Study of the Efficacy and Safety of Tezosentan in Patients With Pre-operative Pulmonary Hypertension, Due to Left Heart Disease, Undergoing Open Heart Surgery

Endothelin-1 levels are increased during and after cardiac surgery with cardiopulmonary
bypass (CPB), and are associated with many deleterious consequences, including increased
pulmonary arterial pressure (PAP), increased pulmonary vascular resistance (PVR), reduced
myocardial contractility, and ultimately right ventricular failure. Right ventricular failure
during weaning from CPB increases the risk of mortality and morbidity, especially in patients
with elevated PAP prior to cardiac surgery. Endothelin receptor antagonists (ERAs) have been
shown to decrease PVR and pulmonary arterial pressure (PAP), and improve right ventricular
function in patients with pulmonary arterial hypertension. In animal models, ERAs have been
shown to decrease the incidence of post-bypass pulmonary hypertensive crises. The primary
objective of this trial is to demonstrate that tezosentan, a dual ERA, reduces the incidence
of clinically relevant right ventricular failure in patients with pre-operative pulmonary
hypertension, due to left heart disease, undergoing CPB.

Inclusion Criteria:

- Patients ≥ 18 years of age

- Male or female patients (females of child-bearing potential must have been surgically
sterilized or use a reliable method of contraception).

- Patients undergoing complex* cardiac surgery on CPB and having systolic PAP > 40 mmHg
or mean PAP > 30 mmHg (*surgery on 2 valves, 1 valve and revascularization, or
reoperation of a valve)

- Patients undergoing cardiac surgery on CPB and having pre-operative pulmonary
hypertension due to left heart disease with systolic PAP > 60 mmHg

- Signed written informed consent

Exclusion Criteria:

- Systolic blood pressure < 100 mmHg

- Significant chronic lung disease

- Emergency surgery

- Pregnant/breast-feeding

- Investigational drug use within 28 days prior to randomization

- Complex adult congenital heart disease.

- Severe concomitant illness limiting life expectancy to < 6 months

- Participation in a device study that will affect the outcome of the study

- Pre-operative use of balloon pump, inotropes/vasopressors, treatment of pulmonary
arterial hypertension

- Known hypersensitivity to tezosentan or drugs of the same class, or any of their
excipients

- Severe liver impairment