A Clinical Trial of Aspirin and Simvastatin in Pulmonary Arterial Hypertension

描述(由申请人提供)： 内皮功能障碍和血小板聚集可导致肺动脉收缩、有丝分裂、血栓形成和血管闭塞。对二十烷类物质代谢异常和内皮素-1(ET-1)产生增加的认识是了解PAH病理生理机制的主要进展。肠外注射前列环素类似物和ET-1受体拮抗剂现在是治疗PAH的标准药物。虽然这些疗法干预内皮功能障碍的下游影响，但没有一种疗法充分解决近端内皮损伤或血小板反应。 HMG-CoA还原酶抑制剂(他汀类)和阿司匹林是数百万人使用的非常安全、高效的心血管疗法。辛伐他汀可降低胆固醇，稳定内皮细胞层，增加一氧化氮的生物利用度，减少氧化应激，并减少炎症。 阿司匹林抑制血小板血栓素A2的产生，抑制血小板聚集。我们已经在动物模型和人类PAH中研究了辛伐他汀和阿司匹林，取得了令人鼓舞的结果。增加一氧化氮和减少血小板聚集可能会降低肺血管阻力和增加心输出量，从而改善PAH的预后。我们设计了一项第二阶段试验，以最高的效率和最低的费用启动对这两种潜在有用疗法的研究。我们提出了一项随机、安慰剂对照的2×2析因辛伐他汀和阿司匹林试验，招募了128名患者来回答这些问题 具体目标： 1)研究辛伐他汀对PAH患者6个月运动功能的影响。 2)研究阿司匹林对PAH患者6个月运动功能的影响。我们假设辛伐他汀和阿司匹林可以增加慢性阻塞性肺疾病患者6分钟步行距离。 啊哈。 3)观察6个月时辛伐他汀对PAH患者血管内皮功能障碍和损伤的影响。我们假设与安慰剂相比，辛伐他汀会增加肱动脉血流介导的扩张和降低von Willebrand因子。 4)确定阿司匹林对PAH患者的血小板功能是否有影响。我们假设，与安慰剂相比，阿司匹林将降低PAH患者6个月内的可溶性P-选择素、血清血栓素B2和/Mh球蛋白。PAH对年轻人造成影响，极大地缩短了他们的寿命。我们的目标是研究安全但创新的治疗方法，以重塑肺血管并改善这种目前无法治愈的疾病的结果。

DESCRIPTION (provided by applicant): Endothelial dysfunction and platelet aggregation cause pulmonary artery vasoconstriction, mitogenesis, thrombosis, and vascular obliteration in pulmonary arterial hypertension (PAH) The recognition of abnormal eicosanoid metabolism and increased endothelin-1 (ET-1) production were major advances in understanding the pathophysiology of PAH. Parenteral prostacyclin analogs and ET-1 receptor antagonists are now the standard of care for PAH. While these therapies intervene on downstream effects of endothelial dysfunction, none adequately addresses the proximal endothelial insult or the platelet response. HMG-CoA reductase inhibitors (statins) and aspirin are very safe, highly-effective cardiovascular therapies used by millions of people. Simvastatin decreases cholesterol, stabilizes the endothelial cell layer, increases the bioavailability of nitric oxide, reduces oxidative stress, and decreases inflammation. Aspirin arrests platelet thromboxane A2 production, inhibiting platelet aggregation. We have studied simvastatin and aspirin in animal models and humans with PAH with encouraging results. Increasing nitric oxide and reducing platelet aggregation will likely decrease pulmonary vascular resistance and increase cardiac output, therefore improving outcomes in PAH. We have designed a Phase II trial to initiate the study of these two potentially useful therapies with maximum efficiency and minimum expense. We propose a randomized, placebo-controlled 2 X 2 factorial trial of simvastatin and aspirin enrolling 128 patients to answer these Specific Aims: 1) To determine whether simvastatin affects exercise function at six months in patients with PAH. 2) To determine whether aspirin affects exercise function at six months in patients with PAH. We hypothesize that simvastatin and aspirin will increase the distance walked in six minutes in patients with PAH. 3) To determine whether simvastatin affects endothelial dysfunction and injury at six months in patients with PAH. We hypothesize that simvastatin will increase brachial artery flow-mediated dilatation and lower von Willebrand factor compared to placebo. 4) To determine whether aspirin affects platelet function in patients with PAH. We hypothesize that aspirin will decrease soluble P-selectin, serum thromboxane B2, and /Mhromboglobulin in patients with PAH compared to placebo over six months. PAH strikes young individuals, drastically shortening their lifespan. We aim to investigate safe but innovative therapies which could remodel the pulmonary vasculature and improve outcomes in this currently incurable disease.