COLLABORATIVE CLINICAL TRIALS IN VASCULAR ACCESS

血管通路的协作临床试验

• 批准号: 6524359
• 负责人: BRADLEY S DIXON
• 金额: $ 27.28万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6524359
• 关键词: HMG coA reductases; arteriovenous shunt surgery; chemoprevention; chronic renal failure; clinical research; clinical trials; combination chemotherapy; cooperative study; dipyridamole; enzyme inhibitors; hemodialysis; human subject; human therapy evaluation; patient /disease registry; sirolimus

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.

爱荷华州东部和伊利诺伊州西部血管通路联盟 (EIWIVAC) 是一个围绕爱荷华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的问题。血液透析血管通路失败是发病的常见原因，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。该过程发生在动静脉移植物（AVG）和自体瘘管（AVF）中。本提议的假设是抑制血管平滑肌细胞（vsmc）增殖的药物将减少新内膜增生并延长血管通路存活期。 HMG CoA 还原酶抑制剂和双嘧达莫均已被证明可以抑制血管平滑肌细胞增殖。 HMG CoA 还原酶抑制剂可防止细胞增殖所需的小 GTP 结合蛋白（例如 Ras）的异戊二烯化。 双嘧达莫可增加细胞外腺苷水平，从而通过尚不清楚的机制抑制增殖。我们实验室的研究表明，低剂量使用这些药物联合治疗在抑制 vsmc 增殖方面具有相加甚至协同作用。因此，我们提出了一项随机安慰剂对照一级预防试验，使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创建的血管通路（AVG 或 AVF）的初级存活率。此外，我们简要提出了两项​​额外的试验。通过通路监测以在通路失败之前检测狭窄，许多流行的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，并且对许多药物具有耐药性。我们建议在第二项试验中检验以下假设：雷帕霉素与 HMG CoA 还原酶抑制剂联合使用，具有更有效的抗增殖作用，可抑制平滑肌细胞增殖，从而导致再狭窄。最后，数据显示上臂原生瘘管 (UAF) 的生存率优于 AVG。然而，UAF 似乎未得到充分利用，部分原因是担心高流速以及增加心力衰竭和远端盗血综合征的可能性。虽然不可能进行随机试验，但我们建议建立一个注册中心来检查 UAF 与 AVG 相比的安全性。如果安全问题能够得到解决，增加 UAF 的利用率可能是最具成本效益的干预措施。