Effects of Tracleer (Bosentan) on Pulmonary Arterial Hypertension Related to Eisenmenger Physiology

Inclusion criteria

• Male or female patients at least 12 years with a body weight at least 40 kg (inclusive) and with a functional class III (1998 WHO classification).
• Patients with pulmonary arterial hypertension related to Eisenmenger physiology echocardiographically established as atrial septal defect at least 2 cm effective diameter and/or ventricular septal defect at least 1 cm effective diameter; PAH confirmed via cardiac catheterization: mean pulmonary arterial pressure >25 mm Hg, pulmonary capillary wedge pressure <15 mm Hg and pulmonary vascular resistance >3 mm Hg/l/min.
• Patients with documented oxygen saturation up to 90%, and >70% (at rest, with room air).
• Patients able to perform a 6-minute walk test at least 150 m, and up to 450 m.
• Patients stable for at least 3 months prior to screening.
• Bosentan naïve patients.
• Female patients who are surgically sterile, postmenopausal or have documented infertility.
• Female patients of childbearing potential using one of the following methods of contraception: Barrier-type devices (e.g., condom, diaphragm) used ONLY in combination with a spermicide. A double-barrier method is recommended; intrauterine devices (IUDs); oral or implanted contraceptives, if used in combination with a barrier method.
• Patients providing written informed consent.

Exclusion criteria

• Pregnant patients, nursing mothers.
• Patients with left ventricular dysfunction (ejection fraction <40%).
• Patients with restrictive lung disease (TLC<70% predicted); obstructive lung disease (FEV1<70% predicted, with FEV1/FVC<60%)
• Patients with systolic blood pressure < 85 mm Hg.
• Patients with other conditions that may affect the ability to perform a 6-minute walk test.
• Patients unable to provide informed consent and comply with the patient protocol.
• Patients with known coronary arterial disease.
• Patients with serum creatinine >125 µM/l.
• Patients with iron deficiency (serum ferritin <10 ng/ml) unless corrected by iron supplement.
• Patients with hemoglobin or hematocrit that is more than 30% below the normal range (patients with secondary polycythemia are permitted).
• Patients with AST and/or ALT values greater than 3 times the upper limit of normal.
• Patients who have started or stopped treatment for PAH within one month of screening, excluding anticoagulation.
• Patients who are receiving glyburide (glibenclamide), cyclosporine A or tacrolimus at inclusion or are expected to receive any of these drugs during the study.
• Patients who are receiving vasodilators including, but not limited to epoprostenol or prostacyclin analogues, or are expected to receive any of these drugs during the study.
• Patients active on organ transplant lists.
• Patients taking phosphodiesterase inhibitors or endothelin receptor antagonists (other than bosentan) or any other investigational drugs/devices.
• Patients with planned surgical intervention during the study period.
• Cardiac catheterization-specific exclusion criteria:

• Patients who cannot safely have catheterization performed as indicated.
• Patients in whom shunting is not at the atrial or ventricular level.
• Patients with nonequal pulmonary venous desaturation that theoretically cannot be corrected with administration of 100% non-rebreather-supplied oxygen.
• Patients with nonpulsatile pulmonary blood flow, or with multiple sources of pulmonary blood flow.
• Patients with discontinuous pulmonary arteries, peripheral pulmonary arterial or venous stenosis > 25% size of native PA or creating unequal bilateral PA mean pressures, PA band with gradient > 20 mm Hg, tetralogy of fallot/pulmonary atresia, VSD/pulmonary atresia, DORV/pulmonary atresia, truncus arteriosus, scimitar syndrome.
• Patients where SVC sampling cannot be performed, or where SVC sampling may be contaminated
• Patients with ductus arteriosus.
• Patients with mitral or pulmonary venous stenosis, intracavitary LV outflow obstruction, sub, valvar or supravalvar aortic stenosis or aortic coarctation.
• Patients with <10 indexed Wood units, greater than moderate mitral regurgitation, mean pulmonary venous pressure > 16 mm Hg, pulmonary venous "v" waves > 20 mm Hg, systemic ventricular end-diastolic pressure > 16 mm Hg; patients with recognized extracardiac systemic venous collaterals to the pulmonary venous circulation, patients with recognized hepatic wedge pressure-inferior vena cava pressure gradient > 12 mm Hg.
• Patients (during catheterization) with uncorrectable hypercarbia with pCO2 >55 mm Hg; patients with uncorrectable acidemia with pH <7.34; patients in active pain or distress; unconscious or mechanically ventilated patients; patients with unstable systemic or pulmonary blood flow; systemic arterial or pulmonary artery pressures or hematocrit (change of > 25% during catheterization); unstable cardiac rhythm dissimilar to baseline cardiac rhythm during physical examination assessments for the entire duration of the catheterization excepting nonsustained arrhythmia; patients with documented or recognized air embolism, hemorrhage, cardiac, cerebral or peripheral organ ischemia occurring during or immediately preceding the catheterization.