Clinical trial NCT00458276: Study of the Efficacy and Safety of Tezosentan in Patients With Pre-operative Pulmonary Hypertension, Due to Left Heart Disease, Undergoing Open Heart Surgery
Official title: Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel-group Study to Assess the Efficacy, Safety and Tolerability of Tezosentan in Patients With Pre-operative Pulmonary Hypertension, Due to Left Heart Disease, Undergoing Cardiac Surgery
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Heart Diseases
Hypertension, Pulmonary
Keywords: Left sided heart disease
Elevated pulmonary arterial pressure
Right ventricular failure
Cardiac surgery
heart-lung machine
cardiopulmonary bypass
tezosentan
Actelion
Lead sponsor: Idorsia Pharmaceuticals Ltd.
Sponsor class: INDUSTRY
First posted: 2007-04-10
Enrollment: 274
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: 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.
timeFrame: During weaning from CPB
Secondary outcomes:
measure: 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
timeFrame: Within 28 days after study initiation
measure: Time to weaning from cardiopulmonary bypass
timeFrame: Defined as time from release of cross-clamp to successful weaning from CPB
measure: Time from end of CPB to final discharge from Intensive Care Unit (ICU)
timeFrame: From end of CPB to final discharge from ICU
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Montefiore Medical Center/Albert Einstein College of Medicine
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Cleveland
country: United States
facility: The Cleveland Clinic
state: Ohio
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Houston
country: United States
facility: Texas Heart Institute/St. Luke's Episcopal Hospital/Baylor College
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Innsbruck
country: Austria
facility: Medical University of Innsbruck
city: Vienna
country: Austria
facility: AKH University of Vienna
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: London
country: Canada
facility: London Health Sciences Centre-University Hospital
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Montreal
country: Canada
facility: Montreal Heart Institute
state: Quebec
city: Quebec
country: Canada
facility: Quebec Heart Institute/Hopital Laval
city: Prague
country: Czechia
facility: Institute for Clinical and Experimental Medicine (IKEM)
city: Paris
country: France
facility: Hopital Pitie Salpetriere
city: Berlin
country: Germany
facility: Deutches Herzzentrum
city: Dresden
country: Germany
facility: Dresden Universitatsklinik/Cardiology Center
city: Frankfurt
country: Germany
facility: Zentrum der Chirugie-Zchir-des Universitatsklinikums
city: Bangalore
country: India
facility: Narayana Hrudayalaya
city: Hyderabaad
country: India
facility: Nizam's Institute of Medical Sciences
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
city: Pavia
country: Italy
facility: Fondazione IRCCS San Matteo Hospital, Cardiac Surgery
city: Torino
country: Italy
facility: Azienda Sanitaria Ospedaliera "San Giovanni Battista", Cardiac Surgery Division
city: Katowice
country: Poland
facility: Medical University of Silesia, 2nd Dept of Cardiac Surgery
city: Krakow
country: Poland
facility: Klinika Chirurgii Serca, Naczyn I Transplantologii, Szpital Jana Pawla II
city: Belgrade
country: Serbia
facility: Dedinje Cardiovascular Institute
city: Bratislava
country: Slovakia
facility: National Institute of Cardiovascular Diseases, Clinic of Heart Surgery
city: Goteborg
country: Sweden
facility: Sahlgrenska University Hospital
city: Cambridge
country: United Kingdom
facility: Papworth Hospital
city: Sheffield
country: United Kingdom
facility: Northern General Hospital
Study officials:
affiliation: Montreal Heart Institute
name: Andre Denault, Prof.
role: STUDY_CHAIR
affiliation: Stanford University
name: Ronald Pearl, MD
role: STUDY_CHAIR
affiliation: Montefiore Medical Center
name: Robert Michler, MD
role: STUDY_CHAIR
affiliation: Papworth Hospital NHS Foundation Trust
name: Steven Tsui
role: STUDY_CHAIR
affiliation: AKH University of Vienna
name: Rainald Seitelberger, Prof.
role: STUDY_CHAIR
affiliation: San Matteo Hospital
name: Andrea D'Armini, Prof.
role: STUDY_CHAIR
References:
citation: Denault AY, Pearl RG, Michler RE, Rao V, Tsui SS, Seitelberger R, Cromie M, Lindberg E, D'Armini AM. Tezosentan and right ventricular failure in patients with pulmonary hypertension undergoing cardiac surgery: the TACTICS trial. J Cardiothorac Vasc Anesth. 2013 Dec;27(6):1212-7. doi: 10.1053/j.jvca.2013.01.023. Epub 2013 Mar 21.