Heart Diseases, Hypertension, Pulmonary
Conditions
Keywords
Left sided heart disease, Elevated pulmonary arterial pressure, Right ventricular failure, Cardiac surgery, heart-lung machine, cardiopulmonary bypass, tezosentan, Actelion
Brief summary
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.
Detailed description
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.
Interventions
DRUGtezosentan
Tezosentan (ACT-050089, Ro 61-0612) as a 1% solution in 0.9% NaCl (i.e., normal saline) for i.v. use.
DRUGplacebo
Placebo (i.e., normal saline) for i.v. use.
Sponsors
Idorsia Pharmaceuticals Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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. | During weaning from CPB |
Secondary
| Measure | Time frame |
|---|---|
| Time to weaning from cardiopulmonary bypass | Defined as time from release of cross-clamp to successful weaning from CPB |
| Time from end of CPB to final discharge from Intensive Care Unit (ICU) | From end of CPB to final discharge from ICU |
| Proportion of patients w/a major clinical event w/in 28 days after study drug initiation like death/major cardiovascular events/infections that prolong hospital stay or require re-admission/new onset of renal failure requiring renal replacement therapy | Within 28 days after study initiation |
Countries
Austria, Canada, Czechia, France, Germany, India, Israel, Italy, Poland, Serbia, Slovakia, Sweden, United Kingdom, United States
Outcome results
None listed