The Impact of Diabetes on Revascularization in BEST-CLI

BEST-CLI 中糖尿病对血运重建的影响

• 批准号: 9082587
• 负责人: JOSHUA A BECKMAN
• 金额: $ 82.24万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-07 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9082587
• 关键词: Accounting; Acute; Affect; Age; Agonist; Amputation; Anatomy; Ankle; Aorta; Arterial Fatty Streak; Basal metabolic rate; Blood Platelets; Blood Vessels; Blood flow; Bypass; C-reactive protein; Cessation of life; Clinical; Clinical Research; Complex; Conduct Clinical Trials; Coronary; Diabetes Mellitus; Disease-Free Survival; Distal; Ensure; Environment; Event; Exercise; Failure; Funding; Future; Gangrene; Goals; Hemoglobin; Human; Incidence; Individual; Inflammation; Injury; Insulin Resistance; Interstitial Collagenase; Ischemia; Laboratories; Leg; Limb structure; Link; Lower Extremity; Matrix Metalloproteinases; Measures; Medical; Metabolic; Myalgia; National Heart, Lung, and Blood Institute; Necrosis; Operative Surgical Procedures; Outcome; PAR-1 Receptor; Pain; Pathway interactions; Patients; Perfusion; Peripheral; Peripheral arterial disease; Population; Prevalence; Procedures; Prothrombin; Randomized; Rest; Risk; Role; Site; Stents; Symptoms; System; Testing; Therapeutic; Therapy trial; Thrombectomy; Thrombin; Thrombin Receptor; Thrombophilia; Tissues; Ulcer; Ultrasonography; United States; Vein graft; Work; adjudicate; antithrombin III-protease complex; claudication; comparative effectiveness; diabetic; diabetic patient; effectiveness trial; experience; foot; glycemic control; graft failure; improved outcome; non-diabetic; novel; prospective; public health relevance; receptor; reconstruction; restenosis; thrombolysis; trial comparing

 DESCRIPTION (provided by applicant): Peripheral artery disease is a condition defined by marked accumulation of atherosclerotic plaque below the distal aorta that reduces lower limb arterial perfusion. Blood flow reductions may be inadequate for exercising limbs and cause ischemic muscle pain, called intermitted claudication, or, in severe cases, the reduction may be inadequate for basal metabolism and cause pain at rest, ulceration, or gangrene. The presence of symptoms at rest or tissue necrosis is a medical urgency and represents a state of critical limb ischemia (CLI) where the risk of amputation, in the absence of revascularization, is high. The ageing of the population and the increasing prevalence of diabetes mellitus ensures this population will continue to grow in the foreseeable future. The impact of diabetes, however, is not limited to PAD incidence. Diabetic patients represent a particularly vulnerable subset of PAD patients and have a four-fold risk of CLI compared to non-diabetic patients. Indeed, in previous studies of CLI, more than half of patients have diabetes. As a result, the combination of diabetes and PAD accounts for more than half of non-traumatic amputations in the United States. Diabetic patients often present with foot ulcerations as their first manifestation of PAD and have challenging anatomy for revascularization. Failed vascular reconstructions, both endovascular or surgical, often result in additional tissue loss and transtibial amputations. Despite these challenges, the mechanisms of restenosis and the impact of diabetes have not been well explored for both types of revascularization in patients with CLI. The BEST-CLI trial is a multi-center, randomized, comparative effectiveness trial comparing open surgical bypass therapy to endovascular therapy in CLI patients with a composite clinical endpoint denoted as Major Adverse Limb Event free survival (MALE-free survival). However, the BEST-CLI trial does not study the mechanisms by which revascularization may fail. This proposal will extend the novel clinical work of the BEST-CLI trial by studying the mechanisms of bypass vein graft and stent failure. We will adjudicate the mode of revascularization (vein graft or stent) in a central core laboratory, measure systemic markers of diabetic dysmetabolism, and study multiple steps along the protease-activated receptor 1 activation pathway, linking these factors with graft failure. No trial conducted to date in either coronary or peripheral revascularization has determined the mechanism of revascularization failure, the impact of diabetes, the contribution of PAR1, nor the relationship between conduit patency and clinical outcomes. Therefore, this trial represents a unique opportunity to investigate the mechanisms by which diabetes affects surgical and endovascular revascularization procedures.

 描述（由申请人提供）：外周动脉疾病是指远端主动脉下方动脉粥样硬化斑块明显积聚，导致下肢动脉血流减少，可能不足以锻炼肢体并导致缺血性肌肉疼痛，称为间歇性跛行。或者，在严重的情况下，基础代谢的减少可能不足，导致静息时疼痛、溃疡或坏疽。静息时出现症状或组织坏死是一种原因。医疗紧迫性，并且代表严重肢体缺血（CLI）状态，在没有血运重建的情况下截肢的风险很高。人口老龄化和糖尿病患病率的增加确保了这一人群在可预见的时间内将继续增长。然而，糖尿病的影响不仅限于 PAD 发病率，在之前的研究中，糖尿病患者是 PAD 患者中特别脆弱的一个群体，其患 CLI 的风险是非糖尿病患者的四倍。 CLI，超过一半的患者患有糖尿病，因此，在美国，一半以上的非创伤性截肢患者都是由糖尿病和 PAD 合并而成，糖尿病患者通常以足部溃疡作为 PAD 的首发表现。血运重建的解剖结构失败，无论是血管内重建还是手术重建，通常都会导致额外的组织损失和经胫骨截肢，尽管存在这些挑战，但对于这两种类型的再狭窄和糖尿病的影响尚未得到很好的探索。 BEST-CLI 试验是一项多中心、随机、比较有效性试验，比较 CLI 患者的开放式手术旁路治疗与血管内治疗，其复合临床终点称为无主要不良肢体事件生存期（无 MALE）。然而，BEST-CLI 试验并未研究血运重建可能失败的机制。该提案将通过研究旁路静脉移植和支架失败的机制来扩展 BEST-CLI 试验的新颖临床工作。将在中央核心实验室判定血运重建模式（静脉移植或支架），测量糖尿病代谢异常的全身标志物，并研究蛋白酶激活受体1激活途径的多个步骤，将这些因素与移植失败联系起来。冠状动脉或外周血运重建的日期已经确定了血运重建失败的机制、糖尿病的影响、PAR1的贡献，也确定了导管通畅与临床结果之间的关系。这是研究糖尿病影响的手术机制和血管内血运重建手术的独特机会。