DIPYRIDAMOLE IN VASCULAR ACCESS FOR HEMODIALYSIS

本提案的长期目标是确定使用双嘧达莫是否有效改善终末期肾病患者慢性血液透析治疗中用于透析通道的扩展聚四氟乙烯（ePTFE）移植物的功能。目前，美国有超过17万名患者接受慢性血液透析治疗。对于这些患者，血管通路通畅的问题被称为透析过程中的“阿喀琉斯之踵”。此外，ePTFE移植物狭窄和血栓形成的发展降低了透析治疗的质量，增加了透析患者的感染风险。维持血液透析患者血管通路通畅每年的成本约为7871美元，估计每年全球成本超过10亿美元。最近的证据表明，在几乎所有病例中，ePTFE移植物血栓形成仅发生在移植物静脉吻合处或更远端的静脉狭窄发展之后。这些静脉狭窄的发生是由于一种称为内膜增生的病理过程。最近一项小型、单中心、前瞻性、随机、安慰剂对照临床试验的证据表明，双吡啶达摩可能降低慢性血液透析患者ePTFE移植物血栓形成率。双嘧达莫的作用机制可能是通过抑制血管平滑肌细胞增殖，从而减少内膜增生和相关静脉狭窄的发生。本研究的具体目的是：1)探讨双嘧达莫在慢性血液透析移植ePTFE患者中预防吻合口和静脉狭窄的疗效；2)探讨双嘧达莫预防新移植ePTFE慢性血液透析患者血栓形成的疗效。为了回答特定目的，提出的研究设计是一项随机、前瞻性、双盲、安慰剂对照、平行组临床试验。需要新的ePTFE假体移植的慢性血液透析患者将在入组后的12个月内随机接受双吡啶达摩或安慰剂治疗，或直到ePTFE移植失败。入选的患者将接受血管通道血流的连续监测，已知这是即将发生的血管通道衰竭的生理预测指标，并采用临床指示的干预措施来预防血管通道衰竭。研究设计将检验双嘧达莫不影响血液透析患者新ePTFE移植物静脉狭窄或血栓形成的零假设。

The long-term objective of this proposal is to establish whether or not the use of dipyridamole is efficacious in improving the function of expanded polytetrafluoroethylene (ePTFE) grafts used for dialysis access in patients with end stage renal disease on chronic hemodialysis therapy. Currently, there are over 170,000 patients in the US on chronic hemodialysis therapy. For these patients, problems with vascular access patency have been called the "Achilles Heel" of the dialysis procedure. Furthermore, the development of ePTFE graft stenosis and thrombosis reduces the quality of delivered dialysis therapy and increases the infection risk for patients on dialysis. Maintaining vascular access patency costs approximately $7,871 per hemodialysis patient per year at risk with an estimated annual global cost of more than one billion dollars. Recent evidence suggests that in almost all cases, ePTFE graft thrombosis occurs only after the development of a stenosis either at the graft vein anastomosis or more distally in the vein. These venous stenoses occur because of a pathological process known as intimal hyperplasia. Recent evidence from a small, single-center, prospective, randomized, placebo-controlled clinical trial has suggested that dipyridamole may reduce the rate of ePTFE graft thrombosis in chronic hemodialysis patients. The mechanism of dipyridamole efficacy may be by inhibiting vascular smooth muscle cell proliferation and thereby reducing the development of intimal hyperplasia and associated venous stenoses. The specific aims of this proposal are: l) To investigate the efficacy of dipyridamole in preventing the development of anastomotic and venous stenoses in patients on chronic hemodialysis with ePTFE grafts; and 2) To investigate the efficacy of dipyridamole in preventing the development of thrombosis in patients on chronic hemodialysis with new ePTFE grafts. In order to answer the Specific Aims, the proposed study design is a randomized, prospective, double-blind, placebo-controlled, parallel group clinical trial. Patients on chronic hemodialysis therapy who require a new prosthetic ePTFE graft will be randomized to receive either dipyridamole or placebo for a period of 12 months after enrollment or until ePTFE graft failure. Enrolled patients will undergo serial monitoring of vascular access blood flow, known to be a physiologic predictor of impending vascular access failure, with clinically indicated interventions to prevent vascular access failure. The study design will test the null hypothesis that dipyridamole does not affect the development of either venous stenosis or thrombosis in new ePTFE grafts in hemodialysis patients.