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: 8460841
• 负责人: Emmanouil Brilakis
• 金额: $ 23.75万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460841
• 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).

描述（由申请人提供）： 主动脉冠状动脉隐静脉旁路移植术（SVG）失败是常见的，并与高发病率和死亡率相关。我们最近证明：（a）尽管在冠状动脉旁路移植术（CABG）之前进行了强化的他汀类药物治疗，但患者具有高心脏风险;（B）>50%的这些患者具有低的高密度脂蛋白胆固醇（HDL-C）水平;和（c）SVG具有大的动脉粥样硬化负担，具有引起心脏事件的快速中间病变进展。内皮祖细胞（EPCs）对于稳定冠状动脉粥样硬化病变是重要的，并且在脆弱的、易于破裂的SVG斑块中可能特别重要。在一项他汀类药物初治患者的试验中，烟酸升高HDL-C，恢复EPCs的再内皮化能力，并减缓SVG动脉粥样硬化的进展。然而，烟酸是否能预防SVG动脉粥样硬化的进展（或导致消退）沿着接受强化他汀类药物治疗的既往CABG患者中EPCs动员增加仍是未知数。我们假设，在接受他汀类药物强化治疗的中度SVG病变患者中，与安慰剂相比，烟酸缓释剂（ER-烟酸）将显著降低SVG病变的动脉粥样硬化体积百分比，并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，该试验将138名具有中度SVG病变（在临床指示的冠状动脉造影中，血管造影直径狭窄30%- 60%）且HDL-C<60 mg/dL的先前CABG患者随机分配至剂量为1500-2000 mg/天的ER-烟酸或匹配的安慰剂，持续12个月。所有患者将接受他汀类药物治疗，目标低密度脂蛋白胆固醇<70 mg/dL。将在随机化时和12个月后对每例患者进行靶向中间SVG病变的冠状动脉造影、血管内超声检查（IVUS）和近红外光谱（NIRS）检查，并在入组时和入组后1、3、6、9和12个月进行沿着运动负荷试验和外周血采样。所提议的研究的具体目的是确定与安慰剂相比，ER-烟酸是否将导致：（1）在12个月IVUS成像时中间SVG病变的动脉粥样化体积百分比（PAV）减少（主要终点）;（2）靶病变总体积和标准化总SVG粥样硬化体积、病变最严重的10 mm亚段中的粥样硬化体积减少，通过近红外冠状动脉内光谱测定的具有脂质核心斑块的亚段中的动脉粥样硬化体积，通过近红外冠状动脉内光谱测定的脂质核心负荷指数，以及12个月随访侵入性SVG成像时的血管造影失败（次要终点）;（3）通过1至12个月的运动负荷试验，改善了运动能力，减少了缺血;（4）从基线到入组后1、3、6和12个月，外周血的EPC-CFU/mL增加更大（次要终点）;和（5）减少主要不良心脏事件（死亡、急性冠状动脉综合征或冠状动脉血运重建的复合终点）（次要终点）。

项目成果

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

缓释烟酸对颈动脉内膜中层厚度、反应性充血和内皮祖细胞动员的影响：在隐静脉移植物中使用烟酸缓释剂干预动脉粥样硬化病变进展的见解

• 发表时间: 2015
• 期刊: The Journal of invasive cardiology
• 作者: Guerra,Andres;Rangan,BavanaV;Coleman,Ameka;Xu,Hao;Kotsia,Anna;Christopoulos,Georgios;Sosa,Alan;Chao,Howard;Han,Henry;Abdurrahim,Guthbudeen;Roesle,Michele;deLemos,JamesA;McGuire,DarrenK;Packer,Milton;Banerjee,Subhash;Brila
• 通讯作者: Brila

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.

缓释烟酸对隐静脉移植物动脉粥样硬化的影响：来自在隐静脉移植物中使用烟酸缓释剂进行动脉粥样硬化病变进展干预 (ALPINE-SVG) 试点试验的见解。

• 发表时间: 2015
• 期刊: The Journal of invasive cardiology
• 作者: Kotsia,AnnaP;Rangan,BavanaV;Christopoulos,Georgios;Coleman,Ameka;Roesle,Michele;Cipher,Daisha;deLemos,JamesA;McGuire,DarrenK;Packer,Milton;Banerjee,Subhash;Brilakis,EmmanouilS
• 通讯作者: Brilakis,EmmanouilS

The AngiographiC Evaluation of the Everolimus-Eluting Stent in Chronic Total Occlusion (ACE-CTO) Study.

依维莫司洗脱支架在慢性完全闭塞 (ACE-CTO) 研究中的血管造影评估。

• 发表时间: 2015
• 期刊: The Journal of invasive cardiology
• 作者: Kotsia,Anna;Navara,Rachita;Michael,TesfaldetT;Sherbet,DanielP;Roesle,Michele;Christopoulos,George;Rangan,BavanaV;Haagen,Donald;Garcia,Santiago;Maniu,Calin;Pershad,Ashish;Abdullah,ShuaibM;Hastings,JeffreyL;Kumbhani,DharamJ