Breathe Easier With Tadalafil Therapy for Dyspnea in COPD-PH

Inclusion Criteria:

1. Outpatients with COPD, defined as airflow limitation with post-bronchodilatorobstruction on baseline visit spirometry, identified by FEV1/FVC < 70% or < thelower limit of normal (5th percentile of a normal population based on Global LungFunction Initiative reference equations), OR any emphysema on chest CT noted in aclinical radiology report confirmed by study investigator review.

2. Eligible subjects must have PH documented as follows:

3. Main Pulmonary Artery/Ascending Aorta (PA/A) diameter > 1.0 on clinicallyavailable CT scans within 12 months OR

4. outpatient echocardiography done within 6 months of enrollment demonstrating PAsys > 34 mmHg OR

5. Mean Pulmonary Artery Pressure > 20 on Right Heart Catheterization done within 6 months of enrollment and when Veteran is clinically stable.

6. Eligible subjects must be dyspneic, as quantitated by a score of at least 20 on thebaseline UCSD Shortness of Breath Questionnaire, assessed at the time of thebaseline visit.

7. Treatment with at least one long-acting bronchodilator for at least 4 weeks,assessed at the time of the baseline visit by chart review and patient interview.

8. Age 35-89 Years

9. Women of childbearing potential must meet one of the following criteria for theprevious three months AND must have a negative pregnancy test on the day of testing.If more than 36 hours since the participant's last pregnancy test, they will betested again at the study visit.

10. have been using a contraceptive measure (an intrauterine device (IUD), acontraceptive implant, oral contraceptives, barrier methods, or abstinence)

11. have a male partner with a vasectomy

12. have a tubal ligation procedure or a medical diagnosis (such as infertility) ortherapies/procedures that precludes pregnancy (such as cancer treatments orendometrial ablation)

13. are in a same-sex relationship

14. have a male partner not capable of fathering children because of congenitalanomalies, other surgery, or medical treatment

15. Women who are not considered to be of childbearing potential who have beensurgically sterilized (for example: removal of ovaries or fallopian tubes, orhysterectomy) or are post-menopausal (no menstrual period for more than 6 months).

Exclusion Criteria:

1. Diagnosis of PH in the following subgroups of the updated WHO ClinicalClassification:

2. Group 1 (Idiopathic, heritable, drug- or toxin-induced, Pulmonary ArterialHypertension associated with connective tissue disease, congenital heartdisease)

3. Group 2 (left atrial hypertension)

4. Group 3 PH not attributable to COPD

5. Group 4 (chronic thromboembolic PH) or other forms of PH not associated withprimary lung disease.

6. Systemic hypotension in the ambulatory setting (at least 3 reproducible measurementsof systolic BP <89 mmHg, recorded by a health care provider over 1 week).

7. Moderate or severe hepatic impairment (Child-Pugh B and C).

8. Severe renal insufficiency (GFR <30 ml/min/1.73 m2)

9. Echocardiography within 3 months showing greater than moderate aortic stenosis (aortic valve area <1.0 cm2), greater than moderate mitral regurgitation, ordiastolic dysfunction (Any two of the following: Average E/e' >14, Septal e'velocity < 7 or lateral e' velocity <10, LA volume index > 34 ml/m2). LVEF < 50%.Any aortic or mitral valve replacement.

10. Any acute or chronic impairment (other than dyspnea) that limits ability to complywith the study requirements.

11. Current unstable angina, myocardial infarction or stroke within 6 months.

12. Requirement for nitrate therapy for any clinical indication.

13. Active prescription for a PDE-5 inhibitor or other pulmonary vasodilator other thanoxygen as a PH treatment.

14. History of the following retinal disorders: retinitis pigmentosa, non-arteriticanterior ischemic optic neuropathy, or crowded optic disc noted on ophthalmologyexaminations recorded in CPRS.

15. Contraindications: PDE-5i allergy, penile anatomical deformations, sickle cellanemia, multiple myeloma, leukemia, bleeding disorders, active peptic ulcer disease,retinitis pigmentosa or other retinal disorders listed above. In accordance with 38USC 7332, this information will be kept confidential and will not be disclosed inpresentations, publications, or any other dissemination of the study results, or toanyone outside of the IRB-approved study team.

16. Use of any of the following: rifampin, systemic anti-fungal azole agents, proteaseinhibitors, phenobarbital, dilantin.

17. Pregnant, possibly pregnant by report, or if breastfeeding. If found to be pregnantat the study visit, the study visit will not be conducted.

18. Pulmonary veno-occlusive disease

19. Hypoxia (reproducible ambulatory SaO2 < 90% on supplemental oxygen at rest recordedby a health care provider over 1 week).

20. Diagnosis of Obstructive Sleep Apnea without a prescription for treatment.

21. Newly prescribed (less than 4 weeks duration) bronchodilator or diuretic therapy ornew enrollment in pulmonary rehabilitation at the time of Baseline.

22. Students, VA employees, persons with impaired decision making, illiterate andnon-English speakers, and terminally ill patients.

23. COPD or CHF exacerbation within the past 4 weeks.

24. On-going therapy with doxazosin.

Women of childbearing potential must have a documented negative pregnancy test and must be using adequate contraception during the study and for 9 months afterward. Monthly pregnancy tests will be done, and compliance with contraception use will be documented at the telephone and clinic visits. Should a female become pregnant at any time during the study, the study medication will be discontinued.

Doxazosin use will be defined as current active prescription and usage of Doxazosin or planned trial (pending prescription) of Doxazosin for treatment of benign prostatic hypertrophy, systemic hypertension, or other indication. A list of alpha-1 antagonists (ex. prazosin, doxazosin, tamulosin, terazosin, etc.) will be included in the patient study medication handout to prompt the patient to avoid any new usage of these drugs during the trial period. On-going therapy with doxazosin is an exclusion criterion due to greater risk of hypotension.