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STATE-OF-THE-ART PAPERS

Value of Exercise ECG forRisk Stratification in Suspectedor Known CAD in the Era ofAdvanced Imaging Technologies

Jamieson M. Bourque, MD, MHS,*y George A. Beller, MD*

JACC: CARDIOVASCULAR IMAGING CME

CME Editor: Ragavendra R. Baliga, MD

This article has been selected as this issue’s CME activity, available online

at http://www.acc.org/jacc-journals-cme by selecting the CME tab on the

top navigation bar.

Accreditation and Designation Statement

The American College of Cardiology Foundation (ACCF) is accredited by

the Accreditation Council for Continuing Medical Education (ACCME) to

provide continuing medical education for physicians.

The ACCF designates this Journal-based CME activity for a maximum

of 1 AMA PRA Category 1 Credit(s) �. Physicians should only claim

credit commensurate with the extent of their participation in the

activity.

Method of Participation and Receipt of CME Certificate

To obtain credit for this CME activity, you must:

1. Be an ACC member or JACC: Cardiovascular Imaging subscriber.

2. Carefully read the CME-designated article available online and in this

issue of the journal.

3. Answer the post-test questions. At least 2 out of the 3 questions

provided must be answered correctly to obtain CME credit.

4. Complete a brief evaluation.

5. Claim your CME credit and receive your certificate electronically by

following the instructions given at the conclusion of the activity.

From the *Cardiovascular Division and the Cardiovascular Imaging Center, D

System, Charlottesville, Virginia; and the yDepartment of Radiology, Un

Virginia. This work is supported by National Institutes of Health K-Award 5

grant support from Astellas Global Development. Dr. Beller has reported th

of this paper to disclose.

Manuscript received July 9, 2015; revised manuscript received September 15

CME Objective for This Article: After reading this article the reader should

be able to: 1) recognize additional tools to increase diagnostic and prog-

nostic utility in patients undergoing exercise stress electrocardiography;

2) compare and contrast the role of exercise stress electrocardiography in

women, the elderly, and patients with diabetes mellitus; and 3) apply a

stress testing algorithm that incorporates provisional myocardial perfu-

sion imaging based on exercise workload and stress ECG changes.

CME Editor Disclosure: JACC: Cardiovascular Imaging CME Editor

Ragavendra R. Baliga, MD, has reported that he has no relationships

to disclose.

Author Disclosures: Dr. Bourque has received research grant support

from Astellas Global Development. Dr. Beller has reported that he has no

relationships relevant to the contents of this paper to disclose.

Medium of Participation: Print (article only); online (article and quiz).

CME Term of Approval

Issue Date: November 2015

Expiration Date: October 31, 2016

epartment of Medicine, University of Virginia Health

iversity of Virginia Health System, Charlottesville,

K23HL119620-02. Dr. Bourque has received research

at he has no relationships relevant to the contents

, 2015, accepted September 23, 2015.

Bourque and Beller J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 8 , N O . 1 1 , 2 0 1 5

Exercise Testing in the Advanced Imaging Era N O V E M B E R 2 0 1 5 : 1 3 0 9 – 2 1

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Value of Exercise ECG for R

isk Stratification inSuspected or Known CAD in the Era ofAdvanced Imaging Technologies

ABSTRACT

Exercise stress electrocardiography (ExECG) is underutilized as the initial test modality in patients with interpretable

electrocardiograms who are able to exercise. Although stress myocardial imaging techniques provide valuable diagnostic

and prognostic information, variables derived from ExECG can yield substantial data for risk stratification, either sup-

plementary to imaging variables or without concurrent imaging. In addition to exercise-induced ischemic ST-segment

depression, such markers as ST-segment elevation in lead aVR, abnormal heart rate recovery post-exercise, failure to

achieve target heart rate, and poor exercise capacity improve risk stratification of ExECG. For example, patients

achieving $10 metabolic equivalents on ExECG have a very low prevalence of inducible ischemia and an excellent

prognosis. In contrast, cardiac imaging techniques add diagnostic and prognostic value in higher-risk populations (e.g.,

poor functional capacity, diabetes, or chronic kidney disease). Optimal test selection for symptomatic patients with

suspected coronary artery disease requires a patient-centered approach factoring in the risk/benefit ratio and cost-

effectiveness. (J Am Coll Cardiol Img 2015;8:1309–21) © 2015 by the American College of Cardiology Foundation.

D espite considerable improvements in theidentification and treatment of coronary ar-tery disease (CAD), this condition remains

highly morbid and is the most common cause of deathin the Western world (1). Concomitantly, the numberof noninvasive radionuclide and echocardiographicimaging studies performed to identify ischemic heartdisease has grown considerably. More than 9 millionmyocardial perfusion imaging (MPI) studies were per-formed in 2008, at a cost of >$1 billion, with theadded risk of radiation exposure (2,3).

The latest American College of Cardiology (ACC)/American Heart Association (AHA) guidelines on ex-ercise testing, diagnosis, and management of stableischemic heart disease and ACC/AHA appropriate usecriteria for cardiac radionuclide imaging recommendexercise stress electrocardiography (ExECG) as theinitial diagnostic test in patients at intermediate pre-test risk who are able to exercise and have an inter-pretable resting electrocardiogram (4–6). Despitethese recommendations, the majority of patients stillundergo stress imaging as the initial testing strategy.In the PROMISE (Prospective Multicenter ImagingStudy for Evaluation of Chest Pain) trial, examiningthe comparative effectiveness of an anatomicalversus functional testing approach to evaluatesymptoms concerning for ischemia at leading aca-demic medical centers, 89.8% of those undergoingstress testing had imaging performed (7). A broaderadministrative database found a similarly high 75%rate of imaging performed with stress testing (8). Thisfinding is stable over time and likely occurs due to a

widespread perception that ExECG alone has insuffi-cient diagnostic accuracy for CAD detection (9).

As many as 60% to 70% of MPI studies ordered forCAD detection are normal (10,11). Advanced imagingmodalities, such as positron emission tomography(PET) and cardiovascular magnetic resonance MPI,and improved single-photon emission computed to-mography (SPECT) hardware and protocols can in-crease the diagnostic accuracy of stress imaging witha reduction in radiation exposure. This shifts thependulum toward the performance of stress MPI.However, the rationale for using ExECG alone as theinitial test for CAD detection, particularly in patientswith good exercise tolerance, has become morecompelling with the publication of new medical data(12,13).

This review will summarize the latest advances inExECG and explore its application in the era ofadvanced imaging technologies. We will show thatthis diagnostic testing modality should still play amajor role in the noninvasive evaluation of patientswith symptoms of suspected ischemic CAD.

DIAGNOSTIC AND PROGNOSTIC VALUE OF

EXERCISE ST-SEGMENT CHANGES

A meta-analysis of 24,047 patients in 147 studiesfound ExECG to have a pooled sensitivity of 68% andspecificity of 77% for detection of CAD (14). Restrict-ing the analysis to the 3 studies free of workup biaslowered sensitivity considerably to 50% andincreased the specificity to 90% (6). ExECG has a

AB BR E V I A T I O N S

AND ACRONYM S

CAD = coronary artery disease

CT = computed tomography

DTS = Duke Treadmill Score

ECG = electrocardiogram

ExECG = exercise stress

electrocardiography

LV = left ventricular

MET = metabolic equivalent

MPI = myocardial perfusion

imaging

PET = positron emission

tomography

SPECT = single-photon

emission computed

graphy

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positive likelihood ratio of 2.18 and a negative likeli-hood ratio of 0.32 for CAD (15). Confounders such asresting ST-segment depression, digoxin usage, andleft ventricular (LV) hypertrophy with repolarizationchanges decrease specificity, whereas mild single-vessel disease decreases sensitivity. Despite theseconfounders, ExECG is still considered diagnostic inmost patients able to reach 85% of their maximumage-predicted heart rate.

Exercise-induced ST-segment depression is also apowerful predictor of cardiac events. Two landmarkstudies of large, predominately male populationsfound the presence and extent of ST-segmentdepression to be a powerful prognostic marker. Inthe Duke study of 2,842 patients, the maximum ST-segment deviation was the strongest predictor ofboth cardiac death and a composite of cardiac deathand nonfatal myocardial infarction (MI (16). A CASS(Coronary Artery Surgery Study) database analysis byWeiner et al. (17) found the extent of ST-segmentdepression to be 1 of the 2 most powerful prognosticmarkers of exercise testing, along with the durationof exercise. Patients who could reach stage 3 of theBruce protocol with <1 mm ST-segment depressionhad a yearly mortality rate of <1%. In contrast, pa-tients with $1 mm ST-segment depression who wereunable to complete stage 1 of the Bruce protocol had a5% yearly mortality rate.

ADDITIONAL TOOLS TO INCREASE

DIAGNOSTIC AND PROGNOSTIC UTILITY

EXERCISE CAPACITY. There are many additionalvariables that supplement ST-segment depressionand add to the diagnostic and prognostic utility ofExECG. The most powerful of these is exercisecapacity.

Multiple studies have correlated exercise workloadto the likelihood of significant myocardial ischemiaon MPI and subsequent events. Bourque et al. (18)found that patients attaining <7 metabolic equiva-lents (METs) had an 18-fold higher prevalence ofsubstantial ($10%) LV ischemia compared with thosereaching $10 METs. The latter group with good ex-ercise tolerance had a very low (0.4%) prevalenceof $10% LV ischemia (Figure 1) (18). A follow-upanalysis of the cohort reaching $10 METs revealedvery low rates of cardiac death (0.1%/year) andnonfatal MI (0.7%/year) (19). The favorable diagnosticand prognostic effect of achieving a high exerciseworkload has been confirmed in multiple subsequentstudies, including a Canadian cohort of 9,605 pa-tients and an analysis using patients who underwentexercise echocardiography (20,21). In the Canadian

population, there was a 1% risk of $10% LVischemia and a death or MI rate <2% even inthose with $5% LV ischemia. Some studieshave shown exercise echocardiography andMPI to retain prognostic significance afteraccounting for workload (22,23). The degreeof benefit and whether improved diagnosticaccuracy and prognostic assessment warrantroutine imaging are key issues. Patients withprior MI might be 1 subgroup that benefits(22).

Prior studies have shown similar prog-nostic utility using exercise capacity as acontinuous variable. The value of exercisecapacity is consistent in both those with andwithout known CAD (17,24). In a cohort of3,400 patients who underwent thallium-201

MPI, exercise capacity was even a stronger predictorof mortality than the extent of perfusion defects.High exercise workload is also a marker of adecreased risk of cardiac events, including cardiacdeath, nonfatal MI, and coronary revascularization(19,25–27). These associations remain even in thesetting of ischemic ST-segment depression.

Other surrogates of exercise capacity have diag-nostic and prognostic value, such as the rate-pressureproduct, which predicts the probability of 3-vessel orleft main CAD (28). Composite clinical scores, such asthe Duke Treadmill Score (DTS), provide addedprognostic information by combining multiple pre-dictors into 1 measure. The DTS incorporates exerciseduration, exercise-induced ST-segment changes, andstress-induced angina (16). It is a strong indicator ofany and multivessel obstructive disease and mortality(Figure 2). The DTS is most useful when it falls in thehigh- and low-risk groups. MPI is useful in riskstratifying patients with an intermediate DTS (29).

STRESS ELECTROCARDIOGRAPHIC FINDINGS

BEYOND ST-SEGMENT DEPRESSION

Markers other than exercise-induced ST-segmentdepression have diagnostic and prognostic value, suchas the rapidity of recovery of ST-segment changes(30,31). Christman et al. (30) found a low 2% rate ofpositive imaging or findings of CAD on angiographyand a 0.7% rate of a composite endpoint of cardio-vascular death, nonfatal MI, or coronary revasculari-zation in patients with a positive exercise treadmilltest but rapid ST-segment recovery (Figure 3). Otherpotential enhancements to the standard dichotomouspresence of $1 mm ST-segment depression includeheart rate adjustment in the form of the ST/heart rateslope and ST/heart rate index.

tomo

FIGURE 2 Duke Tr

DukeTreadmillScore

Angina Index

0 – none, 1 – ty

=

≥ 5

-10 to 4

≤ -11

Score

Low

Inte

Hig

Ris

Equation for calculati

high-risk groupsbase

all-cause mortality. A

FIGURE 1 Prevalence of Increasing Percentages of LV Ischemia Stratified by Exercise Workload in Patients Undergoing

Exercise Stress Electrocardiography

20

16

12

8

4

0

Pat

ien

ts (

%)

Exercise Workload Achieved

< 7 Mets(n = 267)

7.1%

7 - 9 Mets(n = 234)

4.3%

≥ 10 Mets(n = 473)

0.4%

Overallp < 0.001

1 - 4% LV ischemic 5 - 9% LV ischemic ≥ 10% LV ischemic

There was a significant decrease in prevalence of ischemia as the workload achieved increased. LV ¼ left ventricular; METs ¼ metabolic

equivalents. Reprinted with permission from Bourque et al. (18).

Bourque and Beller J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 8 , N O . 1 1 , 2 0 1 5

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Lead aVR is often neglected in ExECG interpretationbut has unique vector positioning. This allows it tofunction as a “pseudo-intracavitary” lead that mayidentify anterior wall transmural ischemia (32). Utha-malingam et al. (33) found a $1 mm aVR elevationduring ExECG to be the strongest predictor of anobstructive left main or ostial left anterior descendingartery stenosis with a diagnostic accuracy of 80% and a

eadmill Score Calculation and Utility

pical angina, 2 – angina causing test cessation

Exercise

(min)

ST5 (Deviation)

(mm)4- - Angina

Index( )

rmediate

h

40.1%

67.3%

99.6%

23.7%

55.0%

93.7%

0.25%

1.25%

5.25%

k GroupStenosis≥ 75%

MultivesselDisease

1-YearMortality

Duration

on of the Duke Treadmill Score and division into low-, intermediate-, and

don likelihoodofhavinga stenosis$75%,multivessel disease, and 1-year

dapted with permission fromMark et al. (16,100) and Shaw et al. (101).

2.6-fold increase in post-test probability. A major lim-itation of the current aVR data is the absence of studiesexamining imaging findings and events in the generalpopulation not undergoing invasive angiography.

Other suggested measurements on standard ExECGthat may have diagnostic value include changes inQRS duration, R-wave amplitude, and length of therate-adjusted QT interval (34). A novel marker notroutinely available but with substantial potential as auseful adjunct to ST-segment depression is high-frequency mid-QRS analysis, an interrogation of thesignal in the 150 to 250 Hz frequency (Figure 4). Anabnormal high-frequency mid-QRS signal increasesthe sensitivity of ischemia detection from 39% to 69%(p < 0.005) and the specificity from 82% to 86%(p < 0.05) (35). This promising tool requires addi-tional validation in independent cohorts and withassessment of cardiac events before it can beroutinely applied in clinical practice.

PHYSIOLOGICAL MARKERS AND SYMPTOMS

Several physiological markers during stress testingcan augment the diagnostic accuracy of ExECG andhave prognostic importance. These include the heartrate and blood pressure responses to exercise andsymptoms during testing (36).

An impaired chronotropic response has beenassociated with a >2-fold increase in perfusion

FIGURE 3 Frequency of Positive Downstream Imaging and Invasive Angiography by Stress ECG Findings

100

80

60

40

20

0

Fre

qu

ency

of

Test

Res

ult

s (%

)

n = 81

+ETT, butRapid Recovery

Yield of Both Noninvasive and Invasive Downstream Testing

yduts gnigami dna htaC evitageNyduts gnigami ro htaC evitisoP Inconclusive imaging study

2%5%

93%

n = 63

-ETT, but

8%

2%

90%

n = 19

+ETT, butBaseline

ECG Changes

16%

84%

n = 74

SubmaximalExercise

19%

4%

77%

n = 41

+TypicalAngina, -ETT

2%

35%

63%

n = 94

+ETT

1%

39%

60%

Reprinted with permission from Christman et al. (30). ECG ¼ electrocardiographic; ETT ¼ exercise treadmill testing.

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defects and a higher risk of CAD and cardiac events(37,38). Heart rate recovery post-exercise also carriessignificant diagnostic and prognostic power. Coleet al. (39) found a relative risk of death of 2.0 (95%confidence interval: 1.5 to 2.7; p < 0.001) for thosewith a <12-beats/min heart rate drop 1 min post-exercise after risk factor adjustment in 2,428 pa-tients. A retrospective analysis of 2,193 men found aheart rate recovery <22 beats/min at 2 min to bepredictive of mortality and the presence of CAD (40).Heart rate recovery retains its prognostic influence inpatients with known CAD (41).

Changes in blood pressure response during ExECGare also potential indicators of CAD, although lessvalidated than changes in heart rate. The systolicblood pressure (SBP) typically decreases at least 15%by 3 min post-exercise. An abnormal SBP recoveryratio of >0.9 (SBP at 3 min/SBP at peak exercise) hasbeen found to have comparable diagnostic accuracy toST-segment depression and incremental value for theidentification of CAD (42). This same ratio correlateswith the extent and severity of thallium-201 perfusiondefects (43). A >10-mm Hg SBP drop during exerciseand a delayed decline in SBP after exercise have beenassociated with high-risk multivessel or left maindisease in men with less specificity in women (44–46).

Treadmill-induced typical angina increases thesensitivity for the diagnosis of CAD and indicates

more extensive myocardial ischemia and higher eventrates, particularly in the setting of ischemic ST-segment depression (47–49). The risk of events issubstantially higher when symptoms are induced at alower workload (47).

SPECIAL POPULATIONS

WOMEN. The pioneering work on ExECG was done inpredominately male populations. Although the prev-alence of CAD is less than in men, the mortality fromCAD in women is higher (49,50). There are uniquechallenges in the female population, as women oftenpresent with more atypical symptoms at an older age(51). Moreover, the diagnostic accuracy of ExECG islower in women. The pooled sensitivity and speci-ficity in 3,721 women from 19 studies were 61% and70%, respectively, compared with 68% and 77% inmen (14,52). The decreased specificity of ST-segmentdepression in women is thought to be partially due toa digoxin-like estrogen effect, lower electrocardio-gram (ECG) voltage, and an increased prevalence ofbaseline ST-T changes (50,51,53,54).

The lower prevalence of CAD in women decreasesthe positive predictive value of a positive testcompared with men (50). Barolsky et al. (55) foundthe positive predictive value in women to be 47%compared with 77% in men; the negative predictive

FIGURE 4 HF-QRS Analysis

High ResolutionECG

2 mV

10 µV

HF

QR

S (µV

)

90 ms

HFQRS Reduction

Alignment andAveraging

Filtering(150 to 250 Hz)

IntensityMeasurement(Root-Mean-Square)

HFQRS Reductionin each Lead

Max HFQRS

Min HFQRS

A

Averaged ECGB

HFQRS SignalC

Time-intensityCurve perLead

D

12 Lead BasedIndex of Ischemia

E

Exercise

Index of Ischemia

Recovery

ƒ

Multiple representative QRS complexes are aligned and averaged. The signal in the 150 to

250 Hz frequency band is measured in each of the standard 12 leads, and a time intensity

curve is generated. A decrease in the HF-QRS signal that is both $50% and $1 mV in 3 or

more leads is concerning for ischemia. ECG ¼ electrocardiogram; HF-QRS ¼ high-

frequency QRS. Reprinted with permission from Sharir et al. (35).

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value was not significantly different (78% for womenvs. 81% for men). Therefore, although an abnormaltest result in women has a higher likelihood of beingfalsely positive, a negative study is equally effectiveat ruling out disease. Due to this high negative pre-dictive value, existing guidelines recommend ExECGas the initial study of choice in women at intermedi-ate risk for CAD who are able to exercise (6,50).

As with men, ExECG has significant prognosticvalue in women, especially when combined withadditional variables such as exercise capacity andheart rate recovery. Exercise capacity is more pre-dictive of mortality in men (hazard ratio: 2.89 in men,0.99 in women). Nevertheless, the DTS has preserved

diagnostic and prognostic power in women (51).Chronotropic incompetence has a stronger relation-ship with MI in women (hazard ratio: 2.79 vs. 1.29)(56). In asymptomatic women, ST-segment depres-sion has not been found to be predictive of cardiac orall-cause mortality (57).

Many clinicians refer women directly to MPI due toconcern about ExECG accuracy. This argument wasrefuted by the WOMEN (What Is the Optimal Methodfor Ischemia Evaluation in Women) trial, in which 824symptomatic women with good exercise tolerancewere randomized to ExECG with or without MPI. Thegroup without MPI had a 48% diagnostic cost savingswith no difference in major adverse cardiac eventsover 2 years of follow-up (58). This study supports astrategy of ExECG as the initial form of ischemiaevaluation in women able to exercise with an inter-pretable ECG, as recommended for men.

DIABETES MELLITUS. Patients with diabetes mellitusare an important subpopulation of those undergoingstress testing. The presence and severity of CAD aregreater in patients with diabetes, and the prevalenceof this comorbidity is rapidly increasing (59). Diabeticpatients are particularly challenging because theyoften present with atypical symptoms, and there is ahigh prevalence of silent ischemia in asymptomaticpatients (60). These factors have led to a high rate ofstress testing in patients with diabetes.

ExECG appears to have similar diagnostic accuracyand prognostic significance in patients with andwithout diabetes (59,61). However, imaging hastypically been performed in this subpopulation, andhistorical rates of SPECT abnormalities as high as 47%to 59.5% have supported this practice (62,63).

However, the prevalence of ischemia and riskof future cardiac events may be decreasing withcontemporary aggressive medical therapy in diabeticpatients. A recent study of predominately symptom-atic stable diabetic outpatients found a 21.8% risk ofany ischemia, a lower than expected 5.0% prevalenceof $10% LV ischemia, and a low rate of cardiac death/nonfatal MI (0.6%/year), especially given that 40.3%of patients had known CAD (64). Diabetic patientswho achieve higher workloads on ExECG ($5 METs inPadala et al. [65], $10 METs in Bourque et al. [18]) incontemporary cohorts have a low risk of future car-diac events similar to nondiabetic patients (Figure 5).

Advanced imaging modalities can provide addi-tional risk stratification in the diabetic population.The presence of a nonzero computed tomographic(CT) coronary calcium score, unrecognized myocardialscar by cardiovascular magnetic resonance, andreduced flow reserve by PET MPI all identify an

FIGURE 5 Survival by Diabetes Status and Stress Exercise Workload Achieved

1.0

0.9

0.8

0.7

0.6

0.5

Cu

mu

lati

ve S

urv

ival

0.0 1.0

Log rank

p < 0.001

2.0 3.0 4.0 5.0 6.0

DM, METs ≥ 5

NDM, METs ≥ 5

DM, METs < 5

NDM, METs < 5

Follow-up Interval (Years)

Patients able to achieve $5 METs of exercise workload have a similar survival irrespective of diabetes status. DM ¼ diabetes mellitus; METs ¼metabolic equivalents; NDM ¼ no diabetes mellitus. Reprinted with permission from Padala et al. (65).

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increased risk of cardiac events (66–69). Whetherthese patients should have more aggressive treatmentgoals remains to be determined.

Given these complex factors, the decision ofwhether to image patients with diabetes must beindividualized. Diabetic patients with good func-tional capacity who are deemed able to achieve a highexercise workload may receive sufficient risk strati-fication with ExECG alone. However, for higher-riskpatients with diabetes, such as those with poor ex-ercise tolerance, LV dysfunction, nephropathy,vascular disease, or an abnormal resting ECG, and inthose in whom microvascular disease is suspected,implementation of cardiac imaging may significantlyaid in risk stratification.

ELDERLY. Age is not a consideration in the recom-mendation for ExECG in the current guidelines onexercise testing (6). However, functional limitationsand comorbidities in the elderly lead to a higher rate ofnecessary conversion to pharmacological stress im-aging. Moreover, the elderly are not well representedin studies examining the diagnostic and prognosticvalue of ExECG. They are an important subgroup giventheir higher prevalence of CAD and cardiac events.

Studies that have been performed in the elderlyconfirm the prognostic importance of exercise ca-pacity (70,71). However, ST-segment depression didnot predict cardiac events in a cohort of 514 elderly

patients $65 years of age; the DTS did not haveprognostic benefit in another elderly cohort (70,72).Yet, SPECT perfusion defects were associated withcardiac death in the same elderly cohort (73).Abnormal SPECT imaging also predicts nonfatal MIand coronary revascularization in the elderly(71,74,75). These findings suggest that imaging shouldbe considered in the initial workup to detect CAD inthe elderly.

Advances in imaging technology have a substantialeffect in the elderly population. Given the lowerlifetime attributable risk of cancer in older patients,reductions in radiation are less of an issue, althoughstill beneficial (76). The shortened protocols possiblewith PET imaging and newer SPECT cameras can behelpful in this cohort with a higher likelihood ofmusculoskeletal pain and other mechanical limita-tions that complicate long table times. Sufficientlevels of stress are less likely in the elderly due todecreases in exercise capacity and a higher potentialfor chronotropic incompetence. Combined protocolscan ameliorate this issue, facilitating the collection ofexercise data followed by vasodilator administrationto ensure a diagnostic test.

BASELINE ECG ABNORMALITIES

Several baseline ECG abnormalities affect the testcharacteristics of ExECG. In a cohort of 1,282 patients

CENTRAL ILLUSTRATION Stress Test Selection and Performance Algorithm

Higher-risk patients with unique clinical needs, such as assessment of microvascular function, can receive advanced ischemia imaging. In the remainder, those unable to

exercise or with an uninterpretable ECG receive pharmacological MPI. Patients able to exercise with known CAD in whom defect quantification is needed undergo

exercise stress MPI. If they do not achieve 85% MAPHR, they receive pharmacological MPI under a combined protocol. All others undergo ExECG with provisional

imaging. If they achieve $10 METs and have no ST-segment changes, they undergo evaluation for nonischemic chest pain or receive medical therapy. Unexpected

negative results in patients with high pre-test risk can trigger calcium scoring for additional risk stratification. All others undergo exercise MPI or a combined protocol

with pharmacological stress if they are unable to achieve an adequate exercise heart rate ($85% MAPHR). CAD ¼ coronary artery disease; CMR ¼ cardiac magnetic

resonance; CT ¼ computed tomography; ECG ¼ electrocardiogram; ExECG ¼ exercise stress electrocardiography; MAPHR ¼ maximum age-predicted heart rate; METs ¼metabolic equivalents; MPI ¼ myocardial perfusion imaging; PET ¼ positron emission tomography; Rx ¼ treatment.

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referred for chest pain evaluation, resting ST-segment depression <1 mm increased the sensitivityof ExECG from 45% to 77% but decreased specificityfrom 84% to 48% with no change in overall diagnosticaccuracy (6,77).

Patients with left bundle-branch block (LBBB)require imaging due to a high false-positive rate(78,79). The role of ExECG in the setting of rightbundle-branch block (RBBB) is less clear. ST-segmentchanges in the anterior precordial leads have a false-positive rate of 66%, but specificity is preserved inleads V5 and V6 (80). Yen et al. (81) found a decreasedsensitivity of 27% but a preserved specificity of 87%using leads V5 and V6 in 133 patients, the largestcohort studied with RBBB. Yet, Susmano and Teran(82) showed an excellent sensitivity of 89%, althoughonly 12 patients were analyzed. The ACC/AHA exer-cise testing guidelines support the use of ExECG inRBBB (6).

IMPORTANCE OF REACHING ‡85% MAXIMUM

AGE-PREDICTED HEART RATE

Given the late occurrence of ECG changes in theischemic cascade and known limited sensitivity ofExECG, reaching an adequate level of workload andheart rate is essential. Heller et al. (83) found thatreaching only 70% compared with $85% of maximumage-predicted heart rate leads to a reduction in theincidence of stress defects from 100% to 47% and areduction in angina from 84% to 26%. Subsequentstudies in patients not achieving target heart rateshave found reductions in the degree and extent ofischemia on MPI, with decreases seen irrespective ofthe number of diseased vessels (84,85). Combinationprotocols with vasodilator administration in thoseunable to achieve sufficient exercise workload sub-stantially improve the diagnosis of ischemia and aresafe and feasible (86,87). In 1 study of symptomaticpatients, receiving a combination protocol increasedischemic segments from 7 to 40 (88).

PATIENT-CENTERED APPROACH TO

ISCHEMIA EVALUATION

Advances in imaging technology have created a broadmenu of options for the evaluation of ischemic heartdisease that facilitate a patient-centered approach toischemia evaluation (89). Patient symptoms, comor-bidities, and functional status are used to identifywhich array of appropriate tests is considered. Pa-tients are referred for the test that provides the mostclinically meaningful information with the least risk,cost, and inconvenience.

In many patients, adequate risk stratification isachieved with a simple strategy of ExECG withoutimaging. A study of the yield of downstream testingand subsequent cardiac events in 3,656 patients un-dergoing ExECG found low rates of referral to MPI(9.0%) and invasive angiography (2.3%) (30). Over a2.5-year mean follow-up, the rate of cardiac death,nonfatal MI, and coronary revascularization was verylow in those with negative (0.2%) and inconclusive(1.3%) stress studies. A large administrative databasefound a similarly low 6.9% rate of invasive angiog-raphy at 1 year. In the functional testing subgroup ofthe PROMISE trial, those who underwent stress elec-trocardiography had a similarly low rate of the com-bined endpoint of adverse cardiac outcomes as thosewho underwent imaging (7). These data support aninitial strategy of ExECG alone in appropriatepatients.

Stress MPI provides minimal incremental value inpatients with a low-risk exercise stress test, a low-riskDTS, or a high rate-pressure product without ST-segment depression (18,28,90,91). In addition, thelow cardiac event rates in stable patients treatedmedically in recent landmark studies such asCOURAGE (Clinical Outcomes Utilizing Revasculari-zation and Aggressive Drug Evaluation) and BARI-2D(Bypass Angioplasty Revascularization Investigation2 Diabetes) have challenged the paradigm of selectingcoronary revascularization as the initial therapeuticstrategy, potentially reducing the need for identifi-cation of low-levels of ischemia (92,93).

However, despite the low risk of events withnegative ExECG, there continues to be widespreaduse of concurrent imaging (9). Novel protocols thatadd additional testing in specific higher-risk situa-tions may encourage a strategy of ExECG alone.

NOVEL PROTOCOLS

Two novel protocols that refine ExECG and reducethe likelihood of missing significant ischemia are theuse of provisional MPI in patients unable to achievea high exercise workload and the incorporation ofcoronary calcium scoring. Given the low prevalenceof significant ischemia and cardiac events in pa-tients able to achieve 10 METs, Duvall et al. (94)reviewed a hypothetical protocol where MPI wouldnot be performed in patients who were <65 yearsof age, had no known CAD and an interpretablerest ECG, and achieved a diagnostic heart rateand $10 METs without significant exercise-inducedECG changes or symptoms. In this low-risk subset,there was a very low rate of significant ($10%) LVischemia (0.6%/year), 5.9% abnormal studies, and a

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98.9% 5-year survival, comparable to the favorablesurvival after negative MPI. Limitations of this pro-visional MPI testing approach include the low numberof patients able to avoid imaging (29% in this study),test supervision issues, patient and physician sup-port, and incompatibility with the current insurancepayment models (95). Further refinement of thisconcept is necessary before it will be ready foradoption.

An additional method of improving the diagnosticaccuracy of ExECG is to add coronary calcium scoringunder certain higher-risk circumstances, such as inpatients with particularly high pre-test risk, a sus-pected false-positive ST-segment response, or typicalangina and negative ExECG. A coronary calciumscore >0 has 98% sensitivity for coronary athero-sclerosis, reducing the likelihood of a false negativeevaluation (96). Identification of nonobstructive CADcan also guide the intensity of medical therapy (97).Rozanski et al. (98) showed a low risk of inducibleischemia in patients with low to intermediate pre-test probability of disease and a coronary calciumscore <400. This approach may be especially usefulif combined with exercise workload. The demon-stration of a 0 coronary calcium score in higher-riskpatients able to achieve 10 METs with negativeExECG would provide further evidence of low post-test risk of significant CAD, thereby eliminating theneed for more costly downstream imaging (CentralIllustration). The optimal protocols to most effec-tively integrate coronary calcium scoring have notbeen developed and would need additional studywith outcomes assessment prior to widespreadadoption.

CONCLUSIONS

The studies cited in this review strongly suggestthat ExECG remains the recommended method ofinitial evaluation in intermediate-risk patients with

symptoms consistent with CAD. This approach issupported by a large and growing number of supple-mentary variables, such as exercise workload achievedand ECG changes beyond ST-segment depression, thatimprove diagnostic accuracy and provide incrementalprognostic information. Moreover, there is increasingevidence in the published data suggesting that revas-cularization may only be beneficial in patients withhigh levels of ischemia (92,99). At the same time, ad-vances in imaging technology have improved diag-nostic accuracy while decreasing test duration andradiation exposure, thereby shifting the risk/benefitratio toward imaging in higher-risk patients whocannot achieve a high workload or attain their targetheart rate on ExECG.

A stress test selection and performance algorithmis provided in the Central Illustration that incor-porates myocardial imaging in select patients withspecial clinical needs, provisional imaging in patientsunable to achieve a high workload, calcium scoring asfurther evaluation after unexpected negative results,and adjunctive pharmacological stress in those un-able to achieve diagnostic heart rates. Novel imagingprotocols and optimal patient selection may assistwith appropriate utilization of cardiac imaging tech-nologies, when necessary, to complement ExECG.Application of an algorithm such as this could resultin substantial savings to the healthcare systemwithout reducing the quality of care. Additionalresearch with prospective outcome studies is neededto refine these approaches.

ACKNOWLEDGMENT The authors thank ChristopherKramer, MD, for his assistance in the preparation ofthis manuscript.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Jamieson M. Bourque, Cardiovascular Division,Department of Medicine, University of Virginia HealthSystem, Box 800158, 1215 Lee Street, Charlottesville,Virginia 22908. E-mail: jbourque@virginia.edu.

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KEY WORDS exercise stresselectrocardiography, myocardial ischemia,risk stratification

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