Tadalafil for Pulmonary Hypertension Associated with Chronic Lung Disease

描述(由申请人提供)： 退伍军人事务部CSR&D临床试验优秀奖介绍了一项为期5年的计划，以支持一项前瞻性的、安慰剂对照的随机临床试验(RCT)，评估他达拉非在12个月内每天40 mg的磷酸二酯酶-5(PDE-5)抑制对至少中度肺动脉高压(PH)患者的运动能力的影响(平均肺动脉压[mPAP]和GT；30 mm Hg，肺血管阻力[PVR]&gt；3.0 Wood单位，肺毛细血管楔压[PCWP]&lt；由于慢性阻塞性肺疾病(COPD)黄金II期或更高，FEV1/FVC&lt；70和FEV1&lt；预测的79%)。PDE-5抑制剂被推荐用于世界卫生组织(WHO)第1组PH，但没有基于证据的建议支持将这些抑制剂用于COPD诱导的PH(WHO第3组)。为了确保最大限度的患者登记，并增加本研究中患者的临床和人口统计学多样性，拟议的研究将在三个退伍军人管理局地点进行：波士顿退伍军人医疗系统、普罗维登斯退伍军人医疗中心和大洛杉矶退伍军人医疗系统。在退伍军人群体中，慢性阻塞性肺病是最常见的慢性病之一，给退伍军人医疗保健系统带来了巨大的临床和经济负担。重要的是，绝大多数与COPD相关的死亡率和发病率，包括住院，都来自于相对精选的患者亚群。有新的证据表明，临床上明显的PH是COPD病情恶化和疾病进展的关键决定因素。在当前的提案中，我们提供了与退伍军人管理局医疗系统相关的新证据来支持这一断言：与患有COPD的类似退伍军人和仅患有轻度PH的退伍军人相比，中度或重度PH与COPD相关的再住院率显著增加。此外，这一趋势不受COPD疾病严重程度的传统测量方法(即FEV1)的差异的影响，也与补充氧气状况无关。这些观察结果支持了其他人先前建立的临床观察，这些观察表明，传统的COPD疗法，包括补充氧气，在调节COPD和PH患者心肺血流动力学的持续改善方面无效。在生理条件下，磷酸二酯酶-5(PDE-5)通过降解cGMP来维持肺血管张力，cGMP是参与一氧化氮(NO)依赖信号转导的关键信号媒介。然而，在肺疾病所致的PH中，肺血管中NO水平降低，而PDE-5水平升高。这增加了一种可能性，即PDE-5抑制是一种潜在的策略，通过它来增加COPD患者的NO生物利用度和减轻PH。目前这项提议的中心假设是，通过6分钟步行试验评估，药物抑制PDE-5将改善COPD引起的中到重度PH患者的功能能力。我们的次要结果指标将评估这种功能状态的改变是否伴随着心肺测试期间最大摄氧量的改善和/或有创心肺血流动力学评估的肺血管重构的变化。将获得的其他信息包括通过二维超声心动图对肺动脉收缩压和右室功能进行的非侵入性评估、呼吸困难的严重程度、通过经过验证的标准化问卷评估的与健康相关的生活质量，以及12个月后COPD恶化的频率。这项研究的结果有望确定PDE-5抑制剂在COPD诱导的PH中的潜在用途。如果成功，这种治疗方案可能会改善因慢性阻塞性肺病而患有PH的大量退伍军人的生活质量和结果。

DESCRIPTION (provided by applicant): This VA CSR&D Merit Review Award for a Clinical Trial proposal describes a 5-year program to support a prospective, placebo-controlled, randomized clinical trial (RCT) evaluating the effect of phosphodiesterase type-5 (PDE-5) inhibition with tadalafil at 40 mg daily over 12 months on exercise capacity in patients with at least moderate pulmonary hypertension (PH) (mean pulmonary artery pressure [mPAP] > 30 mm Hg, pulmonary vascular resistance [PVR]>3.0 Wood units, pulmonary capillary wedge pressure [PCWP] <18 mm Hg) due to chronic obstructive pulmonary disease (COPD) GOLD stage II or higher, FEV1/FVC <70 and FEV1 <79% of predicted). PDE-5 inhibitors are recommended for World Health Organization (WHO) Group 1 PH but there is no evidence based recommendation supporting the use of these inhibitors in COPD-induced PH (WHO Group 3). In order to ensure maximum patient enrollment and to increase the clinical and demographic diversity of patients included in this study, the proposed research will be conducted at three VA sites: Boston VA Healthcare System, Providence VA Medical Center, and the Greater Los Angeles VA Healthcare System. Within the veteran population, COPD ranks among the most common chronic diseases and inflicts a substantial clinical and economic burden on the VA Healthcare System. Importantly, the vast majority of COPD-associated mortality and morbidity, including hospital admissions, is derived from a relatively select subpopulation of patients. There is emerging evidence to suggest that clinically evident PH is a key determinate of risk in COPD for exacerbations and progression of disease. In the current proposal, we provide novel evidence pertinent to the VA Healthcare System to support this assertion: moderate or severe PH is associated with significantly increased rates of COPD-related hospital readmission as compared to similar veterans with COPD and only mild PH. Moreover, this trend was not influenced by differences in conventional measures of COPD disease severity (i.e., FEV1) and was irrespective of supplemental oxygen status. These observations are in support of previously established clinical observations from others demonstrating that traditional COPD therapies, including supplemental oxygen, are ineffective at modulating sustained improvements to cardiopulmonary hemodynamics in patients with COPD and PH. Under physiological conditions, the enzyme phosphodiesterase type-5 (PDE-5) functions to maintain pulmonary vascular tone by degrading cGMP, which is a key signaling intermediary involved in nitric oxide (NO)-dependent signaling. However, in PH due to lung disease, pulmonary vascular levels of NO are diminished while PDE-5 levels are increased. This raises the possibility that PDE-5 inhibition is a potential strategy by which to increase NO bioavailability and attenuate PH in patients with COPD. The central hypothesis of the current proposal is that pharmacological inhibition of PDE-5 will improve functional capacity in patients with COPD-induced moderate to severe PH as assessed by the 6 minute walk test. Our secondary outcome measures will assess whether this change in functional status are accompanied by an improvement in maximal oxygen uptake during cardio-pulmonary testing and/or changes in pulmonary vascular remodeling assessed by invasive cardiopulmonary hemodynamics. Additional information that will be obtained includes non-invasive assessment by 2-dimensional echocardiography of pulmonary artery systolic pressure and right ventricular function, dyspnea severity, health related quality of life assessed by validated standardized questionnaires, and, the frequency of COPD exacerbations at 12 months. Results from this study are expected to define the potential use of PDE-5 inhibitors in COPD-induced PH. If successful, this treatment option may improve quality of life and outcomes for the large number of veterans afflicted with PH due to COPD.