Trans-coronary Cooling and Dilution for Cardioprotection During Revascularisation for ST-elevation Myocardial Infarction

Study Overview
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Brief Summary
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A heart attack (myocardial infarction) occurs when an artery supplying blood to the heart is suddenly blocked resulting in damage to the heart muscle. Patients presenting to hospital with a heart attack undergo an immediate angiogram (x-ray of the arteries in the heart) and are usually treated immediately with a balloon and stent to open their blocked artery. This procedure is called primary percutaneous coronary intervention (or primary PCI for short). An angiogram is a routine procedure that involves insertion of fine plastic tube (catheter) into either the groin or wrist under local anaesthetic. The tube is passed into the artery in the heart and X-ray pictures are taken to find out if the arteries are blocked. Blocked arteries can usually be opened by passing a small balloon into the artery, via the fine plastic tube followed by placement of a stent (a fine metal coil) into the artery to prevent it from blocking again. Although this treatment is very successful, it can result in damage to the heart muscle when the artery is opened. Cooling the entire body has been shown to reduce heart muscle damage during heart attacks in some patients but not in others; however, it is uncomfortable due to the shivering, expensive and can result in delays in opening the blocked artery. The investigators are conducting a series of research studies to find out if cooling the heart muscle directly through the catheter being used for the normal primary angioplasty treatment using room temperature may be effective in preserving heart muscle, without the shortcomings of entire body cooling. The investigators have already published an initial series of ten cases in which this treatment appeared to be feasible without causing significant clinical problems. The present study is a pilot study designed to assess the rate of patient recruitment and feasibility of this new treatment while exploring some detailed outcomes measuring the restoration of blood flow within the coronary artery at the end of the procedure. Ultimately if the present pilot study is successful, the investigators plan to go on to undertake a much larger randomised outcome study to determine definitively whether this treatment can help reduce heart attack size.

Detailed Description
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The study population will comprise 60 patients with ST-Elevation Myocardial Infarction (STEMI) presenting to Harefield Hospital undergoing primary percutaneous coronary intervention (PCI). The primary aim of this pilot trial is to investigate the recruitment rate feasibility and safety of undertaking a randomised trial of simple intracoronary coronary cooling and dilution through the guiding catheter during primary PCI for STEMI to reduce myocardial infarction size. The secondary aims are as follows: The study will explore the invasive haemodynamic assessment of coronary flow and microvascular function The study will explore blood biomarkers before and after treatment for myocardial infarction The study will explore myocardial salvage after treatment for myocardial infarction with magnetic resonance imaging (MRI) and subsequent final infarct size. Patients will be randomised 1:1 in the catheterisation lab when coronary angiography has demonstrated a target lesion with proposed primary PCI. Patients randomised to the intervention will receive transcatheter cooling and dilution in addition to usual clinical care. Patients randomised to control will receive usual care alone. A combined thermistor and pressure wire Coroventis™ (Abbott Vascular) with comparable tip stiffness to standard guidewires and in routine clinical use, will be used to perform the primary PCI procedure and to measure intracoronary temperature and pressure continually throughout all procedures in all patients. This will therefore limit the procedure to a simple single wire throughout strategy in most cases. In the event that the wire fails to function properly during or after the PCI procedure it may be changed for a new wire using standard interventional techniques as appropriate Patients randomised to intracoronary cooling and dilution(n=30), will receive an intracoronary infusion of room temperature 0.9% Normal Saline solution through the guiding catheter which will commence immediately prior to crossing the coronary occlusion with the guidewire. Using a 3-way tap in the procedural manifold an infusion pressure of 150mmHg above systolic blood pressure achieved with a pressure bag will be used to achieve a target intracoronary temperature of 6-8 C° below the baseline temperature. The infusion will continue until 10 minutes after the lesion is crossed and distal flow is restored, with only brief interruptions as required for the clinical procedure. A maximum volume of 750ml will be infused. The primary angioplasty procedure itself will be undertaken according to standard local practice. Patients randomised to the control group (n=30) will undergo primary PCI according to standard local practice. A complete physiological study including Fractional flow reserve (FFR), resting full-cycle ratio (RFR), coronary flow reserve (CFR), resistive reserve ratio (RRR) and index of microvascular resistance (IMR) to assess microcirculation will be measured 10 minutes after reperfusion in all patients. Patients will go on to have blood taken on the next day for the analysis of a panel of biomarkers and comparison with pre-procedure levels and in addition to have a cardiac MRI scan prior to discharge and at 6 months.

Official Title
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Trans-coronary Cooling and Dilution for Cardioprotection During Revascularisation for ST-elevation Myocardial Infarction

Conditions
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Myocardial Infarction, Reperfusion Injury, Myocardial

Intervention / Treatment
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* Other: Transcoronary cooling and dilution
* Other: Standard of care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical ST-elevation myocardial infarction <6Hrs after symptom onset Total ST-segment deviation of at least 1 mm in two contiguous ECG leads Thrombolysis in myocardial infarction (TIMI) 0 coronary flow in a target vessel Able to provide verbal assent and subsequent informed consent Exclusion Criteria: Cardiac arrest, Killip class II-IV on presentation, Severe left ventricular impairment Previous Myocardial Infarction Known estimated glomerular filtration rate (eGFR) <30ml/min, History of severe asthma Recent stroke (<6 months) Hepatic failure, coagulopathy Pregnancy Severe concomitant disease or conditions with a life expectancy of less than one year.

Ages Eligible for Study
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Minimum Age: 18 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: Randomised placebo controlled
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Transcoronary cooling and dilution<br>Intervention with transcoronary cooling and dilution | Other: Transcoronary cooling and dilution<br>* Transcoronary cooling and dilution<br>|
| Placebo Comparator: Standard of care<br>Routine clinical care | Other: Standard of care<br>* Routine clinical care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recruitment rate | Patients recruited per month | 1 year | 
| Feasibility (Number of studies where all the planned measurements have been collected / total studies) | Number of studies where all the planned measurements have been collected / total studies | 1 year | 
| Safety (Adverse events should not be significantly higher in the treatment arm compared to control, nor plausibly caused by the treatment) | Adverse events should not be significantly higher in the treatment arm compared to control, nor plausibly caused by the treatment as assessed by CTCAE v5.0 | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Index of microvascular resistance (IMR) 10 mins after completion of percutaneous coronary intervention and study infusion | Distal coronary pressure during hyperaemia x mean transit time (mmHg·s) | 1 hour | 
| Fractional flow reserve (FFR) 10 mins after completion of percutaneous coronary intervention and study infusion | Distal coronary pressure/aortic pressure during hyperaemia | 1 hour | 
| Coronary flow reserve (CFR) 10 mins after completion of percutaneous coronary intervention and study infusion | Termodilution-based ratio of hyperaemic coronary flow/basal flow | 1 hour | 
| Resistive reserve ratio (RRR) 10 mins after completion of percutaneous coronary intervention and study infusion | Index of microvascular resistance rest/hyperaemia | 1 hour | 
| Resting full-cycle ratio (RFR) 10 mins after completion of percutaneous coronary intervention and study infusion | lowest value of distal coronary pressure/aortic pressure over the entire cardiac cycle at rest | 1 hour | 
| Intracoronary temperature change | Intracoronary temperature change during cooling and dilution (°C) | 1 hour | 
| Infusion volume | Total volume of intracoronary saline infused (ml) | 1 hour | 
| Infusion rate | Total volume of intracoronary saline infused/infusion time (ml/min) | 1 hour | 
| Chest pain during study infusion | Whether new chest pain arises, or chest pain increases during study infusion | 1 hour | 
| ECG changes during study infusion | Amelioration or worsening of the ECG anomalies during study infusion (ST elevation/depression, T wave inversion, QT prolongation) | 1 hour | 
| Heart rhythm changes during study infusion | Appearance or resolution of heart rhythm disturbances during study infusion (sinus tachycardia, supraventricular tachycardia, atrial tachycardia/fibrillation/flutter, ventricular tachycardia/flutter, ventricular fibrillation, sinus bradycardia, grade I, II, or III heart block, asystole. | 1 hour | 
| Myocardial blush grade 10 mins after completion of percutaneous coronary intervention and study infusion | Angiographic myocardial perfusion measurement based on visual assessment of the myocardium after contrast injection. Grading: 0, no myocardial blush or contrast density; 1, minimal myocardial blush or contrast density; 2, moderate myocardial blush or contrast density but less than that obtained during angiography of a contralateral or ipsilateral non-infarct-related coronary artery; and 3, normal myocardial blush or contrast density, comparable with that obtained during angiography of a contralateral or ipsilateral non-infarct-related coronary artery | 1 hour | 
| Thrombolysis in Myocardial Infarction (TIMI) flow 10 mins after completion of percutaneous coronary intervention and study infusion | Visual angiographic assessment of coronary flow. Grade 0 = no perfusion; grade 1 = penetration without perfusion; 2 = partial perfusion; 3 = complete perfusion | 1 hour | 
| ST segment resolution 10 mins after completion of percutaneous coronary intervention and study infusion | Null, partial, or complete resolution of the ST elevation | 1 hour | 
| Heart Rhythm disturbance from baseline to 12 hours | Appearance or resolution of heart rhythm disturbances in the 12 hours after the procedure (sinus tachycardia, supraventricular tachycardia, atrial tachycardia/fibrillation/flutter, ventricular tachycardia/flutter, ventricular fibrillation, sinus bradycardia, grade I, II, or III heart block, asystole. | 12 hours | 
| Haemodynamic compromise from baseline to 12 hours | Society for Cardiovascular Angiography and Interventions (SCAI) class B or above | 12 hours | 
| Left ventricular ejection fraction (LVEF) at 48 hours | Simpson biplane (diastolic-systolic)/diastolic left ventricular volume on echocardiography | 2 days | 
| Left ventricular ejection fraction (LVEF) at 6 months | Simpson biplane (diastolic-systolic)/diastolic left ventricular volume on echocardiography | 6 months | 
| Wall motion score index (WMSI) at 48 hours | The wall motion score index (WMSI) is an echocardiographic parameter that numerically sums the average scores for all left ventricular segments into a single parameter and then dividing by the number of segments. 1 Normal motion; 2 = hypokinesia; 3 = akinesia; 4 = dyskinesia. | 48 hours | 
| Wall motion score index (WMSI) at 6 months | The wall motion score index (WMSI) is an echocardiographic parameter that numerically sums the average scores for all left ventricular segments into a single parameter and then dividing by the number of segments. 1 Normal motion; 2 = hypokinesia; 3 = akinesia; 4 = dyskinesia. | 6 months | 
| Global longitudinal strain (GLS) at 48 hours | Echocardiographic speckle-tracking imaging that measures the systolic shortening of left ventricular segments as percentage of their diastolic length | 48 hours | 
| Global longitudinal strain (GLS) at 6 months | Echocardiographic speckle-tracking imaging that measures the systolic shortening of left ventricular segments as percentage of their diastolic length | 6 months | 
| Length of stay | Duration of hospital length of stay | 3-5 days | 
| Peak high-sensitivity cardiac troponin T (hs-cTnT, ng/l) | Myocardial injury marker. Highest hs-cTnT measurement during hospital stay | 1-3 days | 
| N-terminal pro-brain natriuretic peptide (NT-proBNP, ng/l) | Heart failure marker. Highest NT-proBNP measurement during hospital stay | 1-3 days | 
| Interleukin-1b | Biomarker of inflammation during myocardial infarction | 1 day | 
| Interleukin-1 receptor antagonist | Biomarker of inflammation during myocardial infarction | 1 day | 
| Interleukin-6 | Biomarker of inflammation during myocardial infarction | 1 day | 
| Interleukin-10 | Biomarker of inflammation during myocardial infarction | 1 day | 
| First pass microvascular obstruction extent (FP MVO) | Measured in 3 SAX levels to provide an index of %LV FP MVO | 1-3 days | 
| First pass microvascular obstruction extent (FP MVO) at 6 months | Measured in 3 SAX levels to provide an index of %LV FP MVO | 6 months | 
| Early MVO extent (% of LV) on 1 min post-gadolinium contrast enhanced MRI, adjusted for area at-risk | Cardiac magnetic resonance-based assessment | 1-3 days | 
| Early MVO extent (% of LV) on 1 min post-gadolinium contrast enhanced MRI, adjusted for area at-risk, at 6 months | Cardiac magnetic resonance-based assessment | 6 months | 
| Late MVO (presence / absence) on LGE | Cardiac magnetic resonance-based assessment | 1-3 days | 
| Late MVO (presence / absence) on LGE at 6 months | Cardiac magnetic resonance-based assessment | 6 months | 
| Initial infarct size (LGE) | Mass of infarcted myocardium calculated with the full-width at half-maximum method | 1-3 days | 
| Infarct size (LGE) at 6 months | Mass of infarcted myocardium calculated with the full-width at half-maximum method | 6 months | 
| Initial MSI (area-at-risk minus initial infarct size/area-at-risk) | Percentage of the area at risk (calculated with the Otsu method) that was not infarcted on late gadolinium enhancement (LGE) images using infarct size from the pre-discharge (Acute MSI) | 1-3 days | 
| MSI (area-at-risk minus initial infarct size/area-at-risk) at 6 months | Percentage of the area at risk (calculated with the Otsu method) that was not infarcted on late gadolinium enhancement (LGE) images using infarct size from the follow-up (Final MSI) magnetic resonance imaging | 6 months | 
| Left ventricular end-diastolic volume index (LVEDVI) | Cardiac magnetic resonance-based assessment | 1-3 days | 
| Left ventricular end-diastolic volume index (LVEDVI) at 6 months | Cardiac magnetic resonance-based assessment | 6 months | 
| Left ventricular end-systolic volume index (LVESVI) | Cardiac magnetic resonance-based assessment | 1-3 days | 
| Left ventricular end-systolic volume index (LVESVI) at 6 months | Cardiac magnetic resonance-based assessment | 6 months | 
| CMR-based Left ventricular ejection fraction (LVEF) | Cardiac magnetic resonance-based assessment | 1-3 days | 
| CMR-based Left ventricular ejection fraction (LVEF) at 6 months | Cardiac magnetic resonance-based assessment | 6 months | 
| Myocardial haemorrhage (presence/absence) | Cardiac magnetic resonance-based assessment | 1-3 days | 
| Myocardial haemorrhage (presence/absence) at 6 months | Cardiac magnetic resonance-based assessment | 6 months | 
| Myocardial haemorrhage extent (% of LV) | Cardiac magnetic resonance-based assessment | 1-3 days | 
| Myocardial haemorrhage extent (% of LV) at 6 months | Cardiac magnetic resonance-based assessment | 6 months | 
| Composite of all-cause mortality and hospitalization for heart failure at 6 weeks | Composite of all-cause mortality and hospitalization for heart failure at 6 weeks | 6 weeks | 
| Hospitalization for heart failure at 6 weeks | Hospitalization for heart failure at 6 weeks | 6 weeks | 
| All-cause mortality at 6 weeks | All-cause mortality at 6 weeks | 6 weeks | 
| Hospitalization for heart failure at 6 months | Hospitalization for heart failure at 6 months | 6 months | 
| Composite of all-cause mortality and hospitalization for heart failure at 6 months | Composite of all-cause mortality and hospitalization for heart failure at 6 months | 6 months | 
| All-cause mortality at 6 months | All-cause mortality at 6 months | 6 months | 
| Composite of all-cause mortality and hospitalization for heart failure at 12 months | Composite of all-cause mortality and hospitalization for heart failure at 12 months | 12 months | 
| Hospitalization for heart failure at 12 months | Hospitalization for heart failure at 12 months | 12 months | 
| Cardiovascular mortality at 12 months | Cardiovascular mortality at 12 months | 12 months |