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.

In-hospital measurement of left ventricular ejection fraction and one-year outcomes in acute coronary syndromes: results from the IMMEDIATE Trial.

BACKGROUND: In patients with acute coronary syndrome (ACS), reduced left ventricular ejection fraction (LVEF) is a known marker for increased mortality. However, the relationship between LVEF measured during index ACS hospitalization and mortality and heart failure (HF) within 1 year are less well-defined. METHODS: We performed a retrospective analysis of 445 participants in the IMMEDIATE Trial who had LVEF measured by left ventriculography or echocardiogram during hospitalization. RESULTS: Adjusting for age and coronary artery disease (CAD) history, lower LVEF was significantly associated with 1-year mortality or hospitalization for HF. For every 5 % LVEF reduction, the hazard ratio [HR] was 1.26 (95 % CI 1.15, 1.38, P < 0.001). Participants with LVEF < 40 % had higher hazard of 1-year mortality or HF hospitalization than those with LVEF > 40 (HR 3.59; 95 % CI 2.05, 6.27, P < 0.001). The HRs for the association of LVEF with the study outcomes were similar whether measured by left ventriculography or by echocardiography, (respectively, HR 1.32; 95 % CI 1.15, 1.51 and 1.21; 95 % CI 1.106, 1.35, interaction P = 0.32) and whether done within 24 h or not within 24 h (respectively, HR 1.28; 95 % CI 1.10, 1.50 and 1.23; 95 % CI 1.10, 1.38, interaction P = 0.67). CONCLUSIONS: Among patients with ACS, lower in-hospital LVEF is associated with increased 1-year mortality or hospitalization for HF, regardless of the method or timing of the LVEF assessment. This has prognostic implications for clinical practice and suggests the possibility of using various methods of LVEF determination in clinical research.

C-Reactive protein reactions to glucose-insulin-potassium infusion and relations to infarct size in patients with acute coronary syndromes.

BACKGROUND: Some benefits of glucose-insulin-potassium (GIK) in patients with acute coronary syndromes (ACS) may be from an anti-inflammatory effect. The primary aim of this study was to assess the impact of GIK administration early in the course of ACS on inflammatory marker C-reactive protein (CRP) levels. A secondary aim was to investigate the association between CRP and 30-day infarct size. METHODS AND RESULTS: Retrospective analysis of participants with ACS randomly assigned to GIK or placebo for at least 8 h in the IMMEDIATE Trial biological mechanism cohort (n = 143). High sensitivity CRP (hs-CRP) was measured at emergency department presentation, and 6 and 12 h into infusion. Logarithmically transformed hs-CRP values at 12-hours were lower with GIK vs. placebo (mean =0.65 mg/L in GIK, 0.84 mg/L in placebo), with a marginal trend toward significance (P = 0.053). Furthermore, using mixed models of hs-CRP, time, and study group, there was a significant increase in hs-CRP levels over time, but the rate of change did not differ between treatment arms (P = 0.3). Multivariable analysis showed that an elevation in hs-CRP, measured at 12 h, was an independent predictor of 30-day infarct size (ß coefficient, 6.80; P = 0.04) using sestamibi SPECT imaging. CONCLUSIONS: The results of this study show no significant effect of GIK on hs-CRP. In addition our results show that in patients with ACS, hs-CRP measured as early as 12 h can predict 30-day infarct size.

A community consultation survey to evaluate support for and success of the IMMEDIATE trial.

BACKGROUND: The IMMEDIATE (Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care) Trial, a randomized controlled double-blind clinical effectiveness trial of glucose-insulin-potassium (GIK) administered in ambulances in the out-of-hospital setting, used the Exception from Informed Consent Requirements (EFIC) for Emergency Research under Title 21 of the Code of Federal Regulations. EFIC requirements include community consultation that typically involves using a variety of communication methods and venues to inform the public of the research and to receive their feedback. Although not the primary purpose of the community consultation process, a common concern to research sponsors, staff, and institutional review boards (IRBs) is whether there will be a sufficient number of participants to justify mounting a study in their community. Information from community consultation regarding the community acceptance might inform this question. PURPOSE: We evaluated the utility of telephone survey data done as part of the EFIC process as a way to project the ultimate rate of trial participant enrollment. METHODS: A telephone survey community consultation process was undertaken in nine communities planning to be IMMEDIATE Trial sites using a representative sampling of the target population in the areas covered by participating emergency medical service (EMS) agencies. Survey respondents were read a description of the planned study and its informed consent approach that included the option for patients to decline participation in the trial while being transported for acute care in an ambulance. Survey respondents were then asked whether they would object to participating in the study. At the conclusion of actual trial enrollment, the Coordinating Center compared the survey results with the actual rates of enrollment at each site. RESULTS: Approximately 200 (range = 200-271) respondents completed the survey in each of the study communities. Of 2079 survey respondents, 68% (range = 61%-75%) said that they would not object to participating in the trial if experiencing a heart attack, and 85% (range = 79%-89%) said that they would allow the study to be done in their community. During actual trial enrollment in the communities, 79% (range = 63%-91%) of the 828 potential participants agreed in the ambulance to have the study drug started and provided informed consent at the hospital, an average of 13 percentage-points higher than projected by the survey (95% confidence interval (CI): 9%-17%), 19% higher on a relative scale (CI: 14%-25%). CONCLUSIONS: The survey-based approach to community consultation proved to be an efficient way to obtain representative input from potential clinical trial participants. The survey data generated a relatively good and conservative estimate of the ultimate rate of trial enrollment. This information could be useful to investigators and IRBs in projecting enrollment for clinical trials using EFIC.

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.

Emergency medical service predictive instrument-aided diagnosis and treatment of acute coronary syndromes and ST-segment elevation myocardial infarction in the IMMEDIATE trial.

BACKGROUND: A challenge for emergency medical service (EMS) is accurate identification of acute coronary syndromes (ACS) and ST-segment elevation myocardial infarction (STEMI) for immediate treatment and transport. The electrocardiograph-based acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI) and the thrombolytic predictive instrument (TPI) have been shown to improve diagnosis and treatment in emergency departments (EDs), but their use by paramedics in the community has been less studied. OBJECTIVE: To identify candidates for participation in the Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency Care (IMMEDIATE) Trial, we implemented EMS use of the ACI-TIPI and the TPI in out-of-hospital electrocardiographs and evaluated its impact on paramedic on-site identification of ACS and STEMI as a community-based approach to improving emergency cardiac care. METHODS: Ambulances in the study municipalities were outfitted with electrocardiographs with ACI-TIPI and TPI software. Using a before-after quasi-experimental design, in Phase 1, for seven months, paramedics were provided with the ACI-TIPI/TPI continuous 0-100% predictions automatically printed on electrocardiogram (ECG) text headers to supplement their identification of ACS; in Phase 2, for 11 months, paramedics were told to identify ACS based on an ACI-TIPI cutoff probability of ACS ≥ 75% and/or TPI detection of STEMI. In Phase 3, this cutoff approach was used in seven additional municipalities. Confirmed diagnoses of ACS, acute myocardial infarction (AMI), and STEMI were made by blinded physician review for 100% of patients. RESULTS: In Phase 1, paramedics identified 107 patients as having ACS; in Phase 2, 104. In Phase 1, 45.8% (49) of patients so identified had ACS confirmed, which increased to 76.0% (79) in Phase 2 (p < 0.001). Of those with ACS, 59.2% (29) had AMI in Phase 1 versus 84.8% (67) with AMI in Phase 2 (p < 0.01), and STEMI was confirmed in 40.8% (20) versus 68.4% (54), respectively (p < 0.01). In Phase 3, of 226 patients identified by paramedics as having ACS, 74.3% (168) had ACS confirmed, of whom 81.0% (136) had AMI and 65.5% (110) had STEMI. Among patients with ACS, the proportion who received percutaneous coronary intervention (PCI) was 30.6% (15) in Phase 1, increasing to 57.0% (45) in Phase 2 (p < 0.004) and 50.6% (85) in Phase 3, and the proportions of patients with STEMI receiving PCI rose from 75.0% (15) to 83.3% (45) (p < 0.4) and 82.7% (91). CONCLUSIONS: In a wide range of EMS systems, use of electrocardiographs with ACI-TIPI and TPI decision support using a 75% ACI-TIPI cutoff improves paramedic diagnostic performance for ACS, AMI, and STEMI and increases the proportions of patients who receive PCI.

A percutaneous coronary intervention-thrombolytic predictive instrument to assist choosing between immediate thrombolytic therapy versus delayed primary percutaneous coronary intervention for acute myocardial infarction.

Based on the thrombolytic predictive instrument (TPI), we sought to create electrocardiographically based, real-time decision support to immediate identification of patients with ST-segment elevation myocardial infarction (STEMI) likely to benefit from primary percutaneous coronary intervention (PCI) compared with thrombolysis. Using data from the Atlantic Cardiovascular Patient Outcomes Research Team (C-PORT) Trial, we tested a mathematical model predicting mortality in patients with STEMI if treated with PCI and if treated with thrombolytic therapy. We adapted the model for incorporation into computerized electrocardiograms as a PCI-TPI. For patients with STEMI in the C-PORT Trial, the model yielded unbiased mortality predictions: for those receiving thrombolysis, it predicted 6.3% mortality and actual mortality was 6.0% (95% confidence interval 3.0 to 10.6); for those receiving PCI, it predicted 4.5% mortality and actual mortality was 3.9% (95% confidence interval 1.4 to 8.2). Excellent discrimination was reflected by its receiver operating characteristic curve area of 0.86. According to the model, and validated by actual trial outcomes, 1/3 of subjects accounted for all the mortality benefit from PCI. In conclusion, for STEMI, the PCI-TPI accurately predicts mortality for treatment with PCI and with thrombolytic therapy. Incorporated into electrocardiogram, it may assist targeting PCI to those who benefit most and identifying patients before hospitalization for whom a receiving hospital should prepare for PCI.

A geospatial analysis of emergency transport and inter-hospital transfer in ST-segment elevation myocardial infarction.

Primary percutaneous coronary intervention (PCI) yields better outcomes than thrombolytic therapy in the treatment of patients with ST-segment elevation myocardial infarctions (STEMIs). Emergency medical service systems are potentially important partners in efforts to expand the use of PCI. This study was conducted to explore the probable impact on patient mortality and hospital volumes of competing strategies for the emergency transport of patients with STEMIs. Emergency transport was simulated for 2,000 patients with STEMIs from the Atlantic Cardiovascular Patient Outcomes Research Team (C-PORT) trial in a geospatial model of Dallas County, Texas. Patient mortality estimates were obtained from a recently developed predictive model comparing PCI and thrombolytic therapy. A strategy of transporting patients to the closest hospital and treating with PCI if available and thrombolytic therapy if not yielded a 5.2% 30-day mortality rate (95% confidence interval [CI] 4.2% to 6.3%). A strategy of universal PCI, in which patients were transported only to PCI-capable hospitals, yielded 4.4% (95% CI 3.6% to 5.4%) mortality and an increase in patient volume at 2 full-time PCI hospitals of >1,000%. A strategy of targeted PCI, in which high-benefit patients were transported or transferred to PCI-capable hospitals, yielded 4.5% (95% CI 3.8% to 5.5%) mortality if transfers were decided in the emergency department and 4.2% (95% CI 3.4% to 5.1%) if transport was decided in the emergency vehicle. Targeted PCI strategies increased patient volumes at full-time PCI hospitals by about 700%. In conclusion, the selection of high-benefit patients for transport or transfer to PCI-capable hospitals can reduce mortality while minimizing major shifts in hospital patient volumes.

Comparison of mortality benefit of immediate thrombolytic therapy versus delayed primary angioplasty for acute myocardial infarction.

Primary percutaneous coronary intervention (PPCI) yields superior mortality outcomes compared with thrombolysis in ST-elevation acute myocardial infarction (STEMI) but takes longer to administer. Previous meta-regressions have estimated that a procedure-related delay of 60 minutes would nullify the benefits of PPCI on mortality. Using a combined database from randomized clinical trials and registries (n = 2,781) and an independently developed model of mortality risk in STEMI, we developed logistic regression models predicting 30-day mortality for PPCI and thrombolysis by examining the influence of baseline risk on the treatment effect of PPCI and on the hazard of treatment delay. We used these models to solve mathematically for "time interval to mortality equivalence," defined as the PPCI-related delay that would nullify its expected mortality benefit over thrombolysis, and to explore the influence of baseline risk on this value. As baseline risk increases, the relative benefit of PPCI compared with thrombolytic therapy significantly increases (p = 0.002); patients with STEMI at relatively low risk of mortality accrue little or no incremental mortality benefit from PPCI, but high-risk patients benefit greatly. However, as baseline risk increases, the hazard associated with longer treatment-related delay also increases (p = 0.007). These 2 effects are compensatory and yield a roughly uniform time interval to mortality equivalence of approximately 100 minutes in patients who have at least a moderate degree of mortality risk (> approximately 4%). In conclusion, the mortality benefits of PPCI and the hazard of PPCI-related delay depend on baseline risk. Previous meta-regressions appear to have underestimated the PPCI-related delay that would nullify the incremental benefits of PPCI.

Does concordance with guideline triage recommendations affect clinical care of patients with possible acute coronary syndrome?

BACKGROUND: The Agency for Health Care Policy and Research (AHCPR) Unstable Angina Practice Guideline recommends outpatient management for patients at low risk and admission to a monitored bed for patients at intermediate-high risk of adverse short-term outcomes, but the clinical consequences of adhering to these recommendations are unclear. METHODS: This analysis included 7466 adults who presented to the emergency department (ED) with symptoms of possible acute coronary syndrome (ACS) and who participated in 3 prospective clinical effectiveness trials during the period 1993 to 2001. The authors used logistic regression to assess the impact of concordance with guideline triage recommendations on subsequent diagnostic testing, follow-up care, and 30-day mortality and applied propensity score methods to adjust for selection bias. RESULTS: Among low-risk patients (n = 1099), ED discharge was not associated with higher mortality and did not increase the need for emergency care or hospitalization during follow-up (adjusted odds ratio [OR] = 1.0, 95% confidence interval [CI] = 0.63-1.6 for ED revisits); however, 1.7% of discharged low-risk patients had confirmed ACS. Among intermediate- to high-risk patients (n = 6367), admission to a monitored bed was not associated with reduction in 30-day mortality but significantly reduced the need for follow-up ED care (adjusted OR = 0.81, 95% CI = 0.69-0.96). CONCLUSIONS: This analysis supports the practice of discharging low-risk ED patients with symptoms of possible ACS but highlights the need to arrange timely follow-up (or to perform additional risk stratification in the ED prior to discharge). It also confirms the benefit of admitting ED patients with intermediate- to high-risk characteristics to a monitored bed.

Use of the electrocardiograph-based thrombolytic predictive instrument to assist thrombolytic and reperfusion therapy for acute myocardial infarction. A multicenter, randomized, controlled, clinical effectiveness trial.

BACKGROUND: Deciding which patients should receive thrombolytic therapy or percutaneous transluminal coronary angioplasty (PTCA) for acute myocardial infarction (AMI) can be difficult, especially for less-obvious candidates and when consulting physicians are off site. OBJECTIVE: To test whether the electrocardiograph-based Thrombolytic Predictive Instrument (TPI) improves use of thrombolytic and overall reperfusion therapy. DESIGN: 22-month randomized, controlled, clinical effectiveness trial. SETTING: Emergency departments at 28 urban, suburban, and rural hospitals in the United States. PATIENTS: Persons presenting to the emergency department with AMI and ST-segment elevation on an electrocardiogram (ECG). INTERVENTION: TPI predictions automatically printed on ECG text headers. MEASUREMENTS: Percentages of patients receiving thrombolytic therapy, thrombolytic therapy within 1 hour of initial ECG, and overall reperfusion (thrombolytic therapy or PTCA). RESULTS: Of 2875 patients with AMI, 1243 (43.2%) had ST-segment elevation. Of these, 1197 were randomly assigned to study groups; 732 (61.2%) had inferior AMI, and 465 (38.8%) had anterior AMI. A total of 60.5% of controls and 62.1% of TPI patients (P = 0.2) received thrombolytic therapy, 52.5% of controls and 53.3% of TPI patients received thrombolytic therapy within 1 hour (P > 0.2), and 67.6% of controls and 70.3% of TPI patients received overall reperfusion (P = 0.2). Of patients with inferior AMI in the control group versus the TPI group, 61.1% versus 67.6% (P = 0.03) received thrombolytic therapy, 53.2% versus 58.6% (P = 0.08) received thrombolytic therapy within 1 hour, and 67.7% versus 74.7% (P = 0.03) received overall reperfusion. Of patients with anterior AMI in the control group versus the TPI group, 59.5% versus 53.9% (P > 0.2) received thrombolytic therapy, 51.4% versus 45.3% (P > 0.2) received thrombolytic therapy within 1 hour, and 67.6% versus 63.8% (P > 0.2) received overall reperfusion. Among women (n = 398) in the control group versus the TPI group, 48.1% versus 58.2% (P = 0.03) received thrombolytic therapy, 40.5% versus 48.4% (P = 0.10) received thrombolytic therapy within 1 hour, and 55.7% versus 65.7% (P = 0.04) received overall reperfusion. Of patients who required physician consultation by telephone (n = 271) in the control group versus the TPI group, 47.3% versus 63.2% (P = 0.01) received thrombolytic therapy, 41.1% versus 53.6% (P = 0.04) received thrombolytic therapy within 1 hour, and 50.7% versus 66.4% (P = 0.01) received overall reperfusion. CONCLUSIONS: The TPI increased use of thrombolytic therapy, use of thrombolytic therapy within 1 hour, and use of overall coronary reperfusion by 11% to 12% for patients with inferior AMI, 18% to 22% for women, and 30% to 34% for patients with an off-site physician. Although its effect was minimal on patients with high baseline reperfusion rates, the TPI increased use and timeliness of reperfusion in often-missed groups and when involved physicians were off site.

Serum adiponectin levels in patients with acute coronary syndromes: Serial changes and relation to infarct size.

BACKGROUND: The role of adiponectin in patients with acute coronary syndromes is incompletely defined. This study investigated adiponectin levels in patients with acute coronary syndromes and the association between adiponectin and 30-day infarct size and 1-year clinical outcomes. METHODS: Retrospective analysis of 120 participants with acute coronary syndromes enrolled in the Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care Trial. Blood levels were tested three times within 24 h of onset of ischaemic symptoms. Infarct size was measured at 30 days. The 1-year clinical outcome was the composite of all-cause mortality or hospitalization for heart failure. RESULTS: Using linear mixed models, log adiponectin levels decreased by -0.005 µg/mL per hour (p = 0.035). After stratifying the analysis by gender, there was no decrease in log adiponectin in men; however, levels decreased by -0.01 µg/mL per hour in women (p = 0.02). Results of multivariable regression models showed no association between log adiponectin and infarct size (ß = -1.1, p = 0.64). Log adiponectin levels did not predict 1-year outcomes using Cox-proportional hazard models. CONCLUSION: There was a small decrease in plasma adiponectin shortly after symptoms of ischaemia, more noticeable in women. No relationship was found between adiponectin and infarct size or clinical outcomes. This adds to evidence showing no clear association between adiponectin and adverse outcomes in patients with acute coronary syndromes.

A predictive model to identify patients with suspected acute coronary syndromes at high risk of cardiac arrest or in-hospital mortality: An IMMEDIATE Trial sub-study,,.

BACKGROUND: The IMMEDIATE Trial of emergency medical service use of intravenous glucose-insulin-potassium (GIK) very early in acute coronary syndromes (ACS) showed benefit for the composite outcome of cardiac arrest or in-hospital mortality. OBJECTIVES: This analysis of IMMEDIATE Trial data sought to develop a predictive model to help clinicians identify patients at highest risk for this outcome and most likely to benefit from GIK. METHODS: Multivariable logistic regression was used to develop a predictive model for the composite endpoint cardiac arrest or in-hospital mortality using the 460 participants in the placebo arm of the IMMEDIATE Trial. RESULTS: The final model had four variables: advanced age, low systolic blood pressure, ST elevation in the presenting electrocardiogram, and duration of time since ischemic symptom onset. Predictive performance was good, with a C statistic of 0.75, as was its calibration. Stratifying patients into three risk categories based on the model's predictions, there was an absolute risk reduction of 8.6% with GIK in the high-risk tertile, corresponding to 12 patients needed to treat to prevent one bad outcome. The corresponding values for the low-risk tertile were 0.8% and 125, respectively. CONCLUSIONS: The multivariable predictive model developed identified patients with very early ACS at high risk of cardiac arrest or death. Using this model could assist treating those with greatest potential benefit from GIK.

An independently derived and validated predictive model for selecting patients with myocardial infarction who are likely to benefit from tissue plasminogen activator compared with streptokinase.

BACKGROUND: In the Global Utilization of Streptokinase and tPA for Occluded coronary arteries (GUSTO) trial, patients with myocardial infarction who were treated with tissue plasminogen activator (tPA) had a 6.3% 30-day mortality, compared with a mortality of 7.3% among those treated with streptokinase, despite a greater risk of intracranial hemorrhage with tPA. However, in part because of its higher cost, tPA has not been adopted universally. METHODS: Using an independently developed model, we predicted the benefits of tPA therapy in the 24,146 patients in the GUSTO trial and compared these predictions with the actual benefits of tPA, after classifying patients by their risks of mortality and intracranial hemorrhage. We also performed a "patient-specific" cost-effectiveness analysis among different strata of expected benefit of tPA. RESULTS: Our model predicted that among patients with myocardial infarction, 61% of the benefit of tPA use in reducing mortality accrued to only 25% of patients; treating half of patients could capture 85% of the benefit. Including the risk of intracranial hemorrhage, our model predicted that treating half the GUSTO patients with tPA and the others with streptokinase would yield similar outcomes as treating all patients with tPA, because the additional risk of intracranial hemorrhage exceeded the expected benefit in some patients. When patients were stratified into quartiles of risk, the observed outcomes in the GUSTO patients corresponded well with these predicted results. The estimated cost-effectiveness of tPA was sensitive to patient characteristics. CONCLUSION: For selected patients, use of tPA yields substantially better outcomes than streptokinase, and use of the less expensive agent is difficult to justify. For many patients, however, tPA is unlikely to provide any additional benefit and, in some patients, it may even cause net harm.

Time-dependent predictors of primary cardiac arrest in patients with acute myocardial infarction.

To understand predictors of cardiac arrest early in acute myocardial infarction (AMI), for the Thrombolytic Predictive Instrument, we developed a multivariable regression model predicting primary cardiac arrest using time-dependent variables based on a case-control study of emergency department (ED) patients with AMI: 65 cases with sudden cardiac arrest and 258 without cardiac arrest. Within the first hour of AMI symptom onset, adjusting for age, systolic blood pressure, serum potassium, and infarct size, increased risk of cardiac arrest was associated with electrocardiographic prolonged QTc interval and a greater sum of ST-segment elevation. After 1 hour, the effect of ST-segment elevation was much reduced and the effect of the QTc interval was reversed, so prolonged QTc appeared protective. Accordingly, for patients presenting 30 minutes after chest pain onset, compared with a QTc of 0.44, the risk for cardiac arrest for patients with QTc of 0.50 was more than doubled (odds ratio [OR] 2.20, 95% confidence intervals [CI] 1.17 to 4.13), whereas for those presenting after an hour, it was much lower (e.g., at 1.5 hours, OR 0.21, 95% CI 0.06 to 0.73). Patients presenting 30 minutes after chest pain onset with a sum of ST elevation of 20 mm had a threefold higher risk than patients with a sum of ST elevation of 5 mm (OR 3.37, 95% CI 1.83 to 6.20). However, if presenting 1.5 hours after chest pain onset, the risk was barely elevated (OR 1.18; 95% CI 1.09 to 1.29). Thrombolytic therapy was protective, halving the odds of cardiac arrest (OR 0.51, 95% CI 0.27 to 0.93). Thus, the relation of prolonged QTc interval and substantial ST segment elevation to cardiac arrest in AMI may be obscured because patients with these risks are more likely to die soon after AMI onset, before ED presentation, and are thereby unavailable for study. Those with prolonged QTc or substantial ST elevation who survive the initial 1.5-hour period are those less susceptible to these risks.

Tissue plasminogen activator was cost-effective compared to streptokinase in only selected patients with acute myocardial infarction.

OBJECTIVE: We sought to explore the patient-specific cost-effectiveness in a community-based sample for a therapy for which the average cost-effectiveness in a clinical trial has been well-described. STUDY DESIGN AND SETTING: Based on a validated multivariate model, we generated predictions of the effectiveness and cost-effectiveness of t-PA compared to streptokinase on 921 consecutive patients who received thrombolytic therapy for acute myocardial infarction. RESULTS: The average cost-effectiveness of t-PA was US dollar 40,140 per life-year saved. For the quartile of patients most likely to benefit, the incremental cost-effectiveness of t-PA was US dollar 15,396. However, only 44% of patients who received thrombolytic therapy had an estimated cost-effectiveness ratio below US dollar 50,000 per year of life saved; the ratio was greater than US dollar 100,000 in 37% of treated patients. Patients in the lowest quartile of expected benefit are, overall, more likely to be harmed than to benefit from t-PA. CONCLUSION: Compared to the pattern of thrombolytic agent choice observed, targeting t-PA to the half of patients most likely to benefit could save 247 lives and US dollar 174 million nationally per year.

Factors associated with longer time to treatment for patients with suspected acute coronary syndromes: a cohort study.

BACKGROUND: Rapid treatment of acute coronary syndromes (ACS) is important; causes of delay in emergency medical services care of ACS are poorly understood. METHODS AND RESULTS: We performed an analysis of data from IMMEDIATE (Immediate Myocardial Metabolic Enhancement during Initial Assessment and Treatment in Emergency Care), a randomized controlled trial of emergency medical services treatment of people with symptoms suggesting ACS, using hierarchical multiple regression of elapsed time. Out-of-hospital ECGs were performed on 54,230 adults calling 9-1-1; 871 had presumed ACS, 303 of whom had ST-segment elevation myocardial infarction and underwent percutaneous coronary intervention. Women, participants with diabetes mellitus, and participants without previous cardiovascular disease waited longer to call 9-1-1 (by 28 minutes, P<0.01; 10 minutes, P=0.03; and 6 minutes, P=0.02, respectively), compared with their counterparts. Time from emergency medical services arrival to ECG was longer for women (1.5 minutes; P<0.01), older individuals (1.3 minutes; P<0.01), and those without a primary complaint of chest pain (3.5 minutes; P<0.01). On-scene times were longer for women (2 minutes; P<0.01) and older individuals (2 minutes; P<0.01). Older individuals and participants presenting on weekends and nights had longer door-to-balloon times (by 10, 14, and 11 minutes, respectively; P<0.01). Women and older individuals had longer total times (medical contact to balloon inflation: 16 minutes, P=0.01, and 9 minutes, P<0.01, respectively; symptom onset to balloon inflation: 31.5 minutes for women; P=0.02). CONCLUSIONS: We found delays throughout ACS care, resulting in substantial differences in total times for women and older individuals. These delays may impact outcomes; a comprehensive approach to reduce delay is needed.

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).

The Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care Trial of very early intravenous glucose-insulin-potassium (GIK) for acute coronary syndromes (ACS) in out-of-hospital emergency medical service (EMS) settings showed 80% reduction in infarct size at 30 days, suggesting potential longer-term benefits. Here we report 1-year outcomes. Prespecified 1-year end points of this randomized, placebo-controlled, double-blind, effectiveness trial included all-cause mortality and composites including cardiac arrest, mortality, or hospitalization for heart failure (HF). Of 871 participants randomized to GIK versus placebo, death occurred within 1 year in 11.6% versus 13.5%, respectively (unadjusted hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.57 to 1.23, p = 0.36). The composite of cardiac arrest or 1-year mortality was 12.8% versus 17.0% (HR 0.71, 95% CI 0.50 to 1.02, p = 0.06). The composite of hospitalization for HF or mortality within 1 year was 17.2% versus 17.2% (HR 0.98, 95% CI 0.70 to 1.37, p = 0.92). The composite of mortality, cardiac arrest, or HF hospitalization within 1 year was 18.1% versus 20.4% (HR 0.85, 95% CI 0.62 to 1.16, p = 0.30). In patients presenting with suspected ST elevation myocardial infarction, HRs for 1-year mortality and the 3 composites were, respectively, 0.65 (95% CI 0.33 to 1.27, p = 0.21), 0.52 (95% CI 0.30 to 0.92, p = 0.03), 0.63 (95% CI 0.35 to 1.16, p = 0.14), and 0.51 (95% CI 0.30 to 0.87, p = 0.01). In patients with suspected acute coronary syndromes, serious end points generally were lower with GIK than placebo, but the differences were not statistically significant. However, in those with ST elevation myocardial infarction, the composites of cardiac arrest or 1-year mortality, and of cardiac arrest, mortality, or HF hospitalization within 1 year, were significantly reduced.