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Comparison of Early Dobutamine Stress Echocardiography andExercise Electrocardiographic Testing for Management of Patients

Presenting to the Emergency Department With Chest Pain

Gaetano Nucifora, MD*, Luigi P. Badano, MD, Nizal Sarraf-Zadegan, MD,Apostolos Karavidas, MD, Giuseppe Trocino, MD, Giorgio Scaffidi, MD, Gianni Pettinati, MD,

Costantino Astarita, MD, Vitas Vysniauskas, MD, Dario Gregori, PhD, Baris Ilerigelen, MD,Ricarda Marinigh, MD, and Paolo M. Fioretti, MD, PhD

This study compared the cost-effectiveness of dobutamine-atropine stress echocardiogra-phy (DASE) and electrocardiographic exercise testing (EET) implemented in emergencydepartment accelerated diagnostic protocols for the early stratification of low-risk patientspresenting with acute chest pain (ACP). One hundred ninety-nine patients with ACP,nondiagnostic electrocardiographic results, and negative biomarker results were random-ized to DASE (n � 110) or EET (n � 89) <6 hours after emergency department presen-tation. Patients with negative risk assessment results were immediately discharged andfollowed for 2 months. Ninety patients (82%) in the DASE arm and 78 (88%) in the EETarm were discharged after the diagnosis of nonischemic ACP. The mean lengths of stay inthe hospital were 23 � 12 and 31 � 23 hours in the DASE and EET arms, respectively (p �0.01). No 2-month follow-up events occurred in DASE patients, and the event rate wassignificantly higher in EET patients (0% vs 11%, p � 0.004). The DASE strategy showedlower costs compared with the EET strategy at 1-month ($1,026 � $250 vs $1,329 � $1,288,p � 0.03) and 2-month ($1,029 � 253 vs $1,684 � $2,149, p � 0.005) follow-up. Inconclusion, early DASE in emergency department triage of low-risk patients with ACP issafe and reduces costs of care compared to EET. © 2007 Elsevier Inc. All rights reserved.

(Am J Cardiol 2007;100:1068–1073)

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e designed a prospective, randomized, multicenter trialo compare the use of dobutamine-atropine stress echo-ardiography (DASE) and electrocardiographic exerciseesting (EET) implemented in emergency department ac-elerated diagnostic protocols in terms of hospital admis-ion rate reduction, length of stay, and total costs foratients needing admission for the evaluation of acutehest pain (ACP).

ethods

he Assessment of Cost-Effectiveness of Several Strategiesf Early Diagnosis in Patients With ACP and Non Conclu-ive Electrocardiogram (ASSENCE) study was designed asparallel randomized trial and was performed in 10 emer-

ency departments in 5 different countries (see Appendix).The study protocol is shown in Figure 1. All patients pre-

enting to emergency departments with ACP received evalua-ions consisting of histories, physical examinations, electrocar-iography, 2-dimensional echocardiography, blood cell countsnd chemistry, serial measurements of myocardial injury bi-markers, chest x-rays, and any further testing deemed neces-ary by the attending physicians.

IRCAB Foundation, Udine, Italy. Manuscript received March 22,007; revised manuscript received and accepted May 8, 2007.

*Corresponding author: Tel: 39-432552441; fax: 39-432482353.

nE-mail address: gnucifora@cardionet.it (G. Nucifora).

002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2007.05.027

Exclusion and inclusion criteria for enrollment in thetudy are listed in Table 1. Informed consent forms for studynrollment and management of the clinical data were sub-itted to patients who fulfilled these criteria. The protocolas approved by the ethics committee of all participating

enters and conformed to the ethical guidelines of the Dec-aration of Helsinki.

Patients who fulfilled inclusion and exclusion criteriand gave informed consent were randomly assigned to theASE arm or the EET arm. According to study protocol,

he 2 tests had to be performed �18 hours after random-zation. All patients with negative DASE or EET resultsere immediately discharged after the tests. In case of

nsufficient acoustic windows on echocardiography, pa-ients were followed according to the intention-to-treat pro-ocol. Patients with positive DASE or EET results weredmitted to coronary care units.

Blood samples were taken at admission for the determi-ation of myocardial injury biomarkers (creatine kinase-MBass or subfraction, cardiac troponin level). These testsere repeated 4 hours later. For patients who presented �2ours after the onset of ACP, these tests were performed forthird time 6 hours after the onset of pain to obtain myo-

ardial injury biomarker determinations in all patients �6ours after the onset of pain.

Twelve-lead electrocardiography was performed at ad-ission, before randomization, and whenever patients had

ew episodes of ACP during their in-hospital stays.

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DASE tests were performed according to the availabilityf the echocardiographic laboratory. Only patients withdequate acoustic windows at baseline echocardiographyi.e., the adequate visualization of �13 of 16 myocardialegments in �1 echocardiographic view) underwent DASE.wo-dimensional echocardiography and 12-lead electrocar-iographic monitoring were performed, in combination withigh-dose dobutamine administration (up to 40 �g/kg bodyeight/minute with the coadministration of atropine up to 1g), in accordance with well-established protocols.1 Stan-

ard criteria indicated by currently available guidelines forerminating the tests and for the interpretation of DASEesults as negative or positive were followed.1

EET was performed according to the availability of the

igure 1. Study protocol. CK � creatine kinase; ECG � electrocardiog-aphy.

able 1atient selection criteria

Inclusion criteriaAcute chest pain within the past 24 hours in absence of local trauma

and abnormalities on chest x-rayNondiagnostic electrocardiographic results at admissionNegative myocardial injury biomarkersAbility to perform electrocardiogram exercise testing

Exclusion criteriaAge �30 yrsPrehospital or emergency room complication of acute ischemia or

myocardial infarctionCardiac arrest or ventricular arrhythmiaSyncopeCongestive heart failureHypotension (systolic blood pressure �100 mm Hg)

Premature ventricular beats �6/minAtrial fibrillationDilated or hypertrophic cardiomyopathyComplex congenital heart diseaseSignificant valvular diseaseKnown aortic aneurysm �50 mmUncontrolled proved hypertension (blood pressure �180/100 mm Hg)Complete left bundle branch block

oninvasive laboratory. The type of protocol used was de- t

ermined by the physicians performing the tests. EET resultsere interpreted by the physicians performing the tests.tandard criteria indicated by currently available guidelinesor terminating the tests and for the interpretation of EETesults as negative, positive, or inconclusive were fol-owed.2

Data from the emergency department evaluations as wells stress test results were recorded by the evaluating phy-icians in the emergency departments on the standardizedase report form that was part of the protocol.

After discharge, patients were followed for 2 months byelephone calls performed by registered nurses or physicianst 1 week, 1 month, and 2 months. If telephone contactould not be made, survey sheets were mailed. The charts ofll admitted patients were reviewed to record the dates andimes of cardiovascular procedures and complications andischarge diagnoses.

The main ASSENCE study end point was the assessmentf the cost-effectiveness of the 2 strategies tested. Costsere assessed taking into account the length of hospitaliza-

ion during the index admission, repeated hospitalizations,nd in-hospital and outpatient additional diagnostic proce-ures and treatments (2-dimensional echocardiography,ET, DASE, myocardial scintigraphy, diagnostic catheter-

zation, percutaneous coronary intervention, and coronaryrtery bypass grafting) during 2-month follow-up.

Secondary end points were in-hospital events (percuta-eous coronary intervention, coronary artery bypass graft-ng, myocardial infarction, cardiac death, cardiogenic shockr cardiac arrest, ventricular tachycardia requiring defibril-ation, or ventricular fibrillation) and 2-month follow-upvents (readmission to the hospital for ACP, percutaneousoronary intervention, coronary artery bypass grafting,yocardial infarction, and cardiac death).The probability of rehospitalization within 2 months was

hosen as the target measure for the study. The expectedate in the population under study is about 8%. To detect anbsolute difference of �6% between the 2 arms at an �evel of 0.05 and a power of 0.80, a total of 406 patientsere required for the study (203 per arm). At this sample

ize, the power to detect an absolute difference in directosts of $125 was �0.90 at a significance level of 0.05.

The study was prematurely stopped at midterm analysisfter the inclusion of 199 patients because of a low cumu-ative 2-month rehospitalization rate; no patients in theASE arm and only 3 patients (3%) in the EET arm were

eadmitted to the hospital during follow-up at the timenrollment was interrupted. At this sample size, the powero detect an absolute difference of 6% in rehospitalizationate at an � level of 0.05 was low (�0.70), whereas theower to detect a cost savings of $250 was �0.90 at aignificance level of 0.05.

Analyses were done according to the intention-to-treatrinciple. Values are expressed as mean � SD. Comparisonetween continuous variables was performed using Stu-ent’s t test for normally distributed variables and theann-Whitney test for non-normally distributed variables;

he chi-square test was performed to evaluate differences inategorical variables. A p value �0.05 was considered sta-

istically significant.

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Analyses were done using statistical software (SPSSersion 11.0 for Windows; SPSS, Inc., Chicago, Illinois).

esults

aseline characteristics of the study population are reportedn Table 2. The mean age was 52 � 10 years, and 118atients (59%) were men. Three fourths of the patientsomplained of ACP at admission. The prevalence of coro-ary risk factors was high. Electrocardiographic results atest on admission were normal or showed nondiagnosticbnormalities for acute coronary syndromes in all patients.

able 2emographic and clinical characteristics of study population

ariable DASE Arm(n � 110)

EET Arm(n � 89)

p Value

ge (yrs) 52 � 10 51 � 11 NSen 57 (52%) 61 (69%) 0.017

ast ACP attack (h)0–3 55 (50%) 54 (61%) NS3–6 22 (20%) 17 (19%) NS6–12 25 (23%) 12 (13%) NS�12 8 (7%) 6 (7%) NSCP on admission 80 (73%) 63 (71%) NSCP characteristicsAtypical 28 (25%) 23 (26%) NSTypical 82 (75%) 66 (74%) NSypertension 37 (34%) 30 (34%) NSmoker 48 (44%) 37 (42%) NSiabetes mellitus 9 (8%) 7 (8%) NSypercholesterolemia 36 (33%) 25 (28%) NSistory ofCoronary artery disease 8 (7%) 7 (8%) NSUnstable angina pectoris 2 (2%) 4 (4%) NSMyocardial infarction 3 (3%) 4 (4%) NSCoronary arteriography 2 (2%) 4 (4%) NSCoronary angioplasty 1 (1%) 3 (3%) NSCoronary bypass 1 (1%) 0 (0%) NSsual drug assumptionNo cardioactive drug 66 (60%) 54 (61%) NSAntiplatelet drugs 33 (30%) 20 (22%) NSCalcium channel blockers 21 (19%) 7 (8%) 0.024� blockers 19 (17%) 9 (10%) NSNitrates 13 (12%) 8 (9%) NSOther noncardioactive drugs 28 (25%) 26 (29%) NSlinical presentationSystolic blood pressure (mm Hg) 133 � 17 134 � 18 NSHeart rate (beats/min) 76 � 12 76 � 12 NSSweating 11 (10%) 12 (13%) NSime from admission to ECG

(min)13 � 6 12 � 6 NS

CG: QRS 0.013Normal 109 (99%) 82 (92%)Left ventricular hypertrophy 0 (0%) 5 (6%)Right bundle branch block 0 (0%) 2 (2%)Incomplete left bundle branch

block1 (1%) 0 (0%)

CG: ST �0.0001Normal 49 (45%) 62 (70%)Nonspecific abnormalities 61 (55%) 27 (30%)

Data are expressed as mean � SD or number (percentage).ECG � electrocardiography.

One hundred ten patients (55%) were randomized to the A

ASE arm and 89 (45%) to the EET arm (Table 2). Patientsn the 2 arms had similar time intervals from symptom onseto emergency department admission and mean elapsedimes from emergency department admission to electrocar-iographic assessment.

In-hospital clinical outcomes were not statistically dif-erent between the 2 arms. Particularly, acute coronaryyndromes were diagnosed in 20 patients (18%) in theASE arm and in 11 patients (12%) in the EET arm;onischemic ACP was diagnosed in 90 patients (82%) in theASE arm and in 78 patients (88%) in the EET arm. Oneatient in the DASE arm underwent coronary artery bypassrafting.

In patients randomized to DASE, the test results wereositive in 20 (18%). DASE findings in patients with non-schemic ACP are listed in Table 3; 87 (97%) had negativeASE results and were immediately discharged, and 3atients (3%) did not undergo DASE because of inadequatecoustic windows or organizational problems (feasibility7%).

In patients randomized to EET, the test results wereositive in 11 (12%). EET findings in patients with non-schemic ACP are listed in Table 3; 55 (71%) had negativeET results and were immediately discharged, whereas 23

29%) had nondiagnostic test results.In patients discharged with diagnoses of nonischemic

able 3tress test findings in patients discharged with diagnoses of nonischemichest pain

ariable DASE Arm(n � 90)

EET Arm(n � 78)

eart rate at rest (beats/min) 74 � 12 83 � 18ystolic blood pressure at rest (mm Hg) 128 � 16 132 � 22iastolic blood pressure at rest (mm Hg) 77 � 11 80 � 11eak heart rate (beats/min) 142 � 25 151 � 22eak systolic blood pressure (mm Hg) 166 � 23 178 � 29eak diastolic blood pressure (mm Hg) 94 � 13 96 � 20obutamine at 40 �g/kg/min 60 (69%) —eak workload (W) — 79 � 55egative test results 87 (97%) 55 (71%)

nconclusive results or test notperformed

3 (3%) 23 (29%)

dverse reactions 0 (0%) 0 (0%)

Data are expressed as mean � SD or number (percentage).

able 4dditional diagnostic procedures and admission-to-discharge time inatients discharged with diagnoses of nonischemic chest pain

ariable DASE Arm(n � 90)

EET Arm(n � 78)

pValue

dditional diagnostic procedures, total 6 (6%) 13 (17%) 0.04ransthoracic echocardiography 4 (4%) 9 (12%)ET 1 (1%) 3 (4%)ASE 1 (1%) 1 (1%)echnetium-99 myocardial scintigraphy 0 (0%) 0 (0%)oronary arteriography 0 (0%) 0 (0%)ime from admission to discharge (h) 23 � 12 31 � 23 0.01

Data are expressed as mean � SD or number (percentage).

CP, additional diagnostic procedures and lengths of hospital

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1071Coronary Artery Disease/Cost-Effectiveness of ACP Diagnostic Protocols

tay were significantly greater in the EET arm (Table 4);owever, costs of the index admissions (Figure 2) were nottatistically different between the 2 arms.

In patients discharged with diagnoses of nonischemicCP, no events occurred during follow-up in the DASE

rm, whereas 2-month follow-up events were observed in 9atients (11%) in the EET arm (p � 0.004). Five patients6%) were rehospitalized for ACP, 1 patient (1%) had ancute myocardial infarction 1 week after negative EETesults, and 3 patients (4%) underwent percutaneous coro-ary interventions despite having negative EET results.

During follow-up, patients discharged with diagnoses ofonischemic ACP in the DASE arm underwent significantlyewer additional diagnostic tests than patients in the EETrm (Table 5). As shown in Figure 2, patients assigned tohe EET arm had significantly higher 1- and 2-month hos-ital charges than patients assigned to the DASE arm$1,026 � $250 vs $1,329 � $1,288, p � 0.03, and $1,029

igure 2. Cost analysis in patients discharged with diagnosis of non-schemic chest pain. Discharge costs: $1,024 � $248 in the DASE arm,1,123 � $419 in the EET arm. One-week follow-up costs: $1,025 � $249n the DASE arm, $1,261 � $1,246 in the EET arm. One-month follow-uposts: $1,026 � $250 in the DASE arm, $1,329 � $1,288 in the EET arm.wo-month follow-up costs: $1,029 � $253 in the DASE arm, $1,684 �2149 in the EET arm.

able 5iagnostic exams performed during 2-month follow-up in patientsischarged with diagnosis of nonischemic chest pain

ariable DASE Arm(n � 90)

EET Arm(n � 78)

p Value

dditional diagnosticprocedures, total

6 (7%) 17 (22%) 0.01

ransthoracicechocardiography

1 (1%) 3 (4%)

ET 5 (6%) 6 (8%)ASE 0 (0%) 0 (0%)echnetium-99 myocardial

scintigraphy0 (0%) 5 (6%)

oronary arteriography 0 (0%) 3 (4%)

Data are expressed as number (percentage).

$253 vs $1,684 � $2,149, p � 0.005, respectively). a

iscussion

ur study shows that an accelerated diagnostic protocolith early DASE in emergency department triage of low-

isk patients with ACP is feasible and safe and reduces costsf care compared with EET. The high prevalence of incon-lusive EET results reduces the cost-effectiveness of thistrategy in the long term, mainly because of more additionaliagnostic procedures and rehospitalizations.

Most patients presenting to the emergency departmentith ACP are at relatively low risk for acute coronary

yndromes. However 4% to 5% of patients with acute cor-nary syndromes are inadvertently discharged from themergency department, and these patients are at high-riskor mortality,3 so most physicians practice conservativedmission policies.3–5 In some patients with final diagnosesf noncardiac ACP, this practice may require long andostly in-hospital observation.3–5 Therefore, accelerated di-gnostic protocols have the potential to improve the cost-ffectiveness of triaging patients with ACP with nondiag-ostic electrocardiographic results, obviating the need forraditional hospital admission to rule out acute coronaryyndromes.6–8

Previous studies have validated DASE and EET as usefultrategies9–20; these stress tests have high and comparableegative predictive values, permitting clinicians to rule outyocardial ischemia and stratify higher risk patients.Only 1 single-center randomized study previously com-

ared stress imaging (exercise stress echocardiography orASE) and EET in triaging low-risk patients with ACP,ith immediate discharge in case of negative stress test

esults, in terms of cost-effectiveness.20 The results of ourulticenter randomized study confirm the safety of imme-

iate EET and DASE in such patients and the low rate ofvents of patients judged as nonischemic with either of thestrategies.9–20 However, DASE was feasible and yielded

iagnostic results in 97% of patients without any adverseide effects, whereas inconclusive EET results were rela-ively common (29%). The durations of in-hospital staysnd the need for further diagnostic procedures during indexospitalizations and follow-up were significantly lower inhe DASE arm, and subsequent rehospitalizations were ob-erved only in the EET arm. Moreover, no patient in theASE arm experienced a major adverse cardiac event dur-

ng follow-up. From an economic viewpoint, our studyhows that the costs of patient care were significantly lesshen adopting the DASE strategy than the EET strategy in

he midterm; the need for additional diagnostic proceduresnd further rehospitalizations in patients with inconclusiveET results increased the costs of managing patients ini-

ially assigned to the EET arm.In the real world, EET is the chosen test to stratify

atients with low-risk ACP, and published guidelines sug-est it as the initial test.2,21,22 However, it is inconclusive inany cases, so patients are frequently rehospitalized or

ndergo repeat diagnostic examinations during follow-up,arrying a cost increase at midterm. In the ideal world,ASE should therefore be preferred to EET as the primary

nvestigation method. However, DASE requires experi-nced personnel to perform the test and interpret the results,

nd experienced cardiologists may not be available during

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1072 The American Journal of Cardiology (www.AJConline.org)

ff hours for the performance or interpretation of DASE. Aeasonable alternative strategy could be to perform DASEs a secondary test in patients with uninterpretable, unfea-ible, submaximal, or nondiagnostic EET results.23 Othernvestigators have also previously shown that rule-out pro-ocols using immediate nuclear imaging at a chest painenter may save costs.24–26 However, DASE and EET areore readily available and less costly than nuclear imaging

nd lack the radiation exposure and environmental pollutionssociated with radionuclide use.

This study has a number of limitations that should becknowledged. A misbalance in some baseline characteris-ics was present between the 2 arms, because the trial wastopped early; nevertheless, the 2 groups of patients seemedo be at similar risk for coronary artery disease, as outlinedy the similar prevalence of coronary risk factors and inci-ence of acute coronary syndrome diagnosis at index hos-italization.

Other limitations regard cost analysis and the perfor-ance of stress tests. The trial was a multicenter, interna-

ional experience; costs in medical care may differ amongnstitutions in different countries. Stress tests were per-ormed while patients were taking medications, probablyeducing the accuracy of the tests in detecting ischemia, buthe withdrawal of assumed therapy was deemed impracti-able. No off-site reading of stress echocardiographic re-ults was performed, possibly negatively influencing inter-bserver variability. In any case, the aim of our study was tossess the feasibility of DASE and EET as part of acceler-ted diagnostic protocols, not to evaluate their sensitivitynd accuracy. It has recently been suggested that stresschocardiography is of limited value when used to detectignificant coronary artery stenosis in patients presentingith ACP without signs of myocardial ischemia, because of

ts low sensitivity.27 However, in this context, stress testsre performed to rule out inducible myocardial ischemia andigh-risk patients, not to diagnose coronary artery disease.hus, the imperfect diagnostic accuracy of stress tests is notlimitation to their use in this setting.28

cknowledgment: We are grateful to Gianaugusto Slavich,D, for his thoughtful suggestions on study design and

onduct. We are indebted to Marco Ghidina of the IRCABoundation for data input and database management. Weould also acknowledge the contribution of Alessandroesideri, MD, in providing patients and constructive criti-

ism on the report.

ppendix

nrolling centers and local investigators: Greece: Athenseneral Hospital, Athens (Apostolos Karavidas); Italy:zienda Ospedaliero-Universitaria di Udine, Udine (Luigi. Badano, Paolo M. Fioretti, Ricarda Marinigh, Gaetanoucifora, and Gianaugusto Slavich); San Gerardo Hospital,onza (Giuseppe Trocino); S. Filippo Neri Hospital, Rome

Giorgio Scaffidi); S. Giacomo Hospital, Castelfrancoeneto (Alessandro Desideri); F. Ferrari Hospital, Casarano

Gianni Pettinati); Sorrento Hospital, Sorrento (Costantino

starita); Iran: University of Medical Sciences, Isfahan

Nizal Sarraf-Zadegan); Lithuania: Marijampole Centralospital, Marijampole (Vitas Vysniauskas); Turkey: Istan-ul University, Istanbul (Baris Ilerigelen).

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1073Coronary Artery Disease/Cost-Effectiveness of ACP Diagnostic Protocols

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