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）： 该 VA CSR&D 临床试验优异评审奖描述了一项为期 5 年的计划，旨在支持一项前瞻性、安慰剂对照、随机临床试验 (RCT)，该试验评估他达拉非在 40 岁时抑制 5 型磷酸二酯酶 (PDE-5) 的效果12 个月内每天服用 1 毫克，对至少患有中度肺动脉高压 (PH) 的患者的运动能力（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) 因慢性阻塞性肺疾病 (COPD) GOLD II 期或更高，FEV1/FVC <70 且 FEV1 < 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，但没有基于证据的建议支持在 COPD 引起的 PH（WHO 第 3 组）中使用这些抑制剂。为了确保最大程度的患者入组并增加本研究中患者的临床和人口多样性，拟议的研究将在三个 VA 地点进行：波士顿 VA 医疗系统、普罗维登斯 VA 医疗中心和大洛杉矶 VA 医疗中心系统。在退伍军人群体中，慢性阻塞性肺病是最常见的慢性疾病之一，给退伍军人管理局医疗系统造成巨大的临床和经济负担。重要的是，绝大多数与慢性阻塞性肺病相关的死亡率和发病率，包括住院人数，都来自相对选定的患者亚群。新出现的证据表明，临床上明显的 PH 是 COPD 病情加重和进展风险的关键决定因素。在当前提案中，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点：与患有 COPD 且仅有轻度 PH 的类似退伍军人相比，中度或重度 PH 与 COPD 相关的再入院率显着增加相关。此外，这一趋势不受 COPD 疾病严重程度的常规测量（即 FEV1）差异的影响，并且与补充氧气状态无关。这些观察结果支持了其他人先前建立的临床观察结果，表明传统的 COPD 疗法（包括补充氧气）无法有效调节 COPD 和 PH 患者心肺血流动力学的持续改善。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，cGMP 是参与一氧化氮 (NO) 依赖性信号传导的关键信号中介。然而，在肺病引起的 PH 中，肺血管 NO 水平降低，而 PDE-5 水平升高。这提出了一种可能性，即 PDE-5 抑制是一种潜在策略，可通过该策略增加 COPD 患者的 NO 生物利用度并减弱 PH。当前提案的中心假设是，通过 6 分钟步行测试评估，PDE-5 的药理学抑制将改善 COPD 引起的中度至重度 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/或通过侵入性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进行无创评估、呼吸困难严重程度、通过经过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 恶化的频率。这项研究的结果预计将确定 PDE-5 抑制剂在 COPD 引起的 PH 中的潜在用途。如果成功，这种治疗方案可能会改善大量因慢性阻塞性肺病而患有肺动脉高压的退伍军人的生活质量和预后。