Prasugrel for prevention of early saphenous vein graft thrombosis

描述(由申请人提供)： 早期主动脉-冠状动脉大隐静脉搭桥术(SVG)的失败是常见的，并与高发病率和死亡率相关。阿司匹林显著降低早期隐静脉移植失败的发生率，而氯吡格雷的使用在小型随机研究中提供了相互矛盾的结果。普拉格雷是一种新型的硫代吡啶，与氯吡格雷相比，它能提供更快、更稳定、更强烈的血小板抑制作用。然而，在接受冠状动脉搭桥手术的患者中，尚不清楚普拉格雷是否可以在术后第一年减少大隐静脉移植物的血栓形成，从而减少大隐静脉移植物管壁的增厚，减少大隐静脉管壁的脂质沉积，减少临床事件，而不增加严重出血的风险。我们假设，在接受临床指征的冠状动脉搭桥手术的患者中，从冠状动脉搭桥手术住院指数出院开始服用普拉格雷将导致目标SVG中血栓形成的发生率较低，这是通过手术后12个月进行的光学相干断层扫描与安慰剂进行的评估得出的结果，大出血的发生率与安慰剂相似。我们提出了一项第三阶段、单中心、双盲试验，将120名接受临床指示的冠状动脉搭桥手术的患者随机分成两组，从医院出院时开始，每天服用10毫克的普拉格雷或匹配的安慰剂，为期12个月。所有患者都将服用阿司匹林。12个月后将进行冠脉造影、光学相干断层扫描、血管内超声和近红外光谱检查。这项拟议研究的具体目标是确定与安慰剂相比，给予普拉格雷是否会导致：(1)在随访12个月的光学相干断层成像(主要疗效终点)时，移植物内血栓的发生率降低；(2)使用链激酶和t-PA在冠状动脉闭塞(GUSTO)标准下的相似的严重出血发生率(主要安全终点)；(3)减少总的和归一化总的目标隐静脉移植物动脉粥样斑块体积，并降低12个月随访的隐静脉移植物成像(次要终点)的近红外冠状动脉内光谱学评估的隐静脉移植物脂质核心负荷指数；以及(4)减少主要不良心脏事件，定义为死亡、急性冠脉综合征或冠状动脉血运重建)。 公共卫生相关性： 对退伍军人医疗保健的潜在影响是确定了一种新的疗法(普拉格雷)，该疗法可以防止我们的退伍军人冠状动脉疾病患者的大隐静脉搭桥手术早期失败。

DESCRIPTION (provided by applicant): Early aortocoronary saphenous vein bypass graft (SVG) failure is common and is associated with high morbidity and mortality. Aspirin significantly reduces the incidence of early saphenous vein graft failure, whereas clopidogrel use provided conflicting results in small randomized studies. Prasugrel is a novel thienopyridine that provides more rapid, consistent, and intense platelet inhibition than clopidogrel. However, in patients who undergo coronary artery bypass graft surgery, it remains unknown whether prasugrel may decrease thrombus formation in saphenous vein grafts during the first postoperative year, leading to less saphenous vein graft wall thickening, less lipid deposition in the saphenous vein graft wall and fewer clinical events without increasing the risk for severe bleeding. We hypothesize that in patients undergoing clinically-indicated coronary artery bypass graft surgery, administration of prasugrel starting at dismissal from the index coronary bypass graft surgery hospitalization will result in lower prevalence of thrombus formation in a target SVG, as assessed by optical coherence tomography performed 12 months post surgery compared to placebo, with similar incidence of major bleeding. We propose a phase III, single-center, double-blind trial that will randomize 120 patients undergoing clinically-indicated coronary artery bypass graft surgery to prasugrel at a dose of 10 mg daily or matching placebo for 12 months, starting at the time of hospital dismissal from surgery. All patients will receive aspirin. Coronary angiography, optical coherence tomography, intravascular ultrasonography, and near-infrared spectroscopy of one target saphenous vein graft will be performed at 12 months. The specific objectives of the proposed study are to determine whether compared to placebo, prasugrel administration will result in: (1) reduction of the prevalence of intragraft thrombus at 12-month follow-up optical coherence tomography imaging (primary efficacy endpoint); (2) similar incidence of severe bleeding using the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) criteria (primary safety endpoint); (3) reduction of total and normalized total target saphenous vein graft atheroma volume and reduction of saphenous vein graft lipid core burden index as assessed by near-infrared intracoronary spectroscopy at 12-month follow-up saphenous vein graft imaging (secondary endpoints); and (4) reduction of major adverse cardiac events, defined as the composite of death, acute coronary syndrome, or coronary revascularization) during follow-up (secondary endpoints). PUBLIC HEALTH RELEVANCE: The Potential Impact on Veterans Health Care is the identification of a novel therapy (prasugrel) that could prevent the early failure of saphenous vein bypass grafts in our veteran patients with coronary artery disease.