Prognostic Value of Myocardial Contrast Echocardiography in Patients Presenting to Hospital With Acute Chest Pain and Negative Troponin

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1 Prognostic Value of Myocardial Contrast Echocardiography in Patients Presenting to Hospital With Acute Chest Pain and Negative Troponin Paramjit Jeetley, MBBS, Leah Burden, BSc, Kim Greaves, MD, and Roxy Senior, MD* We hypothesized that myocardial contrast echocardiography (MCE) could be used to stratify risk in patients with suspected acute coronary syndrome but a nondiagnostic electrocardiogram and negative troponin. Pretest Thrombolysis In Myocardial Infarction (TIMI) scores were determined. Exercise electrocardiographic data in those patients undergoing treadmill stress echocardiography as part of risk evaluation were analyzed independently of echocardiographic data. On a separate day, low-power MCE at rest and during vasodilator stress was performed. All patients were followed for cardiac events (cardiac death, myocardial infarction, and revascularization). Of 148 patients, 27 demonstrated abnormal myocardial contrast echocardiographic results and had higher cardiac event rates compared with those with normal myocardial contrast echocardiographic findings (59% vs 7%, p <0.0001) at follow-up (8 5 months). Hard cardiac event rates (death and nonfatal myocardial infarction) were low (3%) in patients with normal myocardial contrast echocardiographic findings. Cardiac events in patients with abnormal myocardial contrast echocardiographic findings (59%) were significantly higher than those predicted by a high-risk TIMI score (33%, p ) and compared with those predicted by high-risk exercise electrocardiography (80% vs 57%, p ). In conclusion, stress MCE was superior to TIMI risk score and exercise electrocardiography in the assessment of risk in patients with suspected acute coronary syndrome, nondiagnostic electrocardiogram, and negative troponin Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99: ) Myocardial contrast echocardiography (MCE) is a relatively new technique that uses intravenously administered contrast microbubbles for the detection of myocardial perfusion. 1,2 Stress MCE has been shown to accurately detect flowlimiting coronary artery disease in a wide variety of clinical scenarios and is a powerful predictor of outcome in patients with suspected coronary artery disease. 3 7 Compared with other competing techniques, vasodilator MCE can be rapidly performed and interpreted, and it can be carried out at bedside. However, there is no current study demonstrating its utility in patients with suspected acute coronary syndrome but negative serum cardiac markers who would require stress testing for further risk stratification. We hypothesized that vasodilator MCE by its ability to detect flow-limiting coronary artery disease could effectively stratify risk in patients with suspected acute coronary syndrome and coronary risk factors but with a nondiagnostic electrocardiogram and normal serum cardiac markers of necrosis. Department of Cardiovascular Medicine, Northwick Park Hospital and Institute for Medical Education and Research, Harrow, Middlesex, United Kingdom. Manuscript received October 20, 2006; revised manuscript received and accepted December 28, The study was supported by a grant from Cardiac Research Fund, Northwick Park Hospital, Harrow, United Kingdom. *Corresponding author: Tel: ; fax: address: roxysenior@cardiac-research.org (R. Senior). Methods Patient selection: Patients were selected from a population who had enrolled in a prospective study investigating risk stratification of patients presenting to the hospital with suspected acute coronary syndrome but with nondiagnostic electrocardiogram and negative troponin. Written informed consent was obtained from all patients, and the study was approved by the local ethics committee. Study design: The study design is shown in Figure 1. A pretest probability of risk was determined on the basis of individual Thrombolysis In Myocardial Infarction (TIMI) risk scores. 8 Patients were categorized as having a low (score 0 and 2), intermediate (score 2 to 4), or high (score 5) pretest risk. Patients underwent further risk stratification using stress echocardiography (SE) with treadmill exercise or pharmacologic (dobutamine) stress using previously described methods. 9 MCE was performed on a separate day. Results of SE were made available to clinical staff directly involved with patient care, which influenced subsequent management. Myocardial contrast echocardiographic data were not disclosed. Myocardial contrast echocardiography: MCE was performed in apical 4-, 3-, and 2-chamber views with triggered replenishment imaging (Sonos 5000, Phillips, Eindhoven, The Netherlands). The contrast agent (SonoVue, Bracco Diagnostics, Inc., Milan, Italy) was administered through a peripheral cannula at a rate of 1 ml/min and adjusted as necessary until optimal myocardial contrast ac /07/$ see front matter 2007 Elsevier Inc. All rights reserved. doi: /j.amjcard

2 1370 The American Journal of Cardiology ( Figure 1. Kaplan-Meier survival curve analysis demonstrating differences in cardiac events in patients with normal and abnormal stress myocardial contrast echocardiograms. tivity had been achieved. Images were acquired during highintensity pulses (mechanical index 1.0) to facilitate microbubble destruction followed by acquisition of 10 endsystolic frames at a low mechanical index (0.1). Vasodilator stress was performed by administration of a dipyridamole infusion (0.56 mg/kg over 4 minutes), and image acquisition was repeated in the same sequence as for the study at rest. In those patients with contraindications to dipyridamole (e.g. asthma), low-dose dobutamine (5 to 15 g/kg/min) was used to elicit hyperemia. Image analysis: Image analysis was performed by an experienced observer (RS) who was blinded to patients clinical details and wall thickening data. A standard 17- segment left ventricular model and a 4-point semiquantitative scale were used to assess contrast opacification, and thus, perfusion. Any myocardial segment with normal contrast replenishment at rest (homogenous opacification 5 seconds after microbubble destruction) that did not fill within 1 to 2 seconds after administration of vasodilator stress was considered to demonstrate a reversible perfusion defect. 3,5,6 A perfusion defect at rest that remained unchanged at stress was considered a fixed defect. When artifacts were seen in 1 myocardial segment in a vascular territory where the remaining segments were considered normal, the region was considered normal. A positive myocardial contrast echocardiogram was defined as the presence of a fixed defect with no previous acute myocardial infarction (AMI) or the presence of a reversible defect at stress in 1 myocardial segment. Stress echocardiography: Studies at rest followed by treadmill exercise (pharmacologic) or dobutamine stress was performed in all patients using previously described methods. 9 Patients with evidence of inducible ischemia at stress, i.e., a new wall motion abnormality or a wall motion abnormality at rest without previous AMI, were considered at high risk. Patients who underwent exercise SE who achieved a workload 7 METs and 85% of maximum predicted heart rate without wall motion abnormality were considered low risk. 10 Those who underwent pharmacologic SE and who achieved the target heart rate or maximum dose of dobutamine with no evidence of wall motion abnormality were considered low risk. All other patients were considered to have an inconclusive test finding. Exercise electrocardiography: Patients who underwent SE with treadmill exercise had their electrocardiograms interpreted independently of echocardiography. Patients who achieved a workload 9 METs without hemodynamic compromise or electrocardiographic changes were considered to have a negative test finding. 11 Patients who developed significant hypotension, arrhythmia, or 1-mm planar or downsloping ST depression during exercise or in recovery were considered to have a positive test result. All other patients were considered to have inconclusive test results. Coronary angiography: Coronary angiography was performed according to standard techniques with the clinician managing the patient with a visual quantitative scoring system for image analysis. Coronary artery disease was defined as 50% luminal diameter narrowing in 1 epicardial artery or its major branches. In patients who underwent previous coronary artery bypass surgery, stenosis 50% was taken to demonstrate coronary artery disease within the graft. Troponin measurements: To be eligible for study entry, patients had cardiac troponin measurements taken at 12 hours after onset of pain using a bedside kit in the case of troponin T or laboratory assay for troponin I. Values considered abnormal were 0.1 and 0.5 ng/nl for troponin T and I, respectively. Follow-up: Follow-up time was calculated from the time of MCE to the end-point date or to the date of final contact with the patient. During follow-up, data were collected regarding further investigations performed and cardiac events. A combined cardiac end point was defined as cardiac death, nonfatal AMI, or coronary revascularization. Cardiac death was defined as death associated with known or suspected AMI, life-threatening arrhythmia, or heart failure (based on clinical assessment, serum cardiac markers, and electrocardiographic or postmortem findings). Nonfatal MI was defined according to recommended guidelines. 12 A hard cardiac end point was defined as cardiac death and nonfatal AMI. Event data were collected by questionnaires sent at 3 monthly intervals with additional telephone follow-up or hospital record review when appropriate. Statistical analysis: Continuous variables are presented as mean SD except for those that are not normally distributed, which are presented as medians with 95% confidence intervals (CIs). All categorical variables are shown as proportions. Comparison of continuous data was made by independent t test or 1-way analysis of variance, whichever was appropriate. For categorical variables, chi-square analysis was used. Cox regression analysis was performed using clinical, electrocardiographic, and myocardial contrast echocardiographic data for the prediction of combined cardiac end points. Multivariable analysis was then performed to assess independent predictors of outcome. Stress echocardiographic data were not compared because these were used to decide patient management. Kaplan-Meier curves were constructed with log-rank analysis to assess outcomes. A p value 0.05 was considered statistically significant.

3 Coronary Artery Disease/Contrast Echocardiography in Acute Chest Pain 1371 Table 1 Baseline characteristics (n 148) Age (yrs) y Body mass index (kg/m 2 ) 27 5 Men 86 (58%) White 67 (45%) Asian 68 (46%) Other 13 (9%) Diabetes mellitus 35 (24%) Hypertension 103 (70%) Hyperlipidaemia 81 (55%) Smoker Current 19 (13%) Former 35 (24%) Previous MI 27 (18%) Previous percutaneous intervention 16 (11%) Previous coronary artery bypass surgery 11 (7%) Presentation Pretest TIMI score Low 28 (19%) Intermediate 111 (75%) High 9 (6%) Statistical analyses were performed using Analyse-it 1.62 (Analyse-it Software Ltd, Leeds, United Kingdom) and StatsDirect (Stats Direct Ltd, Cheshire, United Kingdom). Results In total, 148 patients underwent MCE. All patients previously underwent risk stratification with SE. Baseline characteristics are listed in Table 1. Median time to testing from SE was 7 days (96% CI 6 to 8). Patients were assigned a pretest risk on the basis of their individual TIMI scores. Proportions of patients classified as low, intermediate, and high risk were 19%, 75%, and 6%, respectively. Most patients (83%) underwent MCE at rest followed by vasodilator stress with dipyridamole. Of the remainder, 24 (16%) underwent low-dose dobutamine stress and 2 patients (1%) had only studies at rest performed. Of the 148 patients, 27 (18%) were classified as high risk and 82% as low risk. Of the 148 patients, 88 (59%) had exercise stress, 57 (39%) pharmacologic stress with 3 (2%) having only studies at rest performed. Proportions of patients classified as low, intermediate, and high risk were 75%, 4%, and 21%, respectively. Exercise electrocardiographic data were obtained in the 86 patients who underwent exercise echocardiography. Exercise electrocardiography (ExECG) classified patients as low, intermediate, and high risk in 43%, 41%, and 16%, respectively. Coronary angiography was performed in 34 patients, 25 of whom had coronary artery disease. Hence, 17% of the study cohort had demonstrable coronary artery disease. Of these 34 patients, 29 underwent coronary angiography based on stress echocardiographic results (26 had a positive stress echocardiographic finding, 3 were inconclusive). Myocardial contrast echocardiography was abnormal in 20 of the 25 patients (80%) with significant coronary artery disease. In the remaining 9 patients with no coronary artery disease, the myocardial contrast echocardiograms were normal in 5 (56%). Of the 86 patients in the ExECG group, 24 underwent coronary arteriography. ExECG demonstrated high risk in 9 of 20 patients (45%) with coronary artery disease. Of the 4 patients without coronary artery disease, ExECG was inconclusive in all 4. Follow-up: Follow-up data was obtained in 145 (98%) of the 148 patients. During a follow-up of 8 5 months, there was 1 noncardiac death, 4 patients developed AMI, and 20 underwent revascularization. Thus, the cardiac event rate was 17% (24 of 145) with a hard cardiac event rate of 3%. Event rates classified by risk determined by TIMI score, SE, and MCE are listed in Table 2. MCE classified 27 patients (19%) as having abnormal scans. Overall, patients with an abnormal myocardial contrast echocardiogram had a significantly higher cardiac event rate than those with normal studies (59% vs 7%, p ). Survival curves (Figure 1) for abnormal versus normal myocardial contrast echocardiograms demonstrated a significant difference in outcome between the 2 groups (log-rank statistic, p ). The hard cardiac event rate (i.e., cardiac death or AMI) in patients with a normal myocardial contrast echocardiogram was low at 3%. Comparison of MCE with TIMI risk score: More patients were stratified as low risk by MCE compared with TIMI scoring (81% vs 19%, p ), with no difference seen in the cardiac event rate (7% in each group). More patients were classified as high risk by MCE than by TIMI score (27% vs 9%, p ) with a higher event rate in this group (59% vs 33% for high-risk MCE and TIMI score, respectively, p ). Further, MCE was able to further subclassify patients into low- and high-risk groups in lowand intermediate-risk TIMI groups but marginally failed to do so in the high-risk TIMI group (Figure 2). Comparisons with ExECG: Exercise electrocardiographic data were available in 86 patients who underwent exercise echocardiography. There was no significant difference in cardiac event rates between patients classified as low risk by ExECG and MCE (5% vs 8%, p NS) in these 86 patients. Although there were no differences in the proportion of patients classified as high risk by ExECG and MCE (16% vs 17%, p NS), significantly more patients with a positive myocardial contrast echocardiogram had events compared with those classified as high risk by ExECG (80% vs 57%, p ). Further, except in the low-risk ExECG group, MCE was able to further subclassify patients into low- and high-risk categories in the intermediate- and high-risk ExECG groups (Figure 3). Comparison with SE: In the 148 patients who underwent the 2 tests, there was excellent agreement in the identification of these patients at high and low risk of coronary artery disease (93%, 0.79). Further, at follow-up, the event rates were not significantly different for patients identified as high risk (5% for SE vs 59% for MCE, p 1.0) or low risk (6% for SE vs 7% for MCE, p 1.0). Predictors of outcome: Among the clinical, myocardial contrast echocardiographic, and exercise electrocardiographic predictors of outcome, age (p 0.048), previous ischemic heart disease (p 0.007), administration of aspirin within 7 days (p 0.038), ExECG (p 0.001), and MCE (p 0.001) were the only univariate predictors. The

4 1372 The American Journal of Cardiology ( Table 2 Cardiac events by pretest Thrombolysis In Myocardial Infarction score, exercise electrocardiographic, stress echocardiographic, and myocardial contrast echocardiographic results No. of Patients Cardiac Death AMI Revascularization Total Events Cardiac Event Rate Hard Cardiac Event Rate Pretest TIMI score Low risk % 0% Intermediate risk % 3% High risk % 1% Result by ExECG Low risk % 5% Intermediate risk % 3% High risk % 0% Total % 3% Result by SE Low risk % 3% Intermediate risk % 0% High risk % 3% Result by MCE Low risk (normal study) % 3% High risk (abnormal study) % 0% Figure 2. Prognostic significance of stress MCE in patients with low-, intermediate-, and high-risk TIMI scores. Numbers at top of bar chart represent percentages of cardiac events in the patient group described in the chart. only multivariate predictor of outcome was MCE (odds ratio 20, 95% CI 7 to 57, p 0.001). Discussion The present study first confirms the findings of other studies that patients presenting with cardiac risk factors with suspected acute coronary syndrome are still at risk of events despite negative troponin The cardiac event rate over 8 5 months in our study was 17%, and thus further risk stratification is mandatory in this group of patients. TIMI risk score and ExECG are widely used to achieve this and, in particular, to facilitate rapid discharge of patients from the hospital. However, stress MCE was superior to these 2 techniques in identifying low-risk patients with no difference in cardiac event rate. Further, stress MCE was able to classify patients into high- and low-risk groups in low- and Figure 3. Prognostic significance of stress MCE in patients with low-, intermediate-, and high-risk exercise electrocardiograms. Numbers at top of bar chart represent percentages of cardiac events in the patient group described in the chart. intermediate-risk TIMI groups. MCE could similarly subclassify patients into low- and high-risk groups in the intermediate- and high-risk exercise electrocardiographic arms. A recent study has shown that MCE at rest performed soon after presentation with suspected acute coronary syndrome provided incremental prognostic information compared with clinical data. However, a normal myocardial contrast echocardiogram at rest had an overall event rate of 11% after 30 days. 16 The present study showed the value of performing stress MCE to further stratify risk in such patients. A normal stress myocardial contrast echocardiogram conferred a low cardiac event rate of 7% over 8 5 months, with a hard cardiac event of only 3%. Conversely, patients with an abnormal myocardial contrast echocardiogram predicted a high cardiac event rate (57%).

5 Coronary Artery Disease/Contrast Echocardiography in Acute Chest Pain 1373 Although this study was not designed to test the accuracy of MCE for the detection of significant coronary artery disease, MCE demonstrated a sensitivity of 80% and specificity of 56% in the 34 patients who underwent coronary arteriography compared with a sensitivity of only 45% with ExECG. Patients with normal coronary arteriograms showed inconclusive exercise electrocardiograms. In this study, MCE and SE performed equally well. However, the study was not designed to compare the 2 modalities because physicians were aware of stress echocardiographic results but not of myocardial contrast echocardiographic results, so their decisions were influenced by SE. Further, the study was not sufficiently powered to evaluate SE versus MCE. The major limitation of the study is that cardiac events consisted of predominantly revascularization. However, the decision to proceed to revascularization was mainly taken on the basis of SE. Abnormalities on stress echocardiograms have significant outcome implications. 17 Thus, we believe it is fair to consider revascularization on the basis of an abnormal stress echocardiogram as an end point. 1. Kaul S, Senior R, Dittrich H, Raval U, Khattar, Lahiri A. Detection of coronary artery disease with myocardial contrast echocardiography: comparison with 99mTc-sestamibi single-photon emission computed tomography. Circulation 1997;96: Kaul S, Senior R, Firschike C, Wang XQ, Lindner J, Villaneuva FS, Firozan S, Kontos MC, Taylor A, Nixon IJ, Watson DD, Harrell FE. Incremental value of cardiac imaging in patients presenting to the emergency department with chest pain and without ST-segment elevation: a multicenter study. Am Heart J 2004;148: Senior R, Lepper W, Pasquet A, Chung G, Hoffman R, Vanoverschelde JL, Cerqueira M, Kaul S. Myocardial perfusion assessment in patients with medium probability of coronary artery disease and no prior myocardial infarction: comparison of myocardial contrast echocardiography with 99mTc single-photon emission computed tomography. Am Heart J 2004;147: Peltier M, Vancraeynest D, Pasquet A, Ay T, Roclants V, D hondt AM, Melin JA, Vanoverschelde JL. Assessment of the physiologic significance of coronary disease with dipyridamole real-time myocardial contrast echocardiography. Comparison with technetium-99m sestamibi single-photon emission computed tomography and quantitative coronary angiography. J Am Coll Cardiol 2004;43: Jeetley P, Hickman M, Kamp O, Lang RM, Thomas JD, Vannan MA, Vanoverschelde JL, van der Wouw PA, Senior R. Myocardial contrast echocardiography for the detection of coronary artery stenosis: a prospective multicenter study in comparison with single-photon emission computed tomography. J Am Coll Cardiol 2006;47: Senior R, Janardhan R, Jeetley P, Burden L. 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