Tadalafil for Pulmonary Hypertension Associated with Chronic Lung Disease

他达拉非治疗与慢性肺病相关的肺动脉高压

• 批准号: 8967191
• 负责人: Ronald Howard Goldstein
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8967191
• 关键词: Accident and Emergency department; Activities of Daily Living; Address; Admission activity; Attenuated; Award; Bioavailable; Biological Availability; Blood Vessels; Boston; Cardiopulmonary; Chronic; Chronic Disease; Chronic Obstructive Airway Disease; Chronic lung disease; Clinical; Clinical Management; Clinical Research; Clinical Trials; Cyclic GMP; Data Reporting; Development; Disease; Disease Progression; Double-Blind Method; Dyspnea; Echocardiography; Economic Burden; Enrollment; Ensure; Enzymes; Exercise; Failure; Frequencies; Functional disorder; Future; Gases; Health; Healthcare Systems; Heart failure; Home environment; Hospitalization; Hospitals; Hypoxia; Investigation; Left; Left Ventricular Function; Los Angeles; Lung; Lung diseases; Measures; Mechanics; Medical center; Morbidity - disease rate; Nitric Oxide; Observational Study; Outcome; Outcome Measure; Oxygen; Oxygen Consumption; Oxygen Therapy Care; Patients; Physiological; Placebo Control; Population; Pulmonary Capillary Wedge Pressure; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary artery structure; Quality of life; Questionnaires; Randomized Clinical Trials; Randomized Controlled Trials; Relaxation; Research; Resources; Right Ventricular Function; Risk; Role; Severities; Severity of illness; Signal Transduction; Site; Smooth Muscle Myocytes; Staging; Systolic Pressure; Testing; Therapeutic; Vascular Diseases; Vascular Smooth Muscle; Vascular remodeling; Ventricular; Veterans; Walking; Wood material; World Health Organization; arteriole; effective therapy; evidence based guidelines; exercise capacity; functional status; health care service utilization; health economics; health related quality of life; hemodynamics; hospital readmission; hypertension treatment; improved; inhibitor/antagonist; innovation; mortality; novel; oxidant stress; patient population; phosphoric diester hydrolase; pressure; prevent; primary outcome; programs; prospective; public health relevance; pulmonary arterial hypertension; pulmonary artery endothelial cell; secondary outcome; social; tadalafil; targeted treatment; treatment strategy; trend; two-dimensional; uptake; vasoconstriction

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.

描述（由申请人提供）： 这项VA CSR＆D的临床试验提案的优异审查奖介绍了一项为期5年的计划，该计划支持一项预期的，由安慰剂控制的，随机的，随机临床试验（RCT）评估磷酸二酯酶5型（PDE-5）抑制磷酸二酯酶5（PDE-5）在40 mg每天在40 mg的运动能力中，在40 mg的运动量（至少是适度的刺激性）（至少）的刺激性（至少）的刺激性putmone pulmony（putmone）（至少）putmonary punmonary putmon的pulmon pulmony（pde）（至少）） [MPAP]> 30 mM Hg，肺血管耐药性[PVR]> 3.0木单元，肺毛细管楔压[PCWP] <18 mm Hg），这是由于慢性阻塞性肺疾病（COPD）金II或更高的II或更高，FEV1/FV1/FVC <70和Fev1 <70和Fev1 <79％的预测）。建议对世界卫生组织（WHO）1 pH值进行PDE-5抑制剂，但没有基于证据的建议支持在COPD诱导的PH（WHO 3组）中使用这些抑制剂。为了确保最大的患者入学率并增加了本研究中包括的患者的临床和人口多样性，拟议的研究将在三个VA站点进行：波士顿VA医疗系统，普罗维登斯VA医疗中心和大洛杉矶VA医疗保健系统。在退伍军人人口中，COPD在最常见的慢性疾病中排名，并在VA医疗保健系统上造成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）是从患者的相对选择的亚群中得出的。有新兴的证据表明，临床上明显的pH是对疾病加重和进展的COPD风险的关键确定。在当前的提案中，我们提供了与VA医疗保健系统有关的新证据来支持这一主张：与具有COPD的类似退伍军人相比，中等或重度与COPD相关的医院再入院率显着提高。此外，这种趋势不受COPD疾病严重程度的常规度量差异（即FEV1）的影响，并且不论补充氧状况如何。这些观察结果是支持先前确立的其他观察结果，这些观察表明，包括补充氧在内的传统COPD疗法无效地调节COPD和pH患者的心肺血流动力学的持续改善。在生理条件下，磷酸二酯酶型5型（PDE-5）通过降解CGMP来维持肺血管张力，这是参与一氧化氮（NO）依赖性信号的关键信号中间体。但是，在由于肺部疾病引起的pH值中，肺血管水平的NO降低，而PDE-5水平升高。这增加了PDE-5抑制是一种潜在的策略，该策略是增加了COPD患者的生物利用度和减弱pH值的潜在策略。当前建议的中心假设是，通过6分钟步行测试评估，PDE-5的药理学抑制作用将提高COPD诱导的中度至重度pH的患者的功能能力。我们的次要结果措施将评估这种功能状态的这种变化是否伴随着心肺检测过程中最大氧气摄取的改善和/或通过通过侵入性心肺血液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肺动脉收缩压和右心室功能的二维超声心动图，呼吸困难严重程度，通过验证的标准化问卷评估的健康质量以及12个月（12个月的COPD恶化频率）评估的非侵入性评估。预计这项研究的结果将定义PDE-5抑制剂在COPD诱导的pH中的潜在使用。如果成功，此治疗方案可能会改善由于COPD而受苦的大量退伍军人的生活质量和成果。