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iREVIEWSS T A T E - O F - T H E - A R T P A P E R S

Comparative Definitions for Moderate-Severe Ischemia in Stress Nuclear,Echocardiography, and MagneticResonance Imaging

Leslee J. Shaw, PHD,* Daniel S. Berman, MD,y Michael H. Picard, MD,zMatthias G. Friedrich, MD,x Raymond Y. Kwong, MD,k Gregg W. Stone, MD,¶

Roxy Senior, MD,# James K. Min, MD,** Rory Hachamovitch, MD, MSC,yyMarielle Scherrer-Crosbie, MD,z Jennifer H. Mieres, MD,zz Thomas H. Marwick, MD,xxLawrence M. Phillips, MD,kk Farooq A. Chaudhry, MD,¶¶ Patricia A. Pellikka, MD,##

Piotr Slomka, PHD,*** Andrew E. Arai, MD,yyy Ami E. Iskandrian, MD,zzzTimothy M. Bateman, MD,xxx Gary V. Heller, MD, PHD,kkk Todd D. Miller, MD,##

Eike Nagel, MD,¶¶¶ Abhinav Goyal, MD,* Salvador Borges-Neto, MD,###

William E. Boden, MD,**** Harmony R. Reynolds, MD,kk Judith S. Hochman, MD,kkDavid J. Maron, MD,yyyy Pamela S. Douglas, MD,zzzz for the National Institutes of

Health/National Heart, Lung, and Blood Institute–Sponsored ISCHEMIA Trial Investigators

Atlanta, Georgia; Los Angeles and Stanford California; New York, Manhasset, and Albany, New York;Boston, Massachusetts; Montreal, Quebec, Canada; London, United Kingdom; Cleveland, Ohio;Hobart, Australia; Rochester, Minnesota; Bethesda, Maryland; Birmingham, Alabama;Kansas City, Missouri; Hartford, Connecticut; and Durham, North Carolina

The lack of standardized reporting of the magnitude of ischemia on noninvasive imaging contributes

to variability in translating the severity of ischemia across stress imaging modalities. We identified

the risk of coronary artery disease (CAD) death or myocardial infarction (MI) associated with $10%

ischemic myocardium on stress nuclear imaging as the risk threshold for stress echocardiography

and cardiac magnetic resonance. A narrative review revealed that $10% ischemic myocardium on

stress nuclear imaging was associated with a median rate of CAD death or MI of 4.9%/year

(interquartile range: 3.75% to 5.3%). For stress echocardiography, $3 newly dysfunctional segments

portend a median rate of CAD death or MI of 4.5%/year (interquartile range: 3.8% to 5.9%). Although

imprecisely delineated, moderate-severe ischemia on cardiac magnetic resonance may be indicated

by $4 of 32 stress perfusion defects or $3 dobutamine-induced dysfunctional segments. Risk-based

thresholds can define equivalent amounts of ischemia across the stress imaging modalities, which

will help to translate a common understanding of patient risk on which to guide subsequent

management decisions. (J Am Coll Cardiol Img 2014;7:593–604) ª 2014 by the American College of

Cardiology Foundation

From the *Department of Medicine, Division of Cardiology, Emory University, Atlanta, Georgia; yDepartment of Med-

icine, Division of Cardiac Imaging/Nuclear Cardiology, Cedars-Sinai Medical Center, Los Angeles, California;

zDepartment of Medicine, Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts; xDepartment

of Medicine, Division of Cardiology, Montreal Heart Institute, Montreal, Quebec, Canada; kDepartment of Medicine,

A B B R E V I A T I O N S

A N D A C R O N YM S

CAD = coronary artery

disease

CMR = cardiac magnetic

resonance

MI = myocardial infarction

NHLBI = National Heart,

Lung, and Blood Institute

NIH = National Institutes

of Health

OMT = optimal medical

therapy

PCI = percutaneous

coronary intervention

SIHD = stable ischemic

heart disease

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Stress imaging is commonly used to evaluate sus-pected myocardial ischemia in patients with symp-toms suggestive of stable ischemic heart disease(SIHD). The evidence to support the use of severalstress imaging modalities is substantial and hasbeen synthesized in recent appropriate use criteriaand clinical practice guidelines (1–3). The publishedevidence base for stress nuclear imaging and echo-cardiography as effective tools for diagnosis of cor-onary artery disease (CAD) and risk stratificationis extensive, and there is growing evidence sup-porting the role of stress cardiac magnetic resonance(CMR).However, the optimal evaluation and treatment

algorithm following stress imaging has not beenclearly defined. Although diagnostic coronary angio-graphy is commonly preceded by stress testing,nearly two-thirds of patients manifest no obstructive

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CAD at the time of cardiac catheterization(4,5). Before elective percutaneous coronaryintervention (PCI), less than one-half of pa-tients have had a stress test in the previous 90days (6). These data illustrate the lack of ac-curacy and consistency in clinical practice inthe appropriate use of stress imaging to guidethe management of patients with SIHD(1,7,8).One noteworthy gap in the current evidence

base is the absence of established comparablecategories of the magnitude of ischemia acrossnoninvasive imaging modalities. The lack ofstandardized grading and inconsistency inreporting of the extent and severity of ischemiain clinical practice may contribute to the widevariability in management decisions and high

ascular Division, Brigham and Women’s Hospital, Boston, Massachu

ia University Medical Center/New York-Presbyterian Hospital, N

e, Division of Cardiology, Imperial College London, London, Unit

of Radiology, Weill Cornell Medical College, New York, New York

ogy, Cleveland Clinic Foundation, Cleveland, Ohio; zzDepartment o

ewish Hospital, Manhasset, New York; xxDepartment of Medicine

ia, Hobart, Australia; kkDepartment of Medicine, Division of Cardi

rk; ¶¶Department of Medicine, Division of Cardiology, Icahn Scho

rtment of Medicine, Division of Cardiovascular Medicine, Mayo Cl

of Imaging, Cedars-Sinai Medical Center, Los Angeles, California;

e, National Institutes of Health/National Heart, Lung, and Blood Ins

of Cardiovascular Disease, University of Alabama at Birmingham

of Cardiology, St. Luke’s Mid-America Heart Institute, Kansas City

partment of Medicine, Division of Cardiovascular Medicine, King’s C

f Nuclear Medicine, Division of Radiology, Duke Clinical Research

e, Division of Cardiology, Samuel S. Stratton VA Medical Center, A

ity School of Medicine, Stanford, California; and the zzzzDepartm

h Institute, Durham, North Carolina. Dr. Shaw has received research

h is a board member, advisor, and shareholder for Circle Cardiovascula

has received honoraria from Bracco Diagnostics Inc. and Philips Healt

aker’s bureau for and has received research support from GE Healthca

as received research support from Philips Healthcare; and holds equ

support from Siemens. Dr. Iskandrian is a member of the advisory com

rates of nonobstructive CAD on diagnostic angiog-raphy (5). At a recent Joint Commission/AmericanMedical Association Quality Summit, the variablereporting of the extent and severity of ischemia wasidentified as contributory to the overuse of electivePCI (9). Recent guidance documents support therequirement of moderate-severe ischemia beforeelective PCI (10).

For this report, experts in the field of stress car-diac imaging were enlisted to propose a consensus ofcomparable definitions for moderate-severe ischemiafor stress nuclear imaging (myocardial perfusionsingle-photon emission computed tomography andpositron emission tomography), echocardiography,and CMR (wall motion or perfusion). The cutpoints for moderate-severe ischemia were estab-lished using the selected, published evidence foreach modality correlating stress imaging results withrisk of CAD death or myocardial infarction (MI).The aim of this review was to propose a definitionfor equivalent amounts of ischemia across the stressimaging modalities for patients with SIHD whohave preserved left ventricular function, which willhelp to translate a common understanding of patientrisk on which to guide subsequent managementdecisions.

Targeting Moderate-Severe Ischemia

Most SIHD revascularization strategy trials haveincluded patients with ischemia on stress testing ortypical angina with at least 1 coronary stenosisamenable to revascularization, although only asubset of enrolled patients reported stress test results(11,12). The entry criteria for the COURAGE

setts; ¶Department of Medicine, Division of Cardiology,

ew York, New York; #Department of Cardiovascular

ed Kingdom; **Department of Cardiovascular Medicine,

; yyDepartment of Cardiovascular Medicine, Division of

f Medicine, Division of Cardiology, North Shore Long

, Division of Cardiology, Menzies Research Institute of

ology, New York University Medical Center, New York,

ol of Medicine at Mount Sinai, New York, New York;

inic, Rochester, Minnesota; ***Department of Medicine,

yyyDepartment of Medicine, Division of Cardiovascular

titute, Bethesda, Maryland; zzzDepartment of Radiology,

, Birmingham, Alabama; xxxDepartment of Medicine,

, Missouri; kkkHartford Hospital, Hartford, Connecticut;

ollege London, London, United Kingdom; ###Depart-

Institute, Durham, North Carolina; ****Department of

lbany, New York; yyyyDepartment of Medicine, Stanford

ent of Medicine, Division of Cardiology, Duke Clinical

support from Astellas and Bracco Diagnostics Inc. Dr.

r Imaging. Dr. Senior is a member of the speaker’s bureau

hcare. Dr. Min is a member of the medical advisory board

re; is a member of the medical advisory board for Arineta

ity interest in TC3 and MDDX. Dr. Arai has received

mittee for Rapidscan Pharma. Dr. Bateman is a member

Figure 1. Projected CAD Event Rates

A theoretical plot of the relationship between abnormal stress imaging find-ings and projected CAD events is shown. The lines include the average pro-jected CAD event rate and 95% confidence intervals. As the stress imagingabnormalities become more extensive and severe, the projected CAD eventrate increases. Conversely, for subsets with normal or mildly abnormal studies,the event rates are low. CAD ¼ coronary artery disease.

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595

(Clinical Outcomes Utilizing Revascularizationand Aggressive Drug Evaluation) trial ischemia re-quirements included a minimum of 1 segment witha perfusion defect or typical ischemic ST-segmentchanges with exercise (11), resulting in a represen-tation of patients ranging from those with mild tomoderate ischemia on imaging (13). Given thepotential representation of patients with lessextensive and severe ischemia in the COURAGEtrial, a lingering question is whether SIHD trialoutcomes would have been different if theCOURAGE or National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)-sponsored BARI 2D (Bypass AngioplastyRevascularization Investigation in Type 2 Diabetes)trials enrolled a larger proportion of higher-riskpatients with moderate or severe ischemia (11,12).There is limited evidence to guide treatment forthese higher-risk patients.

Figure 1 shows the projected relationship betweenthe underlying abnormal stress imaging findings andprojected CAD events. For stress imaging, theextent of ischemia is directly related to the rate ofsubsequent CAD events. Yearly CAD event ratesgenerally range fromw1% for normal stress imagingfindings to as high as 10% for severely abnormalstudies. Several observational studies have alsoshown that the degree of relative risk reduction withtreatment is related to the amount of ischemiaobserved on noninvasive imaging (14–18).

Challenges in Uniformly Quantifying IschemiaAcross the Stress Imaging Modalities

A major challenge in defining comparable risk-based thresholds for moderate-severe ischemiaacross modalities is that there are notable differencesin the various imaging techniques regarding what isassessed, interpreted, and quantified. Although it isrecommended that all stress imaging techniques usethe standardized 17-segment model for quantifica-tion of wall motion and perfusion (19), the 17thsegment (i.e., apical cap) is not separately assessedon stress echocardiography or CMR myocardialperfusion imaging. There are also differences in thenumerical scale used to classify the severity ofsegmental perfusion and wall motion abnormalities,

of the advisory committee for and receives research support from Astellas, La

Dynamics. Dr. Miller is a consultant for Astellas. Dr. Nagel has receive

HealthCare. Dr. Borges-Neto is a member of the speaker’s bureau and adviso

and is a member of the advisory board for and has received grant support from

fee and modest honoraria from GlaxoSmithKline. All other authors have repor

of this paper to disclose.

Manuscript received March 20, 2013; revised manuscript received October 1

with various methods and differences in the abilityto distinguish the subendocardial and subepicardiallayers of the myocardium. Nuclear imaging hasseveral validated quantitative software programs fordefining the percentage ischemic myocardium,including the use of percentage total perfusiondefect as used in the COURAGE trial (20). Giventhat other modalities interpret ischemic wall motionand perfusion findings semiquantitatively, this mayalso introduce differences in the quantificationof the extent and severity of stress-induced abnor-malities. These differences can result in considerablevariability in the estimation of the proportion ofischemic myocardium.

There are additional differences in the ischemiccascade that provide challenges to the developmentof comparable definitions of ischemia. Perfusionabnormalities have larger extent, occur earlier in theischemic cascade, and are more often associatedwith intermediate stenosis, whereas wall motionabnormalities occur later in the ischemic cascadeand are more often associated with more severestenosis (21). Given the differences in view orien-tations across the stress imaging modalities,thresholds that focus on comparing specific seg-ments (i.e., anterior, lateral) would be problematic.

ntheus Medical Imaging, GE Healthcare, and Spectrum

d research support from Philips Healthcare and Bayer

ry board for and has received grant support from Astellas

GE Healthcare. Dr. Hochman has received a consulting

ted that they have no relationships relevant to the contents

, 2013, accepted October 1, 2013.

Figure 2.

A theoretacross theAbbreviat

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These conceptual differences may promote a vari-able relationship between a threshold for moderate-severe ischemia and a given associated CAD eventrate.Thus, it remains unlikely that absolute thresholds

of percentage ischemic myocardium could bedefined similarly across the stress imaging modal-ities, resulting in the need for an alternativeapproach. Therefore, we sought to identify thoseparameters on each imaging modality that portendsimilarly elevated risk levels and to use these todevelop comparable thresholds to guide future caredecisions (Fig. 2).There is an important consideration that risk

alone should not be the sole determinant of definingthe potential for therapeutic risk reduction. Thepurpose of the current review is to identify compa-rable risk groups across stress imaging modalities.For some patient subsets, information on the extentand severity of ischemia must be balanced withcorrelative information on the burden of comor-bidity and CAD as well as the presence of under-lying left ventricular dysfunction. As such, for ourreview, we have limited the focus of our discussionto patients with preserved systolic function.Because of variable reporting of prognosis by the

severity of ischemia, we could not perform a sys-tematic review. In some cases, data were reportedonly as survival curves with variable follow-up andwithout inclusion of the number at risk or averageduration of follow-up, included revascularization asan endpoint, reported hazard ratios only, or definedischemia as a dichotomous variable (yes/no). Forthese reasons, we could not systematically collect

Risk-Based Comparisons

ical approach to comparing levels of moderate-severe ischemiastress imaging modalities is used to define similar CAD event rates.ion as in Figure 1.

clinical outcome data for moderate-severe ischemiaand the current review should be considered anarrative that highlights selected published evidencewith available rates of CAD death or MI inmoderate-severe ischemia. Contributing authorsalso identified additional data on prognosis withmoderate-severe ischemia for the 3 stress imagingmodalities. Importantly, we did not use standard-ized search terms or independently judge studyquality; this review represents the opinions of theinvestigators and is not a systematized synthesis ofall available evidence.

The search strategies in MEDLINE includedcoronary disease prognosis and the specific imagingmodality (stress myocardial perfusion imaging,echocardiography, CMR wall motion or perfusionimaging). Selected event rates were derived from thepublished literature by initially focusing on the rateof CAD death or MI in the nuclear cardiologyliterature. We selected a variety of published registryreports with available event data and follow-upduration in the subset of patients with moderate-severe ischemia. The event data were obtainedfrom crude rates or reported survival rates. There areseveral reports on prognosis from selected registriesthat report similar event rates by moderate-severeischemia. However, we did not include event datafrom duplicate patient series.

Published Evidence of Elevated Risk AssociatedWith Moderate-Severe Ischemia

For stress nuclear imaging data, we examined theextensive prognostic evidence reported from multi-ple sites, for different radioisotopes, and for positronemission tomography and single-photon emissioncomputed tomography to define CAD event risk(22). In the nuclear cardiology literature, a thresholdof $10% ischemic myocardium has been applied todenote high-risk status (14–16,22–26). Initialprognostic reports used a summed difference score(summed stress score � summed rest score) toprovide an estimate of the overall magnitude ofischemia, combining both extent of ischemia(i.e., number of myocardial segments) and severity(i.e., depth of the defect) (26–29). Recent reportshave relied on percentage myocardium as a summarymetric to enhance clinical understanding of thecomplexity of findings of ischemia. The percentageischemic myocardium may be measured usingsemiquantitative ([summed difference score/68(maximal segmental score ¼ 4)] $ 100 ¼ percentageischemic myocardium) or computer-based quanti-tative techniques (percentage ischemic myocardium)

Figure 3. Risk of CAD Death or MI for Moderate-Severe Ischemia

The median rates of CAD death or MI (%/year) on the basis of moderate-severeischemia on stress nuclear myocardial perfusion imaging and stress echocar-diography are shown. This narrative review highlights selected published evi-dence of rates of CAD death or MI for stress nuclear imaging andechocardiography; the dashed lines show the interquartile range of the CADevent rates (per year). The expected rate of CAD death or MI across all of thestress imaging modalities is w4% to 6%/year. There are limitations to ourmedian estimate, including that this was not a systematic review because ofdifferential sample size, variable length of follow-up, and the use of mortalityonly or revascularization as an endpoint. MI ¼ myocardial infarction; otherabbreviation as in Figure 1.

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(22). There may be variability when using quanti-tative or semiquantitative approaches for interpre-tation such that a threshold of 10% from 1method may be slightly higher or lower using analternative technique. However, in the nuclear car-diology literature, a threshold of $10% of themyocardium has been reported across a numberof prognostic series to denote moderate-severeischemia (14–16,22–26). For clinical practice pur-poses, the risk associated with a threshold ofw10% ischemic myocardium has been reported andforms the target cut point for our cross-modalityestimation of the risk of CAD death or MI(1,16,22,27,30).

A review of the published literature reveals thatthe median rate of CAD death or MI for patientswith $10% ischemic myocardium was w4.9%/year(interquartile range: w3.7% to 5.3%/year) (Fig. 3)(16,27,30–34). For stress nuclear imaging, the rangeof CAD event rates was from as low as 2.3%/year(32) to as high as 6.9%/year (34). These findings ofa w5% annual CAD event risk are consistent withrecent SIHD trials reporting a similar rate of yearlyendpoints (11,12).

Although not derived from the rigors of a clinicaltrial setting, observational evidence suggests that thethreshold of $10% ischemic myocardium may beused as a benchmark from which to define treatmenteffectiveness (14–16). Observational evidence in-dicates that medical therapy alone is associatedwith a reduced risk of death as compared withrevascularization for patients with less extensive andsevere ischemia (i.e., <10% of the myocardium);conversely, patients with $10% ischemic myocar-dium had a reduced risk of CAD and all-causedeath with coronary revascularization as comparedwith medical therapy (14,15). Selection bias isoperational in observational evidence wherebypatients with significant comorbidity would be lesslikely to undergo revascularization despite theirischemic risk, thus rendering the comparison ofmedical therapy and revascularization for patientswith $10% ischemia as hypothesis generating.Importantly, in a secondary analysis of 468 patientsin the COURAGE trial with site-interpretedmoderate-severe ischemia, randomization to PCIwith optimal medical therapy (OMT) did not resultin improved death or MI-free survival whencompared with OMT alone (p ¼ 0.72) (13).

The published research on stress echocardiogra-phy commonly indicates that the wall motion scoreindex includes a very high risk threshold of >1.5 or>1.7 (17,35–39) with an annual CAD mortality rateof >7% and a significantly elevated hazard for death

of 6 (36,37). This high-risk wall motion score indexis rarely observed in clinical practice. We sought todefine clinically useful criteria at a lower level todefine a threshold of moderate ischemia. Applying athreshold of 3 or more ischemic segments, thehazard for CAD events was elevated w4-fold whencompared with patients with normal stress echo-cardiographic results (35,40,41). The available evi-dence using a definition of $3 newly dysfunctionalsegments revealed an interquartile range from 3.8%to 5.9% (median 4.5%) for annual risk of CADdeath or MI (Fig. 3) (17,35,39,41–49). For stressechocardiography, the CAD event rates ranged fromas low as 2.8%/year (47) to as high as 9.4%/year (45).This result overlaps with the findings of moderate-severe ischemia with stress nuclear imaging.

A review of the published literature on stressCMR does not reveal consistent documentation ofhigher-risk versus lower-risk ischemia but moreoften a dichotomous reporting of normal/abnormalor ischemia (yes/no). However, in one report, asubset of very-high-risk patients with >5 of 16segments with perfusion defects (including ischemicand fixed) had a risk of a CAD event of w14%/year(50). Similarly, a subset of high-risk patients with 2to 3 vessel perfusion defects had a hazard ratio thatwas elevated 4.5-fold to 7.0-fold that of patientswithout perfusion defects (51). There are alsoseveral patient series reporting that patients withevents had an average of 4 of 16 segments with

Figure 4.

Comparabbased thrmagnetic

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stress perfusion defects or dysfunctional segments ascompared with <2 abnormal segments for event-free survivors (50,52,53). Moreover, the unad-justed hazard for CAD death or MI was elevatedw1.2 for every segment with an ischemic perfusiondefect when compared with patients with a normalstress perfusion study who have an observed CADevent rate of w1%/year, suggesting that patientswith >3 ischemic perfusion defects would have anannual risk of CAD death or MI of w5% (52,53).A similar relative hazard per ischemic defect ordysfunctional segment was reported from a largerseries of 908 patients undergoing stress perfusionCMR (54).Specific data with regard to prognosis associa-

ted with dobutamine-induced dysfunctional seg-ments have been reported. The relative hazard forevents was elevated 7.1-fold for 3 to 5 dobutamine-induced wall motion abnormalities when comparedwith a w1% event rate for patients with normalstress CMR (51). Similarly, a relative hazard of 1.2-fold per dysfunctional segment at stress was re-ported, which would equate an annual CAD eventrate of w5% for $3 abnormal segments (52,53).Thus, a reasonable definition for moderate-severe

ischemia with stress CMR (annual rate of CADdeath or MI of w5%) may be $4 of 32 stressperfusion defects ($2 of 16 segments) or $3dobutamine-induced dysfunctional segments (of 16segments), with CAD event rates similar to those ofstress nuclear imaging and echocardiography.

YearYear

(CAD Death/MI)(CAD Death/MI)

≥

Definitions of Moderate-Severe Ischemia

le multimodality estimates of moderate-severe ischemia using risk-esholds of CAD death or MI rates of 4% to 6%/year. CMR ¼ cardiacresonance; other abbreviations as in Figures 1 and 3.

Although differences exist in interpretation ofischemia across the modalities, the overall prog-nostic findings reveal that qualitative or quantitativemeasures can be defined that identify overlap in theannual rates of CAD death or MI of w5%/year(Fig. 4). It remains likely that the thresholdrequirement of moderate-severe ischemia may allowfor greater harmonization in the estimated risk ofCAD events in patients with SIHD.

Consideration of Ancillary High-Risk Markers

We considered revising the criteria for moderate-severe ischemia by including additional high-riskqualifiers using left ventricular function or volumemeasurements in addition to other modality-specificmeasures (such as strain, scarring, edema, or tran-sient ischemic dilation of the left ventricle). There isadded value when multiple parameters are combinedduring the same scan. For example, the presence orabsence of myocardial scarring or edema assessedduring the same scan adds to the informationderived from perfusion and wall motion analyses(55). Data on the impact of combining thesemarkers on prognosis and therapeutic decisionmaking and outcome, however, are lacking. Ourproposed criteria do not distinguish exercise andpharmacological stress and do not incorporate pa-tient clinical risk or functional capabilities thatwould affect the anticipated risk of CAD events.

There was considerable discussion about theuse of imaging-based criteria alone without inclu-sion of ancillary markers. One argument was putforth that simpler is better. The Duke TreadmillScore integrates 3 parameters into an estimation of5-year CAD mortality (56). Although additionalexercise parameters have been reported in the peer-reviewed literature, the novelty of the DukeTreadmill Score is its parsimony and ease of use.Ultimately, it was believed that the use of a simplecriterion would be more reliably applied in clinicalpractice and the data regarding prognosis are lessrobust when additional factors are included. Ideally,this report could serve as the starting point for theestablishment of stress imaging criteria to be appliedclinically. This would then form the basis for furtherrevisions that may refine and integrate importantclinical and stress parameters that improve the pre-cision of CAD risk estimates and the generalizabilityof the findings to varying patient subsets. Impor-tantly, clinicians should use our thresholds as aninitial guide to estimated risk. Inclusion of additionalclinical, stress testing, or imaging parameters mayfurther refine estimates for the individual patient.

Table 1. National Institutes of Health/National Heart, Lung,and Blood Institute–Sponsored ISCHEMIA Trial Criteria forModerate-Severe Ischemia

NuclearPerfusion

EchocardiographicWall Motion

Cardiac MagneticResonance Perfusion

or Wall Motion

$10% ischemicmyocardium

$3 of 16 segmentswith stress-inducedhypokinesisor akinesis*

$4 of 32 stress perfusiondefects ($2 of16 segments)or$3 dobutamine-induceddysfunctional segments(out of 16 segments)

*The one exception to the characterization of ischemic wall motion change isthat when segments change from akinetic to dyskinetic during stress in theabsence of demonstration of a biphasic response, this is considered anonspecific response rather than an ischemic response.

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Study limitations. The extent to which we cannotconsistently identify the prognosis of moderate-severe ischemia from the published literature ex-emplifies the limitations of our current knowledge.The development of more quantitative methodsfor determining perfusion defect or dysfunctionalsegmental analysis could help define risk andguide decisions about treatment. Moreover, thedevelopment of easily defined categories of riskmay further promote quality-based treatment andperformance metrics for laboratory standards. Theprognostic significance of noninvasive testing dif-fers on the basis of the population in which it isapplied. For example, the risk in younger orexercising patients differs from that of older orfunctionally impaired patients. The prevalence ofprior MI or revascularization can also alter theCAD event risk estimates. We attempted to nar-row the width of expected CAD event rates byfocusing on patients with SIHD who hadmoderate-severe ischemia and preserved left ven-tricular function. The sample size and length offollow-up would further contribute variability tothe CAD risk estimates. The smaller sample sizesfor stress echocardiography and CMR (e.g., me-dian sample sizes of 1,737 and 503, respectively)may add variability to the CAD event rates whencompared with the larger stress nuclear series(median sample size: 5,845).

There are also challenges in the reproducibility ofphysician-interpreted moderate-severe ischemia(57). Reproducibility is affected by reader expertise,equipment, image quality, and other factors. Weanticipate greater variability in the reproducibility ofmoderate-severe ischemia when a subjective inter-pretation is used.

Historically, varied analytical approaches havebeen applied in prognostic series to handle thesubsets of patients who undergo coronary revascu-larization during follow-up. Patients who undergoearly revascularization (e.g., #90 days) are excludedfrom analysis in some cases but are censored at thetime of the procedure in other cases (28,43). Therationale for the censoring of patients who undergoearly revascularization is that the procedure isbelieved to affect CAD survival. In this case, theCAD event rates reflect a medical strategy. Morerecent series do not use this method of censoring forrevascularization because recent trials failed to showa clinical benefit from coronary revascularizationwhen compared with OMT (11,12).

Importantly, these factors influence the precisionof our estimate. However, we believe that theattempt to impose rigor in the field of stress CAD

imaging can prompt a greater emphasis on stan-dardized approaches to image interpretation. Wepropose comparable risk-based definitions formoderate-severe ischemia that may help to translatea common understanding of patient risk on whichto guide subsequent management decisions. Ourdefinitions are formed on the basis of a number ofassumptions, including that the stress imagingprotocols, interpretation, and reporting are consis-tent with imaging society standards.

Future Comparative Trial Evidence

In 2012, the NIH/NHLBI-sponsored ISCHEMIA(International Study of Comparative HealthEffectiveness With Medical and Invasive Ap-proaches) trial began enrolling patients withmoderate-severe ischemia on stress nuclear imag-ing, echocardiography, or CMR. The ISCHEMIAeligibility criteria for moderate-severe ischemiaare detailed in Table 1 and correspond to thosediscussed in this report. The primary aim of theISCHEMIA trial is to test the hypothesis thatamong patients with moderate-severe ischemia onstress imaging, a routine early invasive strategywith coronary angiography followed by optimalrevascularization plus OMT is superior to aninitial conservative strategy of OMT alone, withangiography and revascularization reserved forthose who fail to respond to medical therapy. Theprimary endpoint is a composite of incident car-diovascular death or MI over w4 years of follow-up. The ISCHEMIA trial will aid in identifyingpatients who may benefit from coronary angiog-raphy and revascularization, with the trial resultsaffecting the lives of the nearly 10 million patientswho undergo stress imaging each year.

Current evidence indicates that substantialequipoise exists with regard to the decision to refer

Figure 5. Case Examples

(A) (i) Illustrative case of moderate ischemia with stress myocardial perfusion SPECT. Regadenoson stress (upper rows)/rest (lower rows)Tc-99m sestamibi SPECT images show moderate reduction of perfusion in the distal, mid, and basal inferior wall. Semiquantitative visualanalysis (lower right polar maps) reveals 3 abnormal segments at stress with a total score of 7 and normal rest scores. The summed dif-ference score is 7, representing 10% of the myocardium. (ii) Quantitative analysis of the case shown in i. Stress polar maps (middle column)reveal a perfusion defect (black area) on stress images (top) and normal rest images (middle). The TPD at stress is 11% and at rest is zero,indicating an ischemic TPD of 11%.

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a patient for coronary angiography, despite thecommon belief to the contrary in the cardiologycommunity. On the basis of 9 published reportsfrom 51 sites (N ¼ 5,833), the rate of referral fromstress nuclear imaging to coronary angiography inpatients with moderate-severe ischemia was only

35% to 65% (58–66). Contemporary data fromthe NIH/NHLBI SPARC (Study of MyocardialPerfusion and Coronary Anatomy Imaging Rolesin CAD), a 40-center multimodality registryof 3,019 patients enrolled between 2006 and2008, revealed that only 42% of patients with

Figure 5. Continued

(B) Illustrative case of moderate ischemia with stress echocardiography. Apical views from an exercise stress echocardiogram show moderateischemia. Regional wall motion is normal at rest. At peak stress, wall motion abnormalities (severe hypokinesis) are observed in 3 segments:mid anterior, apical anterior, and apical lateral segments (arrows). See Online Videos 1, 2, 3, and 4. (C) Illustrative case of moderate ischemiawith stress cardiac magnetic resonance perfusion imaging. The top row shows stress perfusion imaging, and the bottom row shows lategadolinium enhancement imaging of infarction. In both rows, basal short-axis locations are on the left, mid short-axis locations are in themiddle, and distal short-axis locations are on the right. Note the spatial extent of the stress perfusion defect involving the basal anteroseptal(subendocardial) and inferoseptal (subendocardial and subepicardial), mid anteroseptal (subendocardial and subepicardial), and distal septal(subendocardial and subepicardial) walls. There are 7 subsegments of 32 demonstrated abnormal stress perfusion defects. None of thesesubsegments demonstrated evidence of infarction by late gadolinium enhancement imaging. This case illustrates a patient with moderateischemia without infarction in the left anterior descending territory. SPECT ¼ single-photon emission computed tomography; TPD ¼ totalperfusion deficit.

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moderate-severe ischemia were referred for coro-nary angiography (63).

Conclusions

On the basis of a selected review of the publishedliterature, comparable CAD event rates (rate ofCAD death or MI of w5%/year) for patients withSIHD who have moderate-severe ischemia can beidentified for those undergoing stress nuclear im-aging, echocardiography, or CMR. An example ofeach of the imaging modalities using the proposeddefinition for moderate-severe ischemia is illustrated

in Figure 5 (see Online Videos 1, 2, 3, and 4for stress echocardiography example). Definingcomparable risk-based thresholds for moderate-severe ischemia across the different stress imagingmodalities will help to translate a common under-standing of patient risk and guide management de-cisions. These risk-based thresholds should beapplied only when standardized protocols and inter-pretation are used during stress imaging. Definitiveguidance on the therapeutic effectiveness of anangiographic-guided strategy for patients withmoderate-severe ischemia will be derived fromongoing clinical trials, such as the ISCHEMIA trial.

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Moreover, we put forth a simple criterion thatwe believe could be easily applied in clinicalpractice. We also identified limitations to thedevelopment of comparable definitions. We hopethat this report will serve as a starting point andthat further revisions will ensue to improve theprecision of the CAD risk estimate and thegeneralizability of the findings to varying patientsubsets.

AcknowledgmentThe authors thank Dr. Raymond Gibbons for hiscareful review and comments on this manuscript.

Reprint requests and correspondence: Dr. Leslee J. Shaw,Emory Clinical Cardiovascular Research Institute, EmoryUniversity School of Medicine, 1462 Clifton Road NE,Room 529, Atlanta, Georgia 30324. E-mail: lshaw3@emory.edu.

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Key Words: cardiac imaging -

ischemia - prognosis.

A P P E N D I X

For supplemental videos and legend, please seethe online version of this article.