Proteolytic Enzyme Induction Within the Human Myocardial Interstitium

Not Applicable

Completed

• Conditions: Heart Disease
• Interventions: Other: Vehicle; Drug: 1mg/kg sitaxsentan sodium; Drug: 2mg/kg sitaxsentan sodium

• Registration Number: NCT00744211
• Lead Sponsor: VA Office of Research and Development

Brief Summary

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

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.

Study Timeline

• Study Start: 2008-07
• Study First Submitted: 2008-08-27
• Study First Submitted QC: 2008-08-28
• Study First Posted: 2008-08-29
• Primary Completion: 2011-06
• Study Completion: 2013-04
• Results First Submitted: 2014-11-07
• Status Verified: 2017-11
• Results First Submitted QC: 2017-11-07
• Last Update Submitted: 2017-11-07
• Results First Posted: 2017-11-09
• Last Update Posted: 2017-11-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 29

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Vehicle	Vehicle	Vehicle Group
ET-ARA 1mg/kg	1mg/kg sitaxsentan sodium	ET-ARA 1 mg/kg
ET-ARA 2mg/kg	2mg/kg sitaxsentan sodium	ET-ARA 2 mg/kg

Primary Outcome Measures

Name	Time	Method
Pulmonary Vascular Resistance	Baseline, 0, 6, 12 and 24 hours post-cardiopulmonary bypass (CPB)	Pulmonary Vascular Resistance (d.s.cm-5)

Secondary Outcome Measures

Name	Time	Method
Plasma Endothelin-1	Baseline, 0, 6, 12 and 24 hours post-CPB	Plasma Endothelin-1 (fmol/mL)

Trial Locations

Locations (1)

Ralph H. Johnson VA Medical Center, Charleston, SC; 🇺🇸 Charleston, South Carolina, United States