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

Acute Myocardial Infarction Clinical Trial

— EURO-ICE  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03447834
• Other study ID #: EURO-ICE
• Status: Active, not recruiting
• Phase: N/A
• Start date: January 1, 2019
• Est. completion date: June 30, 2023

Study information

• Verified date: July 2022
• Source: Catharina Ziekenhuis Eindhoven
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 200
• Est. completion date: June 30, 2023
• Est. primary completion date: September 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Myocardial Infarction
• Infarction
• Myocardial Infarction
• Reperfusion Injury
• ST Elevation Myocardial Infarction

Intervention

Other:
• Selective intracoronary hypothermia + PPCI
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.
• Standard PPCI
PPCI per routine

Locations

Country	Name	City	State
Netherlands	Catharina hospital	Eindhoven	North Brabant

Sponsors (9)

Lead Sponsor	Collaborator
Catharina Ziekenhuis Eindhoven	Abbott, Golden Jubilee National Hospital, Mid and South Essex NHS Foundation Trust, Onze Lieve Vrouwziekenhuis Aalst, Örebro University, Sweden, Rigshospitalet, Denmark, Skane University Hospital, University of Belgrade

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Pre-specified subgroup analyses, between the hypothermia and control arm, as well as within each arm, as appropriate.	Comparison of outcomes by baseline features including diabetes status, sex, age and geographic location.	From date of randomization of last patient until 1 year later
Other	Pre-specified subgroup analyses, between the hypothermia and control arm, as well as within each arm, as appropriate.	Comparison of outcomes by lesion location (proximal versus mid LAD)	From date of randomization of last patient until 1 year later
Other	Pre-specified subgroup analyses, between the hypothermia and control arm, as well as within each arm, as appropriate.	Comparison of outcomes by TIMI grade flow (0 versus 1)	From date of randomization of last patient until 1 year later
Other	Pre-specified subgroup analyses, between the hypothermia and control arm, as well as within each arm, as appropriate.	Comparison of outcomes by achieved decrease in distal temperature (using median of cohort for threshold)	From date of randomization of last patient until 1 year later
Primary	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	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	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	Secondary endpoint, all-cause mortality at 3 months	All-cause mortality at 3 months	From date of randomization until 3 months later
Secondary	Secondary endpoint, all-cause mortality at 1 year	All-cause mortality at 1 year	From date of randomization until 1 year later
Secondary	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	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	Secondary endpoint, cardiac death at 3 months	Cardiac death at 3 months	From date of randomization until 3 months later
Secondary	Secondary endpoint, cardiac death at 1 year	Cardiac death at 1 year	From date of randomization until 1 year later
Secondary	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	Secondary endpoint, peak value of creatine kinase (CK)	Peak value of creatine kinase (CK)	From date of randomization until 1 week later
Secondary	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	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	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	Secondary endpoint, echocardiography outcome	Wall motion score index (WMSI) by echocardiography at 3 months	From date of randomization until 3 months later
Secondary	Secondary endpoint, echocardiography outcome	Wall motion score index (WMSI) by echocardiography at 1 year	From date of randomization until 1 year later
Secondary	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	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	Secondary endpoint, MRI outcome at baseline	Late MVO (presence / absence) on LGE	From date of randomization until 5-7 days later; baseline MRI
Secondary	Secondary endpoint, MRI outcome at baseline	Initial infarct size (LGE)	From date of randomization until 5-7 days later; baseline MRI
Secondary	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	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	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	Secondary endpoint, MRI outcome at baseline	Left ventricular global longitudinal strain	From date of randomization until 5-7 days later; baseline MRI
Secondary	Secondary endpoint, MRI outcome at baseline	Left ventricular circumferential strain (mid-LV)	From date of randomization until 5-7 days later; baseline MRI
Secondary	Secondary endpoint, MRI outcome at baseline	Left ventricular ejection fraction (LVEF)	From date of randomization until 5-7 days later; baseline MRI
Secondary	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	Secondary endpoint, MRI outcome at baseline	Wall motion score index (WMSI)	From date of randomization until 5-7 days later; baseline MRI
Secondary	Secondary endpoint, MRI outcome at baseline	Myocardial haemorrhage (presence/absence)	From date of randomization until 5-7 days later; baseline MRI
Secondary	Secondary endpoint, MRI outcome at baseline	Myocardial haemorrhage extent (% of LV)	From date of randomization until 5-7 days later; baseline MRI
Secondary	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	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	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	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	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	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	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	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	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	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	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	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