COLLABORATIVE CLINICAL TRIALS IN VASCULAR ACCESS

血管通路的协作临床试验

• 批准号: 6800089
• 负责人: BRADLEY S DIXON
• 金额: $ 28.09万
• 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 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6800089
• 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.

东爱荷华州西伊利诺伊州血管通路联盟(EIWIVAC)是由爱荷华大学周围的血液透析单位组成的联盟，由一名血管生物学家和一名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。血液透析血管通路故障是导致并发症的常见原因，也是护理血液透析患者的一项主要费用。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)和自然瘘管(AVF)中。目前提出的假设是，抑制血管平滑肌细胞(VSMC)增殖的药物将减少新生内膜增生，延长血管通路存活时间。HMG辅酶A还原酶抑制剂和潘生丁都被证明能抑制血管平滑肌细胞的增殖。HMG CoA还原酶抑制剂可防止细胞增殖所需的小GTP结合蛋白(如RAS)的异戊二烯基化。双嘧达莫可增加细胞外腺苷水平，其抑制增殖的机制尚不清楚。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，我们提出了一项使用析因设计的随机安慰剂对照一级预防试验，以测试双嘧达莫或HMG CoA还原酶抑制剂的治疗是否会增加新创建的血管通路：AVG或AVF的一级存活率。此外，我们还简要地提出了两个额外的试验。有了通路监测，在通路失败之前检测到狭窄，许多普遍的通路将需要血管成形术。然而，血管成形术后再狭窄率很高，且对多种药物耐药。我们建议在第二个试验中验证这样的假设，即雷帕霉素与HMG CoA还原酶抑制剂联合使用具有更强的抗增殖作用，将抑制血管细胞的增殖，从而导致再狭窄。最后，数据显示，上臂先天性瘘管(UAF)的存活率高于AVG。然而，UAF似乎没有得到充分利用，部分原因是担心高流量，以及心力衰竭和远端盗血综合征增加的可能性。虽然随机试验是不可能的，但我们建议建立一个登记处，以检查UAF和AVG的安全性。如果可以解决安全问题，增加UAF的利用率可能是最具成本效益的干预措施。