Journal of the American College of Cardiology Vol. 46, No. 5, by the American College of Cardiology Foundation ISSN /05/$30.

Transcription

1 Journal of the American College of Cardiology Vol. 46, No. 5, by the American College of Cardiology Foundation ISSN /05/$30.00 Published by Elsevier Inc. doi: /j.jacc EXPEDITED REVIEW Myocardial Contrast Echocardiography Versus Thrombolysis in Myocardial Infarction Score in Patients Presenting to the Emergency Department With Chest Pain and a Nondiagnostic Electrocardiogram Khim Leng Tong, MD,* Sanjiv Kaul, MD, FACC,* Xin-Qun Wang, MS, Diana Rinkevich, MD, FACC,* Saul Kalvaitis, MD,* Todd Belcik, RDCS,* Wolfgang Lepper, MD,* William A. Foster, MD,* Kevin Wei, MD, FACC* Charlottesville, Virginia OBJECTIVES BACKGROUND METHODS RESULTS CONCLUSIONS We hypothesized that regional function (RF) and myocardial perfusion (MP) are superior to the Thrombolysis In Myocardial Infarction (TIMI) score for diagnosis and prognostication in patients presenting to the emergency department (ED) with chest pain (CP) and a nondiagnostic electrocardiogram. Rapid diagnosis and prognostication is difficult in patients presenting to the ED with suspected cardiac CP. Contrast echocardiography was performed to assess RF and MP on 957 patients presenting to the ED with suspected cardiac CP and a nondiagnostic electrocardiogram. A modified TIMI (mtimi) score was calculated from six immediately available variables. A full TIMI score also was derived after troponin levels were able to be accessed adequately. Follow-up was performed for early (within 24 h), intermediate (30 day), and late primary (death and myocardial infarction) or secondary (unstable angina and revascularization) events. The mtimi score was unable to discriminate between intermediate- compared to high-risk patients at any follow-up time point, whereas only 2 of 523 patients with normal RF had an early primary event. Regional function provided incremental prognostic value over mtimi scores for predicting intermediate and late events. In patients with abnormal RF, MP further classified patients into intermediate- and high-risk groups. The full TIMI score could not improve upon these results at any follow-up time point. Contrast echocardiography can rapidly and accurately provide short-, intermediate-, and long-term prognostic information in patients presenting to the ED with suspected cardiac CP even before serum cardiac markers are known. Integrating contrast echocardiography into the ED evaluation of CP may improve the risk stratification of such patients. (J Am Coll Cardiol 2005;46:920 7) 2005 by the American College of Cardiology Foundation Chest pain (CP) is a common complaint in patients seeking care from an emergency department (ED). The electrocar- See page 928 diogram (ECG) is effective in helping to diagnose 30% to 50% of patients with acute myocardial infarction (AMI) (1 3), and early determinations of serum cardiac enzymes From the *Cardiovascular Imaging Center, Cardiovascular Division, and the Division of Biostatistics and Epidemiology, Department of Health Evaluation Sciences, University of Virginia School of Medicine, Charlottesville, Virginia. Drs. Tong and Kalvaitis were recipients of Research Fellowship Awards from the National Medical Research Council of Singapore and POINT Biomedical Corporation (San Carlos, California), respectively. Dr. Wei was the recipient of a Mentored Clinical Scientist Development Award (K08-HL03909) from the National Institutes of Health. Current address of Dr. Tong: Changi General Hospital, Singapore. Presented in part at the Samuel Levine Young Investigator Award Competition at the 77th Annual Scientific Session of the American Heart Association, New Orleans, Louisiana. Drs. Kaul and Wei are currently located at the Cardiovascular Division, OHSU, Portland, Oregon. Manuscript received May 6, 2004; revised manuscript received March 27, 2005, accepted March 29, frequently are negative (4,5). The unreliability of these parameters results, on one hand, in the inadvertent discharge of approximately 5% of patients with ongoing AMI and, on the other hand, unnecessary hospital admissions (6). Apart from the identification of ischemia, the accurate risk stratification of these patients also is important. Those patients who are at intermediate or high risk for an adverse outcome may require admission to a coronary care or telemetry unit, treatment with potent antiplatelet agents (7 9), or early referral for cardiac catheterization (10). The presence of elevated levels of troponin identifies those patients at increased risk and is a component of the Thrombolysis In Myocardial Infarction (TIMI) risk score (11). It may, however, not be elevated or immediately available at the time of patient presentation. Thus, complete risk stratification and initiation of therapy may be unnecessarily delayed. We hypothesized that an assessment of left ventricular (LV) regional function (RF) and myocardial perfusion (MP) would be superior to the TIMI score in patients presenting to an ED with suspected cardiac CP and no ST-segment elevation on the ECG.

2 JACC Vol. 46, No. 5, 2005 September 6, 2005:920 7 Tong et al. Contrast Echocardiography for Chest Pain 921 Abbreviations and Acronyms AMI acute myocardial infarction CE contrast echocardiography CP chest pain ECG electrocardiogram ED emergency department LV left ventricular MP myocardial perfusion mtimi modified Thrombolysis In Myocardial Infarction RF regional function TIMI Thrombolysis In Myocardial Infarction METHODS Patient population. This study was approved by the Human Investigation Committee at the University of Virginia. Patients 30 years of age who presented to the ED with a complaint of CP of 30 min in duration that was not easily attributable to an obvious noncardiac cause and who did not exhibit ST-segment elevation on the ECG were enrolled in the study. All patients had their contrast echocardiography (CE) study completed within 12 h of the onset of their symptoms. All patients provided written informed consent. Determination of TIMI risk score. The TIMI risk score was calculated as previously defined (11). A score of 1 was assigned to each of the following seven variables when present: age 65 years, more than three coronary disease risk factors, known coronary luminal diameter narrowing of 50%, ST-segment deviation on ECG, two or more angina events in the previous 24 h, use of aspirin in the previous seven days, and elevated levels of troponin. The TIMI risk score was calculated as the sum of all scores. We also wanted to evaluate the prognostic utility of a score derived from variables that are available immediately at the time of ED presentation. Because of inherent delays in receiving laboratory results and because troponin elevation may be delayed for many hours after the initial presentation, a modified TIMI risk score (mtimi) that excluded this variable was derived (maximum score of 6). Contrast echocardiography. An infusion of 3 ml of Optison (GE Healthcare, Princeton, New Jersey) diluted in 60 ml of saline was administered intravenously at a rate of 3 Table 1. Early Events in Different mtimi and TIMI Groups mtimi Risk Group ml min 1 using a syringe pump (model AS40A, Baxter, Deerfield, Illinois). Imaging was performed using a Sonos 5500 system (Phillips Ultrasound, Andover, Massachusetts). Regional function data were acquired using low mechanical index harmonic imaging and contrast for LV border delineation. For MP, intermittent high mechanical index ultraharmonic imaging was performed using transmit/receive frequencies of 1.3/3.6 MHz, respectively, with ultrasound transmission gated to the ECG at end-systole. Images were acquired digitally at pulsing intervals of 1, 2, 3, 4, and 5 cycles. Compression was set at 75%, and all gain settings were optimized at the beginning of the study and then held constant. If a signal from myocardial regions was discernable despite optimization of ultraharmonic image settings, intermittent harmonic power Doppler was performed to achieve better tissue signal suppression. The transmit focus initially was set at the level of the mitral valve but was moved to the apex when an apical defect was observed to exclude the apical destruction artifact (Video A; see the online version of this article for all videos). Off-axis images were acquired as needed. Regional function and MP data were acquired digitally onto magneto-optical disks. Regional function and MP studies were interpreted separately by experienced observers who were blinded to all data: both were scored visually using a 14-segment model as normal, abnormal, or not interpretable (12). The segments were then grouped into anteroapical, lateral, or inferoposterior territories. Studies were classified as normal if RF or MP in the majority of segments within each perfusion territory were normal. Studies were called abnormal if RF or MP was abnormal in one or more territories, even if all territories were not visualized. If a study could not be classified as previously mentioned, it was deemed not assessable. Study protocol. All patients had a complete history and physical examination as well as a 12-lead ECG. Blood was drawn for troponin I at the time of ED presentation and repeated twice at 6-h intervals. Troponin I levels were measured using a direct chemiluminometric immunoassay (Bayer, Tarrytown, New York). Contrast echocardiography was performed as soon as possible after the patient s TIMI Risk Group (n 586) (n 326) (n 45) (n 560) (n 305) (n 92) AMI 24 (4.1) 35 (11.0) 4 (8.9) 11 (2.0) 29 (9.5) 23 (26.0) All-cause mortality 1 (0.2) 1 (0.3) 0 (0) 1 (0.2) 0 (0) 1 (1.1) Total primary events 25 (4.3) 36 (11.3) 4 (8.9) 12 (2.2) 29 (9.5) 24 (27.1) Unstable angina 11 (1.9) 28 (8.6) 9 (20.0) 8 (1.4) 25 (8.2) 15 (16.0) PCI 1 (0.2) 7 (2.1) 1 (2.2) 1 (0.2) 6 (2.0) 2 (2.2) CABG 1 (0.2) 2 (0.6) 0 (0) 1 (0.2) 1 (0.3) 1 (1.1) Total secondary events 18 (3.1) 44 (13.3) 11 (24.4) 15 (2.7) 37 (14.8) 21 (22.6) AMI acute myocardial infarction; CABG coronary artery bypass graft surgery; mtimi modified Thrombolysis In Myocardial Infarction; PCI percutaneous coronary intervention; TIMI Thrombolysis In Myocardial Infarction.

3 922 Tong et al. JACC Vol. 46, No. 5, 2005 Contrast Echocardiography for Chest Pain September 6, 2005:920 7 Table 2. Early Events in Different CE Groups (n 485) (n 38) (n 164) (n 270) AMI 1 (0.2) 1 (2.6) 16 (9.8) 45 (16.0) All-cause mortality 1 (0.2) 0 (0) 0 (0) 1 (0.37) Total primary events 2 (0.4) 1 (2.6) 16 (9.8) 46 (16.4) Unstable angina 8 (1.6) 0 (0) 9 (5.5) 31 (11.0) PCI 6 (1.2) 1 (2.6) 1 (0.6) 2 (0.7) CABG 1 (0.2) 0 (0) 0 (0) 2 (0.7) Total secondary events 15 (3.0) 1 (2.6) 13 (7.9) 44 (16.2) CE contrast echocardiography; MP myocardial perfusion; RF regional function; other abbreviations as in Table 1. presentation to the ED. Information regarding RF or MP was not shared with the ED physician, and the decision to admit or discharge was based solely on routine clinical, laboratory, and ECG criteria. Follow-up was obtained by questionnaire or telephone interview with the patient, patient s family, physician, or a combination. All reported events were confirmed by review of medical charts or other documents (for example, death certificates). Primary end points included all-cause mortality and AMI, which was defined by an abnormally elevated troponin I level ( 0.6 ng ml 1 ). Secondary events included revascularization (either coronary artery bypass surgery or percutaneous coronary intervention) and unstable angina, defined as ischemic CP of 30 min duration associated with dynamic ECG changes and/or mild troponin elevation (0.08 to 0.6 ng ml 1 ) and requiring hospitalization and/or revascularization. Secondary events occurring before a primary event were ignored. If a patient had more than one event, only the first was considered for analysis. Cumulative patient outcomes were determined at three time points: early (within the first 24 h), intermediate (up to 30 days), and late ( 30 days). Statistical methods. The explanatory variables were the same for all types of models. To test whether RF or RF plus MP had the ability to discriminate between subjects with different TIMI risk scores, logistic regression models (13,14) were applied for cumulative events that had accrued at early and intermediate time points, and Cox proportional hazards regression models (14,15) were used for cumulative events at the late time point. Adjusted survival probabilities for late events also were estimated based on the Cox proportional hazards survival model (16). A Wald chisquare test was used to assess the significance of each predictor and an odds ratio (OR) or a hazard ratio was used to quantify its effect. A log likelihood ratio test was applied to determine whether RF and/or MP provided additional information to the TIMI scores in predicting events. The area under the receiver-operating characteristic curve (or C-index) was used to quantify the discriminatory power of RF or combined RF and MP (14). C-indices of 0.69, 0.70 to 0.79, and 0.79 indicated poor, good, and excellent discrimination, respectively. RESULTS Patient characteristics. Between October 2000 and January 2003, 1,236 patients were recruited. Of these, 86 (7%) had no follow-up, and 151 had RF or MP studies of inadequate quality (12%). Another 42 (3%) developed ST-segment elevation on the ECG after being admitted to the ED and were excluded from analysis. Therefore, a total of 957 patients are presented in this report, of whom 153 (16%) had CE performed during ongoing CP. No significant differences were found in demographics between patients who were excluded and the study group. A little more than one half (52%) of the 957 patients were men; the median age was 60 years (range, 32 to 92 years), 27% were smokers, 28% had diabetes, 53% had hypercholesterolemia, 47% had a family history of coronary artery disease, and 66% had essential hypertension. On the basis of their mtimi or TIMI scores, patients were categorized as either low (score 2), intermediate (score of 3 or 4), or high (score 5) risk. In 485 of the 957 patients (51%), both RF and MP were normal (Video A); in 164 (17%), RF was abnormal but MP was normal (Video B); in 270 (28%), Figure 1. Ability of tests performed in a hierarchical order for predicting early events. See text for details. MP myocardial perfusion; mtimi modified Thrombolysis In Myocardial Infarction; RF regional function; TIMI Thrombolysis In Myocardial Infarction. Open bars mtimi; gray bars mtimi RF; black bars mtimi RF MP; ruled bars TIMI.

4 JACC Vol. 46, No. 5, 2005 September 6, 2005:920 7 Tong et al. Contrast Echocardiography for Chest Pain 923 Table 3. Events in Different mtimi and TIMI Groups mtimi Risk Group TIMI Risk Group (n 586) (n 326) (n 45) (n 560) (n 305) (n 92) AMI 25 (4.3) 37 (11.3) 8 (17.8) 12 (2.1) 30 (9.8) 28 (30.4) All-cause mortality 1 (0.2) 2 (0.6) 1 (2.2) 1 (0.2) 2 (0.6) 3 (3.3) Total primary events 26 (4.4) 41 (12.6) 9 (20.0) 13 (2.3) 32 (10.5) 31 (33.7) Unstable angina 12 (2.0) 31 (9.5) 11 (24.4) 8 (1.4) 28 (9.2) 18 (19.6) PCI 3 (0.5) 10 (3.1) 1 (2.2) 3 (0.5) 9 (3.0) 2 (2.2) CABG 2 (0.3) 5 (1.5) 1 (2.2) 2 (0.4) 4 (1.3) 2 (2.2) Total secondary events 17 (2.9) 46 (14.1) 13 (28.9) 13 (2.3) 41 (13.4) 22 (23.9) Abbreviations as in Table 1. both RF and MP were abnormal (Video C); and in 38 (4%), RF was normal but MP was abnormal. Early events. The incidence of early events based on the mtimi score is shown in Table 1. Acute myocardial infarction was the most common event in all groups. Although patients with a low mtimi score had the lowest incidence of primary events, 24 (4.1%) of these still had an AMI. Patients with an intermediate score had a similar AMI event rate as those with a high-risk score (11% vs. 8.9%, p 0.71). Thus, the mtimi score was unable to discriminate between these groups. Table 2 depicts early events in patients with different RF and MP findings. The presence of normal RF identified a population at low risk of a primary event (n 2, 0.4%). Furthermore, in patients with abnormal RF, those with normal MP had a significantly lower event rate than those with abnormal MP (9.8% vs. 16%; p 0.05). A significant interaction was observed between the mtimi score and RF. In patients with a low mtimi score ( 2), those with normal RF were significantly less likely to have an event compared with those with abnormal RF (OR 0.11; 95% confidence interval 0.05 to 0.25; p 0.001). Likewise, patients with an intermediate mtimi score (3 or 4) who had normal RF were also significantly less likely to have an event (OR 0.14, 95% confidence interval 0.07 to 0.30; p 0.001). In patients with the highest mtimi scores ( 5), however, RF did not provide additional information. After serum cardiac markers were included into the final TIMI score, approximately 5% of patients in the low- and intermediate-mtimi risk groups were reassigned to higher-risk groups. Similar to previous reports (11), the complete TIMI score adequately risk stratified patients into low, intermediate, and high risk for early events. However, because of a primary event rate of 2% even in patients with a low score, use of the TIMI score alone would not allow discharge from the ED. Figure 1 illustrates the predictive value of tests performed in a hierarchical order. By adding RF to the mtimi score, the C-index increased from 0.68 to 0.79, and the model provided 127% additional information compared with the mtimi score alone (p 0.001). The addition of MP provided 148% additional information compared with mtimi score alone (p 0.001). A complete TIMI score did not provide any more information compared with that already available from the combination of the mtimi score and the CE information (C-index of 0.77 vs. 0.80). events. The incidence of events at 30-day follow-up in low-, intermediate-, and high-risk patients based on the mtimi and TIMI scores are shown in Table 3, and those in the different CE groups are shown in Table 4. Similar to the data for early events, RF provided 85% additional prognostic information (p 0.001), whereas RF plus MP provided 99% incremental predictive benefit (p 0.001) compared with the mtimi score alone (Fig. 2). Late events. Patients were followed for up to two years (median, 8.2 months). The incidence of late events in various mtimi and TIMI groups is shown in Table 5, whereas Table 6 depicts the results derived from different RF and MP subgroups. The predictive ability of tests performed in a hierarchical order based on the C-index derived from individual Cox regression models are shown in Figure 3. The mtimi score had the weakest predictive ability and was superseded by Table 4. Events in Different CE Groups (n 485) (n 38) (n 164) (n 270) AMI 1 (0.2) 1 (2.6) 18 (11.0) 50 (18.5) All-cause mortality 2 (0.4) 0 (0) 1 (0.6) 3 (1.1) Total primary events 3 (0.6) 1 (2.6) 19 (11.6) 53 (19.6) Unstable angina 8 (1.6) 0 (0) 12 (7.3) 34 (12.6) PCI 8 (1.6) 1 (2.6) 2 (1.2) 3 (1.1) CABG 4 (0.8) 0 (0) 0 (0) 4 (1.5) Total secondary events 20 (4.0) 1 (2.6) 14 (8.5) 41 (15.2) Abbreviations as in Tables 1 and 2.

5 924 Tong et al. JACC Vol. 46, No. 5, 2005 Contrast Echocardiography for Chest Pain September 6, 2005:920 7 Figure 2. Ability of tests performed in a hierarchical order for predicting intermediate events. See text for details. Abbreviations as in Figure 1. Open bars mtimi; gray bars mtimi RF; black bars mtimi RF MP; ruled bars TIMI. the addition of RF. Myocardial perfusion provided further incremental value to RF. The complete TIMI score provided greater prognostic information compared with that already available from the CE study. Unlike the setting of early events, where troponin markedly improved the ability of the mtimi score for predicting events (0.77 vs. 0.68), it had only a marginal effect on the mtimi score for predicting late events (0.74 vs. 0.69). Figures 4 and 5 show the incremental benefit of RF and MP over clinical variables alone in patients with low ( 2) and intermediate (3 to 4) mtimi scores, respectively. Those with both abnormal RF and MP had a significantly worse two-year event-free survival compared with those with abnormal RF but preserved MP (p 0.01). In patients with a high ( 5) mtimi score, however, CE did not provide any further risk stratification. DISCUSSION Patients presenting to the ED with suspected cardiac CP but no ST-segment elevation on the ECG pose a challenge. Those patients at high risk for developing events and thus requiring immediate hospitalization need to be separated Table 5. Late Events in Different mtimi and TIMI Groups mtimi Risk Group from those who are at low risk and can be safely discharged. The new finding in this study is that before obtaining troponin levels, the use of a composite score calculated from immediately assessable clinical variables (mtimi) does not adequately risk stratify all patients with CP and that the assessment of RF and MP on CE, combined with these clinical variables, provides superior diagnostic and prognostic information when compared with even the complete TIMI score. In the U.S., more than 6 million people present annually to EDs with symptoms that are suggestive of myocardial ischemia (13). The principal tools that are used for diagnosis and prognostication include history and physical examination, ECG, cardiac serum markers, and stress testing. The ECG is nondiagnostic in a significant number of patients with CP (2,3), and the kinetics of biochemical cardiac marker release make them insensitive for myocardial injury at the time of the patient s presentation to the ED (4,5). Consequently, many patients with a nondiagnostic ECG are admitted to the hospital unnecessarily to rule out an acute coronary syndrome. Most of these patients do not have acute myocardial ischemia or even coronary artery disease. Thus, the current rule out strategy wastes billions of dollars annually. The patients admitted for rule out are very heterogeneous and represent a wide risk range for developing a serious cardiac event. However, the assessment of risk is essential for triage to an adequate location for care (regular ward vs. step-down unit vs. coronary care unit) and to determine those who could benefit the most from aggressive therapy. Although single variables (such as ECG abnormalities or elevated serum cardiac markers) (17 21) have prognostic value, the composite TIMI score has been shown to effectively categorize risk of cardiovascular events and has been proposed for use in clinical decision making (11). Early events. In this study, we found that patients with a low mtimi score could not be discharged from the ED because of a substantial event rate within 24 h. In comparison, RF on CE has an excellent negative predictive value only 0.4% of patients had an early primary event. In those with abnormal RF, an assessment of MP provided additional information. Contrast echocardiography also can provide additional information in patients with either a low TIMI Risk Group (n 586) (n 326) (n 45) (n 560) (n 305) (n 92) AMI 37 (6.3) 53 (16.3) 12 (26.7) 23 (4.1) 45 (14.8) 34 (37.0) All-cause mortality 12 (2.2) 18 (5.5) 4 (8.8) 12 (2.1) 14 (4.6) 8 (8.6) Total primary events 49 (8.4) 71 (21.8) 16 (35.6) 35 (6.3) 59 (19.3) 42 (45.7) Unstable angina 17 (2.9) 39 (12.0) 12 (26.7) 13 (2.3) 36 (11.8) 19 (20.7) PCI 6 (1.0) 13 (4.0) 1 (2.2) 6 (1.1) 12 (3.9) 2 (2.2) CABG 4 (0.7) 7 (2.1) 1 (2.2) 4 (0.7) 6 (2.0) 2 (2.2) Total secondary events 27 (4.6) 59 (18.1) 14 (31.1) 23 (4.1) 54 (17.7) 23 (25.0) Abbreviations as in Table 1.

6 JACC Vol. 46, No. 5, 2005 September 6, 2005:920 7 Tong et al. Contrast Echocardiography for Chest Pain 925 Table 6. Late Events in Different CE Groups (n 485) (n 38) (n 164) (n 270) AMI 7 (1.4) 1 (2.6) 24 (14.6) 70 (25.9) All-cause mortality 12 (2.5) 0 (0) 3 (1.8) 19 (6.9) Total primary events 19 (3.9) 1 (2.6) 27 (16.4) 89 (33.0) Unstable angina 13 (2.7) 0 (0) 14 (8.5) 41 (15.2) PCI 11 (2.3) 1 (2.6) 5 (3.0) 4 (1.5) CABG 6 (1.2) 0 (0) 0 (0) 6 (2.2) Total secondary events 30 (6.2) 1 (2.6) 19 (12.6) 51 (18.9) Abbreviations as in Tables 1 and 2. or intermediate mtimi score. Those patients with normal RF had a significantly lower risk of an early event compared with those with abnormal RF. The complete TIMI score that also includes troponin was not found to provide incremental information compared with the combination of the mtimi score and CE. and late events. Previous studies have shown that clinical variables, such as the history, physical examination, and ECG, are suboptimal for identifying patients at high risk for late cardiovascular events that develop 24 h after presentation (22). Because the incidence of late events may be as high as that of early ones (22), early identification of those at risk for future events is imperative for planning further follow-up or diagnostic studies. Our results indicate that CE provides superior information to the mtimi score in these patients and that combining clinical variables with CE provides better risk stratification than clinical variables plus troponin (the complete TIMI score) for predicting late events. A previous study also has reported nonsuperiority of troponin over RF in predicting events (23). Study limitations. Although the performance of CE may be feasible during the day in most medical centers, the logistics of nighttime performance and interpretation of images is not clear. It is imperative for studies to be of high quality and all myocardial segments to be well delineated. Even with state-of-the-art systems and tissue harmonic imaging, endocardial borders are visualized inadequately in a sizeable minority of patients that is reduced markedly when CE is performed. The evaluation of RF abnormalities on echocardiography is one of the most subjective and difficult skills to master. In this context, CE has been shown to improve visualization of endocardial borders, image quality, reader confidence, and observer agreement (24,25). For rapid interpretation at night or on weekends, digitally acquired CE images could be accessed online for RF interpretation (26,27). Patients who have normal resting RF could be safely discharged from the ED and those with abnormal RF could undergo MP imaging. Because RF and MP studies were assessed independently, a small number of patients with artifacts were classified incorrectly as having perfusion defects (those with normal RF at rest). In clinical practice, when RF and MP are assessed simultaneously, such errors will likely be minimized. Clinical implications and conclusions. Contrast echocardiography (including RF and MP data) may be useful in patients presenting to the ED with suspected cardiac CP but no ST-segment elevation on the ECG because it provides incremental diagnostic and prognostic value over clinical variables. Furthermore, in patients with a low or intermediate mtimi score ( 4), it effectively identifies those who will develop events later. Current guidelines recommend observation for 4 to 8 h followed by stress testing in patients with negative serum cardiac markers (28). Because the likelihood of significant ischemia or infarction is exceedingly low in patients with normal resting RF, the observation time could be shortened in patients with this finding, and immediate stress echocardiography could be performed. However, the incidence of positive stress echocardiograms in this population would be low. Patients with abnormal RF but normal MP were found to have an intermediate risk of events. The discordance between RF and MP could be the result of stunning after the resolution of acute ischemia, the presence of abundant collateral flow, or represent nonischemic cardiomyopathy. Figure 3. Ability of tests performed in a hierarchical order for predicting late events. See text for details. Abbreviations as in Figure 1. Open bars mtimi; gray bars mtimi RF; black bars mtimi RF MP; ruled bars TIMI.

7 926 Tong et al. JACC Vol. 46, No. 5, 2005 Contrast Echocardiography for Chest Pain September 6, 2005:920 7 Figure 4. Event-free survival in patients with a low-risk modified Thrombolysis In Myocardial Infarction score ( 0). MP myocardial perfusion; RF regional left ventricular function. Figure 5. Event-free survival in patients with an intermediate-risk modified Thrombolysis In Myocardial Infarction score (3 or 4). Abbreviations as in Figure 4.

8 JACC Vol. 46, No. 5, 2005 September 6, 2005:920 7 Tong et al. Contrast Echocardiography for Chest Pain 927 These patients could follow current guidelines and undergo stress echocardiography if serum cardiac markers remained normal. The incidence of positive stress echocardiograms in this population would be relatively high. Alternatively, early cardiac catheterization could be considered if concurrent clinical variables suggested that the patient belonged to a high-risk cohort. Patients with both abnormal RF and MP are at high risk for early events and could be triaged even before cardiac serum marker results become available. Implementation of this approach in the ED may help streamline the care of patients presenting with suspected cardiac CP and reduce cost significantly. Although the cost effectiveness of this approach needs to be evaluated, echocardiography (even contrast-enhanced) is relatively inexpensive compared with other noninvasive imaging modalities. Further studies are needed to assess the value of such an approach in an ED. Reprint requests and correspondence: Dr. Kevin Wei, Cardiovascular Division, OHSU, UHN62, SW Sam Jackson Park Road, Portland, Oregon weik@ohsu.edu. REFERENCES 1. Sabia P, Afrookteh A, Touchstone DA, Keller MW, Esquivel L, Kaul S. Value of regional wall motion abnormality in the emergency room diagnosis of acute myocardial infarction: a prospective study using two-dimensional echocardiography. Circulation 1991;84 Suppl I:I- 85 I Short D. The earliest electrocardiographic evidence of myocardial infarction. Br Heart J 1970;32: Zarling EJ, Sexton H, Minor P. Failure to diagnose acute myocardial infarction: the clinicopathologic experience at a large community hospital. JAMA 1983;250: Lee TH, Wiesberg MC, Cook EF, Daley K, Brand DA, Goldman L. Evaluation of creatine kinase and creatine kinase-mb for diagnosing myocardial infarction: clinical impact in the emergency room. Arch Intern Med 1987;147: McCord J, Nowak RM, Hudson MP, et al. The prognostic significance of serial myoglobin, troponin I, and creatine kinase-mb measurements in patients evaluated in the emergency department for acute coronary syndrome. Ann Emerg Med 2003;42: Lee TH, Rouan GW, Weisberg MC, et al. Clinical characteristics and natural history of patients with acute myocardial infarction sent home from the emergency room. Am J Cardiol 1987;60: Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) study Investigators. Comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med 1998; 338: (PRISM-PLUS) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non- Q-wave myocardial infarction. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms. N Engl J Med 1998;338: The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. N Engl J Med 1998;339: Cannon CP, Weintraub WS, Demopoulos LA, et al., TACTICS (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy) Thrombolysis In Myocardial Infarction 18 Investigators: comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001;344: Antman E, Cohen M, Bernink PJL, et al. The TIMI risk score for unstable angina/non-st elevation MI. A method for prognostication and therapeutic decision making. JAMA 2000;284: Dawson D, Rinkevich D, Belcik T, et al. Measurement of myocardial blood flow velocity reserve with myocardial contrast echo-cardiography in patients with suspected coronary artery disease: comparison with quantitative gated 99m Tc sestamibi SPECT. J Am Soc Echocardiogr 2003:16; Strussman BJ. National Hospital Ambulatory Medicine Care Survey: 1995 Emergency Department Summary. Advance Data from Vital and Health Statistics of the Center for Disease Control Prevention/ National Center for Health Statistics. 1997;285:15: Collet D. Modeling Binary Data. New York, NY: Chapman & Hall, Harrell FE. Regression Modeling Strategies. New York, NY: Springer, Collet D. Modeling Survival Data in Medical Research. New York, NY: Chapman & Hall, Selker HP, Zalenski RJ. An evaluation of technologies for detecting acute cardiac ischemia in the emergency department: a report of the NIH national heart attack alert program. Ann Emerg Med 1997;29: Cohen M, Hawkins L, Greenberg S, Fuster V. Usefulness of STsegment changes in greater than or equal to 2 leads on the emergency room electrocardiogram in either unstable anginal pectoris or non-qwave myocardial infarction in predicting outcome. Am J Cardiol 1991;67: Nyman I, Areskog M, Areskog NH, Swahn E, Wallentin L. Very early risk stratification by electrocardiogram at rest in men with suspected unstable coronary heart disease. J Intern Med 1993;234: Antman EM, Tanasijevic MJ, Thompson B, et al. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med 1996;335: Luscher MS, Thygesen K, Ravkilde J, Heickendorff L, for the TRIM Study Group. Applicability of cardiac troponin T and I for early risk stratification in unstable coronary artery disease. Circulation 1997;96: Villanueva FS, Sabia PJ, Afrookteh A, Pollock SG, Hwang LJ, Kaul S. Value and limitations of current methods of evaluating patients presenting to the emergency room with cardiac-related symptoms for determining long-term prognosis. Am J Cardiol 1992;69; Swinburn JMA, Stubbs P, Soman P, Collinson P, Lahiri A, Senior R. Independent value of tissue harmonic echocardiography for riskstratification in patients with non-st segment elevation acute chest pain. J Am Soc Echocardiogr 2002;15: Malhotra V, Nwogu J, Bondmass MD, et al. Is the technically limited echocardiographic study an endangered species? Endocardial border delineation with native tissue harmonic imaging and Optison contrast: a review of 200 cases. J Am Soc Echocardiogr 2000;13: Rainbird AJ, Mulvagh S, Oh JK, et al. Contrast dobutamine stress echocardiography: clinical practice assessment in 300 consecutive patients. J Am Soc Echocardiogr 2001;14: Trippi JA, Lee KS, Kopp G, Nelson D, Kovacs R. Emergency echocardiography telemedicine: an efficient method to provide 24- hour consultative echocardiography. J Am Coll Cardiol 1996;27: Trippi JA, Lee KS, Kopp G, Nelson DR, Yee KG, Cordell WH. Dobutamine stress tele-echocardiography for evaluation of emergency department patients with chest pain. J Am Coll Cardiol 1997;30: Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-st segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol 2002;40: APPENDIX Please see the online version of this article for the accompanying videos.