Proteolytic Enzyme Induction Within the Human Myocardial Interstitium

NCT ID: NCT00744211

Last Updated: 2017-11-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 29 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-07-31
• Study Completion Date: 2013-04-30

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.

Conditions

Heart Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: DOUBLE

Study Groups

Vehicle

Vehicle Group

Group Type: PLACEBO_COMPARATOR

Vehicle

Intervention Type: OTHER

Intravenous bolus performed immediately before separation from cardiopulmonary bypass and again at 12 hours after cardiopulmonary bypass.

ET-ARA 1mg/kg

ET-ARA 1 mg/kg

Group Type: EXPERIMENTAL

1mg/kg sitaxsentan sodium

Intervention Type: DRUG

1mg/kg sitaxsentan sodium (intravenous bolus) performed immediately before separation from cardiopulmonary bypass and again at 12 hours after cardiopulmonary bypass.

ET-ARA 2mg/kg

ET-ARA 2 mg/kg

Group Type: EXPERIMENTAL

2mg/kg sitaxsentan sodium

Intervention Type: DRUG

2mg/kg sitaxsentan sodium (intravenous bolus) performed immediately before separation from cardiopulmonary bypass and again at 12 hours after cardiopulmonary bypass.

Interventions

1mg/kg sitaxsentan sodium

1mg/kg sitaxsentan sodium (intravenous bolus) performed immediately before separation from cardiopulmonary bypass and again at 12 hours after cardiopulmonary bypass.

Intervention Type: DRUG

2mg/kg sitaxsentan sodium

2mg/kg sitaxsentan sodium (intravenous bolus) performed immediately before separation from cardiopulmonary bypass and again at 12 hours after cardiopulmonary bypass.

Intervention Type: DRUG

Vehicle

Intravenous bolus performed immediately before separation from cardiopulmonary bypass and again at 12 hours after cardiopulmonary bypass.

Intervention Type: OTHER

Other Intervention Names

TBC11251Na; TBC11251Na; Saline

Eligibility Criteria

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

• Minimum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Medical University of South Carolina

OTHER

Sponsor Role: collaborator

VA Office of Research and Development

FED

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Francis Spinale, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Wm. Jennings Bryan Dorn VA Medical Center, Columbia, SC

Locations

Ralph H. Johnson VA Medical Center, Charleston, SC

Charleston, South Carolina, United States

Countries

United States

References

Spinale FG, Koval CN, Deschamps AM, Stroud RE, Ikonomidis JS. Dynamic changes in matrix metalloprotienase activity within the human myocardial interstitium during myocardial arrest and reperfusion. Circulation. 2008 Sep 30;118(14 Suppl):S16-23. doi: 10.1161/CIRCULATIONAHA.108.786640.

Reference Type: RESULT

PMID: 18824748 (View on PubMed)

Ford RL, Mains IM, Hilton EJ, Reeves ST, Stroud RE, Crawford FA Jr, Ikonomidis JS, Spinale FG. Endothelin-A receptor inhibition after cardiopulmonary bypass: cytokines and receptor activation. Ann Thorac Surg. 2008 Nov;86(5):1576-83. doi: 10.1016/j.athoracsur.2008.06.076.

Reference Type: RESULT

PMID: 19049753 (View on PubMed)

Toole JM, Ikonomidis JS, Szeto WY, Zellner JL, Mulcahy J, Deardorff RL, Spinale FG. Selective endothelin-1 receptor type A inhibition in subjects undergoing cardiac surgery with preexisting left ventricular dysfunction: Influence on early postoperative hemodynamics. J Thorac Cardiovasc Surg. 2010 Mar;139(3):646-54. doi: 10.1016/j.jtcvs.2009.11.046. Epub 2010 Jan 13.

Reference Type: RESULT

PMID: 20074751 (View on PubMed)

Other Identifiers

SURG-001-07F

Identifier Type: -

Identifier Source: org_study_id