Tadalafil for Pulmonary Hypertension Associated with Chronic Lung Disease

描述（由申请人提供）： 这个VA CSR&D临床试验提案的优异评审奖描述了一个为期5年的项目，以支持一个前瞻性的，安慰剂对照的，在至少中度肺动脉高压（PH）患者中评价他达拉非40 mg每日一次对5型磷酸二酯酶（PDE-5）抑制作用持续12个月对运动能力的影响的随机临床试验（RCT）（平均肺动脉压[mPAP] > 30 mm Hg，肺血管阻力[PVR]>3.0 Wood单位，肺毛细血管楔压[PCWP] <18 mm Hg），由于慢性阻塞性肺疾病（COPD）GOLD II期或更高，FEV 1/FVC <70且FEV 1 <预测值的79%）。PDE-5抑制剂被推荐用于世界卫生组织（WHO）第1组PH，但没有证据支持这些抑制剂用于COPD诱导的PH（WHO第3组）。为了确保最大限度地招募患者并增加本研究中纳入的患者的临床和人口统计学多样性，拟定研究将在三个VA中心进行：波士顿VA医疗保健系统、普罗维登斯VA医疗中心和大洛杉矶VA医疗保健系统。在退伍军人群体中，COPD是最常见的慢性疾病之一，给VA医疗保健系统造成了巨大的临床和经济负担。重要的是，绝大多数COPD相关的死亡率和发病率，包括住院率，来自相对选择的患者亚群。有新的证据表明，临床上明显的PH是COPD疾病加重和进展风险的关键决定因素。在目前的提案中，我们提供了与VA医疗保健系统相关的新证据来支持这一论断：与患有COPD和仅轻度PH的类似退伍军人相比，中度或重度PH与COPD相关的再入院率显著增加相关。此外，这种趋势不受COPD疾病严重程度的常规测量差异的影响（即，FEV 1），且与辅助供氧状态无关。这些观察结果支持了先前建立的来自其他人的临床观察结果，这些临床观察结果表明，传统的COPD治疗（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，5型磷酸二酯酶（PDE-5）通过降解cGMP来维持肺血管张力，其是参与一氧化氮（NO）依赖性信号传导的关键信号传导中间体。然而，在肺疾病引起的PH中，NO的肺血管水平减少，而PDE-5水平增加。这增加了PDE-5抑制是增加COPD患者NO生物利用度和减轻PH的潜在策略的可能性。当前提案的中心假设是，PDE-5的药理学抑制将改善COPD诱导的中度至重度PH患者的功能能力，如6分钟步行试验所评估的。我们的次要结局指标将评估这种功能状态的变化是否伴随着心肺测试期间最大摄氧量的改善和/或通过有创心肺血流动力学评估的肺血管重塑的变化。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心室功能、呼吸困难严重程度、通过经验证的标准化问卷评估的健康相关生活质量以及12个月时COPD急性加重的频率进行无创评估。这项研究的结果预计将确定PDE-5抑制剂在COPD诱导的PH中的潜在用途。如果成功，这种治疗选择可能会改善大量因COPD而患有PH的退伍军人的生活质量和结局。

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.