Study of the Efficacy and Safety of Tezosentan in Patients With Pre-operative Pulmonary Hypertension, Due to Left Heart Disease, Undergoing Open Heart Surgery
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 is a powerful substance that may be involved in causing hemodynamic instability
 (problems related to unstable blood pressure) during and after open heart surgery. Tezosentan
 is an investigational intravenous drug that blocks the endothelin receptors. This clinical
 trial will assess the potential benefit of tezosentan compared with placebo in the treatment
 of patients undergoing open heart surgery with cardiopulmonary bypass (CPB). Treatment time
 is from the start of surgery up to 24 hours.
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