Roesle M, Cipher D, de Lemos JA, McGuire DK, Packer M, Banerjee S, Brilakis ES. Effect of Extended-Release Niacin on Saphenous Vein Graft Atherosclerosis: Insights from the Atherosclerosis Lesion Progression Intervention Using Niacin Extended Release in Saphenous Vein Grafts (ALPINE-SVG) Pilot Trial. J Invasive Cardiol. 2015 Oct;27(10):E204-10.
citation: Guerra A, Rangan BV, Coleman A, Xu H, Kotsia A, Christopoulos G, Sosa A, Chao H, Han H, Abdurrahim G, Roesle M, de Lemos JA, McGuire DK, Packer M, Banerjee S, Brilakis ES. Effect of Extended-Release Niacin on Carotid Intima Media Thickness, Reactive Hyperemia, and Endothelial Progenitor Cell Mobilization: Insights From the Atherosclerosis Lesion Progression Intervention Using Niacin Extended Release in Saphenous Vein Grafts (ALPINE-SVG) Pilot Trial. J Invasive Cardiol. 2015 Dec;27(12):555-60.