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: 1. Inability to cool the myocardium timely, i.e. before reperfusion 2. Inability to cool the diseased myocardium selectively 3. Inability to achieve an adequate decrease of temperature quick enough 4. 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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
200
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.
PPCI per routine
Catharina hospital
Eindhoven, North Brabant, Netherlands
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.
Time frame: From date of randomization until the date of the MRI made after 3 months
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
Time frame: 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
Time frame: From date of randomization until 1 year later
Secondary endpoint, all-cause mortality at 3 months
All-cause mortality at 3 months
Time frame: From date of randomization until 3 months later
Secondary endpoint, all-cause mortality at 1 year
All-cause mortality at 1 year
Time frame: From date of randomization until 1 year later
Secondary endpoint, hospitalization for heart failure at 3 months
Hospitalization for heart failure at 3 months
Time frame: From date of randomization until 3 months later
Secondary endpoint, hospitalization for heart failure at 1 year
Hospitalization for heart failure at 1 year
Time frame: From date of randomization until 1 year later
Secondary endpoint, cardiac death at 3 months
Cardiac death at 3 months
Time frame: From date of randomization until 3 months later
Secondary endpoint, cardiac death at 1 year
Cardiac death at 1 year
Time frame: 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)
Time frame: From date of randomization until 1 week later
Secondary endpoint, peak value of creatine kinase (CK)
Peak value of creatine kinase (CK)
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: From date of randomization until 1 year later
Secondary endpoint, echocardiography outcome
Wall motion score index (WMSI) by echocardiography at 3 months
Time frame: From date of randomization until 3 months later
Secondary endpoint, echocardiography outcome
Wall motion score index (WMSI) by echocardiography at 1 year
Time frame: 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
Time frame: 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
Time frame: From date of randomization until 5-7 days later; baseline MRI
Secondary endpoint, MRI outcome at baseline
Late MVO (presence / absence) on LGE
Time frame: From date of randomization until 5-7 days later; baseline MRI
Secondary endpoint, MRI outcome at baseline
Initial infarct size (LGE)
Time frame: 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)
Time frame: From date of randomization until 5-7 days later; baseline MRI
Secondary endpoint, MRI outcome at baseline
Left ventricular end-diastolic volume index (LVEDVI)
Time frame: From date of randomization until 5-7 days later; baseline MRI
Secondary endpoint, MRI efficacy at baseline
Left ventricular end-systolic volume index (LVESVI)
Time frame: From date of randomization until 5-7 days later; baseline MRI
Secondary endpoint, MRI outcome at baseline
Left ventricular global longitudinal strain
Time frame: From date of randomization until 5-7 days later; baseline MRI
Secondary endpoint, MRI outcome at baseline
Left ventricular circumferential strain (mid-LV)
Time frame: From date of randomization until 5-7 days later; baseline MRI
Secondary endpoint, MRI outcome at baseline
Left ventricular ejection fraction (LVEF)
Time frame: 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
Time frame: From date of randomization until 5-7 days later; baseline MRI
Secondary endpoint, MRI outcome at baseline
Wall motion score index (WMSI)
Time frame: From date of randomization until 5-7 days later; baseline MRI
Secondary endpoint, MRI outcome at baseline
Myocardial haemorrhage (presence/absence)
Time frame: From date of randomization until 5-7 days later; baseline MRI
Secondary endpoint, MRI outcome at baseline
Myocardial haemorrhage extent (% of LV)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: From date of randomization until 3 months later; follow-up MRI
Secondary endpoint, MRI outcome at follow-up
Final left ventricular ejection fraction (LVEF)
Time frame: From date of randomization until 3 months later; follow-up MRI
Secondary endpoint, MRI outcome at follow-up
Final left ventricular global longitudinal strain
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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
Time frame: 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)
Time frame: From date of randomization until 3 months later; follow-up MRI
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