Common variants associated with changes in levels of circulating free fatty acids after administration of glucose-insulin-potassium (GIK) therapy in the IMMEDIATE trial.

Glucose-insulin-potassium (GIK) therapy may promote a shift from oxygen-wasteful free fatty acid (FFA) metabolism to glycolysis, potentially reducing myocardial damage during ischemia. Genetic variation associated with FFA response to GIK was investigated in an IMMEDIATE (Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care) sub-study (n=117). In patients with confirmed acute coronary syndromes, associations between 132 634 variants and 12-h circulating FFA response were assessed. Between initial and 6-h measurements, three LINGO2 variants were associated with increased levels of total FFA (P-value for 2 degree of freedom test, P2df ⩽5.51 × 10-7). Lead LINGO2 single-nucleotide polymorphism, rs12003487, was nominally associated with reduced 30-day ejection fraction (P2df=0.03). Several LINGO2 signals were linked to alterations in epigenetic profile and gene expression levels. Between 6 and 12 h, rs7017336 nearest to IMPA1/FABP12 showed an association with decreased saturated FFAs (P2df=5.47 × 10-7). Nearest to DUSP26, rs7464104 was associated with a decrease in unsaturated FFAs (P2df=5.51 × 10-7). Genetic variation may modify FFA response to GIK, potentially conferring less beneficial outcomes.

Genetic modifiers of response to glucose-insulin-potassium (GIK) infusion in acute coronary syndromes and associations with clinical outcomes in the IMMEDIATE trial.

Modifiers of response to glucose, insulin and potassium (GIK) infusion may affect clinical outcomes in acute coronary syndromes (ACS). In an Immediate Myocardial Metabolic Enhancement During Initial Assessment And Treatment In Emergency Care (IMMEDIATE) trial's sub-study (n = 318), we explored effects of 132,634 genetic variants on plasma glucose and potassium response to 12-h GIK infusion. Associations between metabolite-associated variants and infarct size (n = 84) were assessed. The 'G' allele of rs12641551, near ACSL1, as well as the 'A' allele of XPO4 rs2585897 were associated with a differential glucose response (P for 2 degrees of freedom test, P2df ⩽ 4.75 × 10(-7)) and infarct size with GIK (P2df < 0.05). Variants within or near TAS1R3, LCA5, DNAH5, PTPRG, MAGI1, PTCSC3, STRADA, AKAP12, ARFGEF2, ADCYAP1, SETX, NDRG4 and ABCB11 modified glucose response, and near CSF1/AHCYL1 potassium response (P2df ⩽ 4.26 × 10(-7)), but not outcomes. Gene variants may modify glucose and potassium response to GIK infusion, contributing to cardiovascular outcomes in ACS.

Genetic variation at glucose and insulin trait loci and response to glucose-insulin-potassium (GIK) therapy: the IMMEDIATE trial.

The mechanistic effects of intravenous glucose, insulin and potassium (GIK) in cardiac ischemia are not well understood. We conducted a genetic sub-study of the Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care (IMMEDIATE) Trial to explore effects of common and rare glucose and insulin-related genetic loci on initial to 6-h and 6- to 12-h change in plasma glucose and potassium. We identified 27 NOTCH2/ADAM30 and 8 C2CD4B variants conferring a 40-57% increase in glucose during the first 6 h of infusion (P<5.96 × 10(-6)). Significant associations were also found for ABCB11 and SLC30A8 single-nucleotide polymorphisms (SNPs) and glucose responses, and an SEC61A2 SNP with a potassium response to GIK. These studies identify genetic factors that may impact the metabolic response to GIK, which could influence treatment benefits in the setting of acute coronary syndromes (ACS).

Acute cardiac ischemia in patients with cocaine-associated complaints: results of a multicenter trial.

STUDY OBJECTIVE: To describe the characteristics of a large group of patients who presented to emergency departments with cocaine-associated symptoms consistent with acute cardiac ischemia (ACI) and to determine the incidence of confirmed ACI including acute myocardial infarction (AMI) in this population. METHODS: We performed a substudy on all patients in a multicenter prospective clinical trial (the Acute Cardiac Ischemia-Time Insensitive Predictive Instrument [ACI-TIPI] Clinical Trial) that enrolled ED patients with chest pain or other symptoms consistent with ACI including subjects with identified cocaine use. Demographic and clinical features, including initial and follow-up clinical data, ECGs, and tests to determine serum creatine kinase isoenzyme MB subunit concentrations, were analyzed. Diagnoses of AMI followed the World Health Organization criteria for AMI and of angina pectoris, the Canadian Cardiovascular Society Classification. RESULTS: Of the 10,689 patients enrolled in the trial, 293 (2.7%) had cocaine-associated complaints. Among the 10 participating hospitals, the incidence of patients with cocaine-associated symptoms varied from 0.3% to 8.4%. Only 6 patients (2.0%, 95% confidence interval [CI] 0.76% to 4.4%) had a diagnosis of ACI; 4 (1.4%, 95% CI 0.37% to 3.5%) had unstable angina, and 2 (0.7%, 95% CI 0.08% to 2.4%) had AMI. Although patients with cocaine-induced complaints were as likely to be admitted to the coronary care unit compared with all study patients without cocaine use (14% versus 18%, P =.14, difference not significant), these patients were much less likely to have confirmed unstable angina (1.4% versus 9.3%, P <.001) or AMI (0. 7% versus 8.6%, P <.001). Compared with patients younger than 45 years, patients with cocaine usage were more likely to be admitted to the ICU (14% versus 8.0%, P =.0018) but less likely to have confirmed AMI (0.7% versus 2.8%, P =.033). CONCLUSION: Patients presenting to EDs with cocaine-associated chest pain or related symptoms infrequently had ACI, and even less so, AMI. This suggests the need for selectivity in the hospitalization of patients with such cocaine-associated symptoms.

Missed diagnoses of acute cardiac ischemia in the emergency department.

BACKGROUND: Discharging patients with acute myocardial infarction or unstable angina from the emergency department because of missed diagnoses can have dire consequences. We studied the incidence of, factors related to, and clinical outcomes of failure to hospitalize patients with acute cardiac ischemia. METHODS: We analyzed clinical data from a multicenter, prospective clinical trial of all patients with chest pain or other symptoms suggesting acute cardiac ischemia who presented to the emergency departments of 10 U.S. hospitals. RESULTS: Of 10,689 patients, 17 percent ultimately met the criteria for acute cardiac ischemia (8 percent had acute myocardial infarction and 9 percent had unstable angina), 6 percent had stable angina, 21 percent had other cardiac problems, and 55 percent had noncardiac problems. Among the 889 patients with acute myocardial infarction, 19 (2.1 percent) were mistakenly discharged from the emergency department (95 percent confidence interval, 1.1 to 3.1 percent); among the 966 patients with unstable angina, 22 (2.3 percent) were mistakenly discharged (95 percent confidence interval, 1.3 to 3.2 percent). Multivariable analysis showed that patients who presented to the emergency department with acute cardiac ischemia were more likely not to be hospitalized if they were women less than 55 years old (odds ratio for discharge, 6.7; 95 percent confidence interval, 1.4 to 32.5), were nonwhite (odds ratio, 2.2; 1.1 to 4.3), reported shortness of breath as their chief symptom (odds ratio, 2.7; 1.1 to 6.5), or had a normal or nondiagnostic electrocardiogram (odds ratio, 3.3; 1.7 to 6.3). Patients with acute infarction were more likely not to be hospitalized if they were nonwhite (odds ratio for discharge, 4.5; 95 percent confidence interval, 1.8 to 11.8) or had a normal or nondiagnostic electrocardiogram (odds ratio, 7.7; 95 percent confidence interval, 2.9 to 20.2). For the patients with acute infarction, the risk-adjusted mortality ratio for those who were not hospitalized, as compared with those who were, was 1.9 (95 percent confidence interval, 0.7 to 5.2), and for the patients with unstable angina, it was 1.7 (95 percent confidence interval, 0.2 to 17.0). CONCLUSIONS: The percentage of patients who present to the emergency department with acute myocardial infarction or unstable angina who are not hospitalized is low, but the discharge of such patients is associated with increased mortality. Failure to hospitalize is related to race, sex, and the absence of typical features of cardiac ischemia. Continued efforts to reduce the number of missed diagnoses are warranted.

Use of the acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI) to assist with triage of patients with chest pain or other symptoms suggestive of acute cardiac ischemia. A multicenter, controlled clinical trial.

BACKGROUND: Approximately 6 million U.S. patients present to emergency departments annually with symptoms suggesting acute cardiac ischemia. Triage decisions for these patients are important but remain difficult. OBJECTIVE: To test whether computerized prediction of the probability of acute ischemia, used with electrocardiography, improves the accuracy of triage decisions. DESIGN: Controlled clinical trial. SETTING: 10 hospital emergency departments in the midwestern, southeastern, and northeastern United States. PATIENTS: 10689 patients with chest pain or other symptoms suggestive of acute cardiac ischemia. INTERVENTION: The probability of acute ischemia predicted by the acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI), either automatically printed or not printed on patients' electrocardiograms. MEASUREMENTS: Emergency department triage to a coronary care unit (CCU), telemetry unit, ward, or home. Other measurements were the bed capacity of the CCU relative to that of the telemetry unit; training or supervision status of the triaging physician; and patient diagnoses and outcomes based on clinical, electrocardiographic, and creatine kinase data. RESULTS: For patients without cardiac ischemia, in hospitals with high-capacity CCUs and relatively low-capacity cardiac telemetry units, use of ACI-TIPI was associated with a reduction in CCU admissions from 15% to 12%, a change of -16% (95% CI, -30% to 0%), and an increase in emergency department discharges to home from 49% to 52%, a change of 6% (CI, 0% to 14%; overall P=0.09). Across all hospitals, for patients evaluated by unsupervised residents, use of ACI-TIPI was associated with a reduction in CCU admissions from 14% to 10%, a change of -32% (CI, -55% to 3%); a reduction in telemetry unit admissions from 39% to 31%, a change of -20% (CI, -34% to -2%); and an increase in discharges to home from 45% to 56%, a change of 25% (CI, 8% to 45%; overall P=0.008). Among patients with stable angina, in hospitals with high-capacity CCUs, use of ACI-TIPI was associated with a reduction in CCU admissions from 26% to 13%, a change of -50% (CI, -70% to -17%), and an increase in discharges to home from 20% to 22%, a change of 10% (CI, -29% to 71%; overall P=0.02). At hospitals with high-capacity telemetry units, use of ACI-TIPI was associated with a reduction in telemetry unit admissions from 68% to 59%, a change of -14% (CI, -27% to 1%), and an increase in emergency department discharges to home from 10% to 21%, a change of 100% (CI, 22% to 230%; overall P=0.02). Among patients with acute myocardial infarction or unstable angina, use of ACI-TIPI did not change appropriate admission (96%) to the CCU or telemetry unit at hospitals with high-capacity CCUs or telemetry units. CONCLUSIONS: Use of ACI-TIPI was associated with reduced hospitalization among emergency department patients without acute cardiac ischemia. This result varied as expected according to the CCU and cardiac telemetry unit capacities and physician supervision at individual hospitals. Appropriate admission for unstable angina or acute infarction was not affected. If ACI-TIPI is used widely in the United States, its potential incremental impact may be more than 200000 fewer unnecessary hospitalizations and more than 100000 fewer unnecessary CCU admissions.

Insurance type and the transportation to emergency departments of patients with acute cardiac ischemia: the ACI-TIPI Trial Insurance Study.

The relationship of insurance type to treatment-seeking behavior (ie, the transportation to emergency departments of patients with symptoms suggestive of acute cardiac ischemia) was evaluated. The focus was on comparing patients belonging to a health maintenance organization (HMO) with patients who had indemnity insurance. Data were collected prospectively on 10,783 patients presenting to emergency departments of 10 adult care hospitals in the Eastern and Midwestern United States between April and December 1993 as part of a clinical trial. A total of 6,604 patients presented within 24 hours of symptom onset. Although these patients as a group had a wide range of demographic and clinical characteristics, persons belonging to an HMO and those with indemnity insurance were very similar. The main outcome measures were whether the patient was transported by ambulance and the duration of time from symptom onset to emergency department arrival. A hospital-matched sample of HMO-insured and indemnity-insured patients allowed multivariable regression: HMO membership was not associated with a different rate of ambulance use (odds ratio = 1.0; 95% confidence interval = 0.73, 1.35) or duration of time from symptom onset to emergency department presentation (6 minutes less, P = 0.8). HMO participation was not related to treatment-seeking behavior, as reflected by ambulance use and duration of time from symptom onset to emergency department arrival. However, studies of more constrained managed care organizations and of broader ranges of patients are needed.

A logistic regression model when some events precede treatment: the effect of thrombolytic therapy for acute myocardial infarction on the risk of cardiac arrest.

When outcomes occur in clinical trials before treatment can be given, neither intent-to-treat nor according-to-protocol analyses give optimal estimates of the treatment effect. A better approach employs a time-dependent variable for treatment. Intent-to-treat analyses are conservative, biasing against treatment; according-to-protocol analyses bias in favor of treatment. We show how to measure the effect of a time-dependent variable in a logistic regression using person-time intervals as units of measurement and describe appropriate methods for reporting model performance. The method is applied to develop a model to predict the probability that a patient with a myocardial infarction will have a sudden cardiac arrest within 48 hours of presentation to emergency medical services both when treated with thrombolysis and when not treated. We use a time-dependent treatment variable because many patients went into cardiac arrest while awaiting treatment. This technique has been programmed into an electrocardiograph for real-time use in an emergency department.

Causes of chest pain and symptoms suggestive of acute cardiac ischemia in African-American patients presenting to the emergency department: a multicenter study.

This study examines whether race is a significant determinant of the diagnoses of acute myocardial infarction or angina pectoris in patients with symptoms suggestive of acute cardiac ischemia. The study population was comprised of 3401 (34%) African-American and 6600 (66%) white patients who presented to emergency departments with symptoms suggestive of acute cardiac ischemia. The main outcome measure was a diagnosis of acute myocardial infarction or angina pectoris. African Americans were younger, predominantly female, and more often had hypertension, diabetes mellitus, or smoked. The diagnosis of acute myocardial infarction was confirmed in 6% of African-American and 12% of white men, and in 4% of African-American and 8% of white women. After adjusting for age, gender, medical history, signs and symptoms, and hospital, African Americans were half as likely to develop acute myocardial infarction and were 60% as likely to have acute cardiac ischemia. Despite having less acute cardiac ischemia, African Americans in this study had high risk levels for coronary artery disease.

Patient-specific predictions of outcomes in myocardial infarction for real-time emergency use: a thrombolytic predictive instrument.

BACKGROUND: Thrombolytic therapy can be life-saving in patients with acute myocardial infarction. However, if given too late or insufficiently selectively, it may provide little benefit but still cause serious complications and incur substantial costs. OBJECTIVE: To develop a thrombolytic predictive instrument for real-time use in emergency medical service settings that could 1) identify patients likely to benefit from thrombolysis and 2) facilitate the earliest possible use of this therapy. DESIGN: Creation and validation of logistic regression-based predictive instruments based on secondary analysis of clinical data. PATIENTS: 4911 patients who had acute myocardial infarction and ST-segment elevation on electrocardiogram; 3483 received thrombolytic therapy. MEASUREMENTS: Data were obtained from 13 major clinical trials and registries and directly from medical records, including electrocardiograms obtained at presentation. Input variables include presenting clinical and electrocardiography features; predictive models generate probabilities for acute (30-day) mortality if and if not treated with thrombolysis, 1-year mortality rates if and if not treated with thrombolysis, cardiac arrest if and if not treated with thrombolysis, thrombolysis-related intracranial hemorrhage, and thrombolysis-related major bleeding episode requiring transfusion. Together, these models constitute the thrombolytic predictive instrument. RESULTS: The predictive models generated the following mean predictions for patients in the Thrombolytic Predictive instrument Database: 30-day mortality rate, 7.1%; 1-year mortality rate, 10.9%; rate of cardiac arrest, 3.7%; rate of thrombolysis-related intracranial hemorrhage. 0.6%; and rate of other thrombolysis-related major bleeding episodes, 5.0%. They discriminated with between persons having and those not having the predicted outcome; areas under the receiver-operating characteristic (ROC) curve were between 0.77 and 0.84 for the five outcomes. Calibration between each instrument's predicted and observed served rates was excellent. Validation of the predictive instruments of 30-day and 1-year mortality, done on a separate test dataset, yielded areas under the ROC curve of 0.76 for each CONCLUSIONS: After the basic features of a clinical presentation are entered into a computerized electrocardiograph, the predictions of the thrombolytic predictive instrument can be printed on the electrocardiogram report. This decision aid may facilitate earlier and more appropriate use of thrombolytic therapy in patients with acute myocardial infarction.

Hospital mortality in women and men with acute cardiac ischemia: a prospective multicenter study.

OBJECTIVES: This study sought to determine gender differences in hospital mortality in patients with acute cardiac ischemia. BACKGROUND: It is unclear why women experience higher mortality from acute myocardial infarction (AMI) than men and whether this applies to all patients with acute ischemia. METHODS: We analyzed data from a prospective multicenter study involving patients presenting to the emergency department (ED) with symptoms suggestive of acute ischemia. RESULTS: Of 10,783 patients, 5,221 (48.4%) were women. Mean age was 60.5 years for women and 56.9 for men (p < 0.001). Women had more hypertension (54.6% vs. 45.9%, p < 0.001) and diabetes (23.3% vs. 17.0%, p < 0.001) than men but fewer previous AMIs (21.1% vs. 28.9%, p < 0.001). Acute ischemia was confirmed in 1,090 women (20.8%) and 1,451 men (26.1%, p < 0.001), including AMI in 322 women (6.2%) and 572 men (10.3%, p < 0.001). Women with an AMI were in a higher Killip class than men: class I in 60.3% versus 72.2%, class II in 19.3% versus 16%, class III in 15.5% versus 8.7% and class IV in 5% versus 3.1%, respectively (p = 0.001). There was no significant difference in mortality from acute ischemia between genders (4.0% vs. 3.5%, p = 0.6), but there was a trend for higher AMI mortality in women (10.3% vs. 7.4%, p = 0.1). After controlling for age, diabetes, heart failure and presenting blood pressure, gender did not predict mortality from acute ischemia (odds ratio 0.9, 95% confidence interval 0.5 to 1.4, p = 0.5). CONCLUSIONS: Among patients presenting to the ED with acute cardiac ischemia, gender does not appear to be an independent predictor of hospital mortality. The trend for higher mortality in women from AMI can be explained by their older age, greater frequency of diabetes and higher Killip class on presentation.

Presentations of acute myocardial infarction in men and women.

OBJECTIVE: To assess the influence of gender on the likelihood of acute myocardial infarction (AMI) among emergency department (ED) patients with symptoms suggestive of acute cardiac ischemia, and to determine whether any specific presenting signs or symptoms are associated more strongly with AMI in women than in men. DESIGN: Analysis of cohort data from a prospective clinical trial. SETTING: Emergency departments of 10 hospitals of varying sizes and types in the United States. PATIENTS: Patients 30 years of age or older (n = 10,525) who presented to the ED with chest pain or other symptoms suggestive of acute cardiac ischemia. MEASUREMENTS AND MAIN RESULTS: The prevalence of AMI was determined for men and women, and a multivariable logistic regression model predicting AMI was developed to adjust for patients' demographic and clinical characteristics. AMI was almost twice as common in men as in women (10% vs 6%). Controlling for demographics, presenting signs and symptoms, electrocardiogram features, and hospital, male gender was a significant predictor of AMI (odds ratio [OR] 1.7; 95% confidence interval [CI] 1.4, 2.0). The gender effect was eliminated, however, among patients with ST-segment elevations on electrocardiogram (OR 1.1; 95% CI 0.7, 1.7) and among patients with signs of congestive heart failure (CHF) (OR 1.1; 95% CI 0.8, 1.5). Signs of CHF were associated with AMI among women (OR 1.9; 95% CI 1.4, 2.6) but not men (OR 1.0; 95% CI 0.8, 1.3). Among patients who presented to EDs with chest pain or other symptoms suggestive of acute cardiac ischemia, AMI was more likely in men than in women. Among women with ST-segment elevation or signs of CHF, however, AMI likelihood was similar to that in men with these characteristics.

The use of empiric clinical data in the evaluation of practice guidelines for unstable angina.

OBJECTIVE: To determine the applicability to emergency department (ED) clinical practice of a nationally disseminated practice guideline on the disposition of patients with a diagnosis of unstable angina, and to determine the potential impact of the guideline on hospital admissions and demand for intensive care beds. DESIGN: Application of guideline criteria for ED disposition decisions to a validation sample derived from a prospective clinical trial. SETTING: Five hospitals, including 2 urban general teaching hospitals, 2 urban tertiary care university hospitals, and 1 suburban university-affiliated community hospital. PATIENTS: A consecutive sample of 457 patients who presented with symptoms suggestive of acute cardiac ischemia and who had "unstable angina" or "rule out unstable angina" diagnosed by ED physicians. Greater than 90% of eligible patients were enrolled in the clinical trial; follow-up data sufficient for assignment of a definitive diagnosis were obtained for 99% of subjects. MAIN OUTCOME MEASURES: Acute myocardial infarction and unstable angina, based on blind review of initial and follow-up clinical data, including cardiac enzyme levels and electrocardiograms. After completion of the trial, without knowledge of final diagnosis or outcome, the investigators classified patients into risk groups specified by the unstable angina guideline. RESULTS: Of subjects with an ED diagnosis of unstable angina, only 6% (n=28) met the guideline's criteria corresponding to low risk for adverse events and were therefore suitable for discharge directly to home. Fifty-four percent (n=247) met the intermediate-risk criteria; 40% (n=182) met the high-risk criteria and were identified as requiring admission to an intensive care unit. Actual ED disposition differed from guideline recommendations in 2 major areas: only 4% (1/28) of low-risk patients were discharged to home with outpatient follow-up, and only 40% (72/182) of high-risk patients were admitted to an intensive care unit. CONCLUSIONS: Although the guideline was intended to reduce hospitalization by identifying a low-risk group, the small size of this group among ED patients suggests that little reduction in hospitalization can be expected. Indeed, the guideline may increase demand for the limited number of intensive care beds to accommodate patients with unstable angina considered high-risk but currently placed elsewhere. These results emphasize the need to use empiric data from target clinical settings to assess the likely actual impact of guidelines on clinical care prior to national dissemination.

Influence of sex on the use of cardiac procedures in patients presenting to the emergency department. A prospective multicenter study.

BACKGROUND: Reports about the use of cardiac procedures have produced conflicting results as to whether there is a sex bias in the use of thrombolytic therapy, cardiac catheterization, or revascularization procedures. The present study was undertaken with the hope of resolving some of these different findings by examining the use of these therapies in women and men who presented to the emergency department with symptoms suggestive of acute cardiac ischemia. METHODS AND RESULTS: During 7 consecutive months in 1993, 10673 individuals > or = 30 years old who presented with chest pain or other symptoms suggestive of acute cardiac ischemia were enrolled in the Acute Cardiac Ischemia Time-Insensitive Predictive Instrument Clinical Trial at 10 hospitals in the East and Midwest. This study included 2542 patients (24% of all patients) who had confirmed acute myocardial infarction or angina pectoris. There were significant sex differences with respect to demographic and clinical characteristics and the use of cardiac procedures. Among patients with acute myocardial infarction, the use of thrombolytic therapy, cardiac catheterization, and revascularization procedures was similar in women and men after multivariate adjustment. However, in the group with angina pectoris, women were considerably less likely to undergo these procedures, even after adjustment for significant baseline covariates. CONCLUSIONS: Women with angina pectoris were less likely to undergo cardiac catheterization or revascularization procedures, although unmeasured factors could in part explain the observed differences.

Prediction of the infarct-related artery in acute myocardial infarction by a scoring system using summary ST-segment and T-wave changes.

We developed a scoring system to predict the artery responsible for an acute myocardial infarction (AMI) using ST-segment and T-wave changes on the initial electrocardiogram (ECG) using data from 228 patients (development set) with symptoms compatible with AMI and tested in a similar group of 223 patients (test set) from the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI-5) Trial. Using stepwise logistic regression we were able to accurately predict the left anterior descending (LAD), right, or left circumflex (LC) coronary artery as the infarct-related artery using 2 variables: (1) the summation of the ST-segment elevation in leads V1 to V4; and (2) the summation of the T-wave negativity in leads I, aVL, and V5. In the development set, these 2 variables demonstrated respective sensitivity and specificity of 98% and 90% for LAD lesions, 82% and 85% for right narrowings, and 82% and 84% for LC narrowings. In the test set, the sensitivity and specificity were 97% and 95% for LAD lesions, 85% and 86% for right lesions, and 73% and 60% for LC coronary artery lesions. Information easily obtained on the ECG can accurately predict the likelihood of the LAD, right, or LC artery as the infarct-related artery. This may be useful in the decision to administer thrombolytic treatment.

The exclusion of women from clinical trials of thrombolytic therapy: implications for developing the thrombolytic predictive instrument database.

The thrombolytic predictive instrument (TPI) was developed to identify those patients most likely to benefit from thrombolytic therapy for acute myocardial infarction as well as to facilitate the earliest possible administration of this treatment. The TPI consists of predictive models derived from clinical data obtained from both clinical trials and data registries. These models are subject to potential bias due to combinations of primary data from different sources. The purpose of this investigation was to assess the influence of gender in developing the TPI database. In this database, there were 1,096 (22%) women and 3,826 (78%) men; only 38% of the women were enrolled in clinical trials, whereas 46% of the men were (p < 0.0001). Within clinical trials, there were few significant eligibility differences between women and men, as the vast majority of patients met eligibility standards for entry in these trials. However, within clinical registries, the women were older (p < 0.0001) and more often had elevated blood pressure on admission (p = 0.002). Multivariate logistic regression indicated that after adjustment for significant predictors of trial inclusion, women were 25% less likely to be included in clinical trials (odds ratio = 0.76, 95% confidence interval = 0.60, 0.96). In order to counter bias introduced by the exclusion of women from clinical trials, the TPI database included patients from non-trial settings. Carefully including patients from clinical registries or non-trial settings may be an important strategy in constructing generally applicable predictive instruments.

Electrocardiographic left ventricular hypertrophy in patients with suspected acute cardiac ischemia--its influence on diagnosis, triage, and short-term prognosis: a multicenter study.

OBJECTIVE: To understand the diagnostic and short-term prognostic significance of electrocardiographic left ventricular hypertrophy (ECG-LVH) for patients who present to the emergency department with symptoms suggesting acute cardiac ischemia, defined as new or unstable angina pectoris or acute myocardial infarction. DESIGN: Subgroup analysis of a multicenter, prospective study of coronary care unit admitting practices in the prethrombolytic era. SETTING: The emergency departments of six New England hospitals: two urban medical school teaching hospitals, two medical school-affiliated community hospitals in smaller cities, and two rural non-teaching teaching hospitals. PATIENTS: 5,768 patients presenting with symptoms suggesting possible acute cardiac ischemia, including 413 patients who had ECG-LVH defined by the Romhilt-Estes point score criteria and 5,355 patients who had other electrocardiogram (ECG) findings. MAIN RESULTS: Only 26% of the 413 patients who had ECG-LVH were ultimately judged to have had acute cardiac ischemia, compared with 72% of patients who had primary ST-segment and T-wave abnormalities (p < 0.001) and 36% of those who had other ECG abnormalities (p < 0.001). Overall, the ECG-LVH patients were one-third less likely than the patients who did not have ECG-LVH to have had acute cardiac ischemia, after controlling for other predictors of acute ischemia by logistic regression (relative risk = 0.66, 95% CI 0.46 to 0.94). The patients who had ECG-LVH were only one-fourth as likely to have had acute myocardial infarctions as were the patients presenting with primary ST-segment and T-wave changes (12% vs 48%, p < 0.001). Instead, a much larger proportion had had congestive heart failure or hypertension. The admitting physicians had identified ECG-LVH poorly on the admitting ECGs: only 22% of those who had ECG-LVH had been correctly identified, and for more than 70%, the secondary ST-segment and T-wave changes of ECG-LVH had been read as being primary. The short-term mortality for the patients who had ECG-LVH was 7.5%. This was intermediate between the mortality for patients who had primary ST-segment and T-wave abnormalities (10.6%) and those who had other ECG abnormalities (5.1%). Mortality was not affected by whether the admitting physician had recognized ECG-LVH initially. CONCLUSION: ECG-LVH was not a benign ECG finding among the patients who had presented with symptoms suggesting an acute cardiac ischemic syndrome: short-term mortality among the patients who had ECG-LVH (7.5%) approached that for the patients who had primary ST-segment and T-wave abnormalities (10.6%, p = 0.10). However, the patients who had ECG-LVH were one-third less likely to have had any acute cardiac ischemia than were the patients who did not have ECG-LVH, after logistic regression was used to control for other predictors of acute ischemia. Specifically, acute myocardial infarction was only one-fourth as likely when LVH was present on the admitting ECG (12%) as it was when primary ST-segment and T-wave abnormalities were present (48%, p < 0.001). Instead, congestive heart failure and hypertensive heart disease were more common. Thus, routine use of thrombolytic therapy for patients who have ECG-LVH does not seem warranted. ECG-LVH was poorly recognized (in only 22% of cases) by the physicians in the present study. Better recognition of this common ECG finding may lead to more effective patient management.

Presenting pulse pressure predicts thrombolytic therapy-related intracranial hemorrhage. Thrombolytic Predictive Instrument (TPI) Project results.

BACKGROUND: In selecting patients with acute myocardial infarction for thrombolytic therapy, it is important to identify patients who are at high risk for intracranial hemorrhage, for whom thrombolytic therapy is ill advised. We hypothesized that presenting pulse blood pressure, representing the "hammer" effect on cerebral vessels and the effects of age on arterial compliance, might predict thrombolysis-related intracranial hemorrhage better than systolic, diastolic, or mean arterial blood pressures. METHODS AND RESULTS: Of 3483 Thrombolytic Predictive Instrument (TPI) Project subjects receiving thrombolytic therapy for acute infarction, we identified and obtained detailed clinical data on the 19 with treatment-related intracranial hemorrhages confirmed by computed tomography and on 175 matched controls. Systolic, diastolic, mean arterial, and pulse blood pressures were each significantly related to the occurrence of intracranial hemorrhage, with pulse pressure most highly related. The mean pulse pressure in patients who developed intracranial hemorrhage was 63 mm Hg, 34% higher than the 47 mm Hg mean value for those not developing hemorrhage (P = .0001). Excess pulse pressure, defined as the extent to which a patient's pulse pressure exceeded 40 mm Hg for systolic blood pressures of at least 120 mm Hg, was even more strongly related: its mean value of 23 mm Hg for patients was 130% higher than its mean value of 10 mm Hg for controls (P < .0001). With logistic regression models to estimate the relative risks (odds ratios) for intracranial hemorrhage conferred by each form of blood pressure, the relative risk for hemorrhage was greatest for excess pulse pressure: for each 10-point pulse pressure excess, the relative risk for intracranial hemorrhage was increased by 1.85 (P = .0002; 95% confidence interval [CI], 1.34 to 2.55) by itself and 1.76 (P = .001; 95% CI, 1.26 to 2.46) when adjusted for age. In this sample, excess pulse pressure by itself predicted hemorrhage as well as systolic pressure and age together. When excess pulse pressure was combined with age to make a logistic regression model predicting intracranial hemorrhage, age contributed less to the prediction than when combined with the other blood pressure forms, even though this model predicted better than any other combination of age and pressure (receiver-operating characteristic curve area, 0.82 versus 0.77 with systolic pressure and age, 0.75 with mean arterial pressure, 0.71 with diastolic pressure, and 0.81 with both systolic and diastolic pressures). CONCLUSIONS: We found that excess pulse blood pressure predicted thrombolysis-related intracranial hemorrhage better than other forms of pretreatment blood pressure, perhaps better describing the pathophysiology of intracranial hemorrhage, including the effect of age. These findings will need confirmation in larger studies with comparable clinical detail.

Impact of the acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI) on the speed of triage decision making for emergency department patients presenting with chest pain: a controlled clinical trial.

OBJECTIVE: Emergency department (ED) triage for acute cardiac ischemia in the primary teaching hospital in Geneva, Switzerland, is very accurate, but at the cost of very long ED stays. Thus, the authors sought: 1) to determine the impact of the acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI), incorporated into a computerized electrocardiograph, on length of stay and speed of triage decision making for ED patients presenting with symptoms suggesting acute cardiac ischemia, and 2) to study the ACI-TIPI's impact on physicians of different training levels. DESIGN: A seven-month prospective clinical trial with alternating-month experimental and control periods. SETTING: An urban major teaching hospital in Geneva, Switzerland. PARTICIPANTS: Patients over the age of 18 years presenting to the ED with chest pain or other symptoms suggesting acute cardiac ischemia (acute myocardial infarction or unstable angina pectoris). Emergency department physicians, classified as novice (those in their first ED rotations) and experienced (those in their second or later ED rotations). Patients staying overnight in the ED (n = 111) were excluded from the analysis. INTERVENTION: During the experimental months, the computerized electrocardiograph printed the ACI-TIPI probability of acute cardiac ischemia at the top of each subject's electrocardiogram. During control months, the probability was not provided. MEASUREMENTS AND MAIN RESULTS: Among the 418 study subjects, for patients with acute ischemia seen by novice clinicians, the use of the ACI-TIPI decreased ED time from presentation to triage decision and ED release by 0.7 hour (19%) (p = 0.007). Subgroup analyses for patients with acute myocardial infarction, patients with unstable angina pectoris, and patients given thrombolytic therapy also showed analogous decreases in ED time consistent with this finding. Other key determinants of ED length of stay included: age, whether the coronary care unit was full, whether patients received thrombolytic therapy, and whether admission was during the night shift. The experimental and control groups did not differ in triage disposition appropriateness or mortality. CONCLUSIONS: For ED patients with acute cardiac ischemia evaluated by novice clinicians, the ACI-TIPI substantially speeded ED decision making and triage. The suggestion of an impact on different cardiac ischemia subgroups and mortality deserves further larger clinical trials.

Cost-effectiveness of streptokinase for acute myocardial infarction: A combined meta-analysis and decision analysis of the effects of infarct location and of likelihood of infarction.

OBJECTIVE: To determine the effects of infarct location and of the likelihood of infarction on the cost-effectiveness of intravenous streptokinase (IVSK) for suspected acute myocardial infarction (AMI). DESIGN: A meta-analysis of short-term survival was combined with a simple decision tree to determine marginal cost-effectiveness ratios for different infarct locations and different likelihoods of AMI (pMI). SETTING: Six randomized trials comparing IVSK with conservative treatment. PATIENTS: 31,940 patients with onset of symptoms of AMI from four to 24 hours earlier and, with the exception of one trial, electrocardiographic abnormalities. Patients with contraindications to thrombolytic treatment such as uncontrolled hypertension were excluded. MAIN RESULTS: If AMI is certain, treatment with IVSK has marginal cost-effectiveness ratios for each additional life saved of $9,900, $56,600, and $28,400, respectively, for patients with anterior, inferior, and other locations of AMI. If pMI is 50% treatment with IVSK has marginal cost-effectiveness ratios for each additional life saved of $22,700, $131,800, and $63,100, respectively, for patients with anterior, inferior, and other locations of AMI. CONCLUSIONS: The marginal cost-effectiveness ratio for IVSK therapy of inferior infarction is six times that for anterior infarction and rises steeply as the presence of AMI becomes less certain. Assuming society is willing to pay $250,000 per life saved, IVSK therapy should be given if the chance of acute anterior infarction exceeds 7%, if the chance of inferior infarction exceeds 32%, or if the chance of infarction in other locations exceeds 17%. In patients with suspected acute myocardial infarction, IVSK saves lives and is a reasonable use of societal resources.