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J Am Coll Cardiol, 2003; 41:596-602, doi:10.1016/S0735-1097(02)02897-8
© 2003 by the American College of Cardiology Foundation
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CLINCAL STUDY: STRESS ECHOCARDIOGRAPHY

Prognostic value of predischarge dobutamine stress echocardiography in chest pain patients with a negative cardiac troponin T

Radha Bholasingh, MD*, Jan Hein Cornel, MD, PhD{dagger}, Otto Kamp, MD, PhD{ddagger}, Jan P. van Straalen§, Gerard T. Sanders, PhD§, Jan G. P. Tijssen, PhD*, Victor A. W. M. Umans, MD, PhD{dagger}, Cees A. Visser, MD, PhD{ddagger} and Robbert J. de Winter, MD, PhD*,*

* Department of Cardiology, Academic Medical Center, Amsterdam, the Netherlands
{dagger} Department of Cardiology, Medical Center Alkmaar, Alkmaar, the Netherlands
{ddagger} Department of Cardiology, VU Medical Center, Amsterdam, the Netherlands
§ Department of Clinical Chemistry, Academic Medical Center, Amsterdam, the Netherlands

Manuscript received May 7, 2002; revised manuscript received August 4, 2002, accepted September 6, 2002.

* Reprint requests and correspondence: Dr. Robbert J. de Winter, Academic Medical Center, Department of Cardiology, Room B2-137, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
r.j.dewinter{at}amc.uva.nl


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: We prospectively studied the prognostic value of predischarge dobutamine stress echocardiography (DSE) in low-risk chest pain patients with a normal or nondiagnostic electrocardiogram (ECG) and a negative serial troponin T.

BACKGROUND: Noninvasive stress testing is recommended before discharge or within 72 h in patients with low-risk chest pain. The prognostic value of immediate DSE has not been studied in a blinded, prospective fashion.

METHODS: Patients presenting at the emergency room within 6 h of symptom onset and a normal or nondiagnostic ECG were eligible. Dobutamine stress echocardiography was performed after unstable coronary artery disease was ruled out by a standard rule-out protocol and a negative serial troponin T; the occurrence of any new wall motion abnormality was considered positive. Results were kept blinded. End points were cardiac death, myocardial infarction, rehospitalization for unstable angina or revascularization.

RESULTS: In total, 377 patients were included. There were 2 deaths, 2 myocardial infarctions, 8 rehospitalization for unstable angina, and 10 revascularizations at six-month follow-up. The end points occurred in 8/26 (30.8%) patients with a positive versus 14/351 (4.0%) patients with a negative DSE (odds ratio, 10.7; 95% confidence interval, 4.0 to 28.8; p < 0.0001). By multivariate analysis, DSE remained a predictor of end points (p < 0.0001).

CONCLUSIONS: A predischarge DSE had important, independent prognostic value in low-risk, troponin negative, chest pain patients.

Abbreviations and Acronyms
  AMI
  acute myocardial infarction
  CI
  confidence interval
  DSE
  dobutamine stress echocardiography or echocardiogram
  UA
  unstable angina

The evaluation and management of patients presenting to the emergency room with acute chest pain suggestive of myocardial ischemia remains a challenge (1). In patients with a conclusive electrocardiogram (ECG), management is straightforward (2). However, the majority of patients with chest pain as a presenting complaint will have a normal or nondiagnostic ECG on presentation at the emergency room (3). In these patients further evaluation is needed. Several strategies have been proposed to improve decision-making in such patients and to identify both high-risk patients who should be admitted and low-risk patients who can be sent home safely (4–6). The recommended and most widely used strategy is the combination of an observation period, serial ECG, and serial biochemical marker measurements, usually followed by a stress test, either predischarge or within 72 h at the outpatient clinic (7,8). More recently, serial cardiac troponin T, a specific biochemical marker, has been incorporated in such "rule-out" protocols (7,9–11).

While exercise electrocardiography is widely used before discharge for its diagnostic and prognostic information (8,12), it has important limitations, e.g., in patients with an uninterpretable ECG and in patients unable to exercise (8,13). An alternative approach in these patients is either nuclear imaging or dobutamine stress echocardiography (DSE) (7,8). Compared with exercise electrocardiography, DSE does not depend on exercise performance or on electrocardiographic changes for the detection of ischemia; it has better sensitivity and specificity (14); earlier detection of ischemia is possible according to the ischemic cascade (15), and it provides information on cardiac anatomy and left ventricular function (16). Nuclear imaging has a high sensitivity and specificity (17), but is often not acutely available, is costly, and it is not a bedside technique. In contrast, DSE is an available bedside technique, with sensitivity and specificity comparable to nuclear imaging (14).

The diagnostic and prognostic value of DSE was demonstrated in different patient populations, such as in patients with known or suspected coronary artery disease (18) and postmyocardial infarction (19). However, the prognostic value of DSE for risk-stratification in low-risk patients with chest pain before discharge from the emergency room is unclear.

The aim of the present study was to evaluate the prognostic value of a predischarge DSE in low-risk chest pain patients, identified by a standard rule-out protocol and a negative serial troponin T.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
We conducted a prospective, double-blind, multicenter study in low-risk patients presenting at the emergency room with acute chest pain. The study was performed in accordance with the principles set out in the declaration of Helsinki (the procedures followed were in accordance with institutional guidelines) and was approved by local ethics committees on human research.

Patients: selection and management.   Patients presenting at the emergency room within 6 h of chest pain and a normal or a nondiagnostic ECG were eligible for inclusion in the admission cohort. Patients younger than 18 years, patients who were incapable to give informed consent, and patients with any of the following conditions at presentation were not considered for inclusion: atrial fibrillation, conduction disturbances (second or third degree atrial-ventricular block or new bundle branch block), severe uncontrolled hypertension (>180/120 mm Hg) despite adequate therapy, severe heart failure, cardiomyopathy, resuscitation, and serious noncardiac disease (e.g., infection and neoplastic conditions), and pregnancy.

A total of 557 patients gave informed consent. The management of these patients was according to the standard protocols used in the three participating hospitals. In general, patients remained under observation until at least 12 h after the onset of symptoms. Evaluation included careful history taking, physical examination, serial 12-lead ECGs, continuous rhythm monitoring, and serial cardiac troponin T measurements. Serial ECGs were recorded according to protocol directly on admission, after the administration of sublingual nitrates, and during any new episode of chest pain while the patient remained under observation and before discharge. Troponin T was measured at admission (i.e., within 6 h of chest pain) and at 12 h after the onset of chest pain. All patients received aspirin 300 mg on admission, unless they were already on aspirin or when aspirin was contraindicated. Further patient management, e.g., the decision to order additional tests, such as a predischarge exercise ECG, admission to the hospital, or subsequent therapy, was at the discretion of the attending physician.

During the observation period, 119 patients were diagnosed with an acute coronary syndrome, and 34 patients had other serious cardiac or noncardiac diagnoses. After ruling out unstable coronary artery disease, including negative serial cardiac troponin T (defined as peak-value < 0.06 ng/ml at 6 and 12 h after the onset of symptoms), the remaining 404 patients underwent a two-dimensional echocardiography. Of these, 27 patients did not proceed to the DSE because of a poor echocardiogram image (23 patients) or the detection of an abnormality on the resting echocardiogram (4 patients). Thus, 377 patients completed the predischarge DSE protocol ("stress echo cohort"), which was performed within 24 h after admission (Fig. 1). The DSE results were kept blinded to the attending physician, the patient, or anyone involved in patient management.



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  		Figure 1 The admission cohort was formed by patients with chest pain who met the inclusion criteria and gave informed consent (557 patients). The observation period was uneventful, and serial cardiac troponin T was negative in 404 patients. These patients were eligible to undergo dobutamine stress echocardiography. However, in 27 patients dobutamine stress echocardiography could not be performed. The remaining 377 patients underwent dobutamine stress echo cohort and were considered for further analysis.

 
Follow-up
The follow-up period of the stress echocardiogram cohort was six months.

The patients were discharged home with aspirin and a beta-blocker (unless contraindicated), at least until the first outpatient visit at four weeks after discharge. All patients returned for a study follow-up visit at six months.

The primary end point was defined as the combination of cardiac death, nonfatal acute myocardial infarction (AMI), and rehospitalization for unstable angina (UA). The secondary end point was coronary revascularization procedure (percutaneous transluminal coronary angioplasty or coronary artery bypass grafting or the decision to perform either). A combined end point was defined as the combination of primary and secondary end point.

In case any end point was reached, the patient’s cardiologist or general practitioner was consulted, and hospital records or other documentation was collected to confirm the diagnosis. In case of more than one cardiac event, the following order was used: 1) cardiac death, 2) nonfatal AMI, 3) rehospitalization for UA, 4) revascularization.

Cardiac death was defined as death associated with known or suspected AMI, life-threatening arrhythmia, or pulmonary edema (based on clinical assessment, cardiac isoenzymes, ECG, or autopsy). Unexpected death without an identified noncardiac cause was also classified as cardiac death. Nonfatal AMI was defined according to the World Health Organization criteria, including a typical history, defined changes on the ECG, and a rise in cardiac markers. Rehospitalization for UA was defined as recurrent episode of chest pain requiring hospital admission and intravenous treatment with heparin and nitrates to relieve symptoms.

DSE
The DSE was performed according to the standard protocol (13): dobutamine was infused intravenously based on 3-min stages of 10, 20, 30, and 40 µg/kg/min. Atropine (0.25 to 1 mg intravenously) was given if the 85% of the age predicted maximal heart rate was not achieved (i.e., target heart rate) or other end points were not reached at peak dobutamine dose. End points included severe and/or extensive new wall motion abnormality, target heart rate, significant tachyarrhythmias, significant changes on the ECG, severe chest pain, significant increase or decrease in blood pressure (>240/120 mm Hg or reduction of systolic pressure > 40 mm Hg), or any intolerable side effect. A beta-blocker was administered intravenously to reverse the effects, if they did not revert spontaneously and quickly after stopping the infusion. For purpose of analysis, the left ventricular wall was divided into 16 segments and scored using a 4-point scale (1, normal; 2, hypokinesis; 3, akinesis; and 4, dyskinesis) (20). Ischemia was not considered if akinetic segments at rest became dyskinetic during stress (21). The images of the DSE were compared off-line side by side in quad screen format by two experienced investigators without knowledge of the patients’ clinical data. In case of disagreement, a majority decision was achieved by a third investigator (J.H.C., O.K., R.B.). The results were dichotomized as either positive or negative for ischemia. A positive DSE was defined as the occurrence of new wall motion abnormality in at least one segment.

Electrocardiographic criteria
The ECG of the qualifying episode of chest pain, the admission ECG, and subsequent ECGs during the observation period were collected. One of the authors (R. dW.), who was blinded to all clinical data, reevaluated and scored the ECGs off-line as normal or nondiagnostic (signs of left ventricular hypertrophy, bundle branch block, prior AMI, or the presence of nonspecific ST-segment abnormalities).

Statistical analysis
Univariate analysis for categorical variables was performed using chi-square test or Fisher exact test where appropriate. Continuous variables were expressed as mean ± SD and were compared by the independent samples t test. Stepwise multiple logistic regression analyses were used to identify independent predictors regarding the predefined primary and combined end point. In the logistic regression model, criterion for entry of variables was set on 0.20, and criterion for removal was set on 0.25. Variables included in this analysis were age ≥65 years, history of coronary artery disease, prior use of aspirin, prior use of beta-blocker, prior use of nitrate, and positive DSE. The difference in risk was expressed as the odds ratio with the corresponding 95% confidence intervals (CI).

A p value of < 0.05 was considered statistically significant. The SPSS statistical package (SPSS 10.01 for Windows, SPSS Inc., Chicago, Illinois) was used for analysis.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Baseline characteristics.   The baseline characteristics of the DSE cohort are displayed in Table 1. Distribution of variables was typical for a low-risk population at the emergency room. Additional stress tests were ordered in 222/377 (59%).


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  		Table 1 Baseline Characteristics

 
DSE results
The mean time from admission to DSE performance was 17.8 ± 6.4 h. Atropine was administered in 196/377 (52.0%) patients, of which 58/196 (29.6%) used a beta-blocker. Dobutamine-atropine infusion increased heart rate from 67 ± 13 beats/min to 132 ± 18 beats/min, systolic blood pressure from 133 ± 24 mm Hg to 139 ± 29 mm Hg, and double (rate-pressure) product from 8,994 ± 2,447 mm Hg x beats/min to 18,458 ± 4,809 mm Hg x beats/min. In 302/377 (80.1%) patients, the target heart rate was achieved. In 75/377 (19.9%) patients, the protocol was not completed because of the prespecified criteria: extensive new wall motion abnormality (1 patient), electrocardiographic changes (7 patients), chest pain (28 patients), intolerable side effects (39 patients) such as arrhythmia and severe hypertension or hypotension.

In total, 26/377 (6.9%) patients had positive DSE, defined as the development of at least one segment of new wall motion abnormality. The mean time between admission and DSE was similar for patients with positive versus negative DSE result (17.7 ± 6.4 h vs. 18.0 ± 5.6 h, p = NS).

Clinical outcome
The follow-up was 100% complete. Although discharge was planned, 7/377 (1.8%) patients remained in the hospital for further evaluation after DSE was performed; two of these patients underwent revascularization during hospitalization, and one patient was eventually diagnosed with UA and treated medically. During the subsequent six-month follow-up, two patients died of cardiac cause, two had a nonfatal AMI, seven were rehospitalized for UA, and another eight patients underwent revascularization. Thus, 22/377 (5.8%) patients reached a combined end point (Table 2).


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  		Table 2 Clinical Outcomes at Six Months According DSE Results

 
Variables associated with outcome
Clinical variables associated with combined end point (univariate analysis) during follow-up were age ≥65 years (p = 0.008); a history of documented coronary artery disease (p = 0.001); and prior use of beta-blocker (p < 0.0001), nitrate (0.004), or aspirin (p = 0.004). A positive DSE was associated with the combined end point (p < 0.0001) (Table 3).


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  		Table 3 Frequencies and Odds Ratios of the Combined End Point According to the Presence of a Characteristic

 
Multivariate analysis
The variables associated with combined end point in the univariate analysis were compared using multivariate stepwise logistic regression analysis (Table 4). A positive DSE had independent prognostic value, both for the primary end point (odds ratio, 6.2; 95% CI, 1.6 to 24.3) and for the combined end point (odds ratio, 7.1; 95% CI, 2.5 to 20.2). Prior use of a beta-blocker was the only independent clinical predictor for the combined end point (odds ratio, 4.6; 95% CI, 1.7 to 12.1) (Table 4). There were no clinical predictors for the primary end point.


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  		Table 4 Multivariate (Stepwise) Logistic Regression Analysis, Including Clinical Variables and DSE

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
This study demonstrates that predischarge DSE has important, independent prognostic value in low-risk chest pain patients with a normal or nondiagnostic ECG, an uneventful observation period at the cardiac emergency department, and a negative serial cardiac troponin T. The incidence of death or nonfatal AMI at six months was low: 1.1% (4/377). The total cardiac event rate was 8/26 (30.8%) in patients with a positive DSE and 14/351 (4.0%) in patients with a negative DSE (p < 0.0001).

Chest pain patients with serial negative troponin T.   The prognostic value of a negative cardiac troponin in patients with chest pain at the emergency room was previously described by Hamm et al.(10) who reported that, after excluding unstable coronary artery disease and noncardiac disease by a standard rule-out protocol, patients with a negative troponin T had a 1.1% incidence of cardiac death or nonfatal AMI at 30-day follow-up. Depending on the clinical presentation, a negative cardiac troponin does not, by itself, exclude significant disease (22). Indeed, in the present study, 63 of the 119 patients from the original cohort of 557 patients that were admitted with a diagnosis of acute coronary syndrome had a normal serial cardiac troponin T (Fig. 1). Recently, it was demonstrated that in 69% to 86% of the patients with an acute coronary syndrome and major complications during short-term follow-up, cardiac troponin was negative (11,23,24). The same holds for long-term follow-up (25). Therefore, in patients with negative serial troponin T, additional tests are needed to identify patients at risk for cardiac events in the short and long term.

Predischarge stress tests
Although recommended in the American College of Cardiology/American Heart Association guidelines (7), the prognostic value of a predischarge exercise stress test in low-risk chest pain patients has not yet been studied in great detail. Only two large, but retrospective, studies showed that a negative or nondiagnostic predischarge exercise ECG was able to identify patients at very low risk (12,26). Few prior studies have evaluated (dobutamine) stress echocardiography for risk-stratification in patients with chest pain in the emergency room (27–30). In these small studies, a negative (dobutamine) stress echocardiography was associated with a low cardiac event rate (0% to 4.5%), which was confirmed by our study (14/351 [4.0%]). In the only prospective study, Geleijnse et al. (27) evaluated DSE in patients with chest pain after ruling out unstable coronary artery disease. The six-month event rate was higher than in our study (11/80 [13.8%] vs. 22/377 [7.6%]), which may be explained by the inclusion of relatively higher risk patients; DSE was more often positive (36/80 [45.0%] vs. 26/377 [6.7%]), a history of coronary artery disease was present more often (56.3% vs. 20.4%), the percentage of nondiagnostic ECGs was higher (60% vs. 40%), and the rule-out protocol used serial creatine kinase measurements instead of serial troponin T. Moreover, DSE results were not blinded and may have caused a higher revascularization rate: 12/80 (15.0%) versus 10/377 (2.7%), of which 7/12 (58.3%) versus 2/10 (20.0%) were in-hospital revascularizations.

Only one large prospective study (31) showed that, in patients with negative serial troponin T (<0.06 µg/l), a predischarge exercise ECG had prognostic value; the five-month risk of cardiac death or myocardial infarction was 1/84 (1.2%) in patients with a low-risk exercise test response and 2/9 (22.2%) in patients with a high-risk exercise test response. However, this study comprised patients with UA, i.e., high-risk patients. In our low-risk population, we found a six-month risk of cardiac death or myocardial infarction of 1/351 (0.3%) in patients with a negative DSE and 3/26 (11.5%) in patients with positive DSE.

Predischarge coronary angiography
In a study evaluating routine predischarge coronary angiography in patients with chest pain after ruling out unstable coronary artery disease, deFillipi et al. (32) showed that the coronary angiogram was not superior to a predischarge exercise ECG in predicting risk. It was superior in detecting coronary artery disease, which resulted in more (but potentially unnecessary) revascularizations (14/123 [11%] vs. 5/125 [4%]). It has been shown before that revascularization itself has a risk of procedure-related complications (33). For this reason predischarge coronary angiography without prior ischemia detection test is not recommended in low-risk chest pain patients (34).

Independent mechanisms of risk factors
The independent prognostic value of DSE in patients with negative serial troponin T can be explained as follows: troponin T is a specific marker of myocardial damage. The major mechanism in the occurrence of myocardial damage in the setting of acute coronary syndrome is plaque rupture, superimposed thrombus formation, and transient decrease of coronary flow and/or distal embolization of a coronary artery, not necessarily in combination with a severe coronary artery stenosis (35). Dobutamine stress (or exercise) induced ischemia results from regional supply-demand imbalance of oxygen in presence of a fixed coronary artery stenosis (36). Development of regional ischemia may result in transient segmental myocardial wall motion abnormality, which precedes ECG changes and angina pectoris, and can be detected by echocardiography (15). Either one or both mechanisms may be involved in patients presenting with chest pain. In our study population, myocardial damage was ruled out by serial troponin T. In these patients, ischemia detection by DSE was able to identify patients at high and at low risk for future cardiac events.

Study limitations
Dobutamine stress echocardiography could not be performed in 23/404 (5.7%) patients because of poor acoustic window. This percentage is comparable with what has been previously reported (5%) (14).

The performance of DSE requires personnel experienced in the procedure. Therefore, occasionally patients had to wait until experienced personnel were available. However, all stress echocardiograms were performed within 24 h after admission, which was according with the recommendations outlined in the American College of Cardiology/American Heart Association guidelines (7) (stress test to be performed before discharge or within 72 h after discharge).

Financial implications
A true cost analysis comparing the use of DSE with current clinical practice cannot be performed with our data. However, the results of the present study and of previous studies indicate that DSE has similar diagnostic and prognostic accuracy as immediate nuclear imaging in this patient population. It has been shown that rule-out protocols using immediate nuclear imaging at a chest pain center may be cost saving (37,38). Dobutamine stress echocardiography is more readily available and less costly than nuclear imaging, and, depending on the protocol, may also be cost-saving.

Clinical implications
This is the first prospective study that evaluated a predischarge DSE in a blinded fashion in patients with chest pain in whom an acute coronary syndrome was ruled out by a standard protocol and a negative serial troponin T. We showed that, in such patients, a predischarge DSE had important, independent predictive value. We conclude that, DSE can be a valuable diagnostic technique for predischarge risk assessment in patients with chest pain in addition to a standard rule-out protocol and a negative serial troponin T.


   Acknowledgments
 
The authors would like to thank the participating centers: Academic Medical Center (Amsterdam), VU Medical Center (Amsterdam), and Medical Center Alkmaar (Alkmaar). The authors would also like to thank the personnel of the laboratory of clinical chemistry, the heads of the department of clinical chemistry (A. Sturk, PhD [Academic Medical Center]; M. A. Blankenstein, PhD, and A. A. Bouman, PhD [VU Medical Center]; P. C. M. Bartels, PhD, and F. P. W. Tegelaers, PhD [Medical Center Alkmaar]), the echo technicians, the nursing staff, and the physicians of the three participating centers for their help in completing this study.


   Footnotes
 
Supported by the Dutch Heart Foundation (grant NHS 96.172).


   References
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 Methods
 Results
 Discussion
 References
 

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