Project Summary/Abstract 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) PH (mean pulmonary artery pressure (mPAP) \> 25 mm Hg, pulmonary vascular resistance (PVR)\>3.0 Woods units, pulmonary capillary wedge pressure (PCWP) \<18 mm Hg) due to chronic obstructive pulmonary disease (COPD) GOLD stage II or higher, FEV1FVC \<70). PDE-5 inhibitors are recommended for World Health Organization (WHO) Category 1 PH but there is no evidence based recommendation supporting the use of these inhibitors in COPD-induced PH (WHO Category 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 four VA sites: Boston VA Healthcare System, Providence VA Medical Center, the Greater Los Angeles VA Healthcare System , Atlanta VA and Denver VA. The research team includes senior investigators with extensive experience in the clinical management of patients with COPD and PH. The principal investigators (PI) for this study is Dr. Ronald H. Goldstein (Chief, Pulmonary Medicine at the Boston Healthcare System) and Dr Sharon Rounds (Chief, Medical Service, Providence VA). Dr Shelley Shapiro will serve as site PI at 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. The investigators found that 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., forced expiratory volume in 1 second \[FEV1\]) 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. It is established in specific forms of PH in which hypoxia is not the central mediator of disease progression that restoration of NO--dependent signaling in pulmonary vascular tissue is effective at attenuating pulmonary vascular remodeling to improve cardiopulmonary hemodynamics, exercise tolerance, and quality of life. The extent to which therapies that preserve NO--dependent signaling in pulmonary vascular tissue are effective in PH due to chronic lung disease, however, is not known.

Under physiological conditions, the enzyme phosphodiesterase type-5 (PDE-5) functions to maintain pulmonary vascular tone by degrading cGMP a key signaling intermediary involved in 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, and sets the framework for the central hypothesis of the current proposal is that pharmacological inhibition of PDE-5 will improve functional capacity as assessed by 6 minute walk test in patients with COPD-induced moderate to severe PH. The secondary outcome measures will assess whether this change in functional status is accompanied by an improvement in maximal oxygen uptake during cardiopulmonary testing (VO2) and changes in vascular remodeling as assessed by cardiopulmonary hemodynamics. To test this hypothesis, a RCT will be conducted using tadalafil (40 mg orally daily) or placebo. The primary outcome measurements will be the six minute walk test. The secondary outcome measures will be functional assessment using peak volume of oxygen consumption (VO2) and the hemodynamic measures of PVR and mPAP. Additional information will be obtained related to the non-invasive assessment of pulmonary artery systolic pressure and right ventricular (RV) function including tricuspid annular plane systolic excursion, pulmonary artery acceleration time, and changes to the pulmonary outflow tract Doppler envelope, dyspnea, health related quality of life assessed by validated standardized questionnaires and the frequency of COPD exacerbations after 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.