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Substantial experimental and translational evidence has accumulated over the last four decades to suggest that metabolic support of the ischemic myocardium can prolong the time window until the occurrence of irreversible necrosis. In clinical studies, metabolic support in the form of glucose-insulin-potassium (GIK) infusions has demonstrated mixed results from studies large and small. This likely reflects: a) different GIK formulations, b) inadequate study designs, c) variable prevalence and degrees of reperfusion, and, most importantly d) administration of GIK at a time point too late to impact salvage of ischemic myocardium. The IMMEDIATE Trial has been specifically designed to deliver metabolic support to the ischemic myocardium in the setting of a threatened or established acute myocardial infarction (AMI) in a manner based on what the experimental evidence would suggest is optimal for salvage. That is, infusion of GIK will begin almost immediately upon the patient’s presentation to the medical system, via the EMS ambulances. Basic and translational research would suggest that the earliest possible administration of metabolic support in this form, combined with aggressive contemporary reperfusion strategies, will optimize the likelihood and extent of myocardial salvage, reduce the early risk of sudden death, and result in improved clinical outcomes. These concepts form the basis of the IMMEDIATE Trial hypotheses.
Estimates of the potential impact of immediate GIK on acute coronary syndromes (ACS) i.e., AMI or unstable angina pectoris (UAP) are too conjectural to consider for other than framing purposes, but they give a sense of the possible scale of impact. Yearly in the US there are approximately 1.1 million new and recurrent cases of acute coronary attack (AMI or fatal coronary artery disease [CAD]).1 Based on the GUSTO Trials,2 the C-PORT Trial,3 the TIMI-19 Trial,4 and prior trials run by Tufts Medical Center’s (Tufts-NEMC) Center for Cardiovascular Health Services Research (CCHSR), the TPI5 and ACI-TIPI Trials6, it is estimated that there will be a 6.0% 30-day mortality rate for such patients in the IMMEDIATE Trial control group. Recent clinical trials of GIK other than the CREATE ECLA Trial (see section 1.4.5) lead to a conservative estimate of a 30% reduction of AMI 30-day mortality by early GIK administration, resulting in a 4.2% 30-day mortality in the GIK treated group. Assuming 1.1 million AMIs annually in the US and a 1.8% absolute reduction (from 5.0 to 3.5%) in 30-day mortality rate, it is estimated that early GIK could save approximately 19,800 lives per year in the initial 30 days post-myocardial infarction (MI). An additional 2% mortality rate occurs following hospital discharge in the first year post-MI. It is estimated that this could be reduced to 1.4% by early GIK treatment. This suggests an additional 6,600 lives saved during the first year post-MI. Beyond these estimates are the potential benefits for patients with non-AMI ACS, i.e. unstable angina pectoris (UAP), some of whom also will be included in the IMMEDIATE Trial, and the potential additional thousands of lives saved.
Very early GIK treatment of threatened or established AMI should have an even bigger impact on the incidence and severity of heart failure (HF). Once AMI occurs, HF develops during the index hospitalization in almost 30% of patients, based on the National Registry of Myocardial Infarction (NRMI).7 The most important determinant of the development of HF post-MI is MI size, i.e., the amount of myocardial cell death due to ischemic necrosis. By reducing myocardial necrosis, early GIK should decrease the incidence of post-MI HF. Assuming that approximately 30% of the annual 1.1 million patients with AMIs will develop HF7, there will be approximately 330,000 new post-MI cases of HF annually. In experimental studies of early GIK during 2.5 hours of severe ischemia, myocardial damage was reduced by 60% by GIK.8 Conservatively estimating half such an effect clinically, i.e., 30% reduction in myocardial damage by early GIK, then about 99,000 HF cases would be prevented per year in patients with AMI, not including avoided HF by preventing progression of UAP to AMI.
Benefits on such a large scale will accrue only if immediate GIK is used commonly. Facilitating the widespread use of GIK is that it is inexpensive easily administered, safe and that glucose, potassium, and insulin are stable at room temperature, so GIK components can be readily kept in ambulances, EDs, and clinics. Thus, if demonstrated effective in the EMS and ED settings in the IMMEDIATE Trial, it should be widely adopted.
1American Heart Association. Heart Disease and Stroke Statistics-2003 Update. Dallas, Tex.: American Heart Association;2002.
2The GUSTO investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329:673-682.
3Aversano T, Aversano LT, Passamani E, et al. Atlantic Cardiovascular Patient Outcomes Research Team (C-PORT). Thrombolytic therapy vs. primary percutaneous coronary intervention for myocardial infarction in patients presenting to hospitals without on-site cardiac surgery: a randomized controlled trial. Multicenter Study. JAMA. 2002;287:1943-1951.
4Morrow DA, Antman EM, Sayah AJ, et al. Evaluation of the Time Saved by Prehospital Initiation of Retaplase for ST Elevation MI: Results of the Early Retevase (ER) TIMI 19 Trial. J Am Coll Cardiol. 2002;40:71-77.
5Selker HP, Beshansky JR, Griffith JL, for the TPI Trial Investigators. Use of the electrocardiograph-based thrombolytic predictive instrument to assist thrombolytic and reperfusion therapy for acute myocardial infarction. Ann Intern Med. 2002;137:87-95.
6Selker HP, Beshansky JR, Griffith JL, et al. The use of the acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI) to assist emergency department triage of patients with chest pain or other symptoms suggestive of acute cardiac ischemia: a multicenter controlled clinical trial. Ann Intern Med. 1998;129:845-855
7Spencer FA, Meyer TE, Gore JM, Goldberg RJ. Heterogeneity in the management of patients with acute myocardial infarction complicated by heart failure. Circulation. 2002;105:2605-2610.
8Eberli FR, Weinberg EO, Grice WN, Horowitz GL, Apstein CS. Protective effect of increased glycolytic substrate against systolic and diastolic dysfunction and increased coronary resistance from prolonged global underperfusion and reperfusion in isolated rabbit hearts perfused with erythrocyte suspensions. Circ Res. 1991;68: 466-481.
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