Short-term Endothelin A Receptor Blockade in Patients With On-pump Coronary Artery Bypass Grafting
试验速览
- 阶段
- 2 期
- 入组人数
- 120
- 试验地点
- 1
- 主要终点
- enzymatic infarct size
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
BQ-123
干预措施: BQ-123 (Drug)
NaCl
干预措施: NaCl (Drug)
结局指标
主要结局
enzymatic infarct size
时间窗: 72h
次要结局
- Catecholamines(5h)
- Liver function(72h)
- catecholamine requirement(72h)
研究者
Alfred A Kocher, MD
Professor, Principal Investigator
Medical University of Vienna