Tadalafil for Pulmonary Hypertension Due to Chronic Lung Disease

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.