IMMEDIATE Trial - Out of Hospital Administration of Glucose, Insulin and Potassium. (IMMEDIATE)

Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency Care Trial

The purpose of this study is to test the impact of pharmacological myocardial metabolic support, in the form of intravenous (IV) glucose, insulin and potassium (GIK), for the treatment of patients with threatened or established acute myocardial infarction (AMI).

BACKGROUND: Basic and clinical research suggests intravenous GIK metabolic myocardial support reduces ischemia-induced arrhythmias, progression from unstable angina pectoris (UAP) to acute myocardial infarction (AMI), myocardial infarction (MI) size, and mortality. Also, for ST elevation MI (STEMI), GIK may prolong time of benefit of coronary reperfusion. These effects should reduce short- and long-term mortality from ACS, including AMI and UAP, and the propensity for heart failure (HF). These benefits are related to the earliness of ACS, when both risk and opportunity to save lives are highest. DESIGN NARRATIVE: This is a randomized, placebo-controlled, double-blinded, multicenter clinical trial of IMMEDIATE GIK as early as possible in ACS in the prehospital emergency medical service (EMS) setting. Distinct from prior and ongoing GIK trials, this will test GIK for all ACS rather than only for AMI or STEMI in prehospital EMS. The primary hypothesis is that early GIK will prevent or reduce the size of acute myocardial infarction. Major secondary hypotheses posit GIK will reduce mortality (30 days and 1 year), reduce pre- or in-hospital cardiac arrest and the propensity for heart failure. Other hypotheses address mechanisms of these effects.

Angina, Unstable, Cardiovascular Diseases, Heart Diseases, Coronary Disease, Myocardial Infarction, Heart Failure, Congestive

GIK = glucose-insulin-potassium; In one-liter: Dextrose 30% + 80 mEq Potassium Chloride + 50 units Regular Insulin; infused at 1.5 ml/kg/hour for a total of 12 hours.

Outcome for all participants during the first 24 hours of hospitalization; evidence of myocardial infarction is determined by ECG and biomarker results.

Outcome for all participants who had a cardiac arrest from initial contact in the prehospital setting through their subsequent hospitalization.

Outcome for all participants (composite of re-hospitalization for heart failure or death within 30 days)

Inclusion Criteria: Symptoms of threatened or established AMI including but not limited to: Chest pain, discomfort, or tightness Arm or shoulder pain Jaw pain Epigastric discomfort Shortness of breath 12-lead electrocardiogram (ECG) with two or more contiguous leads with ST elevation greater than 1 mm, ST depression greater than 0.5 mm, T wave inversion or other T wave abnormalities (hyperacute T waves), or left bundle branch block (not known to be old). Identification aided by the acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI)and thrombolytic predictive instrument (TPI) decision support software (ACI-TIPI >= 75% and TPI detection of suspected STEMI). Exclusion Criteria: End-stage kidney failure requiring dialysis Rales present more than halfway up the back Unable to comply with the requirements of the study Incarcerated Known to be pregnant

Selker HP, Beshansky JR, Ruthazer R, Sheehan PR, Sayah AJ, Atkins JM, Aufderheide TP, Pirrallo RG, D'Agostino RB, Massaro JM, Griffith JL. Emergency medical service predictive instrument-aided diagnosis and treatment of acute coronary syndromes and ST-segment elevation myocardial infarction in the IMMEDIATE trial. Prehosp Emerg Care. 2011 Apr-Jun;15(2):139-48. doi: 10.3109/10903127.2010.545478.

Selker HP, Beshansky JR, Griffith JL, D'Agostino RB, Massaro JM, Udelson JE, Rashba EJ, Ruthazer R, Sheehan PR, Desvigne-Nickens P, Rosenberg YD, Atkins JM, Sayah AJ, Aufderheide TP, Rackley CE, Opie LH, Lambrew CT, Cobb LA, Macleod BA, Ingwall JS, Zalenski RJ, Apstein CS. Study design for the Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency Care (IMMEDIATE) Trial: A double-blind randomized controlled trial of intravenous glucose, insulin, and potassium for acute coronary syndromes in emergency medical services. Am Heart J. 2012 Mar;163(3):315-22. doi: 10.1016/j.ahj.2012.02.002.

Ellis KL, Zhou Y, Rodriguez-Murillo L, Beshansky JR, Ainehsazan E, Selker HP, Huggins GS, Cupples LA, Peter I. Common variants associated with changes in levels of circulating free fatty acids after administration of glucose-insulin-potassium (GIK) therapy in the IMMEDIATE trial. Pharmacogenomics J. 2017 Jan;17(1):76-83. doi: 10.1038/tpj.2015.84. Epub 2015 Dec 8.

Ellis KL, Zhou Y, Beshansky JR, Ainehsazan E, Selker HP, Cupples LA, Huggins GS, Peter I. Genetic modifiers of response to glucose-insulin-potassium (GIK) infusion in acute coronary syndromes and associations with clinical outcomes in the IMMEDIATE trial. Pharmacogenomics J. 2015 Dec;15(6):488-95. doi: 10.1038/tpj.2015.10. Epub 2015 Mar 17.

Alkofide H, Huggins GS, Beshansky JR, Ruthazer R, Peter I, Ray M, Mukherjee JT, Selker HP. C-Reactive protein reactions to glucose-insulin-potassium infusion and relations to infarct size in patients with acute coronary syndromes. BMC Cardiovasc Disord. 2015 Dec 3;15:163. doi: 10.1186/s12872-015-0153-7.

Alkofide H, Huggins GS, Ruthazer R, Beshansky JR, Selker HP. Serum adiponectin levels in patients with acute coronary syndromes: Serial changes and relation to infarct size. Diab Vasc Dis Res. 2015 Nov;12(6):411-9. doi: 10.1177/1479164115592638. Epub 2015 Jul 20.

Selker HP, Beshansky JR, Sheehan PR, Massaro JM, Griffith JL, D'Agostino RB, Ruthazer R, Atkins JM, Sayah AJ, Levy MK, Richards ME, Aufderheide TP, Braude DA, Pirrallo RG, Doyle DD, Frascone RJ, Kosiak DJ, Leaming JM, Van Gelder CM, Walter GP, Wayne MA, Woolard RH, Opie LH, Rackley CE, Apstein CS, Udelson JE. Out-of-hospital administration of intravenous glucose-insulin-potassium in patients with suspected acute coronary syndromes: the IMMEDIATE randomized controlled trial. JAMA. 2012 May 9;307(18):1925-33. doi: 10.1001/jama.2012.426. Epub 2012 Mar 27.

Selker HP, Udelson JE, Massaro JM, Ruthazer R, D'Agostino RB, Griffith JL, Sheehan PR, Desvigne-Nickens P, Rosenberg Y, Tian X, Vickery EM, Atkins JM, Aufderheide TP, Sayah AJ, Pirrallo RG, Levy MK, Richards ME, Braude DA, Doyle DD, Frascone RJ, Kosiak DJ, Leaming JM, Van Gelder CM, Walter GP, Wayne MA, Woolard RH, Beshansky JR. One-year outcomes of out-of-hospital administration of intravenous glucose, insulin, and potassium (GIK) in patients with suspected acute coronary syndromes (from the IMMEDIATE [Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency Care] Trial). Am J Cardiol. 2014 May 15;113(10):1599-605. doi: 10.1016/j.amjcard.2014.02.010. Epub 2014 Mar 1.

Beshansky JR, Sheehan PR, Klima KJ, Hadar N, Vickery EM, Selker HP. A community consultation survey to evaluate support for and success of the IMMEDIATE trial. Clin Trials. 2014 Apr;11(2):178-86. doi: 10.1177/1740774514526476.

Sullivan AL, Beshansky JR, Ruthazer R, Murman DH, Mader TJ, Selker HP. Factors associated with longer time to treatment for patients with suspected acute coronary syndromes: a cohort study. Circ Cardiovasc Qual Outcomes. 2014 Jan;7(1):86-94. doi: 10.1161/CIRCOUTCOMES.113.000396. Epub 2014 Jan 14.