PAHTCH Pulmonary Arterial Hypertension Treatment With Carvedilol for Heart Failure (Carvedilol)

Pulmonary arterial hypertension (PAH) is a serious condition characterized by endothelial
dysfunction leading to pulmonary vascular constriction, smooth muscle and endothelial
proliferation, and progressive right-sided heart failure. The severity of pulmonary
hypertension is mostly determined by the response of the right ventricle (RV) to the
increased afterload or pulmonary pressures, and RV failure is the leading cause of death in
PAH. Most accepted therapies for PAH have been aimed at vasodilation of the pulmonary
vasculature, and there has been little thought that PAH patients would benefit from
traditional left heart failure treatments. A cornerstone therapy in left heart failure is
£]-adrenergic receptor blockade because of its ability to reverse cardiac remodeling and
improve clinical outcomes, despite decades of concern regarding its propensity to exacerbate
heart failure. It has been reported to reduce mortality by about 30% in patients, and while
the precise mechanisms that contribute to its beneficial effects remain to be elucidated,
there is evidence that patients with underlying contractile reserve (i.e., via recruitment of
viable myocardium with £]-adrenergic receptor stimulation) may experience greater recovery of
their cardiac function. In a study using rats with pulmonary hypertension treated with £]
blocker, RV function improved, and maladaptive myocardial remodeling was prevented.

Inclusion Criteria:

- Men and women age 18 or older not greater than age 65 years

- Diagnosis of pulmonary arterial hypertension class 1, 3, 4, 5 (Dana Point 2008)

- NYHA (New York Health Association)/WHO (World Health Organization) Class I-III

- PAH medications must have been initiated according to the latest consensus statement
recommendations and remained stable for the last 30 days

- Women of child-bearing age must use a double-barrier local contraception till
completion of the study

- Subjects must demonstrate understanding of the study, sign the informed consent, and
have a reliable method of communication for contact and ability to comply with the
study requirements

Exclusion Criteria:

- Participation in any other treatment studies during enrollment

- Significant illness in the past 30 days requiring hospitalization

- Hepatic insufficiency (transaminase levels > 4 fold the upper limit of normal or
bilirubin > 2 fold the upper limit of normal),

- History of HIV, Hepatitis B or C

- Serum creatinine > 2.8 mg/dl

- Pregnancy, breast-feeding, or lack of safe contraception

- Acute decompensated heart failure within past 30 days

- Known allergy or intolerance to carvedilol or other β blockers

- Significant, persistent bradycardia (resting heart rate < 50 bpm) or hypotension
(systolic blood pressure < 100 mmHg or mean blood pressure < 70 mmHg) at the time of
enrollment

- Second or third-degree AV (Atrial Ventricular) block without pacemaker

- Use of CYP2D6 isoenzyme inhibitors (such as quinidine, fluoxetine, paroxetine,
propafenone) which increase drug levels and result in greater vasodilating effects and
hypotension

- Use of hypotensive drugs that deplete catecholamines (such as reserpine and monoamine
oxidase inhibitors) which may lead to greater signs of hypotension or bradycardia

- Other medical and psychosocial conditions as determined by principal investigator
deemed unsuitable for enrollment