Selective Intracoronary Hypothermia in Patients With ST-elevation Myocardial Infarction to Reduce Infarct Size
试验速览
- 阶段
- 不适用
- 发起方
- 入组人数
- 200
- 试验地点
- 2
- 主要终点
- Primary endpoint- Infarct size
研究概览
简要总结
In acute myocardial infarction, early restoration of epicardial and myocardial blood flow is of paramount importance to limit infarction size and create optimum conditions for favourable long-term outcome. Currently, restoration of epicardial blood flow is preferably and effectively obtained by primary percutaneous coronary intervention (PPCI). After opening the occluded artery, however, the reperfusion process itself causes damage to the myocardium, the so called "reperfusion injury". The phenomenon of reperfusion injury is incompletely understood and currently there is no established therapy for preventing it. Contributory factors are intramyocardial edema with compression of the microvasculature, oxidative stress, calcium overload, mitochondrial transition pore opening, micro embolization, neutrophil plugging and hyper contracture. This results in myocardial stunning, reperfusion arrhythmias and ongoing myocardial necrosis. There is general agreement that a large part of the cell death caused by myocardial reperfusion injury occurs during the first few minutes of reperfusion, and that early treatment is required to prevent it.
Myocardial hypothermia may attenuate the pathological mechanisms mentioned above. However, limited data are available on the beneficial effects of hypothermia to protect the myocardium from reperfusion damage. In animals, several studies demonstrated a protective effect of hypothermia on the infarction area. This effect was only noted when hypothermia was established before reperfusion. Hypothermia is therefore thought to attenuate several damaging acute reperfusion processes such as oxidative stress, release of cytokines and development of interstitial or cellular edema. Furthermore, it has been shown that induced hypothermia resulted in increased ATP-preservation in the ischemic myocardium compared to normothermia. The intracoronary use of hypothermia by infused cold saline in pigs was demonstrated to be safe by Otake et al. In their study, saline of 4°C was used without complications (such as vasospasm, hemodynamic instability or bradycardia) and it even attenuated ventricular arrhythmia significantly.
Studies in humans, however, have not been able to confirm this effect, which is believed to be mainly due to the fact that the therapeutic temperature could not reached before reperfusion in the majority of patients or not achieved at all. Furthermore, in these studies it was intended to induce total body hypothermia, which in turn may lead to systemic reactions such as shivering and enhanced adrenergic state often requiring sedatives, which may necessitate artificial ventilation.
In fact, up to now any attempt to achieve therapeutic myocardial hypothermia in humans with myocardial infarction, is fundamentally limited because of four reasons:
- Inability to cool the myocardium timely, i.e. before reperfusion
- Inability to cool the diseased myocardium selectively
- Inability to achieve an adequate decrease of temperature quick enough
- Inability to achieve an adequate decrease of temperature large enough
Consequently, every attempt to achieve effective hypothermia in ST-segment myocardial infarction in humans has been severely hampered and was inadequate. In the last two years, the investigators have developed a methodology overcoming all of the limitations mentioned above. At first, the investigators have tested that methodology in isolated beating pig hearts with coronary artery occlusion and next, the investigators have tested the safety and feasibility of this methodology in humans.
Therefore, the time has come to perform a proof-of-principle study in humans, which is the subject of this protocol.
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
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Acute anterior wall ST-elevation myocardial infarction
- •Total ST-segment deviation of at least 5 mm
- •Presenting within 6 hours after onset of complaints
- •TIMI 0 or 1 flow in the LAD
- •Hemodynamically stable and in an acceptable clinical condition
- •Able to give informed consent
排除标准
- •Age <18 year or >80 year
- •Cardiogenic shock or hemodynamically unstable patients
- •Patients with previous myocardial infarction in the culprit artery of with previous bypass surgery
- •Very tortuous or calcified coronary arteries
- •Complex or long-lasting primary PCI expected
- •Severe concomitant disease or conditions with a life expectancy of less than one year
- •Inability to understand and give informed consent
- •Known contra-indication for MRI
- •Pregnancy
- •Severe conduction disturbances necessitating implantation of temporary pacemaker
结局指标
主要结局
Primary endpoint- Infarct size
时间窗: From date of randomization until the date of the MRI made after 3 months
The primary endpoint is the final infarct size (expressed in % of left ventricular mass) on MRI, made 3 months after the infarction revealed by late gadolinium enhancement.
次要结局
- Secondary endpoint, MRI efficacy at baseline(From date of randomization until 5-7 days later; baseline MRI)
- Secondary endpoint, peak value of high-sensitivity troponin T (hs-TnT)(From date of randomization until 1 week later)
- Secondary endpoint, peak value of creatine kinase (CK)(From date of randomization until 1 week later)
- Secondary endpoint, composite of all-cause mortality and hospitalization for heart failure at 3(From date of randomization until 3 months later)
- Secondary endpoint, hospitalization for heart failure at 3 months(From date of randomization until 3 months later)
- Secondary endpoint, hospitalization for heart failure at 1 year(From date of randomization until 1 year later)
- Secondary endpoint, peak value of creatine kinase-MB mass (CK-MB)(From date of randomization until 1 week later)
- Secondary endpoint, all-cause mortality at 3 months(From date of randomization until 3 months later)
- Secondary endpoint, cardiac death at 1 year(From date of randomization until 1 year later)
- Secondary endpoint, MRI outcome at follow-up(From date of randomization until 3 months later; follow-up MRI)
- Secondary endpoint, composite of all-cause mortality and hospitalization for heart failure at 1 year(From date of randomization until 1 year later)
- Secondary endpoint, all-cause mortality at 1 year(From date of randomization until 1 year later)
- Secondary endpoint, cardiac death at 3 months(From date of randomization until 3 months later)
- Secondary endpoint, echocardiography outcome(From date of randomization until 1 year later)
- Secondary endpoint, MRI outcome at baseline(From date of randomization until 5-7 days later; baseline MRI)
- Secondary endpoint, MRI outcome, difference between baseline and follow-up(From date of randomization until 3 months later; follow-up MRI)
研究者
Nico Pijls
N.H.J Pijls, MD, PhD, Professor of Cardiology
Catharina Ziekenhuis Eindhoven