EUROpean Intracoronary Cooling Evaluation in Patients With ST-elevation Myocardial Infarction.

Study Overview
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Brief Summary
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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.

Official Title
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Selective Intracoronary Hypothermia in Patients With ST-elevation Myocardial Infarction to Reduce Infarct Size

Conditions
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Acute Myocardial Infarction, Reperfusion Injury

Intervention / Treatment
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* Other: Selective intracoronary hypothermia + PPCI
* Other: Standard PPCI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomized in a 1:1 fashion to either routine PPCI (control arm) or intracoronary hypothermia in addition to PPCI (hypothermia arm). For the patients randomized to intracoronary hypothermia will follow the steps below. For the routine PPCI a regular guidewire will be advanced across the occlusion followed by pre-dilatation and/or (direct) stenting according to the operator's preference.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Selective intracoronary hypothermia + PPCI<br>Patients will be eligible for this study if they are admitted for acute anterior wall ST-elevation myocardial infarction with total ST-segment deviation of at least 5 mm. If the patient has TIMI grade flow 0 or 1, the experimental arm will be treated by selective intracoronary hypothermia just before and after reperfusion, in addition to routine PPCI. | Other: Selective intracoronary hypothermia + PPCI<br>* Selective intracoronary hypothermia is a new technique, recently tested for safety and feasibility in the SINTAMI trial. The procedure starts by advancing a guidewire beyond the occlusion in the culprit artery, followed by an OTWB that is inflated at the location of the occlusion, at a low pressure (4 atm), to prevent reperfusion. After that, a pressure/temperature wire will be advanced along the inflated OTWB and is placed in the distal coronary artery. Then the guidewire is removed and the lumen is used for infusion of saline. During the 'occlusion phase', saline at room temperature is infused for 10 minutes with distal coronary temperature 6-8°C below body temperature. After that, the balloon of the OTWB is deflated. Simultaneously, infusion is started with saline of 4°C, the so called 'reperfusion phase'. This is continued for 10 more minutes. After that, the OTWB can be retracted and the procedure can continue not different from routine PPCI.<br>* Other names: Selective intracoronary hypothermia;|
| Other: Standard PPCI<br>The control group will receive routine PPCI. | Other: Standard PPCI<br>* PPCI per routine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary endpoint- Infarct size | 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. | From date of randomization until the date of the MRI made after 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary endpoint, composite of all-cause mortality and hospitalization for heart failure at 3 | Composite of all-cause mortality and hospitalization for heart failure at 3 months | From date of randomization until 3 months later | 
| Secondary endpoint, composite of all-cause mortality and hospitalization for heart failure at 1 year | 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 3 months | All-cause mortality at 3 months | From date of randomization until 3 months later | 
| Secondary endpoint, all-cause mortality at 1 year | All-cause mortality at 1 year | From date of randomization until 1 year later | 
| Secondary endpoint, hospitalization for heart failure at 3 months | Hospitalization for heart failure at 3 months | From date of randomization until 3 months later | 
| Secondary endpoint, hospitalization for heart failure at 1 year | Hospitalization for heart failure at 1 year | From date of randomization until 1 year later | 
| Secondary endpoint, cardiac death at 3 months | Cardiac death at 3 months | From date of randomization until 3 months later | 
| Secondary endpoint, cardiac death at 1 year | Cardiac death at 1 year | From date of randomization until 1 year later | 
| Secondary endpoint, peak value of high-sensitivity troponin T (hs-TnT) | 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) | Peak value of creatine kinase (CK) | From date of randomization until 1 week later | 
| Secondary endpoint, peak value of creatine kinase-MB mass (CK-MB) | Peak value of creatine kinase-MB mass (CK-MB) | From date of randomization until 1 week later | 
| Secondary endpoint, echocardiography outcome | Left ventricular ejection fraction measured by echocardiography (biplane Simpson's method) at 3 months | From date of randomization until 3 months later | 
| Secondary endpoint, echocardiography outcome | Left ventricular ejection fraction measured by echocardiography (biplane Simpson's method) at 1 year | From date of randomization until 1 year later | 
| Secondary endpoint, echocardiography outcome | Wall motion score index (WMSI) by echocardiography at 3 months | From date of randomization until 3 months later | 
| Secondary endpoint, echocardiography outcome | Wall motion score index (WMSI) by echocardiography at 1 year | From date of randomization until 1 year later | 
| Secondary endpoint, MRI outcome at baseline | First pass microvascular obstruction extent (FP MVO); NB first pass will be acquired in 3 SAX levels to provide an index of %LV FP MVO | From date of randomization until 5-7 days later; baseline MRI | 
| Secondary endpoint, MRI outcome at baseline | Early MVO extent (% of LV) on 1 min post-gadolinium contrast enhanced MRI, adjusted for area at-risk | From date of randomization until 5-7 days later; baseline MRI | 
| Secondary endpoint, MRI outcome at baseline | Late MVO (presence / absence) on LGE | From date of randomization until 5-7 days later; baseline MRI | 
| Secondary endpoint, MRI outcome at baseline | Initial infarct size (LGE) | From date of randomization until 5-7 days later; baseline MRI | 
| Secondary endpoint, MRI outcome at baseline | Initial MSI (area-at-risk minus initial infarct size/area-at-risk) | From date of randomization until 5-7 days later; baseline MRI | 
| Secondary endpoint, MRI outcome at baseline | Left ventricular end-diastolic volume index (LVEDVI) | From date of randomization until 5-7 days later; baseline MRI | 
| Secondary endpoint, MRI efficacy at baseline | Left ventricular end-systolic volume index (LVESVI) | From date of randomization until 5-7 days later; baseline MRI | 
| Secondary endpoint, MRI outcome at baseline | Left ventricular global longitudinal strain | From date of randomization until 5-7 days later; baseline MRI | 
| Secondary endpoint, MRI outcome at baseline | Left ventricular circumferential strain (mid-LV) | From date of randomization until 5-7 days later; baseline MRI | 
| Secondary endpoint, MRI outcome at baseline | Left ventricular ejection fraction (LVEF) | From date of randomization until 5-7 days later; baseline MRI | 
| Secondary endpoint, MRI outcome at baseline | Systolic wall thickening in the culprit artery territory | From date of randomization until 5-7 days later; baseline MRI | 
| Secondary endpoint, MRI outcome at baseline | Wall motion score index (WMSI) | From date of randomization until 5-7 days later; baseline MRI | 
| Secondary endpoint, MRI outcome at baseline | Myocardial haemorrhage (presence/absence) | From date of randomization until 5-7 days later; baseline MRI | 
| Secondary endpoint, MRI outcome at baseline | Myocardial haemorrhage extent (% of LV) | From date of randomization until 5-7 days later; baseline MRI | 
| Secondary endpoint, MRI outcome at follow-up | Final myocardial salvage index (area-at-risk minus final infarct size/area-at-risk) | From date of randomization until 3 months later; follow-up MRI | 
| Secondary endpoint, MRI outcome at follow-up | Change in infarct size 3 months after procedure (LGE at baseline minus LGE at 3 months) | From date of randomization until 3 months later; follow-up MRI | 
| Secondary endpoint, MRI outcome at follow-up | Final left ventricular end-diastolic volume index (LVEDVI) | From date of randomization until 3 months later; follow-up MRI | 
| Secondary endpoint, MRI outcome at follow-up | Final left ventricular end-systolic volume index (LVESVI) | From date of randomization until 3 months later; follow-up MRI | 
| Secondary endpoint, MRI outcome at follow-up | Final left ventricular ejection fraction (LVEF) | From date of randomization until 3 months later; follow-up MRI | 
| Secondary endpoint, MRI outcome at follow-up | Final left ventricular global longitudinal strain | From date of randomization until 3 months later; follow-up MRI | 
| Secondary endpoint, MRI outcome at follow-up | Final left ventricular circumferential strain (mid-LV) | From date of randomization until 3 months later; follow-up MRI | 
| Secondary endpoint, MRI outcome, difference between baseline and follow-up | Change from baseline left ventricular end-diastolic volume index (LVEDVI) | From date of randomization until 3 months later; follow-up MRI | 
| Secondary endpoint, MRI outcome, difference between baseline and follow-up | Change from baseline left ventricular end-systolic volume index (LVESVI) | From date of randomization until 3 months later; follow-up MRI | 
| Secondary endpoint, MRI outcome, difference between baseline and follow-up | Change from baseline left ventricular ejection fraction (LVEF) | From date of randomization until 3 months later; follow-up MRI | 
| Secondary endpoint, MRI outcome, difference between baseline and follow-up | Change in left ventricular global longitudinal strain | From date of randomization until 3 months later; follow-up MRI | 
| Secondary endpoint, MRI outcome, difference between baseline and follow-up | Change in left ventricular circumferential strain (mid-LV) | From date of randomization until 3 months later; follow-up MRI | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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intracoronary cooling