Efficacy of a Glucagon-like-peptide-1 Agonist and Restrictive vs. Liberal Oxygen Supply in Patients Undergoing Coronary Artery Bypass Grafting or Aortic Valve Replacement - a 2-by-2 Factorial Designed, Randomized Clinical Study
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 入组人数
- 1,400
- 试验地点
- 1
- 主要终点
- Time in days to the first occurring of the following co-primary end-points throughout the follow-up period
研究概览
简要总结
Patients undergoing open heart surgery are at risk of suffering damage to the heart, brain and kidneys.
This study is designed as a 2-by-2 randomized clinical trial with the purpose of investigating the organ protective effects of the glucagon-like-peptide-1 (GLP-1) agonist Exenatide versus placebo and restrictive versus liberal oxygenation during weaning from cardio-pulmonary bypass.
详细描述
Patients with coronary artery disease (CAD) have associated atherosclerotic renal and cerebral disease making these organs especially vulnerable to ischemia during open heart surgery. At the Heart Center at Rigshospitalet in Copenhagen the investigators perform more than 1000 open heart surgery operations yearly. The primary indication is CAD with or without associated valvular disease.
Surgical treatment of patients with CAD is performed as coronary artery bypass grafting (CABG) or off- pump coronary artery bypass grafting (OPCAB). CABG requires the use of extracorporeal circulation, while this is not the case for OPCAB.
During extracorporeal circulation the heart is arrested and anticoagulated. Blood is exposed to artificial surfaces and mechanical stress potentially resulting in increased risk of a systemic inflammatory response syndrome (SIRS), arterial emboli and organ hypoperfusion with the potential for multi organ failure.
The 30-day mortality following elective CABG is 1-2%, increasing to 7% if associated with valve surgery. The elderly patients with reduced renal function and more concomitant disease have a 30-day mortality as high as 20%. Patients dying following open heart surgery often have severe heart failure including cardiogenic shock, occlusion of grafts or native coronary arteries, renal failure, stroke/transient ischemic attack and severe inflammation prior to death.
The incidence of renal failure requiring dialysis is dependent on renal function prior to surgery. With more elderly patients having surgery this incidence is increasing. Renal failure is often seen in conjunction with progression of heart failure or development of new onset heart failure. Factors associated with brain involvement in cardiac surgery are macro embolism, systemic hypotension, systemic venous hypertension and maldistribution of cerebral blood flow. The incidence of postoperative cognitive deficits are above 50% depending on when this is measured. After 12 months the figure is approximately 30%. Known factors associated with cognitive deficits are age and duration of bypass, however type of surgery (valve insertion), temperature, equipment (oxygenators, filters) and techniques of de-airing may be important. For the neuropsychological deficits micro embolism, altered brain flow and a systemic inflammatory response are probably involved. The incidence of these complications during OPCAB is unknown, but expected to be slightly lower.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, 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
- •Before any study-specific procedure, including assessments for screening, the appropriate written informed consent must be obtained.
- •≥ 18 years of age at the time of signing informed consent.
- •Ischemic heart disease requiring coronary artery bypass grafting (multi-vessel coronary artery disease or coronary anatomy not suitable for percutaneous coronary intervention) and/or aortic valve disease scheduled for aortic valve replacement, irrespective of other concomitant valve surgery.
排除标准
- •Active treatment with GLP-1 agonists
- •Obstructive hypertrophic cardiomyopathy, active myocarditis, constrictive pericarditis, untreated hypothyroidism or hyperthyroidism or history of or active acute pancreatitis.
- •Acute (i.e. off hours, within hours surgery), Sub-acute surgery (i.e. the following days) are eligible.
- •Known allergy towards Exenatide/Byetta or albumin (vehicle).
- •On the urgent waiting list for a heart transplant (UNOS category 1A or 1B, or equivalent). Patients on the non-urgent waiting list for a heart transplant (UNOS category 2 or 7, or equivalent) are eligible for inclusion in the study.
- •Recipient of any major organ transplant (e.g. lung, liver, heart)
- •Receiving or has received cytotoxic or cytostatic chemotherapy and/or radiation therapy for treatment of a malignancy within 6 month before randomization or clinical evidence of current malignancy, with the following exceptions: basal or squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, prostate cancer (if stable localized disease, with a life expectancy of > 2.5 years in the opinion of the investigator)
- •Currently enrolled in, or at least 30 days not yet elapsed since ending participation in other investigational drug trial(s) for the treatment of diabetes or malignant obesity investigating the use of GLP-1 agonists or receiving other investigational agent(s). Concomitant participation in other non-pharmacological trials is not an exclusion criterion.
- •Recent (within 3 months) history of alcohol or illicit drug abuse disorder, based on self-report.
- •Pregnant, based on investigator evaluation (e.g., positive human chorionic gonadotropin test) or currently breast feeding.
- •Any condition (e.g., psychiatric illness) or situation that, in the investigator's opinion, could put the subject at significant risk, confound the study results, or interfere significantly with the subject's participation in the study.
- •Previous participation in the trial.
研究组 & 干预措施
GLP-1
700 patients will be randomized to GLP-1, that will be administered as follows:
248.5 mL of isotonic sodium chloride added 1.5 mL of 20% human albumin added 25 microg Byetta (Lilly, Exenatide).
The study drug infusion is initiated immediately before open heart surgery and ended after 6 hours and 15 minutes. A set dose of 17.4 microg will be given.
干预措施: Byetta (Lilly, Exenatide) (Drug)
Placebo
20% Human Albumin is given as placebo. 700 patients will be randomized to placebo, that will be administered as follows:
248.5 mL of isotonic sodium chloride added 1.5 mL of 20% human albumin.
The placebo infusion is initiated immediately before open heart surgery and ended after 6 hours and 15 minutes at the same rate as the study drug.
干预措施: 20% Human Albumin (Drug)
Restrictive Oxygenation
The intervention is FiO2 of 50%, given as 'Conoxia (AGA, oxygen)'. 700 patients will be randomized to a FiO2 of 50% as long as the arterial O2 saturation (Sa02) remains above 91% during cardiopulmonary bypass, when weaning from and the following hour after weaning from cardiopulmonary bypass. The oxygenation strategy is discontinued and the patient is treated at the discretion of the attending physician after
- a maximum of 1 hours of intervention or
- the patient is slid from the operating table to a hospital bed for transfer to the intensive care unit, whichever comes first.
干预措施: Conoxia (AGA, oxygen) (Drug)
Liberal Oxygenation
The intervention is a FiO2 of 100%, given as 'Conoxia (AGA, oxygen)'. 700 patients will be randomized to a FiO2 of 100% during cardiopulmonary bypass, when weaning from and the following hour after weaning from cardiopulmonary bypass. The oxygenation strategy is discontinued and the patient is treated at the discretion of the attending physician after
- a maximum of 1 hours of intervention or
- the patient is slid from the operating table to a hospital bed for transfer to the intensive care unit, whichever comes first.
干预措施: Conoxia (AGA, oxygen) (Drug)
结局指标
主要结局
Time in days to the first occurring of the following co-primary end-points throughout the follow-up period
时间窗: Minimum 12 months
1. Death from any cause or 2. Any of the following adverse events 1. Renal failure requiring any type of renal replacement therapy 2. Stroke, defined as persisting (\>24 hours) of any neurological sign or symptom of neurological dysfunction as determined by the treating physician based on available clinical information or CT-scan 3. New onset/worsening heart failure defined as need for mechanical circulatory support at the ICU, inability to close the sternotomy due to post-surgical hemodynamic instability and/or persistent (\> 48 hours from initiation of first surgical procedure after randomization) need for inotropic hemodynamic support. In addition admission for heart failure during follow-up following discharge from the index admission.
次要结局
- Incidence of serious adverse events(12 months)
- Time in days to the occurrence of individual end-points throughout the follow-up period(Minimum 12 months)
研究者
Lars Kober
MD, Professor
Rigshospitalet, Denmark