Reappraisal of GIK in Acute STEMI by Pre-hospital Administration

Study Overview
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Brief Summary
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The purpose of this study is: to assess whether pre-hospital glucose-insulin-potassium (GIK) administration in acute STEMI patients would reduce infarct size and ischemia/reperfusion damage using comprehensive tissue characterization by cardiovascular magnetic resonance (CMR) at an early post-infarction phase. to explore the putative cardioprotective mechanisms of pre-hospital GIK administration

Detailed Description
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Background - After an acute ST-segment elevation myocardial infarction (STEMI), early and successful myocardial reperfusion with primary percutaneous coronary intervention (PCI) is the most effective strategy for reducing the infarct size and improving clinical outcome. The process of restoring blood flow to the ischemic myocardium, however, can induce injury per se, paradoxically increasing the extent of final infarction (i.e., reperfusion injury). Research has been focusing for years on a strategy to effectively counteract reperfusion injury and, thereby, reduce the final infarct size with salutary effects on clinical outcome. Robust experimental evidences support Glucose-Insulin-Potassium (GIK) as an effective cardioprotective agent being capable to metabolically protect the myocardium against ischemia and ischemia/reperfusion injury. These benefits are clearly related to the time that GIK is administered in the course of cardiac ischemia, with effectiveness increasing with early administration. However, clinical trials in the reperfusion era have lost the opportunity to translate the beneficial effects seen in the laboratory to the clinical setting, because of the unacceptably prolonged delay from the onset of ischemic symptoms to GIK administration. A properly-designed prospective trial with double-blinded randomization to placebo or GIK in the out-of-hospital setting would straightforwardly overcome this limitation, thereby providing convincing evidences in favor or disfavor of GIK treatment. Notable, GIK is an un-expensive compound, and upon the verification of its efficacy, GIK treatment would be ready for primetime clinical application with matchless cost/effectiveness profile. Aims to assess whether pre-hospital GIK administration in acute STEMI patients would reduce infarct size and ischemia/reperfusion damage using comprehensive tissue characterization by cardiovascular magnetic resonance (CMR) at an early post-infarction phase. to explore the putative cardioprotective mechanisms of pre-hospital GIK administration Methods - The investigators will conduct a single-center randomized, placebo-controlled, double-blinded trial for testing the efficacy of pre-hospital GIK administration in patients with acutely reperfused STEMI. The pre-specified primary end-point is the reduction of infarct size, as quantitated by late gadolinium enhancement CMR in the early post-infarction phase. Major secondary end-points are: 1) reduction of ischemia/reperfusion injury quantitated by CMR, and 2) investigation of the putative cardioprotective mechanisms ofGIK treatment in subjects with acute STEMI. Outlook: The investigators study results, if positive, will persuade the scientific community to reconsider pre-hospital GIK treatment as adjunctive to primary PCI in acute STEMI patients and revitalize the field of metabolism-based cardioprotection. They will illustrate by which mechanisms cardioprotection is achieved in the clinical setting, prompting large prospective multicentre trials to test the efficacy of pre-hospital GIK administration on hard clinical end-points.

Official Title
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Reappraisal of Glucose-insulin-potassium Therapy in Acute St-segment Elevation Myocardial Infarction by Pre-hospital Administration

Conditions
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Myocardial Infarction

Intervention / Treatment
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* Drug: Glucose-Insulin-Potassium
* Drug: Glucose 5%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with the diagnosis of acute STEMI age≥ 18 informed consent for study participation. Exclusion Criteria evaluated during ambulance transport to primary PCI center: end-stage renal failure requiring dialysis, prior MI or coronary revascularization (PCI or CABG), active malignances, Pregnancy, Hemodynamic instability (systolic blood pressure <100mmHg or significant pulmonary congestion defined as O2 saturation <90% on ambient air at pulso-oxymetry) Exclusion Criteria evaluated after hospital admission at the primary PCI center (all patients will be re-evaluated for study continuation): total ischemic time more than 8 hours (from symptoms onset to infarct-related artery mechanical re-opening) evidence at diagnostic angiograms of TIMI flow-grade >1 of infarct-related artery or significant epicardial collaterals to the ischemic myocardium at risk (Rentrop flow-grade >1), moderate-to-severe renal failure (estimated glomerular filtration rate < 30 ml/min/1.73 m2 by Cockcroft-Gault formula) and urgent CABG.

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Glucose-Insulin-Potassium<br>Rackley's Glucose-Insulin-Potassium formula consisting of 30% glucose (300 mg/L), 50 units of regular insulin per liter and 80 mEqu of KCL per liter. | Drug: Glucose-Insulin-Potassium<br>* Rackley's GIK formula by continuous I.V. infusion at 1.5 ml/Kg/hour for 12 hours (about 100 ml/hour for a 70 kg patient).<br>* Other names: GIK;|
| Placebo Comparator: Glucose 5%<br>Glucose 5% | Drug: Glucose 5%<br>* Glucose 5% (Placebo) by continuous I.V. infusion at 1.5ml/kg/hour for 12 hours (about 100 ml/hour for 70 Kg patient)<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Infarct size quantified by Late Gadolinium Enhancement using Cardiovascular Magnetic Resonance |  | 12 to 72 hours after the acute event | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The severity of ischemia/reperfusion injury (myocardial edema, microvascular obstruction and myocardial hemorrhage) | The of ischemia/reperfusion injury will be assessed by multiparametric CMR | 12 to 72 hours after the acute event | 
| Major Adverse Cardiovascular Events |  | at 7-day, 30-day, 4-month and at 1-year follow-up | 
| Post-infarction Remodeling | Adverse post-infarction remodeling is defined as increase of LV end-systolic volume more than 15% between the first CMR (12 to 72 hours after the acute event) and second CMR (4-month after the acute event) | 4-month follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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myocardial infarction, glucose-insulin-potassium