Very early administration of glucose-insulin-potassium by emergency medical service for acute coronary syndromes: Biological mechanisms for benefit in the IMMEDIATE Trial.

AIMS: In the IMMEDIATE Trial, intravenous glucose-insulin-potassium (GIK) was started as early as possible for patients with suspected acute coronary syndrome by ambulance paramedics in communities. In the IMMEDIATE Biological Mechanism Cohort substudy, reported here, we investigated potential modes of GIK action on specific circulating metabolic components. Specific attention was given to suppression of circulating oxygen-wasting free fatty acids (FFAs) that had been posed as part of the early GIK action related to averting cardiac arrest. METHODS: We analyzed the changes in plasma levels of FFA, glucose, C-peptide, and the homeostasis model assessment (HOMA) index. RESULTS: With GIK, there was rapid suppression of FFA levels with estimated levels for GIK and placebo groups after 2 hours of treatment of 480 and 781 µmol/L (P<.0001), even while patterns of FFA saturation remained unchanged. There were no significant changes in the HOMA index in the GIK or placebo groups (HOMA index: placebo 10.93, GIK 12.99; P = .07), suggesting that GIK infusions were not countered by insulin resistance. Also, neither placebo nor GIK altered endogenous insulin secretion as reflected by unchanging C-peptide levels. CONCLUSION: These mechanistic observations support the potential role of FFA suppression in very early cardioprotection by GIK. They also suggest that the IMMEDIATE Trial GIK formula is balanced with respect to its insulin and glucose composition, as it induced no endogenous insulin secretion.

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.

BACKGROUND: Experimental studies suggest that metabolic myocardial support by intravenous (IV) glucose, insulin, and potassium (GIK) reduces ischemia-induced arrhythmias, cardiac arrest, mortality, progression from unstable angina pectoris to acute myocardial infarction (AMI), and myocardial infarction size. However, trials of hospital administration of IV GIK to patients with ST-elevation myocardial infarction (STEMI) have generally not shown favorable effects possibly because of the GIK intervention taking place many hours after ischemic symptom onset. A trial of GIK used in the very first hours of ischemia has been needed, consistent with the timing of benefit seen in experimental studies. OBJECTIVE: The IMMEDIATE Trial tested whether, if given very early, GIK could have the impact seen in experimental studies. Accordingly, distinct from prior trials, IMMEDIATE tested the impact of GIK (1) in patients with acute coronary syndromes (ACS), rather than only AMI or STEMI, and (2) administered in prehospital emergency medical service settings, rather than later, in hospitals, after emergency department evaluation. DESIGN: The IMMEDIATE Trial was an emergency medical service-based randomized placebo-controlled clinical effectiveness trial conducted in 13 cities across the United States that enrolled 911 participants. Eligible were patients 30 years or older for whom a paramedic performed a 12-lead electrocardiogram to evaluate chest pain or other symptoms suggestive of ACS for whom electrocardiograph-based acute cardiac ischemia time-insensitive predictive instrument indicated a ≥75% probability of ACS, and/or the thrombolytic predictive instrument indicated the presence of a STEMI, or if local criteria for STEMI notification of receiving hospitals were met. Prehospital IV GIK or placebo was started immediately. Prespecified were the primary end point of progression of ACS to infarction and, as major secondary end points, the composite of cardiac arrest or in-hospital mortality, 30-day mortality, and the composite of cardiac arrest, 30-day mortality, or hospitalization for heart failure. Analyses were planned on an intent-to-treat basis, on a modified intent-to-treat group who were confirmed in emergency departments to have ACS, and for participants presenting with STEMI. CONCLUSION: The IMMEDIATE Trial tested whether GIK, when administered as early as possible in the course of ACS by paramedics using acute cardiac ischemia time-insensitive predictive instrument and thrombolytic predictive instrument decision support, would reduce progression to AMI, mortality, cardiac arrest, and heart failure. It also tested whether it would provide clinical and pathophysiologic information on GIK's biological mechanisms.

Out-of-hospital administration of intravenous glucose-insulin-potassium in patients with suspected acute coronary syndromes: the IMMEDIATE randomized controlled trial.

CONTEXT: Laboratory studies suggest that in the setting of cardiac ischemia, immediate intravenous glucose-insulin-potassium (GIK) reduces ischemia-related arrhythmias and myocardial injury. Clinical trials have not consistently shown these benefits, possibly due to delayed administration. OBJECTIVE: To test out-of hospital emergency medical service (EMS) administration of GIK in the first hours of suspected acute coronary syndromes (ACS). DESIGN, SETTING, AND PARTICIPANTS: Randomized, placebo-controlled, double-blind effectiveness trial in 13 US cities (36 EMS agencies), from December 2006 through July 31, 2011, in which paramedics, aided by electrocardiograph (ECG)-based decision support, randomized 911 (871 enrolled) patients (mean age, 63.6 years; 71.0% men) with high probability of ACS. INTERVENTION: Intravenous GIK solution (n = 411) or identical-appearing 5% glucose placebo (n = 460) administered by paramedics in the out-of-hospital setting and continued for 12 hours. MAIN OUTCOME MEASURES: The prespecified primary end point was progression of ACS to myocardial infarction (MI) within 24 hours, as assessed by biomarkers and ECG evidence. Prespecified secondary end points included survival at 30 days and a composite of prehospital or in-hospital cardiac arrest or in-hospital mortality, analyzed by intent-to-treat and by presentation with ST-segment elevation. RESULTS: There was no significant difference in the rate of progression to MI among patients who received GIK (n = 200; 48.7%) vs those who received placebo (n = 242; 52.6%) (odds ratio [OR], 0.88; 95% CI, 0.66-1.13; P = .28). Thirty-day mortality was 4.4% with GIK vs 6.1% with placebo (hazard ratio [HR], 0.72; 95% CI, 0.40-1.29; P = .27). The composite of cardiac arrest or in-hospital mortality occurred in 4.4% with GIK vs 8.7% with placebo (OR, 0.48; 95% CI, 0.27-0.85; P = .01). Among patients with ST-segment elevation (163 with GIK and 194 with placebo), progression to MI was 85.3% with GIK vs 88.7% with placebo (OR, 0.74; 95% CI, 0.40-1.38; P = .34); 30-day mortality was 4.9% with GIK vs 7.7% with placebo (HR, 0.63; 95% CI, 0.27-1.49; P = .29). The composite outcome of cardiac arrest or in-hospital mortality was 6.1% with GIK vs 14.4% with placebo (OR, 0.39; 95% CI, 0.18-0.82; P = .01). Serious adverse events occurred in 6.8% (n = 28) with GIK vs 8.9% (n = 41) with placebo (P = .26). CONCLUSIONS: Among patients with suspected ACS, out-of-hospital administration of intravenous GIK, compared with glucose placebo, did not reduce progression to MI. Compared with placebo, GIK administration was not associated with improvement in 30-day survival but was associated with lower rates of the composite outcome of cardiac arrest or in-hospital mortality. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00091507.

Hormones and coronary atherosclerosis in women.

Heart disease is the major health issue facing women in the United States today. Yet, less than 50% of women are aware cardiovascular disease is a health problem. Atherosclerosis begins in childhood and lipid streaks have been identified in girls ages 15-19 in the abdominal aorta and the right coronary artery. Risk factors for cardiovascular disease in women include smoking, diabetes, hypertension, lipid disorders, and menopause. Observational studies have reported a 30-50% reduction in cardiovascular events when estrogen was administered to younger women for menopausal symptoms, yet randomized trials in older patients have failed to show benefit with hormonal replacement therapy. Recent studies have reported preservation of lipid and vascular vasodilatation with low-dose conjugated equine estrogens (CEE) in women and an absence of inflammatory and clotting changes that were observed in high-dose CEE. Recommendations for reducing cardiovascular risk in postmenopausal women include smoking cessation, regular exercise, and weight control. Should hormone therapy be continued beyond management of menopausal symptoms and treatment for osteoporosis, a statin drug should be added to eliminate future cardiovascular complications. Future research will examine low-dose hormonal therapy, earlier administration after menopause, newer agents, and routes of estrogen administration.

New clinical markers predictive of cardiovascular disease: the role of inflammatory mediators.

Identification of persons at risk for developing cardiovascular disease has focused attention on blood pressure, smoking, and serum cholesterol levels. Modification of these factors has resulted in reduction of overall morbidity and mortality within the population. While significant, these risk factors do not predict all cardiovascular events, because the causes of cardiovascular disease are multifactorial and the risk associated with any given factor is compounded by the presence of other risk factors. Additional risk factors that may also identify risk for cardiovascular disease may include inflammatory mediators such as C-reactive protein, interleukin 6, cell adhesion molecules, and fibrinogen. Although additional studies are needed to establish the clinical utility of these markers, they may improve the identification and assessment of patients at risk for future cardiovascular events.

Strategies for the prevention of atherosclerotic progression in women.

Atherosclerosis is an inflammatory and fibrotic process that begins early in life in females. The pathogenesis involves the oxidation of the low-density lipoprotein molecule aggravated by smoking, hypertension, lipid abnormalities, and hormonal changes. Risks for progression of atherosclerosis can now be tabulated for the female based on age, cholesterol, smoking, high-density lipoprotein, and systolic blood pressure. During the reproductive years, emphasis should be placed on lifestyle changes, but women at increased risk for diabetes should be aggressively treated with lipid-lowering agents. During the menopausal phase of life, an important consideration is the use of hormone replacement along with lifestyle changes, smoking cessation, blood pressure control, and lipid modification. In the female with established coronary heart disease, standard cardiac medications are indicated along with more aggressive approaches to risk factors and target goals for cholesterol, low-density lipoprotein, and triglycerides. The effect of hormone replacement in established coronary artery disease is uncertain. Therefore, strategies for slowing the progression of atherosclerosis should begin during the reproductive years, with particular emphasis in patients during menopause and in patients with coronary heart disease.