COLLABORATIVE CLINICAL TRIALS IN VASCULAR ACCESS

东爱荷华州西伊利诺伊州血管通路联盟（EIWIVAC）是围绕爱荷华州大学的血液透析单位联盟，由血管生物学家和临床试验设计专家共同创立，旨在解决血管通路失败问题。血液透析血管通路故障是一种常见的发病原因，也是护理血液透析患者的主要费用。通路失败的原因是新生内膜增生导致狭窄和血栓形成。这一过程发生在动静脉移植物（AVG）和自体瘘（AVF）中。本研究的假设是，抑制血管平滑肌细胞（vsmc）增殖的药物可以减少新生内膜增生并延长血管通路存活。HMG CoA还原酶抑制剂和双嘧达莫均显示出抑制血管平滑肌细胞增殖。HMG CoA还原酶抑制剂防止细胞增殖所需的小GTP结合蛋白如Ras的异戊二烯化。 双嘧达莫增加细胞外腺苷水平，可通过不清楚的机制抑制增殖。我们实验室的研究表明，低剂量的这些药物联合治疗在抑制vsmc增殖方面是相加的，甚至是协同的。因此，我们提出了一项随机安慰剂对照一级预防试验，采用析因设计来测试双嘧达莫或HMG CoA还原酶抑制剂治疗是否会增加新建血管通路（AVG或AVF）的一级生存率。此外，我们简要地提出了两个额外的试验。通过通路监测在通路失效之前检测狭窄，许多常见通路将需要血管成形术。然而，血管成形术后的再狭窄率非常高，并且对许多药理学试剂具有抗性。我们建议在第二项试验中测试雷帕霉素与HMG CoA还原酶抑制剂组合的更有效的抗增殖作用将抑制平滑肌细胞增殖导致再狭窄的假设。最后，数据显示上臂自体瘘管（UAF）的生存率上级AVG。然而，UAF似乎未得到充分利用，部分原因是担心高入路流速以及心力衰竭和远端盗血综合征增加的可能性。虽然不可能进行随机试验，但我们建议建立一项登记研究，以检查UAF与AVG相比的安全性。如果安全性问题能够得到解决，增加UAF的使用可能是最具成本效益的干预措施。

The Eastern Iowa Western Illinois Vascular Access Consortium (EIWIVAC) is a consortium of hemodialysis units surrounding the University of Iowa co-founded by a vascular biologist and an expert in clinical trials design to address the problem of vascular access failure. Hemodialysis vascular access failure is a frequent cause of morbidity and a major expense in caring for hemodialysis patients. The cause of access failure is neointimal hyperplasia leading to stenosis and thrombosis. This process occurs in both arteriovenous grafts (AVG) and native fistulas (AVF). The hypothesis underlying the present proposal is that pharmacological agents that inhibit vascular smooth muscle cell (vsmc) proliferation will decrease the neointimal hyperplasia and prolong vascular access survival. Both HMG CoA reductase inhibitors and dipyridamole have been shown to inhibit vascular smooth muscle cell proliferation. HMG CoA reductase inhibitors prevent the isoprenylation of small GTP binding proteins such as Ras that are needed for cell proliferation. Dipyridamole increases extracellular adenosine levels that can inhibit proliferation by unclear mechanisms. Studies from our lab have shown that combined treatment with these agents in low doses is additive or even synergistic at inhibiting vsmc proliferation. Therefore, we propose a randomized placebo controlled primary prevention trial using a factorial design to test whether treatment with either dipyridamole or an HMG CoA reductase inhibitor will increase primary survival of a newly created vascular access: either an AVG or an AVF. In addition, we briefly propose two additional trials. With access monitoring to detect stenosis before access failure, many prevalent accesses will require angioplasty. However, the restenosis rate after angioplasty is very high and resistant to many pharmacological agents. We propose in a second trial to test the hypothesis that the more potent antiproliferative effects of rapamycin in combination with an HMG CoA reductase inhibitor will inhibit the smooth muscle cell proliferation leading to restenosis. Finally, data shows that an upper arm native fistula (UAF) has superior survival to an AVG. However, the UAF appears to be underutilized in part because of concerns over high access flow rates and the possibility of increased heart failure and distal steal syndromes. While a randomized trial is not possible, we propose to establish a registry to examine the safety of a UAF compared to an AVG. If safety issues can be addressed, increased utilization of UAF may be the most cost-effective intervention.