Beta-blockers in Pulmonary Arterial Hypertension

Phase 2

Terminated

Brief Summary: The investigators will conduct a, randomized, phase 2, placebo-controlled, double-blinded, crossover trial of carvedilol in 26 PAH patients with World Health Organization functional class II or III symptoms and RV ejection fraction (EF) \< 45% for 6 months.

Detailed Description: Adult PAH patients on a stable dose of an approved PAH medication will undergo the following baseline assessments: cardiac magnetic resonance imaging (MRI), right heart catheterization (RHC), echocardiogram, 6-minute walk test (6-MWT), plasma NT-ProBNP (biomarkers of RV function) and serum catecholamine (measure of sympathetic activation), and quality of life. Patients will be randomized to carvedilol (3.125 mg bid and escalated to 9.375 mg bid, as tolerated, over 3 months) or placebo in a 1:1 fashion. After 6 months, testing is repeated and patients are crossed over to the alternate treatment. Testing is repeated at the end of the study (month 13).

Recruitment & Eligibility

Inclusion Criteria

Age > 18 years
WHO category 1 pulmonary arterial hypertension (Nice 2013)
WHO functional class II-III
RVEF by cardiac MRI < 45%
Stable on PAH-specific therapy as defined by no change in PAH-specific treatment and functional class in the past 3 months. Patient can be on either mono or combination PAH-specific therapy

Exclusion Criteria

Subjects will be excluded from participation in the study if any of the following conditions exist:
Significant persistent bradycardia (resting heart rate < 60 bpm) without a permanent pacemaker
Second or third degree AV block without a permanent pacemaker
Significant sinus tachycardia (resting heart rate > 110 bpm)
Use of anti-arrhythmic drugs
Hypotension defined as systolic blood pressure < 100 mmHg at the time of enrollment
Significant illness in the past 30 days requiring hospitalization
Acute decompensated right heart failure within past 30 days
Known allergy or intolerance to carvedilol or other β blockers
Cardiac index < 2 l/min/m2 or right atrial pressure > 15 mm Hg by right heart catheterization within last 3 months
Asthma
Positive pregnancy test in patients of child bearing-potential

Arm && Interventions

Group	Intervention	Description
Placebo First	Placebo	Crossover Design: Participants receive placebo first and Carvedilol second
Carvedilol First	Placebo	Crossover Design: Participants receive Carvedilol first and placebo second
Carvedilol First	Carvedilol	Crossover Design: Participants receive Carvedilol first and placebo second
Placebo First	Carvedilol	Crossover Design: Participants receive placebo first and Carvedilol second