Short-term Endothelin A Receptor Blockade in Patients With On-pump CABG

This study is enrolling participants by invitation only.
Sponsor:
Information provided by (Responsible Party):
Alfred A Kocher, MD, Medical University of Vienna
ClinicalTrials.gov Identifier:
NCT01658410
First received: July 26, 2012
Last updated: August 2, 2012
Last verified: August 2012
  Purpose

Background: Although selected cardiac surgery can be performed off-pump, the vast majority of cardiac surgical procedures today are performed with the support of cardiopulmonary bypass (CPB). Blood cardioplegia is used to protect the heart during aortic cross-clamping. However, negative effects of myocardial hypoxia during surgery are often aggravated by ischemia/reperfusion injury. In addition, cardiopulmonary bypass leads to an inflammatory response including endothelial cell activation.

Comparable to the reperfusion injury following acute myocardial infarction resolved by percutaneous coronary intervention, the microcirculatory impairment observed after cardiac surgery may be caused by endothelin 1 (ET-1). ET-1 is a potent vasoconstrictor peptide upregulated in myocardial ischemia-reperfusion injury. Short-term administration of the selective ETA receptor blocker BQ-123 was found safe in a pilot study including patients with acute myocardial infarction.

Hypothesis: Acute local ETA receptor blockade by intracoronary administered BQ-123 reduces myocardial injury.

Methods: BQ-123 will be administered in patients undergoing on-pump aorto-coronary bypass grafting to the left anterior descending coronary artery with the use a left inner mammary artery graft and at least one vein graft. Subjects will be randomized to receive the endothelin-A receptor blocker BQ-123 or placebo administered intracoronarily in combination with cardioplegia in a double-blind manner. The primary endpoint will be enzymatic infarct size.

Clinical perspective: The implementation of BQ-123 as an add-on pharmacologic therapy in cardiac surgery performed with the use of cardiopulmonary bypass could lead to improved tissue reperfusion and reduced ischemia/reperfusion injury, potentially impacting clinical long-term outcome.


Condition Intervention Phase
Coronary Artery Disease
Aorto-coronary Bypass Grafting
Drug: BQ-123
Drug: NaCl
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Short-term Endothelin A Receptor Blockade in Patients With On-pump Coronary Artery Bypass Grafting

Resource links provided by NLM:


Further study details as provided by Medical University of Vienna:

Primary Outcome Measures:
  • enzymatic infarct size [ Time Frame: 72h ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Catecholamines [ Time Frame: 5h ] [ Designated as safety issue: Yes ]
  • Liver function [ Time Frame: 72h ] [ Designated as safety issue: Yes ]
  • catecholamine requirement [ Time Frame: 72h ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 120
Study Start Date: July 2012
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: BQ-123 Drug: BQ-123
BQ-123 (Clinalfa, Läufelfingen, Switzerland) Dosage: 15µmol in two equal amounts (7.5µmol); in the first and last cardioplegia Route: intracoronary
Other Name: Cyclo(-D-Trp-D-Asp-Pro-D-Val-Leu) sodium salt
Placebo Comparator: NaCl Drug: NaCl
NaCl, Route: intracoronary

Detailed Description:

Background: Although selected cardiac surgery can be performed off-pump, the vast majority of cardiac surgical procedures today are performed with the support of cardiopulmonary bypass (CPB). Blood cardioplegia is used to protect the heart during aortic cross-clamping. However, negative effects of myocardial hypoxia during surgery are often aggravated by ischemia/reperfusion injury. In addition, cardiopulmonary bypass leads to an inflammatory response including endothelial cell activation.

Comparable to the reperfusion injury following acute myocardial infarction resolved by percutaneous coronary intervention, the microcirculatory impairment observed after cardiac surgery may be caused by endothelin 1 (ET-1). ET-1 is a potent vasoconstrictor peptide upregulated in myocardial ischemia-reperfusion injury. Short-term administration of the selective ETA receptor blocker BQ-123 was found safe in a pilot study including patients with acute myocardial infarction. Patients with posterior-wall STE-ACS (n=57) were randomly assigned to receive intravenous BQ-123 at 400nmol/minute or placebo over 60 minutes, starting immediately prior to primary percutaneous coronary intervention (PCI). No side branch occlusions, bleeding complications or severe systemic hypotensive episodes occurred and all patients were alive at 30 days.

Hypothesis: Acute local ETA receptor blockade by intracoronary administered BQ-123 reduces myocardial injury.

Methods: BQ-123 will be administered in patients undergoing on-pump aorto-coronary bypass grafting to the left anterior descending coronary artery with the use a left inner mammary artery graft and at least one vein graft. After a 1:1 randomized pilot safety-phase with 30 patients administering half the dose, 90 subjects will be randomized to receive 15µmol BQ-123 dissolved in NaCl 0.9% or placebo (NaCl 0.9% ) administered intracoronarily in combination with cardioplegia in a double-blind manner. The primary endpoint will be enzymatic infarct size assessed by the area under the curve of myocard specific creatine kinase-MB isoform (CK-MB). Left ventricular ejection fraction, diastolic dysfunction and, perioperative echocardiography, postoperative levels of myeloperoxidase and matrixmetalloproteinase-9 activity as well as MACE will serve as secondary endpoints.

Clinical perspective: The implementation of BQ-123 as an add-on pharmacologic therapy in cardiac surgery performed with the use of cardiopulmonary bypass could lead to improved tissue reperfusion and reduced ischemia/reperfusion injury, potentially impacting clinical long-term outcome.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Patients undergoing on-pump coronary artery bypass grafting using the left mammary artery to the left anterior descendent artery and at least one vein graft due to coronary artery disease, aged 18 years and above.

Exclusion Criteria:

  • Significant liver disease (Transaminases and/or gamma-GT > 3 fold upper limit)
  • Glomerular filtration rate <40mL/h
  • History of severe congestive heart failure (Left ventricular ejection fraction <35%)
  • Current atrial fibrillation
  • Significant valvular heart disease requiring valve replacement Department of Cardiac Surgery
  • Primary myocardial disease
  • Acute coronary syndrome or cardiogenic shock (sRR <90mmHg or need for inotropic support)
  • Women with child-bearing potential
  • Subjects with contraindications for CMR (cardiac magnetic resonance)
  • Inability to read, understand and sign the informed consent
  • Life expectancy <1y
  • Prior organ transplantation
  • Participation in a clinical trial using an investigational medical product
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01658410

Locations
Austria
Medical University of Vienna
Vienna, Austria, 1090
Sponsors and Collaborators
Medical University of Vienna
Investigators
Principal Investigator: Alfred Kocher, MD Medical University of Vienna
  More Information

No publications provided

Responsible Party: Alfred A Kocher, MD, Professor, Principal Investigator, Medical University of Vienna
ClinicalTrials.gov Identifier: NCT01658410     History of Changes
Other Study ID Numbers: 2010-023552-90
Study First Received: July 26, 2012
Last Updated: August 2, 2012
Health Authority: Austria: Austrian Agency for Health and Food Safety (AGES)

Keywords provided by Medical University of Vienna:
Coronary artery disease
bypass grafting

Additional relevant MeSH terms:
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Cyclo(Trp-Asp-Pro-Val-Leu)
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 22, 2014