Proteolytic Enzyme Induction Within the Human Myocardial Interstitium

VA Office of Research and Development

Status: Completed

Conditions: Heart Disease

Treatments: Drug: 1mg/kg sitaxsentan sodium; Drug: 2mg/kg sitaxsentan sodium; Other: Vehicle

Study type: Interventional

Funder types: Other; Other U.S. Federal agency

Identifiers

NCT00744211

SURG-001-07F

Details and patient eligibility

About

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.

Full 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.

Enrollment: 29 patients

Sex: All

Ages: 60+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Other

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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29 participants in 3 patient groups, including a placebo group

Vehicle

Placebo Comparator group

Description:

Vehicle Group

Treatment:

Other: Vehicle

ET-ARA 1mg/kg

Experimental group

Description:

ET-ARA 1 mg/kg

Treatment:

Drug: 1mg/kg sitaxsentan sodium

ET-ARA 2mg/kg

Experimental group

Description:

ET-ARA 2 mg/kg

Treatment:

Drug: 2mg/kg sitaxsentan sodium