Proteolytic Enzyme Induction Within the Human Myocardial Interstitium

Study Overview
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Brief Summary
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A robust release of endothelin-1-1 (ET) with subsequent ETA subtype receptor (ET-AR) activation occurs in patients following cardiac surgery requiring cardiopulmonary bypass (CPB). Increased ET-AR activation has been identified in patients with poor left ventricular (LV) function (reduced ejection fraction; EF). Accordingly, this study tested the hypothesis that a selective ET-AR antagonist (ET-ARA) administered peri-operatively would favorably affect post-CPB hemodynamic profiles in patients with a pre-existing poor LVEF.

Detailed Description
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Patients with a reduced LVEF were prospectively randomized, in a blinded fashion, at the time of elective coronary revascularization and/or valve replacement requiring CPB, to infusion of the highly-selective and potent ET-ARA, sitaxsentan at 1 or 2 mg/kg (IV bolus) or vehicle (saline). Infusion of the ET-ARA/vehicle was performed immediately prior to separation from CPB and again at 12 hrs post-CPB. ET and hemodynamic measurements were performed at baseline, at separation from CPB (Time 0) and at 0.5, 6, 12, 24 hrs post-CPB.

Official Title
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Proteolytic Enzyme Induction Within the Human Myocardial Interstitium

Conditions
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Heart Disease

Intervention / Treatment
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* Drug: 1mg/kg sitaxsentan sodium
* Drug: 2mg/kg sitaxsentan sodium
* Other: Vehicle


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: >60 years of age Body mass index <40 kg/m2 Left ventricular ejection fraction less than or equal to 50% documented by a pre-operative echocardiogram Patients undergoing coronary artery bypass (CABG), aortic and/or mitral valve replacement or combined CABG and valve procedures requiring CPB. If diabetic, be under proper control, (fasting glucose <350 mg/dL or recent hemoglobin A1c [HgbA1c] <9%). If hypertensive, be on a stable medical regimen with no significant changes over the past 30 days. Female of child bearing potential with a negative pregnancy test, or post-menopausal for at least 2 years The patient is an appropriate study candidate as determined by the Investigator on the basis of medical history and physical examination Exclusion Criteria: Emergent revascularization Previous stroke or thrombo-embolic event in the 3 months prior to study entry A previous myocardial infarction within the last 7 days Documented coagulopathy Hepatic dysfunction as defined by aspartate transaminase (AST) or alanine transaminase (ALT) > 1.5 times the upper limit of normal Patient is pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Vehicle<br>Vehicle Group | Other: Vehicle<br>* Intravenous bolus performed immediately before separation from cardiopulmonary bypass and again at 12 hours after cardiopulmonary bypass.<br>* Other names: Saline;|
| Experimental: ET-ARA 1mg/kg<br>ET-ARA 1 mg/kg | Drug: 1mg/kg sitaxsentan sodium<br>* 1mg/kg sitaxsentan sodium (intravenous bolus) performed immediately before separation from cardiopulmonary bypass and again at 12 hours after cardiopulmonary bypass.<br>* Other names: TBC11251Na;|
| Experimental: ET-ARA 2mg/kg<br>ET-ARA 2 mg/kg | Drug: 2mg/kg sitaxsentan sodium<br>* 2mg/kg sitaxsentan sodium (intravenous bolus) performed immediately before separation from cardiopulmonary bypass and again at 12 hours after cardiopulmonary bypass.<br>* Other names: TBC11251Na;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulmonary Vascular Resistance | Pulmonary Vascular Resistance (d.s.cm-5) | Baseline, 0, 6, 12 and 24 hours post-cardiopulmonary bypass (CPB) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Endothelin-1 | Plasma Endothelin-1 (fmol/mL) | Baseline, 0, 6, 12 and 24 hours post-CPB |