Proteolytic Enzyme Induction Within the Human Myocardial Interstitium

Heart Disease Clinical Trial

Official title:

Proteolytic Enzyme Induction Within the Human Myocardial Interstitium

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00744211
• Other study ID #: SURG-001-07F
• Status: Completed
• Phase: N/A
• First received: August 27, 2008
• Last updated: November 7, 2017
• Start date: July 2008
• Est. completion date: April 2013

Study information

• Verified date: November 2017
• Source: VA Office of Research and Development
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 29
• Est. completion date: April 2013
• Est. primary completion date: June 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Heart Disease
• Heart Diseases

Intervention

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

Locations

Country	Name	City	State
United States	Ralph H. Johnson VA Medical Center, Charleston, SC	Charleston	South Carolina

Sponsors (2)

Lead Sponsor	Collaborator
VA Office of Research and Development	Medical University of South Carolina

Country where clinical trial is conducted

United States, 

References & Publications (3)

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.athora — View Citation

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: 10.11 — View Citation

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 he — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Sitaxsentan Levels	Sitaxsentan levels (microg/mL)	0, 6, 12 and 24 hours post-CPB
Other	Number of Other Adverse Events By Type	Other (non-serious) Adverse Events (reported by arm/group)	up to 24-hours post-CPB
Primary	Pulmonary Vascular Resistance	Pulmonary Vascular Resistance (d.s.cm-5)	Baseline, 0, 6, 12 and 24 hours post-cardiopulmonary bypass (CPB)
Secondary	Plasma Endothelin-1	Plasma Endothelin-1 (fmol/mL)	Baseline, 0, 6, 12 and 24 hours post-CPB