This study evaluates the effects of bosentan on oxygen saturation, hemodynamics and exercise
capacity in patients with pulmonary arterial hypertension related to Eisenmenger physiology.
Patients receive bosentan or placebo for 16 weeks.
Minimum age: 12 Years.
Maximum age: N/A.
1. 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).
2. 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
3. Patients with documented oxygen saturation up to 90%, and >70% (at rest, with room
4. Patients able to perform a 6-minute walk test at least 150 m, and up to 450 m.
5. Patients stable for at least 3 months prior to screening.
6. Bosentan naïve patients.
7. Female patients who are surgically sterile, postmenopausal or have documented
8. 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
9. Patients providing written informed consent.
1. Pregnant patients, nursing mothers.
2. Patients with left ventricular dysfunction (ejection fraction <40%).
3. Patients with restrictive lung disease (TLC<70% predicted); obstructive lung disease
(FEV1<70% predicted, with FEV1/FVC<60%)
4. Patients with systolic blood pressure < 85 mm Hg.
5. Patients with other conditions that may affect the ability to perform a 6-minute walk
6. Patients unable to provide informed consent and comply with the patient protocol.
7. Patients with known coronary arterial disease.
8. Patients with serum creatinine >125 µM/l.
9. Patients with iron deficiency (serum ferritin <10 ng/ml) unless corrected by iron
10. Patients with hemoglobin or hematocrit that is more than 30% below the normal range
(patients with secondary polycythemia are permitted).
11. Patients with AST and/or ALT values greater than 3 times the upper limit of normal.
12. Patients who have started or stopped treatment for PAH within one month of screening,
13. Patients who are receiving glyburide (glibenclamide), cyclosporine A or tacrolimus at
inclusion or are expected to receive any of these drugs during the study.
14. 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
15. Patients active on organ transplant lists.
16. Patients taking phosphodiesterase inhibitors or endothelin receptor antagonists (other
than bosentan) or any other investigational drugs/devices.
17. Patients with planned surgical intervention during the study period.
18. Cardiac catheterization-specific exclusion criteria:
1. Patients who cannot safely have catheterization performed as indicated.
2. Patients in whom shunting is not at the atrial or ventricular level.
3. Patients with nonequal pulmonary venous desaturation that theoretically cannot be
corrected with administration of 100% non-rebreather-supplied oxygen.
4. Patients with nonpulsatile pulmonary blood flow, or with multiple sources of
pulmonary blood flow.
5. 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,
6. Patients where SVC sampling cannot be performed, or where SVC sampling may be
7. Patients with ductus arteriosus.
8. Patients with mitral or pulmonary venous stenosis, intracavitary LV outflow
obstruction, sub, valvar or supravalvar aortic stenosis or aortic coarctation.
9. 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.
10. 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.
Royal Prince Alfred Hospital - Central Clinical School, Camperdown NSW 2050, Australia
The Royal Melbourne Hospital, Victoria 3050, Australia
Universitatsklinikum fur Innere Medizin II, Wien AT-1090, Austria
UZ Gasthuisberg, Leuven BE-3000, Belgium
Hospital Necker-Enfants Malades, Paris 75007, France
Deutsches Herzzentrum Munchen, Munchen D-80636, Germany
Herzzentrum NRW, Bad Oeynhausen D-32545, Germany
San Matteo Hospital, Pavia 27100, Italy
University of Bologna, Bologna 40138, Italy
Academisch Ziekenhuis Groningen, Groningen 9713 GZ, Netherlands
Unidad Medico Quirurgica de Cardiologia - Edificio General, Madrid 28046, Spain
Scottish Vascular Unit - Western Infirmary, Glasgow G11 6NT, United Kingdom
Royal Brompton Hospital, London SW3 6NP, United Kingdom
The Peter Lougheed Centre, Calgary, Alberta T1Y 6J4, Canada
BACH Pulmonary Hypertension Service, Boston, Massachusetts 02115, United States
Toronto General Hospital, Toronto, Ontario M5G 2C4, Canada
Texas Children's Hospital, Houston, Texas 77030-2303, United States