Clinical trial NCT03447834: EUROpean Intracoronary Cooling Evaluation in Patients With ST-elevation Myocardial Infarction.
Official title: Selective Intracoronary Hypothermia in Patients With ST-elevation Myocardial Infarction to Reduce Infarct Size
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Acute Myocardial Infarction
Reperfusion Injury
Keywords: intracoronary cooling
Lead sponsor: Catharina Ziekenhuis Eindhoven
Sponsor class: OTHER
Collaborators: name: Abbott
name: Golden Jubilee National Hospital
name: Onze Lieve Vrouwziekenhuis Aalst
name: Rigshospitalet, Denmark
name: Örebro University, Sweden
name: Skane University Hospital
name: University of Belgrade
name: Mid and South Essex NHS Foundation Trust
First posted: 2018-02-27
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Primary endpoint- Infarct size
timeFrame: From date of randomization until the date of the MRI made after 3 months
Secondary outcomes:
measure: Secondary endpoint, composite of all-cause mortality and hospitalization for heart failure at 3
timeFrame: From date of randomization until 3 months later
measure: Secondary endpoint, composite of all-cause mortality and hospitalization for heart failure at 1 year
timeFrame: From date of randomization until 1 year later
measure: Secondary endpoint, all-cause mortality at 3 months
timeFrame: From date of randomization until 3 months later
measure: Secondary endpoint, all-cause mortality at 1 year
timeFrame: From date of randomization until 1 year later
measure: Secondary endpoint, hospitalization for heart failure at 3 months
timeFrame: From date of randomization until 3 months later
measure: Secondary endpoint, hospitalization for heart failure at 1 year
timeFrame: From date of randomization until 1 year later
measure: Secondary endpoint, cardiac death at 3 months
timeFrame: From date of randomization until 3 months later
measure: Secondary endpoint, cardiac death at 1 year
timeFrame: From date of randomization until 1 year later
measure: Secondary endpoint, peak value of high-sensitivity troponin T (hs-TnT)
timeFrame: From date of randomization until 1 week later
measure: Secondary endpoint, peak value of creatine kinase (CK)
timeFrame: From date of randomization until 1 week later
measure: Secondary endpoint, peak value of creatine kinase-MB mass (CK-MB)
timeFrame: From date of randomization until 1 week later
measure: Secondary endpoint, echocardiography outcome
timeFrame: From date of randomization until 3 months later
measure: Secondary endpoint, echocardiography outcome
timeFrame: From date of randomization until 1 year later
measure: Secondary endpoint, echocardiography outcome
timeFrame: From date of randomization until 3 months later
measure: Secondary endpoint, echocardiography outcome
timeFrame: From date of randomization until 1 year later
measure: Secondary endpoint, MRI outcome at baseline
timeFrame: From date of randomization until 5-7 days later; baseline MRI
measure: Secondary endpoint, MRI outcome at baseline
timeFrame: From date of randomization until 5-7 days later; baseline MRI
measure: Secondary endpoint, MRI outcome at baseline
timeFrame: From date of randomization until 5-7 days later; baseline MRI
measure: Secondary endpoint, MRI outcome at baseline
timeFrame: From date of randomization until 5-7 days later; baseline MRI
measure: Secondary endpoint, MRI outcome at baseline
timeFrame: From date of randomization until 5-7 days later; baseline MRI
measure: Secondary endpoint, MRI outcome at baseline
timeFrame: From date of randomization until 5-7 days later; baseline MRI
measure: Secondary endpoint, MRI efficacy at baseline
timeFrame: From date of randomization until 5-7 days later; baseline MRI
measure: Secondary endpoint, MRI outcome at baseline
timeFrame: From date of randomization until 5-7 days later; baseline MRI
measure: Secondary endpoint, MRI outcome at baseline
timeFrame: From date of randomization until 5-7 days later; baseline MRI
measure: Secondary endpoint, MRI outcome at baseline
timeFrame: From date of randomization until 5-7 days later; baseline MRI
measure: Secondary endpoint, MRI outcome at baseline
timeFrame: From date of randomization until 5-7 days later; baseline MRI
measure: Secondary endpoint, MRI outcome at baseline
timeFrame: From date of randomization until 5-7 days later; baseline MRI
measure: Secondary endpoint, MRI outcome at baseline
timeFrame: From date of randomization until 5-7 days later; baseline MRI
measure: Secondary endpoint, MRI outcome at baseline
timeFrame: From date of randomization until 5-7 days later; baseline MRI
measure: Secondary endpoint, MRI outcome at follow-up
timeFrame: From date of randomization until 3 months later; follow-up MRI
measure: Secondary endpoint, MRI outcome at follow-up
timeFrame: From date of randomization until 3 months later; follow-up MRI
measure: Secondary endpoint, MRI outcome at follow-up
timeFrame: From date of randomization until 3 months later; follow-up MRI
measure: Secondary endpoint, MRI outcome at follow-up
timeFrame: From date of randomization until 3 months later; follow-up MRI
measure: Secondary endpoint, MRI outcome at follow-up
timeFrame: From date of randomization until 3 months later; follow-up MRI
measure: Secondary endpoint, MRI outcome at follow-up
timeFrame: From date of randomization until 3 months later; follow-up MRI
measure: Secondary endpoint, MRI outcome at follow-up
timeFrame: From date of randomization until 3 months later; follow-up MRI
measure: Secondary endpoint, MRI outcome, difference between baseline and follow-up
timeFrame: From date of randomization until 3 months later; follow-up MRI
measure: Secondary endpoint, MRI outcome, difference between baseline and follow-up
timeFrame: From date of randomization until 3 months later; follow-up MRI
measure: Secondary endpoint, MRI outcome, difference between baseline and follow-up
timeFrame: From date of randomization until 3 months later; follow-up MRI
measure: Secondary endpoint, MRI outcome, difference between baseline and follow-up
timeFrame: From date of randomization until 3 months later; follow-up MRI
measure: Secondary endpoint, MRI outcome, difference between baseline and follow-up
timeFrame: From date of randomization until 3 months later; follow-up MRI
Other outcomes:
measure: Pre-specified subgroup analyses, between the hypothermia and control arm, as well as within each arm, as appropriate.
timeFrame: From date of randomization of last patient until 1 year later
measure: Pre-specified subgroup analyses, between the hypothermia and control arm, as well as within each arm, as appropriate.
timeFrame: From date of randomization of last patient until 1 year later
measure: Pre-specified subgroup analyses, between the hypothermia and control arm, as well as within each arm, as appropriate.
timeFrame: From date of randomization of last patient until 1 year later
measure: Pre-specified subgroup analyses, between the hypothermia and control arm, as well as within each arm, as appropriate.
timeFrame: From date of randomization of last patient until 1 year later
Locations:
city: Eindhoven
country: Netherlands
facility: Catharina hospital
state: North Brabant
Study officials:
References:
citation: El Farissi M, Good R, Engstrom T, Oldroyd KG, Karamasis GV, Vlaar PJ, Lonborg JT, Teeuwen K, Keeble TR, Mangion K, De Bruyne B, Frobert O, De Vos A, Zwart B, Snijder RJR, Brueren GRG, Palmers PJ, Wijnbergen IF, Berry C, Tonino PAL, Otterspoor LC, Pijls NHJ. Safety of Selective Intracoronary Hypothermia During Primary Percutaneous Coronary Intervention in Patients With Anterior STEMI. JACC Cardiovasc Interv. 2021 Sep 27;14(18):2047-2055. doi: 10.1016/j.jcin.2021.06.009. Epub 2021 Aug 25.