The Combination Ambrisentan Plus Spironolactone in Pulmonary Arterial Hypertension Study

The purpose of this study is to find out if spironolactone added to ambrisentan for Pulmonary Arterial Hypertension (PAH) will increase exercise capacity. We also want to find out if spironolactone and ambrisentan effect the cardiac output (amount of blood the heart pumps every minute), right ventricle function and quality of life.

A prospective, double blind, placebo-controlled clinical study involving 30 patients with World Health Organization (WHO) Group 1 pulmonary arterial hypertension being treated with ambrisentan randomized to receive placebo or spironolactone (50 mg/d) for 90 days using a cross-over trial design.

Eligible participants will be randomized to receive placebo or spironolactone (50 mg/d) for 90 days (Phase I). At the completion of Phase I, participants will undergo repeat end-point assessment followed by a 21-day drug washout period. Then, the 90 day crossover phase of the trial will occur (Phase II), in which participants randomized to placebo in Phase I will be treated with spironolactone (50 mg/d) in Phase II and vice versa. At the conclusion of Phase II, end-point measures are reassessed.

Spironolactone is a diuretic used in treatment of PAH patients. Spironolactone is usually added to medical treatment when doses of Lasix/Torsemide are increased and patients are at risk for hypokalemia.

Study procedures being done for this research study are the standard procedures performed on all PAH patients when they are in clinic for follow-up except for the Cardiopulmonary Exercise Test (CPET) with Innocor.

Eligibility Criteria:
Inclusion Criteria:

1. Voluntarily gives informed consent to participate in the study.
2. Right heart catheterization demonstrating conventional mean pulmonary artery pressure (mPAP) \>25, pulmonary vascular resistance (PVR) \>3.0 Wood Units, pulmonary capillary wedge pressure (PCWP) \<16 mmHg within two years of enrollment
3. Subject is 18 years of age or older at Screening.
4. Diagnosis of symptomatic idiopathic or heritable PAH, PAH associated with Connective Tissue Disease (CTD), PAH associated with repaired/unrepaired congenital systemic-to-pulmonary shunt, Portopulmonary hypertension or PAH associated with HIV infection.
5. New York Heart Association Functional Class II or III
6. Stable therapy with ambrisentan 5 or 10 mg every day for \> 90 days.
7. Baseline 6-Minute Walk Distance 50-450m

Exclusion Criteria:

1. Substantial Primary Lung disease

   * forced expiratory volume at one second (FEV-1)/forced vital capacity (FVC) \<0.6 and FEV-1 \<70% predicted
   * diffusing capacity of lung for carbon monoxide (DLCO) \<30% predicted
   * Pulmonary fibrosis
2. Left ventricular ejection fraction \< 50%
3. Pulmonary capillary wedge pressure \> 16 mm Hg
4. Aortic valve disease
5. Ischemic heart disease
6. Systemic hypotension (SBP \<90 mm Hg)
7. Co-existing treatment with other endothelin receptor antagonists or prostacyclin analogues
8. New York Heart Association Functional Class IV
9. Chronic thromboembolic pulmonary hypertension
10. Known or suspected pulmonary veno-occlusive disease
11. Serum creatinine \>2.0 mg/dL in women, Serum creatinine \>2.5 mg/dL in men
12. Baseline serum potassium \>5.0 milliequivalent (mEq)/L
13. Participation in ongoing drug/intervention-based clinical trial
14. Pregnancy
15. Unable to provide consent