Tadalafil for Pulmonary Hypertension Due to Chronic Lung Disease
Tadalafil for Pulmonary Hypertension Due to Chronic Lung Disease
The functional, social, and economic burden of chronic obstructive lung disease (COPD) on the
 healthcare system is extraordinary. COPD is the fourth leading cause of death in the United
 States, and some estimates attribute up to $33.2 billion in health care costs to
 COPD-associated morbidity and mortality annually. The burden of COPD to the VA Healthcare
 system parallels these findings. According to the VA HSR&D Health Economics Resource Center,
 COPD ranks 5th among the 40 most common chronic clinical conditions in the U.S. Veteran
 patient population, is responsible for >14,000 VA hospital admission annually, and increases
 by $1,051/patient the total annual health care cost burden on the VA Healthcare system.
 Importantly, COPD is associated with frequent emergency room visitation and/or
 hospitalization patients. Pulmonary hypertension is a common co-morbid condition that worsen
 morbidity and mortality in patients with COPD. This study will examine the potential for
 tadalafil, a phosphodiesterase type-5 (PDE-5) inhibitor to improve functional status by
 decreasing pulmonary hypertension. Results from this study are expected to define the
 potential use of PDE-5 inhibitors in COPD-induced pulmonary hypertension. If successful, this
 treatment option may improve quality of life and outcomes for the large number of Veterans
 afflicted with PH due to COPD.
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.
Inclusion Criteria:

 -  Male and female U.S. Veteran patients 40-85 years old, with Gold Stage II COPD by
 pulmonary function testing (FEV1/FVC <0.70; performed within 6 months of recruitment.

 -  Eligible subjects must have PH documented on transthoracic echocardiogram within 6
 months of baseline visit demonstrating an RV systolic pressure >40mmHg. To confirm the
 presence of PH, a right-heart catheterization will be performed, with subjects
 randomized to treatment only if catheterization shows a:

 -  mPAP >25 mm Hg

 -  PVR >2.5 Wood units

 -  pulmonary artery capillary wedge pressure 18 mm Hg or less at rest

 -  PH belonging to the following subgroup of the updated Dana Point Clinical
 Classification:

 -  Group 3 (PH associated with lung disease and/or hypoxemia) specifically, Group
 3.1 (chronic obstructive pulmonary disease [COPD]) as the major criteria.
 Patients may also have minor clinical features associated with 3.2 (Interstitial
 disease) (such as mild fibrosis on high resolution chest CT, but total lung
 capacity>80% predicted) and 3.3 (sleep disordered breathing) (AHI <15 or
 20/hour).

 -  6-minute walk distance between 50-450 meters at screening visit.

 Exclusion Criteria:

 -  PH belonging to the following subgroups of the updated Dana Point Clinical
 Classification:

 Group 1

 -  Idiopathic

 -  heritable

 -  drug or toxin-induced

 -  Associated Pulmonary Arterial Hypertension (APAH) with:

 -  connective tissue disease

 -  congenital heart disease

 -  or HIV

 Group 2

 -  left atrial hypertension

 Group 4

 -  chronic thromboembolic PH

 -  or other forms of PH not associated with primary lung disease

 Also

 -  Patients with a history of systemic hypotension in the ambulatory setting
 (reproducible measurements of systolic blood pressure <89 mmHg) on chart review.

 -  Patients with moderate or severe hepatic impairment (Child-Pugh B and C)

 -  Patients with severe renal insufficiency (GFR <30 ml/min/1.73 m2)

 -  Severe aortic stenosis (aortic valve area <1.0 cm2)

 -  Patients with any acute or chronic impairment:

 -  (other than dyspnea), limiting the ability to comply with the study requirements,
 including the 6-minute walk test and right heart catheterization.

 -  Patients with a recent stroke

 -  Patients with untreated hypoxemia (SaO2 <92%) at rest

 -  Patients with untreated moderate or severe obstructive sleep apnea (AHI>15)

 -  Patients with any coagulopathy

 -  Patients requiring nitrate therapy for any clinical indication

 -  Patients with an active prescription for pulmonary vasodilator medication other than
 oxygen

 -  Patients with a history of nonarteritic anterior ischemic optic neuropathy

 -  Contraindication to tadalafil use including allergy to:

 -  any PDE-5 inhibitor

 -  anatomical deformations of the penis

 -  sickle cell anemia

 -  multiple myeloma

 -  leukemia

 -  bleeding disorders

 -  active peptic ulcer disease

 -  retinitis pigmentosa or other retinal disorders.