Clinical trial NCT00744211: Proteolytic Enzyme Induction Within the Human Myocardial Interstitium
Official title: Proteolytic Enzyme Induction Within the Human Myocardial Interstitium
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Heart Disease
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
Collaborators: name: Medical University of South Carolina
First posted: 2008-08-29
Enrollment: 29
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.

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

Primary outcomes:
measure: Pulmonary Vascular Resistance
timeFrame: Baseline, 0, 6, 12 and 24 hours post-cardiopulmonary bypass (CPB)
Secondary outcomes:
measure: Plasma Endothelin-1
timeFrame: Baseline, 0, 6, 12 and 24 hours post-CPB
Other outcomes:
measure: Sitaxsentan Levels
timeFrame: 0, 6, 12 and 24 hours post-CPB
measure: Number of Other Adverse Events By Type
timeFrame: up to 24-hours post-CPB
Locations:
city: Charleston
country: United States
facility: Ralph H. Johnson VA Medical Center, Charleston, SC
state: South Carolina
Study officials:
affiliation: Wm. Jennings Bryan Dorn VA Medical Center, Columbia, SC
name: Francis Spinale, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
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: 10.1161/CIRCULATIONAHA.108.786640.
citation: 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.
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 hemodynamics. J Thorac Cardiovasc Surg. 2010 Mar;139(3):646-54. doi: 10.1016/j.jtcvs.2009.11.046. Epub 2010 Jan 13.