DIPYRIDAMOLE IN VASCULAR ACCESS FOR HEMODIALYSIS

本提案的长期目标是确定使用潘生丁是否能有效改善接受长期血液透析治疗的终末期肾病患者透析通路所用的膨体聚四氟乙烯（ePTFE）移植物的功能。目前，美国有超过170，000名患者接受慢性血液透析治疗。对于这些患者，血管通路通畅性问题被称为透析过程的“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输送的透析治疗的质量，并增加了透析患者的感染风险。维持血管通路通畅性的成本约为每名血液透析患者每年7，871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静脉更远端处发生狭窄后。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，双嘧达莫可以降低慢性血液透析患者的ePTFE移植物血栓形成率。潘生丁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展。本提案的具体目的是：1）研究潘生丁在预防使用ePTFE移植物进行慢性血液透析的患者发生吻合口和静脉狭窄方面的疗效; 2）研究潘生丁在预防使用新型ePTFE移植物进行慢性血液透析的患者发生血栓形成方面的疗效。为了实现特定目的，拟定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。需要新的人工ePTFE移植物的长期血液透析治疗患者将在入组后随机接受双嘧达莫或安慰剂治疗12个月或直至ePTFE移植物失效。入组的患者将接受血管通路血流的系列监测，已知血管通路血流是即将发生血管通路失败的生理预测因子，采用临床指征干预措施预防血管通路失败。研究设计将检验零假设，即双嘧达莫不会影响血液透析患者新ePTFE移植物中静脉狭窄或血栓形成的发生。

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.