NCT03447834: EURO-ICE

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

Status unknown NA Last updated 6 July 2022

What this trial tests

NA trial testing Selective intracoronary hypothermia + PPCI in Acute Myocardial Infarction in 200 participants. Status unknown.

Timeline

1 January 2019

Primary endpoint
30 September 2022

30 June 2023

Quick facts

Lead sponsor	Catharina Ziekenhuis Eindhoven
Phase	NA
Status	Status unknown
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	200
Start date	1 January 2019
Primary completion	30 September 2022
Estimated completion	30 June 2023
Sites	1 location across Netherlands

Drugs / interventions tested

• Selective intracoronary hypothermia + PPCI
• Standard PPCI

Conditions studied

• Acute Myocardial Infarction — all drugs for Acute Myocardial Infarction →
• Reperfusion Injury — all drugs for Reperfusion Injury →

Sponsor

Catharina Ziekenhuis Eindhoven — full company profile →

Who can join

Adults 18 to 80, any sex, with Acute Myocardial Infarction or Reperfusion Injury. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Pathophysiology and diagnosis of coronary microvascular dysfunction in ST-elevation myocardial infarction.
   Konijnenberg LSF, Damman P, Duncker DJ, Kloner RA, et al · · 2020 · cited 195× · PMID 31710673 · DOI 10.1093/cvr/cvz301
2. Microvascular Obstruction and Intramyocardial Hemorrhage in Reperfused Myocardial Infarctions: Pathophysiology and Clinical Insights From Imaging.
   Vora KP, Kumar A, Krishnam MS, Prato FS, et al · · 2024 · cited 22× · PMID 38613553 · DOI 10.1016/j.jcmg.2024.02.003
3. Safety of Selective Intracoronary Hypothermia During Primary Percutaneous Coronary Intervention in Patients With Anterior STEMI.
   El Farissi M, Good R, Engstrøm T, Oldroyd KG, et al · · 2021 · cited 22× · PMID 34454860 · DOI 10.1016/j.jcin.2021.06.009
4. Predictors of Microvascular Reperfusion After Myocardial Infarction.
   Doherty DJ, Sykes R, Mangion K, Berry C. · · 2021 · cited 20× · PMID 33624185 · DOI 10.1007/s11886-021-01442-1
5. Effects of Therapeutic Hypothermia on Normal and Ischemic Heart.
   Yamada KP, Kariya T, Aikawa T, Ishikawa K. · · 2021 · cited 16× · PMID 33659283 · DOI 10.3389/fcvm.2021.642843
6. Microvascular Obstruction in Acute Myocardial Infarction, a Potential Therapeutic Target.
   Ghobrial M, Bawamia B, Cartlidge T, Spyridopoulos I, et al · · 2023 · cited 11× · PMID 37762875 · DOI 10.3390/jcm12185934
7. Hypothermia for Cardioprotection in Patients with St-Elevation Myocardial Infarction: Do Not Give It the Cold Shoulder Yet!
   El Farissi M, Mast TP, van de Kar MRD, Dillen DMM, et al · · 2022 · cited 9× · PMID 35207350 · DOI 10.3390/jcm11041082
8. A randomised trial of selective intracoronary hypothermia during primary PCI.
   El Farissi M, Pijls NHJ, Good R, Engström T, et al · · 2024 · cited 8× · PMID 38887884 · DOI 10.4244/eij-d-23-01042