TftkiwevgpsecvKp

Trcdv

M

utwptdsbpr

FaaNr

Fp

©T

Use of a Scoring Model CombiningClinical, Exercise Test, and

Echocardiographic Data to PredictMortality in Patients With Known orSuspected Coronary Artery Disease

Abdou Elhendy, MD, PhD, Douglas W. Mahoney, MSc, Robert B. McCully, MD,James B. Seward, MD, Kelli N. Burger, BSc, and Patricia A. Pellikka, MD

PduImls1AgmmesI

he aim of this study was to derive and validate a modelor predicting mortality by combining clinical, exerciseesting, and echocardiographic data in patients withnown or suspected coronary artery disease. We stud-ed 5,679 patients (aged 62 � 12 years; 3,231 men)ho were followed for a mean of 3 years after treadmillxercise echocardiography. Patients were randomly di-ided into 2 groups of equal size. (1) The modelingroup underwent multivariate analysis to define inde-endent predictors of mortality. Three hundred boot-trap resamplings were performed to determine param-ter coefficients. Patients were divided into 5 riskategories according to their composite score and sur-ival rate in each category was estimated by theaplan-Meier method. (2) The validation group com-rised patients for whom the risk model was applied.

cebsibfai

wctbiww

apiewemw1datricia@mayo.edu.

2004 by Excerpta Medica, Inc. All rights reserved.he American Journal of Cardiology Vol. 93 May 15, 2004

atients were divided into 5 risk categories based onata obtained from the modeling group. During follow-p, 315 patients died (151 in the modeling group).ndependent predictors of mortality were exercise wallotion score index (chi-square 22.4, p <0.0001), work-

oad (chi-square 17.1, p <0.0001), male gender (chi-quare 15.4, p <0.0001), and age (chi-square 5.5, RR.02, 95% confidence interval 1 to 1.04; p � 0.02).pplication of the composite score in the validationroup resulted in an effective stratification of patients forortality and cardiac events. This study provides aodel for assessing risk of death by combining clinical,

xercise testing, and echocardiographic data using aingle composite score. �2004 by Excerpta Medica,nc.

(Am J Cardiol 2004;93:1223–1228)

he aim of this study was to derive a model tocalculate the expected mortality and cardiac event

ates after exercise echocardiography by combininglinical, exercise electrocardiographic and echocar-iographic data in a composite risk score, and toalidate this model in another cohort of patients.

ETHODSPatients: The study included 6,444 patients who

nderwent exercise echocardiography at our institu-ion from January 1990 to December 1995. Patientsere excluded if they had poor imaging quality (259atients), refused participation in research (120 pa-ients), or were lost to follow-up (259 patients). Ad-itional exclusions were the presence of moderate orevere valvular heart disease, left bundle branchlock, and atrial fibrillation (127 patients). The finalopulation comprised 5,679 patients. The institutionaleview board approved the study.

Hypercholesterolemia was defined as total serum

rom the Division of Cardiovascular Diseases and Internal Medicinend the Section of Biostatistics, Mayo Clinic, Rochester, Minnesota;nd the Department of Cardiology, University of Nebraska, Omaha,ebraska. Manuscript received July 25, 2003; revised manuscript

eceived and accepted January 21, 2004.Address for reprints: Patricia A. Pellikka, MD, Mayo Clinic, 200

irst Street SW, Rochester, Minnesota 55905. E-mail: pellikka.

holesterol �200 mg/dl or use of a cholesterol-low-ring agent. Hypertension was defined as systoliclood pressure �140 mm Hg or diastolic blood pres-ure �90 mm Hg or use of an antihypertensive med-cation. Diabetes mellitus was defined as a fastinglood glucose concentration of �140 mg/dl or needor insulin or oral hypoglycemic agents. Pretest prob-bility of coronary artery disease was determined us-ng a previously described method.1

Exercise echocardiographic protocol: Patients under-ent symptom-limited treadmill exercise testing ac-

ording to the Bruce protocol (88%), Naughton pro-ocol (6%), or modified Bruce protocol (6%). Standardlood pressure and 12-lead electrocardiographic mon-toring were performed. Echocardiographic imagesere obtained from the parasternal and apical viewsith the patient at rest and immediately after exercise.

Exercise echocardiographic interpretation: Digitizednd videotape recorded images were used for inter-retation.2 Ejection fraction at rest was measured us-ng the method of Quinones as validated by Dujardint al3 or by visual estimation.4 Regional wall motionas assessed semiquantitatively by an experienced

chocardiographer who was blinded to clinical infor-ation and exercise test data. Wall motion at rest andith exercise was scored as 1 to 5 according to a6-segment model.5 Wall motion score index was

etermined at rest and at exercise as the sum of the

12230002-9149/04/$–see front matterdoi:10.1016/j.amjcard.2004.01.064

ssmea

sdcw

1

egmental scores divided by the number of visualizedegments. Development of new or worsening wallotion was considered indicative of myocardial isch-

mia. Exercise echocardiographic results were defined

TABLE 1 Clinical Features of Patients in the Modeling and Valid

Modeling(n � 2,840)

Va(n �

Clinical featuresAge (yrs) 62 � 12 62Men 1,644 (58%) 1,587History of typical angina 519 (18%) 595Hypercholesterolemia 1,525 (54%) 1,585Cigarette smoking 1,498 (53%) 1,461Systemic hypertension 2,055 (72%) 2,049Diabetes mellitus 284 (10%) 275Previous myocardial infarction 523 (18%) 552

Exercise test and echocardiographic dataExercise heart rate 164 � 24 165Exercise systolic blood pressure 179 � 33 177Exercise rate–pressure product 26,267 � 6,670 25,879Workload (METs) 8.5 � 2.9 8.5Achievement of target heart rate 2,056 (72%) 2,019Angina during test 268 (9%) 281Electrocardiographic results

Ischemia 548 (19%) 566Nondiagnostic 678 (24%) 650Negative 1,614 (57%) 1,623

Ejection fraction at rest 57% � 9 57Abnormal exercise echocardiogram 1,379 (49%) 1,389Wall motion score index at rest 1.16 � 0.32 1.17Exercise wall motion score index 1.26 � 0.4 1.26% Ischemic segments with exercise 8 � 17 8

Continuous data are presented as mean � SD; categorical data as number of*The p value is for the overall differences in exercise electrocardiographic re

TABLE 2 Univariate Association of Clinical, Exercise Test, and EVariables With Risk of Mortality and Cardiac Events in the Mod

Variables

All-cause Mortality C

WaldChi-square

Risk Ratio(95% CI)

WaldChi-squa

Baseline characteristicsAge* 35 1.63 (1.34–1.97) 20Previous myocardial infarction 21 2.19 (1.57–3.05) 39History of typical chest pain 6 1.60 (1.11–2.30) 14Diabetes mellitus 14 2.17 (1.45–3.26) 8

Exercise stress variableWorkload (METs) 37 0.83 (0.78–0.88) 17

Echocardiographic variablesAbnormal exerciseechocardiogram

32 2.91 (2.02–4.21) 42

New wall motionabnormalities (ischemia)

9 1.64 (1.18–2.27) 10

Percentage of ischemicsegments†

11 1.38 (1.14–1.67) 10

Ejection fraction at rest* 63 0.95 (0.94–0.96) 67Wall motion score index atrest‡

61 3.59 (2.61–4.95) 72

Exercise wall motion scoreindex‡

64 3.24 (2.43–4.33) 74

Change in wall motion scoreindex

12 2.79 (1.55–5.01) 12

*Per 10-unit or year increment.†Per 25% increment.‡Per 1-unit increment.

s abnormal if ischemia or fixed wall motion abnor- c

224 THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 93

malities were present.6 The exerciseelectrocardiogram was consideredpositive for ischemia if there was ahorizontal or downsloping ST-seg-ment depression of �1 mm at 80 msafter the J point and nondiagnostic ifthe baseline ST segment was abnor-mal. Workload was measured in met-abolic equivalents.

Follow-up: Follow-up data wereobtained from mailed questionnairesand scripted telephone interviews.Events were verified by contactingthe patients’ primary physicians andreviewing medical records and deathcertificates. The end points were (1)all-cause mortality and (2) cardiacevents, defined as nonfatal myocar-dial infarction or cardiac death. Dur-ing follow-up, patients were cen-sored at coronary revascularizationfor the end points of cardiac events.No censoring was performed for all-cause mortality.

Statistical analysis: Continuousvariables were reported as mean �SD and comparisons between groupswere based on the Wilcoxon rank-sum test. Categorical variables weresummarized as percentages, andgroup comparisons were based onthe chi-square test. Survival free ofthe end point of interest was esti-mated by the Kaplan-Meier method.Univariable and multivariable asso-ciations of clinical, exercise stress,and echocardiographic variableswith the end points were assessedwith the Cox proportional-hazardsmodel. Variables were selected in astepwise forward selection mannerwith entry and retention set at a sig-nificance level of 0.05. The results ofthese analyses were summarized asrisk ratios with corresponding 95%confidence intervals (CIs).

The population of the study wasrandomly divided into 2 groups ofequal size. (1) The modeling group:in these patients, multivariate analy-sis was performed using clinical, ex-ercise test, and echocardiographicdata to define independent predictorsof end points of interest. To deter-mine parameter coefficients, 300bootstrap resamplings were per-formed. A composite prognostic

core of clinical, exercise test, and echocardiographicata were derived from the estimated values of each �oefficient from the Cox regression model. Patientsere divided into 5 risk categories according to their

n Groups

tion39) p Value

12 0.66%) 0.11%) 0.016%) 0.12%) 0.32%) 0.90%) 0.79%) 0.32

25 0.529 0.016,695 0.052.9 0.21%) 0.30%) 0.6

0.6*0%)3%)7%)9 0.59%) 0.80.32 0.40.4 0.716 0.2

ents (% of sample).ses.

cardiographicg Group

iac Events

Risk Ratio(95% CI)

.48 (1.22–1.63)

.87 (2.06–4.01)

.08 (1.41–3.06)

.98 (1.24–3.16)

.88 (0.83–0.94)

.79 (2.53–5.67)

.73 (1.24–2.41)

.38 (1.13–1.68)

.95 (0.93–0.96)

.03 (2.92–5.55)

.59 (2.68–4.80)

.90 (1.58–5.31)

atio

lida2,8

�(5(2(5(5(7(1(1

����(7(1

(2(2(5�(4���

patispon

choelin

ard

re

1221

0

3

1

1

04

3

2

omposite score. Survival rate in each of these risk

MAY 15, 2004

Ft

Fcardiac death for patients in the modeling group according to their ri

CORONARY ARTERY DISEASE/MODEL TO P

categories was estimated by theKaplan-Meier method. (2) The vali-dation group: in this group, the riskmodel was applied. Patients were di-vided into 5 risk categories accord-ing to the estimated quintiles of therisk score obtained from the model-ing set. Groups were labeled as low,low-intermediate, intermediate, in-termediate-high, and high risk.Event-free survival rate in each ofthe predefined risk categories wasestimated in an analog fashion.

RESULTSThe study consisted of 3,231 men

and 2,448 women (mean age 62 � 12years). Of these patients, 1,075 (19%)had previous myocardial infarctions,4,104 (72%) had systemic hyperten-sion, 3,110 (55%) had hypercholester-olemia, and 2,959 (52%) were smok-ers. The pretest probability of coronaryartery disease was low in 1,618 pa-tients and intermediate in 1,460 pa-tients, and 2,601 patients had a knownor high probability of coronary arterydisease. Reasons for terminating theexercise stress test were fatigue in3,436 patients (61%), dyspnea in1,584 patients (28%), angina in 296patients (5%), arrhythmia in 45 pa-tients (1%), ST-segment changes in128 patients (2%), and leg distress in559 patients (10%), with some patientshaving �1 reason for terminating thestress test. Characteristics of patientsin the modeling and validation groupswere similar and are listed in Table 1.

Cardiac events: During follow-up(median 3 years, maximum 8), 315patients died. Cardiac events oc-curred in 282 patients, including car-diac death in 139 and nonfatal myo-cardial infarction in 143. Theseevents occurred at a median of 2years (range 1 day to 7.5 years) afterexercise echocardiography. Revascu-larization was performed in 460 pa-tients before any cardiac event. Re-vascularization procedures werecoronary artery bypass grafting in175 patients and coronary angio-plasty in 282 patients, and both pro-cedures in 3 patients. Revasculariza-tion was performed early (�3months) in 178 patients and late (�3months) in 282 patients. Univariatepredictors of all-cause mortality andcardiac events are listed in Table 2.All univariate predictors were con-sidered for inclusion in the model.

roup according

al infarction orsk categories.

ermined by

low-up (%)

4 yr

1.10.6

2.81.2

34.7

6.57

12.716.1

IGURE 1. Kaplan-Meier survival curves for patients in the modeling go their risk categories.

IGURE 2. Kaplan-Meier survival curves with freedom from myocardi

TABLE 3 Cumulative Mortality Rate According to Risk Category DetComposite Score

Risk Category (no. of patients)

Cumulative Mortality Rate at Fol

1 yr 2 yr 3 yr

LowModeling (566) 0 0.8 1.1Validation (630) 0 0.6 0.6

Low-intermediateModeling (568) 0.7 2 2.3Validation (560) 0.4 0.6 1.2

IntermediateModeling (566) 0.5 1.7 2.3Validation (572) 0.9 2.1 3.5

Intermediate-highModeling (568) 1.1 2.8 5.2Validation (511) 1.6 2.7 5.1

HighModeling (566) 1.8 6.7 9.9Validation (559) 3.8 8.3 12

REDICT MORTALITY BY EXERCISE ECHOCARDIOGRAPHY 1225

Ft

Fcardiac death for patients in the validation group according to their r

1226 THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 93

Prediction of events in the model-ing group: There were 151 deaths(5.3%; 66 cardiac deaths) and 77 non-fatal myocardial infarctions (143 hardcardiac events) during follow-up. Bymultivariate analysis of clinical, exer-cise stress, and echocardiographic datain the modeling group, predictors ofmortality were exercise wall motionscore index (chi-square 22.4, RR 2.17,95% CI 1.57 to 2.98, p �0.0001),workload (chi-square 17.1, RR 0.86,95% CI 0.8 to 0.92, p �0.0001), malegender (chi-square 15.4, RR 0.45, 95%CI 0.3 to 0.67, p �0.0001), and age(chi-square 5.5, RR 1.02, 95% CI 1 to1.04, p � 0.02). Predictors of hardcardiac events were exercise wall mo-tion score index (chi-square 32.7, RR2.58, 95% CI 1.86 to 3.57, p�0.0001), history of typical angina(chi-square 6, RR 1.57, 95% CI 1.1 to2.25, p � 0.01), male gender (chi-square 13.5, RR 0.46, 95% CI 0.3 to0.69, p � 0.002), and workload (chi-square 13, RR 0.89, 95% CI 0.83 to0.95, p � 0.0003).

Formulas were derived to definethe risk category by consideringscores for the independent predictorsof each end point.

All-cause mortality: Risk score �(�0.801 � gender [1 for men and 2for women]) � (0.022 � age inyears) � (�0.151 � metabolicequivalents) � (0.772 � exercisewall motion score index). Groupswere identified according to riskscores as: low risk, score ��0.8;low-intermediate risk, between �0.8and ��0.3; intermediate risk, be-tween �0.3 and �0.08; intermedi-ate-high risk, between 0.08 and�0.6; and high risk, �0.6.

Cardiac events: Risk score �(�0.783 � gender [men � 1, women� 2]) � (0.451 � chest pain code [1for the presence and 0 for the absenceof typical chest pain] � (�0.118 �metabolic equivalents) � (0.947 � ex-ercise wall motion score index).Groups were identified according torisk scores as: low risk, ��1.4; low-intermediate risk, between �1.4 and��1.1; intermediate risk, between�1.1 and ��0.8; intermediate-highrisk, between �0.8 and ��0.3; andhigh risk, ��0.3. Event-free survivalin the predefined risk categories areshown in Figure 1 for all-cause mor-tality and in Figure 2 for cardiac

y Determined

ollow-up (%)

4 yr

0.72.6

3.71.8

3.73.5

7.36.5

11.513.2

group according

al infarction or

TABLE 4 Cumulative Cardiac Event Rate According to Risk Categorby Composite Score

Risk Category (no. of patients)

Cumulative Cardiac Event Rate at F

1 yr 2 yr 3 yr

LowModeling (562) 0 0.2 0.2Validation (582) 0.2 1.1 1.1

Low-intermediateModeling (572) 0.3 1.5 1.8Validation (548) 0.5 1.3 1.8

IntermediateModeling (566) 0.8 1.7 2.9Validation (579) 0.3 1.4 2.5

Intermediate-highModeling (568) 1.1 1.5 4Validation (531) 1.9 3 4.8

HighModeling (566) 3 6.5 9.2Validation (566) 3 6.7 9.7

IGURE 3. Kaplan-Meier survival curves for patients in the validationo their risk categories.

IGURE 4. Kaplan-Meier survival curves with freedom from myocardi

events.isk categories.

MAY 15, 2004

d(cttesco

D

ccpe

crclewipplp

fidtc

Foequivalents.

Ftmotion score index (WMSI). Abbreviation as in Figure 5.

Validation group: There were 164 deaths (73 car-iac deaths) and 66 nonfatal myocardial infarctions139 cardiac events) in the validation group. Five riskategories were identified by applying the scores fromhe modeling group. The cumulative event rates inhese categories are listed in Tables 3 and 4. Estimatedvent-free survival by the Kaplan- Meier method ishown in Figure 3 for mortality and Figure 4 forardiac events. Examples of risk categorization basedn the score models are provided in Figures 5 and 6.

ISCUSSIONProper assessment of the risk of mortality and

ardiac events in patients with known or suspectedoronary artery disease is an important task for thehysician to select the appropriate management strat-

gy. Clinical, exercise stress testing, and exercise im- a

CORONARY ARTERY DISEASE/MODEL TO P

aging data have previously beenshown to be predictive of cardiacevents.7–16 However, the diversity ofparameters that predict cardiacevents may make it challenging forthe physician to estimate the risk in apatient. This is particularly evidentin patients who have some parame-ters predictive of a good prognosisand others parameters that predictadverse outcomes. The other diffi-culty lies in integrating the continu-ous variables. The use of parameters,such as wall motion score index andworkload, as continuous variablesprovides more information than theuse of cut-off values that do not takeinto account the differences withineach group. Additionally, estimationof risk requires knowledge of therelative contribution of each param-eter to the outcome.

This study included 5,697 pa-tients followed for a median of 3years after a symptom-limited exer-cise echocardiogram. Patients wereplaced into a modeling group, inwhich the predictors of events weredetermined. Independent predictorsof mortality were exercise wall mo-tion score index, lower workload,male gender, and age. Independentpredictors of cardiac events (cardiacdeath and nonfatal myocardial in-farction) were exercise wall motionscore index, a history of typical an-gina, male gender, and workload. Acomposite prognostic score of clini-cal, exercise, electrocardiographic,and echocardiographic data were de-rived. The derived score was used todivide patients into 5 risk categories.The applied risk model effectivelystratified patients into the validationgroup (p �0.0001). Patients whose

omposed scores indicated moderate-high and highisk had the highest event rates for mortality and hardardiac events. The differences between patients in theowest 3 quintiles were less striking. This may bexplained by the relatively low event rate in patientsho are able to perform an exercise stress test and the

nclusion of a large number of patients with lowretest probability of coronary artery disease. Theseatients have previously been shown to have a veryow event rate, and stress testing provided marginalrognostic information.17

Study limitations: We excluded patients with atrialbrillation and left bundle branch block because ofifferences in risk, feasibility, and image interpreta-ion in these patients. Thus, the results are not appli-able to these groups. Numbers used in the risk score

s combinationsmetabolic

a woman withance and wall

IGURE 5. Mortality risk in a 65-year-old woman according to variouf exercise performance and wall motion score index (WMSI). METs �

IGURE 6. Risk of cardiac death and nonfatal myocardial infarction inypical angina according to various combinations of exercise perform

re not simple and would require integration in a

REDICT MORTALITY BY EXERCISE ECHOCARDIOGRAPHY 1227

dGiei

1Ps12re13at4gw5Gmo6roCd7D

eAJ8p19Ocl1mt1d11vC1Ie41c21vs1D1e

1

atabase to enable utilization in clinical practice.rouping patients with regard to risk levels is appeal-

ng. However, it should be remembered that the modelxpresses a continuum of risk, and some informations lost with attempts to condense it into groups.

. McCully R, Roger V, Mahoney D, Karon B, Oh J, Miller FJ, Seward J,ellikka P. Outcome after normal exercise echocardiography and predictors ofubsequent cardiac events: follow-up of 1,325 patients. J Am Coll Cardiol998;31:144–149.. Attenhofer C, Pellikka P, Oh J, Roger V, McCully R, Shub C, Seward J. Iseview of videotape necessary after review of digitized cine-loop images in stresschocardiography? A prospective study in 306 patients. J Am Soc Echocardiogr997;10:179–184.. Dujardin K, Sarano M, Rossi A, Bailey K, Seward J. Echocardiographicssessment of left ventricular remodeling: are left ventricular diameters suitableools? J Am Coll Cardiol 1997;30:1534–1541.. Stamm R, Carabello B, Mayers D, Martin R. Two-dimensional echocardio-raphic measurement of left ventricular ejection fraction: prospective analysis ofhat constitutes an adequate determination. Am Heart J 1982;104:136–144.. Schiller N, Shah P, Crawford M, DeMaria A, Devereux R, Feigenbaum H,utgesell H, Reichek N, Sahn D, Schnittger I, Silverman N, Tajik A. Recom-endations for quantitation of the left ventricle by two-dimensional echocardi-

graphy. J Am Soc Echocardiogr 1989;2:358–367.. Armstrong W, Pellikka P, Ryan T, Crouse L, Zoghbi W. Stress echocardiog-aphy: recommendations for performance and interpretation of stress echocardi-graphy. Stress Echocardiography Task Force of the Nomenclature and Standardsommittee of the American Society of Echocardiography. J Am Soc Echocar-iogr 1998;11:97–104.. Gibbons R, Balady G, Beasley J, Bricker J, Duvernoy W, Froelicher V, Mark

, Marwick T, McCallister B, Thompson P, et al. ACC/AHA guidelines for p

228 THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 93

xercise testing: a report of the American College of Cardiology/American Heartssociation Task Force on practice guidelines (Committee on Exercise Testing).Am Coll Cardiol 1997;30:260–311.. Beller G, Zaret B. Contributions of nuclear cardiology to diagnosis andrognosis of patients with coronary artery disease. Circulation 2000;101:1465–478.. McCully R, Roger V, Mahoney D, Burger K, Click R, Seward J, Pellikka P.utcome after abnormal exercise echocardiography for patients with good exer-

ise capacity: prognostic importance of the extent and severity of exercise-relatedeft ventricular dysfunction. J Am Coll Cardiol 2002;39:1345–1352.0. Marwick T, Case C, Vasey C, Allen S, Short L, Thomas J. Prediction ofortality by exercise echocardiography: a strategy for combination with the Duke

readmill score. Circulation 2001;103:2566–2571.1. Elhendy A, Arruda A, Mahoney D, Pellikka P. Prognostic stratification ofiabetic patients by exercise echocardiography. J Am Coll Cardiol 2001;37:551–1557.2. Arruda A, Das M, Roger V, Klarich K, Mahoney D, Pellikka P. Prognosticalue of exercise echocardiography in 2,632 patients � 65 years of age. J Am Collardiol 2001;37:1036–1041.3. Bigi R, Desideri A, Galati A, Bax J, Coletta C, Fiorentini C, Fioretti P.ncremental prognostic value of stress echocardiography as an adjunct to exerciselectrocardiography after uncomplicated myocardial infarction. Heart 2001;85:17–423.4. Vasey C, Usedom J, Allen S, Koch G. Prognostic value of exercise echo-ardiography in women in the community setting. Am J Cardiol 2000;85:258–60.5. Arruda A, McCully R, Oh J, Mahoney D, Seward J, Pellikka P. Prognosticalue of exercise echocardiography in patients after coronary artery bypassurgery. Am J Cardiol 2001;87:1069–1073.6. Marcovitz P. Prognostic issues in stress echocardiography. Prog Cardiovascis 1997;39:533–542.7. Elhendy A, Shub C, McCully R, Mahoney D, Burger K, Pelllikka P. Exercisechocardiography for the prognostic stratification of patients with low pretest

robability of coronary artery disease. Am J Med 2001;111:18–23.

MAY 15, 2004