Q1997 by Excerpta Medica, Inc. 0002-9149/97/$17.00 713All rights reserved. PII S0002-9149(96)00855-7

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Comparison of Arbutamine and ExerciseEchocardiography in Diagnosing

Myocardial IschemiaAriel Cohen, MD, PhD, Hele`ne Weber, MD, Christophe Chauvel, MD,

Jean-Luc Monin, MD, Jean-Claude Dib, MD, Benoit Diebold, MD, PhD, andPascal Gueret, MD

Arbutamine is a new catecholamine designed for use asa pharmacologic stress agent. This study compared thesensitivity of arbutamine with symptom-limited exerciseto induce echocardiographic signs of ischemia. Arbu-tamine was administered by a computerized closed-loopdelivery system that controls the infusion rate of arbu-tamine toward a predefined rate of heart rate increaseand maximum heart rate limit. Beta blockers werestopped 48 hours before both tests. Stress wasstopped for intolerable symptoms, or clinical, electro-cardiographic or echocardiographic signs of ischemia(new or worsening wall motion abnormality), targetheart rate (85% age predicted maximum heart rate),or plateau of heart rate response. Thirty-seven patientswere entered into the study (35 arbutamine and exer-cise, 1 arbutamine only, 1 exercise only), of which 30had angiographic evidence of coronary artery disease(50% lumen diameter narrowing). Rate-pressure prod-uct increased significantly in response to both stress mo-dalities (p 0.001) and was significantly greater withexercise (11,308{ 2,443) than with arbutamine (9,486{ 2,479, p 0.001). The time to maximum heart rate

was longer during arbutamine stress echocardiographythan during exercise testing (17.3 { 9.4 versus 9.3 {4.2 minutes, respectively, p 0.001). There were morepatients with interpretable echo data for arbutamine(82%) than for exercise (67%). Sensitivity for recognitionof myocardial ischemia was 94% (95% confidence in-terval 70% to 100%) and 88% (95% confidence interval62% to 98%), respectively. The most frequent adverseevents during arbutamine (n 36) were dyspnea (5.6%)and tremor (5.6%). Two arbutamine stress tests were dis-continued due to arrhythmias: 1 patient had prematureatrial and ventricular beats, and the other had prema-ture atrial contractions and atrial fibrillation. Arrhyth-mias were well tolerated and resolved without sequelae.In conclusion, the sensitivity of arbutamine to induceechocardiographic signs of ischemia was similar to thatof exercise despite a lower rate-pressure product. Ar-butamine was well tolerated and provides a reliable al-ternative to exercise echocardiography. Q1997 byExcerpta Medica, Inc.

(Am J Cardiol 1997;79:713716)

Exercise tolerance tests have been used with elec-trocardiographic (ECG) monitoring to assist inthe diagnosis of coronary artery disease.1 Unfortu-nately, 20% to 30% of all patients for whom exercisetolerance testing is indicated are unable to exercise,and approximately 30% of those able to exercisehave inconclusive exercise tolerance tests/ECG re-sults.24 It is in this group of patients that pharma-cologic stress testing has become clinically estab-lished. Arbutamine has been shown to simulate thecardiac effects of exercise by increasing heart rate,myocardial contractility, and systolic blood pres-sure.5 In patients with documented coronary arterydisease, arbutamine has induced symptoms and ECGand echocardiographic changes diagnostic of myo-cardial ischemia.68 Unlike any other pharmacologicstress agent, arbutamine is administered by a com-puterized closed-loop delivery system that controls

From the Saint-Antoine University Hospital, the Henri Mondor Univer-sity Hospital, and the Broussais University Hospital, Paris and Creteil,France. This study was supported in part by a grant from GensiaEurope, Ltd., Brackwell, Berkshire, United Kingdom. Manuscript re-ceived July 25, 1996; revised manuscript received and acceptedOctober 21, 1996.

Address for reprints: Ariel Cohen, MD, PhD, Cardiology Depart-ment, Saint-Antoine University Hospital, 184, rue du Faubourg Saint-Antoine, 75571 Paris cedex 12, France.

the infusion rate in response to changes in the pa-tients heart rate to achieve a predefined rate of heartrate increase (heart rate slope) toward a maximalheart rate limit (target heart rate) selected by the phy-sician. This study examines the efficacy and safetyof arbutamine administered by its delivery systemand compares the sensitivity of arbutamine withsymptom-limited exercise to induce echocardio-graphic signs of ischemia.

METHODSPatients: A total of 37 patients from 3 centers in

France (Saint-Antoine, Henri-Mondor, and Brous-sais University Hospitals), who were of the legal ageof consent and with symptom and/or signs of coro-nary artery disease, were entered into the study. Pa-tients with coronary angiography within 12 weeks ofthe study and those for whom coronary angiographywas planned within 4 weeks after the study wereincluded. Coronary artery disease, defined as thepresence of 50% diameter stenosis in any majorartery, was present in 30 patients. All patients gavewritten informed consent and the protocol was ap-proved by a central ethics committee in France.

Patients were excluded if they had inadequatebaseline echocardiograms, unstable angina, or myo-cardial infarction within 30 days of the study, a his-

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TABLE I Hemodynamic Parameters During Arbutamine and ExerciseEchocardiography

ArbutamineEchocardiography

ExerciseEchocardiography p Value

BaselineHR (beats/min) 71 { 12 82 { 14* 0.001SBP (mm Hg) 134 { 21 138 { 20* 0.886

Rate-pressure product 9,486 { 2,479 11,308 { 2,443 0.001Maximum stage

HR (beats/min) 126 { 20 144 { 19* 0.001SBP (mm Hg) 168 { 25 187 { 28* 0.002

Rate-SBP product 18,983 { 4,603 26,537 { 4,961* 0.001*Exercise versus arbutamine.HR heart rate; SBP systolic blood pressure.

tory of significant arrhythmias, a pacemaker, heartfailure (New York Heart Association functional classIII or IV), cardiomyopathy or significant valvulardisease, uncontrolled systolic hypertension, aorticaneurysm or dissection, and hypokalemia. In addi-tion to the above exclusions, b blockers werestopped 48 hours before both stress tests, and an-ticholinergics were not permitted within 24 hours ofeach stress test. Patients performed both exercise andarbutamine tests with 20 hours to 14 days betweenthe tests. The stress test order was randomly assignedand kept blinded from the investigators until the pa-tient had fulfilled the entry criteria and was enteredinto the study.

Arbutamine test: Arbutamine was administered in-travenously using a computerized closed-loop deliv-ery system. The system controls the amount of ar-butamine infused according to the rate of heart rateincrease (heart rate slope) and maximum heart rate(heart rate target) selected by the physician beforethe test. The heart rate slope for this study was se-lected as 8 beats/min/min and the heart rate targetwas 85% of the age-predicted maximum heart rate.The system controlled arbutamine administration sothat the rate of infusion or the maximum dose didnot exceed 0.8 mg/kg/min or 10 mg/kg, respectively.The system monitored heart rate at 5-second inter-vals and blood pressure at 2-minute intervals duringthe infusion period. The physicians were notified ofany significant changes in blood pressure or heartrate by audible and visual alerts and alarms issuedby the system. If the heart rate or blood pressurechanges exceeded preprogrammed limits then thesystem would interrupt the arbutamine infusion.Echocardiographic and 12-lead ECG monitoring wasperformed continuously throughout the infusion pe-riod. Digitally acquired images of the 4 standardechocardiographic views were collected at baseline,15 beats/min above baseline, at the end of infusion,and 10 minutes into recovery.

Exercise test: Exercise was performed using an up-right bicycle ergometer to a protocol of 30 W for thefirst 2 minutes, increasing by 30 W every subsequent2 minutes. Target heart rate was 85% of the age-predicted maximum heart rate. Heart rate and bloodpressure were recorded at the end of each stage.

Twelve-lead ECG monitoring was performed contin-uously throughout the test. Digitally acquired imagesof the 4 standard echocardiographic views were col-lected at baseline, within 30 seconds of completionof exercise, and 10 minutes into recovery.

Stress test end points: Arbutamine infusion andexercise were stopped for intolerable symptoms,ischemia, or achievement of target heart rate. Addi-tionally, arbutamine infusion was stopped for echo-cardiographic signs of ischemia or heart rate satu-ration. All expected and unexpected events wererecorded and ECG tracings of all arrhythmias werecollected.

Echocardiographic analysis: The 4 standard trans-thoracic echocardiographic views (parasternal long-and short-axis and apical 2- and 4-chamber) wereobtained at each stage during the stress tests. Imageswere acquired digitally and on videotape and wereanalyzed at a central analysis center. Analysis wasperformed by 2 independent, medically qualified ob-servers who were blinded to all the stress test resultsand angiographic data. For each set of images, theleft ventricle was divided into 16 segments and eachsegment was assigned a score (compared with base-line views) as follows: x unable to interpret; 1 normal or hyperkinetic; 2 hypokinetic; 3 aki-netic; or 4 dyskinetic. Patients included were thosewho had 13 interpretable segments. A wall motionscore index was calculated at each stage by sum-mation of individual segment scores divided by thenumber of interpreted segments. Stress-induced isch-emia was defined by echocardiography as new orworsening wall motion abnormality in 2 adjacentsegments of the posterior/inferior wall or at least 1segment of the anterior wall.

Coronary angiography: Coronary angiography wasperformed according to the standard clinical practiceat each center. The location and maximum percentstenosis of each lesion were noted. Significant cor-onary artery disease was defined as the presence of50% lumen diameter narrowing in any majorvessel.

Statistical analysis: Continuous variables are pre-sented as mean { SD. Differences were consideredto be statistically significant at p 0.05. Hemody-namic changes were compared between the 2 stress

tests using a repeated-measuresanalysis of variance or a rank-trans-formed analysis of variance. Wallmotion score indexes were com-pared using a 1-sample t test. Thevalue and 95% confidence intervalestimates for sensitivity in the di-agnosis of ischemia and coronaryartery disease were calculated foreach test. Positive predictive valueand accuracy were determined us-ing a standard formula.

RESULTSPatients: The study group com-

prised 37 patients (30 men and 7

CORONARY ARTERY DISEASE/ARBUTAMINE AND EXERCISE ECHOCARDIOGRAPHY 715

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TABLE II Adverse Effects During Arbutamine andExercise Echocardiography

ArbutamineEchocardiography

ExerciseEchocardiography

Patients with event 8 (22%) 1 (3%)Dyspnea 2 (6%) 0Tremor 2 (6%) 0Premature atrial

contraction2 (6%) 0

Other* 11 (31%) 1

*Paroxysmal atrial fibrillation (n 1), bigeminy ventricular (n 1), trigeminyventricular (n 1), chest pain (n 1), dizziness (n 1), fatigue (n 1), hy-potension (n 1), nausea (n 1), paresthesia (n 1), rash (n 1), sweatingincreased (n 1), angina pectoris (1 during exercise test).

TABLE III Expected Events During Arbutamine andExercise Echocardiography

ArbutamineStress Test

ExerciseStress Test

Total number of events 36 21Total number of patients with events 22 (61%) 21 (58%)Angina 12 (33%) 12 (33%)Palpitations 7 (19%) 0Dyspnea 4 (11%) 1 (3%)Other 13 (36%) 8 (25%)

TABLE IV Atrial and Ventricular Arrhythmias During Arbutamineand Exercise Echocardiography

ArbutamineEchocardiography

ExerciseEchocardiography

Patients with arrhythmias 16 (44%) 5 (14%)Ventricular arrhythmias 14 (39%) 5 (14%)

Premature ventricular contractions 11 (31%) 3 (8%)Bi/trigeminy 8 (22%) 2 (6%)Idioventricular rhythm 3 (8%) 0Couplets 1 (3%) 0

Atrial arrhythmias 9 (25%) 1 (3%)Atrial fibrillation 1 0

TABLE V Wall Motion Score Index (WMSI) During Arbutamineand Exercise Echocardiography

ArbutamineEchocardiography

ExerciseEchocardiography p Value

WMSI baseline 1.53 { 0.39 1.46 { 0.38 0.463WMSI peak 1.67 { 0.44 1.61 { 0.42 0.573WMSI recovery 1.57 { 0.41 1.51 { 0.41 0.554

women, mean age 57 { 10 years [range 36 to 74]).Thirty patients had angiographic evidence of signif-icant coronary artery disease. Eighteen patients(49%) had a history of myocardial infarction. Nine-teen patients (51%) had undergone a prior coronaryrevascularization procedure, including 2 patientswho had coronary bypass. Fifteen patients had hy-pertension. Thirty-five patients had both tests, 1 pa-tient had arbutamine echocardiography, and 1 patienthad exercise echocardiography only.

Hemodynamic response to arbutamine and exercise:Comparison of the hemodynamic response between

tests in these patients is shown in Table I. Heart rate,systolic blood pressure and rate-pressure product in-creased significantly in response to both stress mo-dalities. The maximum value of these 3 parameterswere significantly greater with exercise than with ar-butamine. The time to maximum heart rate waslonger during arbutamine stress echocardiographythan during exercise test (17.3 { 9.4 vs 9.3 { 4.2minutes, respectively, p 0.001).

Safety: There were no deaths or serious adverseevents during the study. All adverse events (TableII) were described as either mild (resolved withoutintervention) or moderate (tolerated or resolved withintervention). An expected event occurred duringstress in 22 of 36 patients (61%) during arbutaminestress and in 21 patients (58%) during exercise test(Table III). Hypotension was observed in 1 case(2.8%) during arbutamine infusion. Ventricular ar-rhythmias were observed in 14 patients (39%) duringarbutamine echocardiography and 5 patients (14%)during exercise stress testing (Table IV). Atrial ar-rhythmias were also more common during arbutam-ine stress testing. However, arbutamine stress testingwas stopped due to arrhythmias in 2 patients (par-oxysmal atrial fibrillation and significant prematureventricular beats). We did not observe any episode

of sustained or nonsustained ven-tricular tachycardia.

Diagnostic efficacy of arbutamineand exercise echocardiography: Stressechocardiograms were interpretablein 82% of patients during arbutam-ine echocardiography and in 67%during exercise echocardiography.The overall incidence of arbutamineprovoking myocardial ischemia(new or worsening wall motion ab-normalities) in patients with signif-icant coronary artery disease and in-terpretable echocardiograms was94% (95% confidence interval 70%

to 100%) and 88% (95% confidence interval 62% to98%), respectively. Positive predictive values and di-agnostic accuracies were 86% and 78%, respec-tively, for arbutamine stress test, and 85% and 81%,respectively, for exercise stress testing. Wall motionscore index were not significantly different at eachstage during both stress tests (Table V).DISCUSSION

Arbutamine echocardiography can accuratelyidentify myocardial ischemia. The efficacy of thisnew stress modality was numerically greater than ex-ercise echocardiography, despite a lower rate-pres-sure product. Arbutamine was well tolerated but hada higher frequency of atrial and ventricular arrhyth-mias.

Adverse effects: The frequency of anticipatedevents during arbutamine and exercise stress testingwas similar to that reported with dobutamine echo-cardiography.9 Noncardiac side effects (dyspnea,tremor) appear more frequently during arbutamine

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or dobutamine infusion than during exercise stresstesting.10 Complicating hypotension during dobuta-mine stress echocardiography has been reported in14%9 to 20%,11 and has been related to dobutamine-induced cavity obliteration12 and vasovagal mecha-nisms.13 The frequency of hypotension seems lowerduring arbutamine infusion: 2.8% in our series and4% in the report of Cohen et al.8 These differencesmay be linked to different hemodynamic effects ofthe 2 catecholamines as demonstrated in a dogmodel.5

Arrhythmias were more common with arbutam-ine than with exercise. Supraventricular arrhythmiasincluding premature atrial contractions occurred in25% of cases during arbutamine infusion in ourstudy as well as in the report of Cohen et al.8 Thefrequency of ventricular arrhythmias was lower thanthat reported by Cohen et al8 (39% vs 59%). How-ever, significant arrhythmias represented the causefor terminating stress testing in 5% and 2.7% ofcases, respectively. With regard to dobutamine-in-duced arrhythmias, the safety profile as reported byMertes et al10 was similar to that found with arbu-tamine infusion.

Efficacy of arbutamine echocardiography: In thepresent study, the sensitivity of arbutamine was sim-ilar to that of exercise echocardiography despite alower rate-pressure product. Quantitative analysis ofechocardiographic regional function did not showany significant differences between the 2 stress mo-dalities at each stage.

These results are in agreement with those com-paring exercise and dobutamine stress tests.14,15 Inaddition, the chronotropic properties of arbutamineeffectively induced ischemia without the addition ofatropine, which is required in 30% to 40% of patientsundergoing dobutamine echocardiography.10,16,17However, echocardiograms were not interpretable,using the stringent criteria imposed by the protocol,in one third of exercise and 18% of arbutamine stresstests. These findings point to the actual limitationsin postexercise echocardiography related to inade-quate image acquisition because of respiratory inter-ference and various patient positioning problems.4,18Therefore, arbutamine echocardiography seemsmore feasible than exercise echocardiography.

Study limitations: Several factors may have en-hanced the sensitivity of both stress tests, such asinclusion of patients with previous myocardial in-farction (49%) and/or coronary revascularization(51%). Furthermore, women were poorly repre-sented in our study as well as in the report of Cohenet al.8 Finally, our study included 3 centers; however,

echocardiographic data were analyzed centrally byexperienced investigators.19

1. Gianrossi R, Detrano R, Mulvihill D, Lehmann K, Dubach P, Colombo A,Mc Arthur D, Froelicher V. Exercise-induced ST depression in the diagnosis ofcoronary artery disease: a meta-analysis. Circulation 1989;80:8798.2. Mairesse GH, Marwick TH, Vanoverschelde JLJ, Baudhuin T, Wijns W,Melin JA, Detry JMR. How accurate is dobutamine stress electrocardiographyfor detection of coronary artery disease? Comparison with two-dimensionalechocardiography and technetium-99m methoxy isobutyl isonitrile (MIBI) per-fusion scintigraphy. J Am Coll Cardiol 1994;24:920927.3. Marwick T, Willemart B, DHondt A, Baudhuin T, Wijns W, Detry J, MelinJ. Selection of the optimal nonexercise stress for the evaluation of ischemicregional myocardial dysfunction and malperfusion. Circulation 1993;87:345354.4. Marwick TH, Nemec JJ, Pashkow FJ, Stewart WJ, Salcedo EE. Accuracyand limitations of exercise echocardiography in a routine clinical setting. J AmColl Cardiol 1992;19:7481.5. Young M, Pan W, Wiesner J, Bullough D, Browne G, Balow G, Potter S,Metzner K, Mullane K. Characterization of arbutamine: a novel catecholaminestress agent for diagnosis of coronary artery disease. Drug Dev Res 1994;32:1928.6. Kiat H, Iskandrian AS, Villegas BJ, Starling MR, Berman DS. Arbutaminestress thallium-201 single-photon emission computed tomography using a com-puterized close-loop delivery system. Multicenter trial for evaluation of safetyand diagnostic accuracy. J Am Coll Cardiol 1995;26:11591167.7. Dennis CA, Pool PE, Perrins EJ, Mohiuddin SM, Sklar J, Kostuk WJ, MullerDWM, Starling MR. Stress testing with closed-loop arbutamine as an alternativeto exercise. J Am Coll Cardiol 1995;26:11511158.8. Cohen JL, Chan KL, Jaarsma W, Bach DS, Muller DWM, Starling MR,Armstrong WF. Arbutamine echocardiography: efficacy and safety of a newpharmacologic stress agent to induce myocardial ischemia and detect coronaryartery disease. J Am Coll Cardiol 1995;26:11681175.9. Mazeika PK, Nadazdin A, Oakley CM. Paradoxic hypotension during do-butamine stress echocardiography: clinical and diagnostic implications. Am JCardiol 1992;21:10801086.10. Mertes H, Sawada SG, Ryan T, Segar D, Kovacs R, Foltz J, FeigenbaumH. Symptoms, adverse effects, and complications associated with dobutaminestress echocardiography Experience in 1118 patients. Circulation 1993;88:1519.11. Marcovitz PA, Bach DS, Mathian W, Shayna V, Armstrong WF. Paradoxichypotension during dobutamine stress echocardiography: clinical and diagnosticimplications. Am J Cardiol 1992;21:10801086.12. Pellikka PA, Oh JK, Bailey KR, Nichols BA, Monahan KH, Tajik AJ.Dynamic intraventricular obstruction during dobutamine stress echocardiogra-phy. Circulation 1992;86:14291432.13. Tanimoto M, Pai RG, Jintapakorn W, Shah PM. Mechanisms of hypoten-sion during dobutamine stress echocardiography in patients with coronary arterydisease. Am J Cardiol 1995;76:2630.14. Previtali M, Lanzarini L, Fetiveau R, Poli A, Ferrazio M, Falcone C, Mus-sini A. Comparison of dobutamine stress echocardiography, dipyridamole stressechocardiography and exercise stress testing for diagnosis of coronary arterydisease. Am J Cardiol 1993;72:865870.15. Beleslin B, Ostojic M, Stepanovic J, Dordjevic-Dikic A, Stojkovic S, Ned-eljkovic M, Stankovic G, Petrasinovic Z, Gojkovic L, Vasiljevic-Pikrajcic Z,Nedeljkovic S. Stress echocardiography in the detection of myocardial ischemia:head-to-head comparison of exercise, dobutamine and dipyridamole tests. Cir-culation 1994;90:11681176.16. Poldermans D, Fioretti PM, Boersma E, Forster T, Van Urk H, Cornell JH,Arnese M, Roelandt JRTC. Safety of dobutamine-atropine stress echocardiog-raphy in patients with suspected or proven coronary artery disease. Am J Cardiol1994;73:456459.17. Picano E, Mathias W Jr, Pingitore A, Bigi R, Previtali M. Safety and tol-erability of dobutamine-atropine stress echocardiography: a prospective, mul-ticentre study. Lancet 1994;344:11901192.18. Hecht HS, Debord L, Shaw R, Dunlop R, Ryan C, Stertzer SH, Myler RK.Digital supine bicycle stress echocardiography: a new technique for evaluatingcoronary artery disease. J Am Coll Cardiol 1993;21:950956.19. Picano E, Lattanzi F, Orlandini A, Marini C, lAbbate A. Stress echographyand the human factor: the importance of being expert. J Am Coll Cardiol1991;17:666669.