Proteolytic Enzyme Induction Within the Human Myocardial Interstitium

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.

Study Overview

• Status: Completed
• Conditions: Heart Disease
• Intervention / Treatment: Other: Vehicle; Drug: 1mg/kg sitaxsentan sodium; Drug: 2mg/kg sitaxsentan sodium

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 Type: Interventional
• Enrollment (Actual): 29
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • South Carolina
    • Charleston, South Carolina, United States, 29401-5799
      • Ralph H. Johnson VA Medical Center, Charleston, SC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Vehicle; Vehicle Group	Other: Vehicle; Intravenous bolus performed immediately before separation from cardiopulmonary bypass and again at 12 hours after cardiopulmonary bypass.; Other Names: Saline
Experimental: ET-ARA 1mg/kg; ET-ARA 1 mg/kg	Drug: 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.; Other Names: TBC11251Na
Experimental: ET-ARA 2mg/kg; ET-ARA 2 mg/kg	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.; Other Names: TBC11251Na

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sitaxsentan Levels	Sitaxsentan levels (microg/mL)	0, 6, 12 and 24 hours post-CPB
Number of Other Adverse Events By Type	Other (non-serious) Adverse Events (reported by arm/group)	up to 24-hours post-CPB

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Collaborators: Medical University of South Carolina
• Investigators: Principal Investigator: Francis Spinale, MD PhD, Wm. Jennings Bryan Dorn VA Medical Center, Columbia, SC

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: July 1, 2008
• Primary Completion (Actual): June 1, 2011
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: August 27, 2008
• First Submitted That Met QC Criteria: August 28, 2008
• First Posted (Estimate): August 29, 2008

Study Record Updates

• Last Update Posted (Actual): November 9, 2017
• Last Update Submitted That Met QC Criteria: November 7, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Molecular Mechanisms of Pharmacological Action; Endothelin Receptor Antagonists; Sitaxsentan
• Other Study ID Numbers: SURG-001-07F

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO