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 Description

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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.

Condition or disease	Intervention/treatment	Phase
Heart Diseases; Hypertension, Pulmonary	Drug: tezosentan; Drug: placebo	Phase 3

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	274 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Triple (Participant, Care Provider, Investigator)
Primary Purpose:	Treatment
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 Start Date :	April 2007
Actual Primary Completion Date :	February 2008
Actual Study Completion Date :	March 2008

Arms and Interventions

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Arm	Intervention/treatment
Experimental: 1; Tezosentan	Drug: tezosentan; Tezosentan (ACT-050089, Ro 61-0612) as a 1% solution in 0.9% NaCl (i.e., normal saline) for i.v. use.
Placebo Comparator: 2; Placebo	Drug: placebo; Placebo (i.e., normal saline) for i.v. use.

Outcome Measures

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Primary Outcome Measures :

1. 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. [ Time Frame: During weaning from CPB ]

Secondary Outcome Measures :

1. 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 [ Time Frame: Within 28 days after study initiation ]
2. Time to weaning from cardiopulmonary bypass [ Time Frame: Defined as time from release of cross-clamp to successful weaning from CPB ]
3. Time from end of CPB to final discharge from Intensive Care Unit (ICU) [ Time Frame: From end of CPB to final discharge from ICU ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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

Contacts and Locations

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  Show 33 Study Locations

Sponsors and Collaborators

Actelion

Investigators

Study Chair:	Andre Denault, Prof.	Montreal Heart Institute
Study Chair:	Ronald Pearl, MD	Stanford University
Study Chair:	Robert Michler, MD	Montefiore Medical Center
Study Chair:	Steven Tsui	Papworth Hospital
Study Chair:	Rainald Seitelberger, Prof.	AKH University of Vienna
Study Chair:	Andrea D'Armini, Prof.	San Matteo Hospital

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

Responsible Party:	Elisabet Lindberg, MD, International Clinical Leader, Actelion
ClinicalTrials.gov Identifier:	NCT00458276 History of Changes
Other Study ID Numbers:	AC-051-350
First Posted:	April 10, 2007
Last Update Posted:	February 15, 2010
Last Verified:	February 2010

Keywords provided by Actelion:

Left sided heart disease; Elevated pulmonary arterial pressure; Right ventricular failure; Cardiac surgery	heart-lung machine; cardiopulmonary bypass; tezosentan; Actelion

Additional relevant MeSH terms:

Heart Diseases; Hypertension; Hypertension, Pulmonary; Vascular Diseases; Cardiovascular Diseases; Lung Diseases	Respiratory Tract Diseases; Tezosentan; Epoprostenol; Vasodilator Agents; Antihypertensive Agents; Platelet Aggregation Inhibitors