Trial design for assessing analytical and clinical performance of high-sensitivity cardiac troponin I assays in the United States: The HIGH-US study.

BACKGROUND: High-sensitivity cardiac troponin I (hs-cTnI) assays have been developed that quantify lower cTnI concentrations with better precision versus earlier generation assays. hs-cTnI assays allow improved clinical utility for diagnosis and risk stratification in patients presenting to the emergency department with suspected acute myocardial infarction. We describe the High-Sensitivity Cardiac Troponin I Assays in the United States (HIGH-US) study design used to conduct studies for characterizing the analytical and clinical performance of hs-cTnI assays, as required by the US Food and Drug Administration for a 510(k) clearance application. This study was non-interventional and therefore it was not registered at clinicaltrials.gov. METHODS: We conducted analytic studies utilizing Clinical and Laboratory Standards Institute guidance that included limit of blank, limit of detection, limit of quantitation, linearity, within-run and between run imprecision and reproducibility as well as potential interferences and high dose hook effect. A sample set collected from healthy females and males was used to determine the overall and sex-specific cTnI 99th percentile upper reference limits (URL). The total coefficient of variation at the female 99th percentile URL and a universally available American Association for Clinical Chemistry sample set (AACC Universal Sample Bank) from healthy females and males was used to examine high-sensitivity (hs) performance of the cTnI assays. Clinical diagnosis of enrolled subjects was adjudicated by expert cardiologists and emergency medicine physicians. Assessment of temporal diagnostic accuracy including sensitivity, specificity, positive predictive value, and negative predictive value were determined at presentation and collection times thereafter. The prognostic performance at one-year after presentation to the emergency department was also performed. This design is appropriate to describe analytical characterization and clinical performance, and allows for acute myocardial infarction diagnosis and risk assessment.

Cardiac troponin T in chest pain unit patients without ischemic electrocardiographic changes: angiographic correlates and long-term clinical outcomes.

OBJECTIVES: We prospectively evaluated the relation between cardiac troponin T (cTnT) level, the presence and severity of coronary artery disease (CAD) and long-term prognosis in patients with chest pain but no ischemic electrocardiographic (ECG) changes who had short-term observation. BACKGROUND: Cardiac TnT is a powerful predictor of future myocardial infarction (MI) and death in patients with ECG evidence of an acute coronary syndrome. However, for patients with chest pain with normal ECGs, it has not been determined whether cTnT elevation is predictive of CAD and a poor long-term prognosis. METHODS: In 414 consecutive patients with no ischemic ECG changes who were triaged to a chest pain unit, cTnT and creatine kinase, MB fraction (CK-MB) were evaluated > or = 10 h after symptom onset. Patients with adverse cardiac events, including death, MI, unstable angina and heart failure were followed for as long as one year. RESULTS: A positive (>0.1 ng/ml) cTnT test was detected in 37 patients (8.9%). Coronary artery disease was found in 90% of 30 cTnT-positive patients versus 23% of 144 cTnT-negative patients who underwent angiography (p < 0.001), with multivessel disease in 63% versus 13% (p < 0.001). The cTnT-positive patients had a significantly (p < 0.05) higher percent diameter stenosis and a greater frequency of calcified, complex and occlusive lesions. Follow-up was available in 405 patients (98%). By one year, 59 patients (14.6%) had adverse cardiac events. The cumulative adverse event rate was 32.4% in cTnT-positive patients versus 12.8% in cTnT-negative patients (p = 0.001). After adjustment for baseline clinical characteristics, positive cTnT was a stronger predictor of events (chi-square = 23.56, p = 0.0003) than positive CK-MB (>5 ng/ml) (chi-square = 21.08, p = 0.0008). In a model including both biochemical markers, CK-MB added no predictive information as compared with cTnT alone (chi-square = 23.57, p = 0.0006). CONCLUSIONS: In a group of patients with chest pain anticipated to have a low prevalence of CAD and a good prognosis, cTnT identifies a subgroup with a high prevalence of extensive and complex CAD and increased risk for long-term adverse outcomes.

Randomized comparison of a strategy of predischarge coronary angiography versus exercise testing in low-risk patients in a chest pain unit: in-hospital and long-term outcomes.

OBJECTIVES: This randomized trial compared a strategy of predischarge coronary angiography (CA) with exercise treadmill testing (ETT) in low-risk patients in the chest pain unit (CPU) to reduce repeat emergency department (ED) visits and to identify additional coronary artery disease (CAD). BACKGROUND: Patients with chest pain and normal electrocardiograms (ECGs) have a low likelihood of CAD and a favorable prognosis, but they often seek repeat evaluations in EDs. Remaining uncertainty regarding their symptoms and diagnosis may cause much of this recidivism. METHODS: A total of 248 patients with no ischemic ECG changes triaged to a CPU were randomized to CA (n = 123) or ETT (n = 125). All patients had a probability of myocardial infarction < or =7% according to the Goldman algorithm, no biochemical evidence of infarction, the ability to exercise and no previous documented CAD. Patients were followed up for > or =1 year and surveyed regarding their chest pain self-perception and utility of the index evaluation. RESULTS: Coronary angiography showed disease (> or =50% stenosis) in 19% and ETT was positive in 7% of the patients (p = 0.01). During follow-up (374+/-61 days), patients with a negative CA had fewer returns to the ED (10% vs. 30%, p = 0.0008) and hospital admissions (3% vs. 16%, p = 0.003), compared with patients with a negative/nondiagnostic ETT. The latter group was more likely to consider their pain as cardiac-related (15% vs. 7%), to be unsure about its etiology (38% vs. 26%) and to judge their evaluation as not useful (39% vs. 15%) (p < 0.01 for all comparisons). CONCLUSIONS: In low-risk patients in the CPU, a strategy of CA detects more CAD than ETT, reduces long-term ED and hospital utilization and yields better patient satisfaction and understanding of their condition.

Racial differences in the prevalence of left ventricular hypertrophy among chronic cocaine abusers.

There are racial differences in the prevalence and pattern of left ventricular (LV) hypertrophy in hypertension. This study was performed to determine whether racial differences also exist in LV hypertrophy among chronic cocaine users. We studied 112 chronic cocaine abusers < 45 years old in whom normal blood pressures (< or = 140/90 mm Hg) were recorded 3 times daily for 3 weeks. LV wall thickness and mass were measured echocardiographically. Technically adequate studies were obtained in 79 blacks and 33 whites. Self-reported cocaine use was higher in whites than in blacks (688 +/- 516 vs 431 +/- 468 $/week, p = 0.03). There were no group differences in terms of duration of cocaine use, age, height, weight, blood pressure, LV dimensions, or left atrial size. However, posterior wall thickness (1.13 +/- 0.17 vs 1.03 +/- 0.14 cm, p = 0.0035) and LV mass index (113 +/- 25 vs 94 +/- 19 g/m2, p = 0.0001) were significantly greater in blacks. LV hypertrophy, defined as an M-mode LV mass index > or = 134 g/m2, was present in 24 blacks (30%) and 2 whites (6%) (p = 0.011). When defined as a posterior wall thickness > or = 1.2 cm and a 2-dimensional echocardiographic LV mass index > or = 105 g/m2, LV hypertrophy was present in 37 of 79 blacks (47%) and in 6 of 33 whites (18%) (p = 0.0086). Cocaine-related LV hypertrophy is more prevalent in black men than in white men.(ABSTRACT TRUNCATED AT 250 WORDS)

Real-time 3-dimensional echocardiography imaging for right ventricular endomyocardial biopsy: a comparison with fluoroscopy.

Real-time 3-dimensional (RT3D) echocardiography has the potential to precisely identify the position of an object in 3-dimensional space. Therefore, we hypothesized that RT3D echocardiography could rapidly facilitate accurate placement of a bioptome within the right ventricle and may offer advantages over a fluoroscopically guided approach. During 63 routine right ventricular biopsy procedures (total of 315 biopsy attempts) in 33 cardiac allograft recipients, the bioptome was initially guided against the intraventricular septum with the use of biplane fluoroscopy. Bioptome position was then evaluated by RT3D echocardiography by using the Volumetrics Model 1 with the transducer placed at the apex. Multiple long-axis and short-axis planes were simultaneously visualized and customized to identify the tip of the bioptome. Bioptome placement was prospectively classified as septal, free wall/septal junction, or free wall. Of the 36 patients studied, 33 (91%) had adequate RT3D images. Of 315 bioptome placements visualized by RT3D echocardiography after fluoroscopic placement, bioptome position against the septum was confirmed in 113 (36%), against the septal/free wall (anterior or posterior) junction in 140 (44%), against the free wall in 60 (19%), and in the coronary sinus in 2 (1%). RT3D echocardiography is readily feasible for use in the majority of transplant patients undergoing right ventricular endomyocardial biopsy. Visualization of the bioptome in multiple simultaneous planes allows accurate localization of the biopsy site. The potential for improved localization of the bioptome tip in the right ventricle may have important clinical implications for augmenting the efficacy of this procedure.

Morphology of the mitral valve as displayed by multiplane transesophageal echocardiography.

This study was performed to (1) describe how multiplane transesophageal echocardiography (TEE) facilitates imaging of the entire mitral valve apparatus, and (2) prospectively compare the morphology of the different segments of the mitral apparatus as determined by multiplane TEE and direct surgical inspection. The study consisted of 30 consecutive patients examined by multiplane TEE less than 24 hours before mitral valve surgery. The mitral valve was displayed in transgastric and transesophageal views with the imaging planes specifically aligned to demonstrate continuity between the papillary muscles, chordae tendineae, and leaflet edges. The character and location of morphologic abnormalities identified by findings of preoperative TEE were highly concordant with surgical inspection of the valve (p < 0.0001). Thus multiplane TEE offers the ability to visualize the entire mitral apparatus as a functional unit and to identify morphologic abnormalities of the valve correctly.

Evaluating the chest pain patient. Scope of the problem.

With an understanding of the pathophysiology of ACS and an increasing number of early therapeutic options, there has been a shift in focus from ruling-out MI to identifying and stratifying risk in all patients with potential ACS. The presenting symptoms and ECG still remain the cornerstone of immediate diagnosis and triage. Through the application of new technologies, such as the cardiac troponins, and a reassessment of techniques, such as perfusion imaging and echocardiography, the clinician has an increasing selection of methods to rapidly assess chest pain of potential ischemic etiology. Coinciding with the evaluation of technology has been the development of the concept of the CPU and associated rapid diagnostic protocols. These protocols, whether they utilize the assistance of mathematic predictive instruments or represent simple triage schemes, form the backbone of a system to improve the care of patients with ACS in the current milieu of cost containment.

Effect of high-altitude exposure in the elderly: the Tenth Mountain Division study.

BACKGROUND: More than 5 million people/year over age 60 visit high altitude, which may exacerbate underlying cardiac or pulmonary disease. We hypothesized that the elderly would exhibit an impaired functional capacity at altitude, with increased myocardial ischemia compared with sea level (SL). METHODS AND RESULTS: Twenty veterans (68+/-3 years) were studied at (1) SL, (2) acute simulated altitude to 2500 m, and (3) after 5 days of acclimatization to 2500 m. With acute altitude, PaO2 and oxyhemoglobin saturation decreased and pulmonary artery pressure increased 43%, associated with sympathetic activation. VO2peak decreased 12% acutely but normalized after acclimatization. The best predictor of VO2peak with acute altitude was VO2peak at SL (r=.94). The double product that induced 1-mm ST depression during exercise with acute altitude was 5% less than SL but normalized after acclimatization. One patient with severe coronary disease sustained a myocardial infarction after an exercise test. CONCLUSIONS: Moderate altitude exposure in the elderly is associated with hypoxemia, sympathetic activation, and pulmonary hypertension resulting in a reduced exercise capacity that is predictable based on exercise performance at SL. Patients with coronary artery disease who are well compensated at SL do well at moderate altitude, although acutely ischemia may be provoked at modestly lower myocardial and systemic work rates. The elderly acclimatize well with normalization of SL performance after 5 days. A prudent policy would be for elderly individuals, particularly those with coronary artery disease, to limit their activity during the first few days at altitude to allow this acclimatization process to occur.

Diagnostic accuracy, angiographic correlates and long-term risk stratification with the troponin T ultra sensitive Rapid Assay in chest pain patients at low risk for acute myocardial infarction.

AIMS: This prospective study of acute chest pain patients clinically at low risk for a myocardial infarction was designed to: determine the diagnostic accuracy of a cardiac troponin T (cTnT) ultra sensitive Rapid Assay (RAII) compared with the quantitative cTnT assay; evaluate the association of a positive RAII with the presence and severity of coronary artery disease (CAD); and determine the ability of the RAII result to predict adverse events during long-term follow-up. METHODS AND RESULTS: A total of 199 patients referred for chest pain, without ST segment elevation on presenting ECG, underwent RAII, quantitative cTnT, CK and CK-MB tests drawn simultaneously > or = 10 h after symptom onset. An abnormal value for cTnT was defined as >0.1 ng.mL(-1). The presence and extent of CAD was recorded in patients undergoing angiography. Adverse events, including cardiac death, non-fatal infarction, and readmission for unstable angina or heart failure, were assessed long-term. An abnormal RAII was found in 41 (20-6%) patients. The RAII sensitivity for detecting abnormal quantitative cTnT levels was 100%, specificity 96.3% (158/164) and overall concordance 97.5%. Although the presenting ECG was normal or non-specific in 95%, ST depression or T wave inversion occurred in 17% of RAII-positive versus 2%, RAII-negative patients (P=0.004). Of RAII-positive patients who underwent angiography (79%), 87% had CAD and 60% had multivessel disease. Kaplan Meier event-free survival curves showed early separation and continued to modestly diverge for patients with positive and negative RAII (69% versus 90% one-year event-free survival, P=0.002). CONCLUSION: In a chest pain population anticipated to have a low prevalence of acute coronary syndromes and a good prognosis, the RAII is a quick and reliable test. It provides an important initial opportunity to identify patients with a high prevalence of CAD and increased incidence of future cardiac events.

Comparison of myocardial contrast echocardiography and low-dose dobutamine stress echocardiography in predicting recovery of left ventricular function after coronary revascularization in chronic ischemic heart disease.

BACKGROUND: Dobutamine stress echocardiography (DSE) and myocardial contrast echocardiography (MCE) can predict recovery of left ventricular function after myocardial infarction. DSE also has been shown to predict left ventricular functional recovery after revascularization in chronic ischemic heart disease, whereas MCE has not been evaluated in such patients. This study was performed to compare DSE and MCE in the prediction of left ventricular functional recovery after revascularization in patients with chronic ischemic heart disease. METHODS AND RESULTS: MCE and DSE were performed in 35 patients with chronic coronary artery disease and significant wall motion abnormalities (mean ejection fraction, 0.36 +/- 0.09). Regional wall motion was scored by use of a 16-segment model wherein 1 = normal or hyperkinetic, 2 = hypokinetic, 3 = akinetic, and 4 = dyskinetic. Each segment was evaluated for contractile reserve by DSE and perfusion by MCE. Revascularization (coronary artery bypass graft [n = 13] and percutaneous transluminal coronary angioplasty [n = 10]) was successful in 23 patients. Follow-up echocardiograms were done to assess wall motion 30 to 60 days later. In 238 segments with resting wall motion abnormalities, perfusion was more likely to present than contractile reserve (97% versus 91%, P < .02). Revascularization resulted in functional recovery in 77 of 95 hypokinetic segments (81%) but only 18 of 57 akinetic segments (32%, P < .0001). DSE and MCE were not significantly different in predicting functional recovery of hypokinetic segments. In akinetic segments, DSE and MCE had similar sensitivities (89% versus 94%, respectively) and negative predictive values (93% and 97%, respectively) in predicting functional recovery. However, DSE had a higher specificity (92% versus 67%, P < .02) and positive predictive value (85% versus 55%, P < .02) than MCE in predicting functional recovery. CONCLUSIONS: Both contractile reserve by DSE and perfusion by MCE are predictive of functional recovery in hypokinetic segments after coronary revascularization in patients with chronic coronary revascularization in patients with chronic coronary artery disease. In akinetic segments, myocardial perfusion by MCE may exist in segments that do not recover contractile function after revascularization. Thus, contractile reserve during low-dose dobutamine infusion is a better predictor of functional recovery after revascularization in akinetic segments than perfusion.

Dobutamine stress echocardiography identifies hibernating myocardium and predicts recovery of left ventricular function after coronary revascularization.

BACKGROUND: The identification of hibernating myocardium is important in selecting patients who will benefit from coronary revascularization. This study was performed to determine whether dobutamine stress echocardiography (DSE) could identify hibernating myocardium and predict improvement in regional systolic wall thickening after revascularization. METHODS AND RESULTS: DSE was performed in 49 consecutive patients with multivessel coronary disease and depressed left ventricular function. Contractile reverse during DSE was defined by the presence of two criteria: (1) improved systolic wall thickening in at least two adjacent abnormal segments and (2) > or = 20% improvement in regional wall thickening score. Postoperative echocardiograms were evaluated for improved regional wall thickening in 25 patients at least 4 weeks after successful coronary revascularization. All studies were read in blinded fashion. Contractile reserve during DSE was present in 24 (49%) of 49 patients. The presence or absence of contractile reserve on preoperative DSE predicted recovery of ventricular function in the 25 patients who underwent successful revascularization. Thus, 9 of 11 patients with contractile reserve had improved systolic wall thickening after revascularization (hibernating myocardium), whereas 12 of 14 patients without contractile reserve did not improve (P = .003). CONCLUSIONS: Dobutamine stress echocardiography provides a simple, cost-effective, and widely available method of identifying hibernating myocardium and predicting improvement in regional left ventricular wall thickening after coronary revascularization. This technique may be clinically valuable in the selection of patients for coronary revascularization.

Queuing for coronary angiography during severe supply-demand mismatch in a US public hospital: analysis of a waiting list registry.

CONTEXT: Adverse cardiac events have been reported in patients waiting for either coronary surgery or angioplasty. However, data on the risk of adverse events while awaiting coronary angiography are limited, and none are available from a US population. OBJECTIVE: To quantify cardiac outcomes in patients waiting for elective coronary angiography. DESIGN, SETTING, AND PARTICIPANTS: Observational cohort study of 381 adult outpatients (mean [SD] age, 55 [12] years; 64% male; 61% white) on a waiting list for coronary angiography at a US tertiary care public teaching hospital during 1993-1994. MAIN OUTCOME MEASURES: Rates of cardiac death, nonfatal myocardial infarction, and hospitalizations for unstable angina or heart failure as a function of amount of time spent on a waiting list. RESULTS: Sixty-six patients were dropped from the waiting list but were included in the study analysis. During a mean (SD) follow-up of 8.4 (6.5) months, cardiac death, myocardial infarction, and hospitalization occurred in 6 (1.6%), 4 (1.0%), and 26 (6.8%) patients, respectively. The probability of events was minimal in the first 2 weeks and increased steadily between 3 and 13 weeks. By Cox multivariate analysis, 2 variables independently identified an increased risk of adverse events: a strongly positive treadmill exercise electrocardiogram or positive stress imaging result at referral (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.22-4.16; P=.01) and the use of 2 to 3 anti-ischemic medications (OR, 1.98; 95% CI, 1.19-3.96; P=.04). Among 311 patients who ultimately underwent angiography, those with adverse events had a higher prevalence of coronary disease (96% vs 60%; P<.001), more frequently required revascularization (93% vs 53%; P<.001), and had longer hospital stays (mean [SD], 6.2 [4.3] vs 1.3 [0.7] days; P=.001). CONCLUSION: Our data suggest that in a cohort referred for coronary angiography, delaying the procedure places some patients at risk for death, myocardial infarction, unplanned hospitalization, a longer hospital stay, and, potentially, a poorer prognosis. Waits longer than 2 weeks should be avoided, and patients with strongly positive stress test results and those who require 2 to 3 anti-ischemic medications should be prioritized for early intervention.