Effect of Extended-Release Niacin on Saphenous Vein Graft Atherosclerosis

缓释烟酸对隐静脉移植物动脉粥样硬化的影响

• 批准号: 8121393
• 负责人: Emmanouil Brilakis
• 金额: $ 25.2万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8121393
• 关键词: Angiography; Arterial Fatty Streak; Atherosclerosis; Blood specimen; Bypass; Caliber; Cardiac; Cessation of life; Colony-forming units; Coronary; Coronary Angiography; Coronary Arteriosclerosis; Coronary Artery Bypass; Coronary artery; Diagnostic; Dose; Double-Blind Method; Enrollment; Event; Exercise; Exercise stress test; Failure; Flushing; Goals; High Density Lipoprotein Cholesterol; Hospitalization; Image; Incidence; Institution; Intravascular Ultrasonography; Ischemia; LDL Cholesterol Lipoproteins; Lesion; Lipids; Low-Density Lipoproteins; Measures; Morbidity - disease rate; Near-Infrared Spectroscopy; Nicotinic Acids; Operative Surgical Procedures; Outcome; Patients; Phase; Placebos; Prior Therapy; Public Health; Randomized; Risk; Rupture; Saphenous Vein; Senile Plaques; Spectrum Analysis; Stem cells; Stenosis; Symptoms; acute coronary syndrome; follow-up; graft failure; improved; indexing; mortality; novel; peripheral blood; prevent; public health relevance

DESCRIPTION (provided by applicant): Aortocoronary saphenous vein bypass graft (SVG) failure is common and is associated with high morbidity and mortality. We recently demonstrated that: (a) in spite of intensive statin therapy prior coronary bypass graft surgery (CABG) patients have high cardiac risk; (b) >50% of those patients have low high-density lipoprotein cholesterol (HDL-C) levels; and (c) SVGs have large atherosclerotic burden with rapid intermediate lesion progression causing cardiac events. Endothelial progenitor cells (EPCs) are important for stabilizing coronary atherosclerotic lesions and may be of particular importance in the friable, prone to rupture SVG plaques. Niacin raises HDL-C, restores the re-endothelialization capacity of EPCs, and slowed the progression of SVG atherosclerosis in one trial of statin-naove patients. However, it remains unknown whether niacin can prevent progression (or cause regression) of SVG atherosclerosis along with increased mobilization of EPCs in prior CABG patients who receive intensive statin therapy. We hypothesize that in patients with an intermediate SVG lesion receiving intensive statin therapy, extended-release niacin (ER-niacin) will significantly reduce the percent atheroma volume of the SVG lesion and will increase mobilization of peripherally circulating endothelial progenitor cell colony forming units (EPC-CFU/mL) compared to placebo. We propose 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 for 12 months. All patients will receive a statin with goal low-density lipoprotein cholesterol <70 mg/dL. Coronary angiography, intravascular ultrasonography (IVUS) and near-infrared spectroscopy (NIRS) of the target intermediate SVG lesion will be performed at randomization and after 12 months in each patient, along with exercise stress testing at 1 and 12 months and peripheral blood sampling performed at enrollment and at 1, 3, 6, 9 and 12 months post enrollment. The specific objectives of the proposed study are to determine whether compared to placebo, ER-niacin will result in: (1) reduction of percent atheroma volume (PAV) of the intermediate SVG lesion at 12-month IVUS imaging (primary endpoint); (2) reduction of the target lesion total and normalized total SVG atheroma volume, atheroma volume in the most diseased 10-mm subsegment, atheroma volume in the subsegment with lipid core plaque by near-infrared intracoronary spectroscopy, lipid core burden index as assessed by near-infrared intracoronary spectroscopy, and angiographic failure at 12-month follow-up invasive SVG imaging (secondary endpoints); (3) improved exercise capacity and less ischemia by exercise stress testing from 1 to 12 months; (4) greater increase in EPC-CFU/mL of peripheral blood from baseline to 1, 3, 6, and 12 months post enrollment (secondary endpoint); and (5) reduction of major adverse cardiac events (composite of death, acute coronary syndrome, or coronary revascularization) during follow-up (secondary endpoint). PUBLIC HEALTH RELEVANCE: The Potential Impact on Public Health is the identification of a novel therapy (extended release niacin) that could prevent the failure of saphenous vein bypass grafts in patients with coronary artery disease.

描述(由申请人提供)： 主动脉冠脉大隐静脉搭桥术(SVG)失败是常见的，且与高发病率和死亡率相关。我们最近证实：(A)尽管在冠状动脉旁路移植术(CABG)之前接受了强化的他汀类药物治疗，但患者的心脏风险很高；(B)这些患者中有50%的人高密度脂蛋白胆固醇(HDL-C)水平较低；以及(C)SVG有较大的动脉粥样硬化负担，病变进展迅速，会导致心脏事件。内皮祖细胞(EPC)对于稳定冠状动脉粥样硬化病变很重要，在易碎、易破裂的SVG斑块中可能特别重要。在他汀类药物患者的一项试验中，烟酸提高了高密度脂蛋白-C，恢复了内皮祖细胞的再内皮化能力，并减缓了SVG动脉粥样硬化的进展。然而，在接受强化他汀类药物治疗的冠脉搭桥术患者中，烟酸是否能随着内皮祖细胞动员的增加而阻止SVG动脉粥样硬化的进展(或导致退化)，目前尚不清楚。我们假设，在接受强化他汀类药物治疗的中度SVG病变患者中，与安慰剂相比，缓释烟酸(ER-烟酸)将显著减少SVG病变的动脉粥样硬化体积百分比，并将增加外周循环内皮祖细胞集落形成单位(EPC-CFU/mL)的动员。我们提出了一项II期、单中心、双盲试验，将138名有中度SVG病变(临床显示冠状动脉造影显示血管直径狭窄30%-60%)的CABG患者随机分成两组，高密度脂蛋白-C和高密度脂蛋白胆固醇60 mg/dL，剂量为每天1500-2000 mg，或服用相应的安慰剂，为期12个月。所有患者都将接受目标低密度脂蛋白胆固醇为70 mg/dL的他汀类药物治疗。每个患者将在随机和12个月后对目标中间SVG病变进行冠状动脉造影、血管内超声(IVUS)和近红外光谱(NIRS)检查，并在1和12个月进行运动负荷测试，并在登记时和登记后1、3、6、9和12个月进行外周血液采样。拟议研究的具体目标是确定与安慰剂相比，ER-烟酸是否会导致：(1)在12个月的IVUS成像(主要终点)时，中间SVG病变的动脉粥样硬化体积(PAV)减少；(2)目标病变总的和归一化的SVG动脉粥样硬化体积、病变最严重的10 mm亚节段的动脉粥样硬化体积、近红外冠状动脉内光谱分析的有脂核心斑块的亚节段的动脉粥样硬化体积、近红外冠状动脉内光谱分析评估的脂质核心负荷指数以及12个月随访的侵入性SVG成像(次级终点)的血管造影失败；(3)通过1至12个月的运动负荷测试提高运动能力和减少缺血；(4)外周血EPC-CFU/ml从基线增加到登记后1、3、6和12个月(次要终点)；以及(5)在随访期间(次要终点)减少主要不良心脏事件(包括死亡、急性冠脉综合征或冠状动脉血运重建)。 公共卫生相关性： 对公众健康的潜在影响是确定了一种新的疗法(缓释烟酸)，可以防止冠状动脉疾病患者的大隐静脉搭桥失败。