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Journal of the American College of Cardiology Vol. 55, No. 10, 2010© 2010 by the American College of Cardiology Foundation ISSN 0735-1097/10/$36.00P

STATE-OF-THE-ART PAPER

The Present State of CoronaryComputed Tomography AngiographyA Process in Evolution

James K. Min, MD,* Leslee J. Shaw, PHD,† Daniel S. Berman, MD‡

New York, New York; Atlanta, Georgia; and Los Angeles, California

In the past 5 years since the introduction of 64-detector row cardiac computed tomography angiography (CCTA),there has been an exponential growth in the quantity of scientific evidence to support the feasibility of its use inthe clinical evaluation of individuals with suspected coronary artery disease (CAD). Since then, there has beenconsiderable debate as to where CCTA precisely fits in the algorithm of evaluation of individuals with suspectedCAD. Proponents of CCTA contend that the quality and scope of the available evidence to date support the re-placement of conventional methods of CAD evaluation by CCTA, whereas critics assert that clinical use of CCTAis not yet adequately proven and should be restricted, if used at all. Coincident with the scientific debate under-lying the clinical utility of CCTA, there has developed a perception by many that the rate of growth in cardiac im-aging is disproportionately high and unsustainable. In this respect, all noninvasive imaging modalities and, inparticular, more newly introduced ones, have undergone a higher level of scrutiny for demonstration of clinicaland economic effectiveness. We herein describe the latest available published evidence supporting the potentialclinical and cost efficiency of CCTA, drawing attention not only to the significance but also the limitations of suchstudies. These points may trigger discussion as to what future studies will be both necessary and feasible fordetermining the exact role of CCTA in the workup of patients with suspected CAD. (J Am Coll Cardiol 2010;55:957–65) © 2010 by the American College of Cardiology Foundation

ublished by Elsevier Inc. doi:10.1016/j.jacc.2009.08.087

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ardiac computed tomography angiography (CCTA) hasmerged in recent years as a promising noninvasive ana-omic imaging modality for coronary artery and cardiactructural and functional evaluation (1). Developments inomputed tomography (CT) technology, driven principallyy improvements in temporal resolution, spatial resolution,nd volume coverage, now permit routine evaluation of theoronary arteries and cardiovascular structures with clarity.CTA has experienced resultant rapid clinical adoption by

ome for assessment of patients with suspected coronaryrtery disease (CAD). This year, scientific guidelines forerformance, interpretation, and reporting of CCTA wereublished that can aid the clinician-imager in the properxecution of CCTA. Nevertheless, despite the rapid growthn the scientific evidence base that has supported theormation of these guidelines, numerous evidence gapsontinue to exist in this still nascent field, thus precluding

rom the *Department of Medicine and Radiology, Weill Medical College of Cornellniversity, The New York Presbyterian Hospital, New York, New York; †Emoryniversity School of Medicine, Atlanta, Georgia; and the ‡Cedars-Sinai Medicalenter, Los Angeles, California. Dr. Min is on the Speakers’ Bureau of GEealthcare, and has received research support from GE Healthcare and Vital Images.r. Berman has received grant support from GE Healthcare.

wManuscript received May 14, 2009; revised manuscript received July 29, 2009,

ccepted August 4, 2009.

he development of practice guidelines that can endorse theroper clinical application of CCTA.The purpose of this review is to highlight contemporary

evelopments that have occurred in the field of CCTA thatay help to bridge certain evidence gaps. We focus our

iscussion on issues related to diagnostic accuracy, prognos-ic risk stratification, cost-effectiveness, and safety.

iagnostic Coronary Artery Evaluation by CCTA

iagnostic accuracy of CCTA for obstructive CAD.ince the introduction of 64-detector row CCTA in 2005,50 studies have been published that compared the diag-

ostic performance of CCTA with that of invasive coronaryngiography (ICA) as the reference standard. Several poolednalyses have been performed that showed the diagnosticerformance of 64-detector row CCTA, with high per-atient sensitivity and specificity ranging from 91% to 99%nd 74% to 96%, respectively (2–6). These early studiesere uniformly retrospective in design and limited to single

enters, thus possessing numerous limitations includingeferral bias (patients already being referred for ICA),pectrum bias (patients had a high pretest CAD likelihoodnd did not represent those for whom noninvasive imagings generally performed), workup bias (overlooking patients

ho may have otherwise been found to have false-negative

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958 Min et al. JACC Vol. 55, No. 10, 2010Present State of CCTA March 9, 2010:957–65

findings), ascertainment bias (us-ing nonrandom samples resultingin altered results), and publica-tion bias (emphasizing only pos-itive results). To address many ofthese limitations, 3 prospectivemulticenter studies were recentlyreported that detail the diagnos-tic performance of CCTA in dif-ferent populations (Table 1).

The purpose of these studieswas to define the concordancebetween CCTA and a referencestandard of ICA, and, thus, eachof these studies was limited topatients being clinically referredfor ICA. The first of these trialswas the ACCURACY (Assess-ment by Coronary Computed

omographic Angiography of Individuals Undergoing In-asive Coronary Angiography) trial, a 16-center U.S.-basedtudy that restricted analysis to patients without knownAD undergoing CCTA before elective ICA (7). Reasons

or ICA referral included stable chest pain syndrome and/orbnormal functional stress testing results. Among the 230ubjects, only 13.9% were found to have obstructive CAD athe �70% stenosis threshold by quantitative coronary an-iography. Although the prevalence of CAD in the AC-URACY trial cohort highlighted the imperfections of

urrent clinical and imaging algorithms for the properdentification of individuals with obstructive CAD, it nev-rtheless permitted an assessment of CCTA diagnosticerformance in a patient population for whom CCTA use isenerally advocated. The diagnostic sensitivity, specificity,nd positive predictive value (PPV) and negative predictivealue (NPV) of CCTA to detect a �70% stenosis in thisopulation were 94%, 83%, 48%, and 99%, respectively.mportantly, these test characteristics were calculated re-orting all vessel segments, without exclusion of patients foraseline heart rate, coronary artery calcium score (CACS),r body mass index; which is in contrast to many previousingle-center studies that reported higher diagnostic perfor-ance characteristics. The area under the receiver-operator

haracteristic curve, which describes the discriminatoryower of diagnostic testing across a wide range of cutoffalues, for identification of patients with �70% stenosis was.95, thereby definitively establishing the high diagnostic

ummary of Diagnostic Performance of 64-Detector Row CCTA FroTable 1 Summary of Diagnostic Performance of 64-Detector Ro

n CAD Prevalence

Pa

Stable Unstable

ACCURACY (7) 230 25% X

CORE64 (8) 291 56% X

Meijboom et al. (9) 360 68% X X

Abbreviationsand Acronyms

CAD � coronary arterydisease

CACS � coronary arterycalcium score(s)

CCTA � cardiac computedtomography angiography

CT � computedtomography

ICA � invasive coronaryangiography

MPS � myocardialperfusion scintigraphy

NPV � negative predictivevalue

PPV � positive predictivevalue

AD � coronary artery disease; CCTA � cardiac computed tomography angiography; NPV � negative pre

ccuracy for both detection and exclusion of obstructiveoronary artery stenosis in individuals without known CADith a low prevalence of CAD (Fig. 1).In contrast, the 291 patients enrolled in the multicenter

ORE64 (Coronary Evaluation on 64) study, encompassedn admixture of patients both with and without knownAD with baseline CACS �600 Agatston units (8). As

uch, the prevalence of obstructive CAD at the 50%ntraluminal stenosis threshold was higher than that ob-erved in the ACCURACY trial, with a prevalence of 56%espite exclusion for elevated CACS of �600 Agatstonnits. In the CORE64 study, the per-patient sensitivity,pecificity, PPV, and NPV were 85%, 90%, 91%, and 83%,espectively. These findings are in accord with those of theCCURACY trial because the higher prevalence of CAD

esulted in predictably lower NPVs and higher PPVs. Inhis study population, the area under the curve was 0.91 forCA-confirmed CAD and similar to ICA for the predictionf subsequent coronary artery revascularization.The most recent prospective multicenter study evaluated

60 patients without known CAD presenting with bothcute and stable chest pain (9). As expected, the CADrevalence was high (68%), and diagnostic performance ofCTA revealed a per-patient sensitivity, specificity, PPV,

nd NPV of 99%, 64%, 86%, and 97%, respectively. Inonjunction with the ACCURACY trial, the high sensitiv-ty and NPV in individuals without known CAD highlighthe ability of CCTA to detect and exclude obstructiveoronary artery stenosis across wide disease prevalences,lbeit with comparatively low specificity and PPVs. Theatter of these diagnostic performance characteristics under-cores an excessive rate of false-positive CCTA findings inhich intraluminal stenosis severity by CCTA is errone-usly overestimated. This fact necessitates careful consider-tion when using CCTA because false-positive findingsay precipitate unnecessary referral for ICA. Particularly in

he lower risk diagnostic population, this may result in theerformance of layered noninvasive and invasive proceduresor individuals who may, in fact, not have needed any testingt all.

iagnostic accuracy of CCTA for myocardial ischemia.esults of functional myocardial perfusion scintigraphy

MPS) have proven robust for diagnosis, risk stratification,nd guidance of treatment decision making (10–21). Botharge prospective, observational registries and multicenterandomized, controlled trials support a symptom benefitnd potential risk reduction of revascularization for those

spective Multicenter StudiesTA From Prospective Multicenter Studies

Type

Sensitivity Specificity PPV NPVnown CAD Known CAD

X 95% 83% 64% 99%

X X 85% 90% 91% 83%

X 99% 64% 86% 97%

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959JACC Vol. 55, No. 10, 2010 Min et al.March 9, 2010:957–65 Present State of CCTA

ith moderate to severe ischemia (16,17,22). The conversef this finding is also true; namely, among patients withoutvident extensive myocardial ischemia by MPS, an adverseAD prognosis is higher for patients undergoing coronary

evascularization than receiving medical therapy. As such,here has been an effort to determine whether CAD stenosiseverity detection by CCTA successfully identifies individ-als with myocardial ischemia.In a prospective study of 78 patients undergoing sequen-

ial CCTA, MPS, and ICA, the sensitivity and NPV forCTA to detect any perfusion defect was high (94%),

lthough the specificity and PPV were only 64% and 63%,espectively (23). Given that increasing rates of false-ositive results will reduce both specificity and PPV, thesendings suggest an overestimation of CAD stenoses byCTA. Interestingly, these findings did not reflect a failuref CCTA per se to accurately assess coronary artery stenosis

Figure 1 CCTA Examples

(A) Cardiac computed tomography angiography (CCTA) of the right coronary arterysignificant coronary artery plaque. (B) CCTA (left) and left anterior descending artery (

ecause the probabilistic odds of CCTA to detect myocar- C

ial ischemia were identical to those of ICA. Rather, anxcessively high rate of false-positive results is seen by anyethod of anatomic evaluation, thus questioning the rele-

ance of coronary artery stenosis detection by anatomicethods for identification of individuals who may most

enefit from revascularization. In a similar study of 79atients undergoing CCTA and ICA with fractional floweserve measurements, comparable findings were observed.lthough the sensitivity of CCTA by visual estimation toetect lesions with a fractional flow reserve �0.75 was high94%), the specificity to detect such lesions was poor (40%)24). A quantitative CCTA-based method improved diag-ostic accuracy but at the loss of sensitivity; these findingsere similar to those observed for quantitative coronary

ngiography.A similar theme emerges from pooled analyses of studies

pecifically examining the association between MPS and

nd left anterior descending artery (right), which demonstrates nowhich demonstrates high-grade obstructive and mild plaque, respectively.

(left) aright),

CTA findings (25). CCTA judged as revealing �50%

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960 Min et al. JACC Vol. 55, No. 10, 2010Present State of CCTA March 9, 2010:957–65

tenosis at the per-patient level generally portends a normalPS, in keeping with the high NPV of CCTA. Con-

ersely, however, CCTA noted to reveal �50% stenosis isssociated with abnormal MPS only approximately half ofhe time (Fig. 2) (26). Collectively, these findings demon-trate that anatomic measures of stenosis severity andunctional measures of myocardial perfusion provide dis-rete and potentially complementary information regardingAD (i.e., anatomic detection of atherosclerosis and func-

ional detection of ischemia). When the criterion of �50%r �70% stenosis has been used, a criterion now consideredo be a superior standard for hemodynamic significance anduiding decisions regarding revascularization, higher PPVsf CCTA regarding ischemia by MPS have been shown27,28).

Nevertheless, although CCTA and MPS do provideomplementary information, early studies suggested meth-ds by which CCTA plaque identification may enhancerediction of functional information, thereby lessening theschemic gap between these 2 types of studies. Previousvaluations of CCTA relied primarily on binary measures oforonary artery stenosis severity (i.e., �50% [or 70%]tenosis). Recent CCTA studies extended this categoriza-ion to a more comprehensive plaque assessment beyondntraluminal stenosis severity, including plaque location,istribution, composition, and overall burden, to determinehether these combined measures can augment the predic-

ion of myocardial ischemia.Lin et al. (29) evaluated 163 patients undergoing both

4-detector row CCTA and MPS. In addition to binarylassification of patients with or without obstructive CAD,laque by CCTA at the per-patient level was also graded byeveral scores that aimed to describe overall coronary arterylaque burden, accounting for both plaque burden andlaque location. These scores were expressed as a segmenttenosis score, a segments-at-risk score, and a modified

Figure 2 Relationship Between CCTA and Ischemia

Predictive value by according to 5 studies of cardiac computed tomographyangiography (CCTA) to detect myocardial ischemia by myocardial perfusion scin-tigraphy. Reprinted, with permission, from Hachamovitch et al. (26). NPV �

negative predictive value; PPV � positive predictive value.

C

uke CAD score, respectively. Plaques at the per-patientevel were also described by plaque composition scores,hich tallied the numbers of coronary segments (based on aodified 16-segment American Heart Association model)

xhibiting primarily noncalcified plaque (�70% noncalci-ed), mixed plaque (30% to 70% noncalcified), and calcifiedlaque (�30% noncalcified).In keeping with previous studies, CCTA identification of

bstructive CAD did not successfully identify individualsith abnormal MPS findings. However, measures of per-atient coronary artery plaque burden, proximity, and loca-ion, including the segment stenosis score, the segments-at-isk score, and the modified Duke CAD score, wereredictive of identifying individuals with abnormal MPSndings. Increasing numbers of segments exhibiting mixedlaque similarly identified individuals with abnormal MPSndings. An extension of these findings was observed in atudy of 165 patients undergoing treadmill exercise testingn which the modified Duke CAD score by CCTA suc-essfully identified individuals with increasing severity ofxercise-induced ST-segment depression as well as a de-reasing Duke treadmill score (30). Notably, increasingradations of CAD by CCTA from none to nonobstructiveo obstructive also predicted a stepwise reduction in overallruce treadmill protocol exercise times. Collectively, thesendings suggest that comprehensive assessment of coronaryrtery plaque by CCTA, beyond binary categorization oftenosis severity, may enhance the prediction of individualsith inducible myocardial ischemia.isk stratification by CCTA in individuals with stable

hest pain. Of importance in the diagnostic performancef any test is its prognostic potential. The robustness ofunctional stress testing, by electrocardiography or imaging,o provide valuable information regarding risk stratificationn a diversity of patient types explains, in large part, itsopularity of use and critical importance in the evaluation ofatients with suspected CAD. In contrast to the wealth ofata that support the clinical effectiveness of functionaltress testing, relatively few studies exist to support therognostic implications of CCTA. This is due to the recentntroduction of CT scanners capable of performing routineCTA, which has limited the time required for accrual of

ardiac events after testing. Despite the multitude of plaqueharacteristics that are available for identification by CCTA,arly work in this field has primarily focused on theelationship of obstructive CAD to the incidence of adverseAD prognosis.An initial publication examined coronary artery stenosis

everity in relation to the incidence of all-cause death in,127 patients undergoing CCTA by 16-detector rowCTA (31). At an intermediate-term follow-up of 15onths, CCTA measures of CAD severity, extent, location,

nd distribution were independent predictors of the risk ofll-cause mortality. Both moderate (�50% to 69%) andevere (�70%) luminal diameter stenoses revealed by

CTA were associated with a higher mortality risk com-

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961JACC Vol. 55, No. 10, 2010 Min et al.March 9, 2010:957–65 Present State of CCTA

ared with less obstructive plaques, and the risk of deathncreased with numbers of major epicardial vessels affected.CTA characteristics predicting a high risk of death frommodified Duke CAD score (listed by increasing risk)

ncluded: 1) 2 segments with moderate stenosis or 1egment with severe stenosis; 2) 3 segments with moderatetenosis, 2 segments with severe stenosis, or severe stenosisn the proximal left anterior descending artery; 3) 3 seg-

ents with severe stenosis or 2 segments with severetenosis that included the proximal left anterior descendingrtery; and 4) moderate or severe left main artery stenosis,ith a 15% 1.5-year mortality rate. Of equal importance,CTA was able to accurately identify individuals with a low

ncidence of risk of all-cause mortality. Among 333 patientsith no detectable coronary artery plaque by CCTA, the

nnualized death rate was 0.3%, suggesting the detection oflow-risk group.Although long-term prognostic studies using current-

eneration CT scanners are as yet unavailable, studies usinglder generation scanners (including electron beam CCTA)ave accumulated a longer accumulated experience of study.n a recent analysis of 2,538 consecutive patients withoutnown CAD undergoing electron beam CCTA followedor 6.5 years for all-cause mortality, a higher mortality riskas identified for individuals with greater numbers of major

picardial coronary artery vessels exhibiting obstructiveAD (32). In comparison with patients without CAD, theortality incidence increased 2- to 3-fold. Even among

ndividuals without evident obstructive CAD, the presencef nonobstructive CAD in all 3 major coronary vesselsonferred a significantly increased risk of mortality. Impor-antly, for patients without evident CAD, the annualizedortality rate was 0.3% in this follow-up of nearly 7 years,

uggesting that the “warranty” period of a normal CCTAay be extensive. Furthermore, risk prediction by CT-

dentified plaque was independent of and additive to tradi-ional CAD risk factor scoring and CACS.

CCTA has also been evaluated for its ability to identifyndividuals at risk of other major adverse cardiovascularvents. In the largest of these studies, 1,256 patientsndergoing 64-detector row CCTA were studied for all-ause death in relation to CAD severity. Individuals withbstructive CAD experienced significantly higher rates ofevere major adverse cardiovascular events (odds ratio: 17.3,5% confidence interval [CI]: 3.6 to 82.5, p � 0.001), asefined as cardiac death, myocardial infarction, or unstablengina requiring hospitalization. Conversely, those individ-als without obstructive CAD by CCTA experienced majordverse cardiovascular events at a substantially lower ratehan would have been predicted by traditional Framinghamisk factor scoring.

Pooled analyses of studies of individuals undergoingCTA indicate an inordinately high annualized event rate

11.1%, 95% CI: 5.1% to 2.5%) for those with obstructiveAD, which is by and large higher than that observed for

ndividuals with abnormal perfusion shown by MPS (6.2%, h

5% CI: 5.9% to 6.5%) or inducible wall motion abnormal-ties by stress echocardiography (7.5%, 95% CI: 5% to3.4%), albeit with overlapping CIs (33,34). These obser-ations have prompted the question as to the relativerognostic risk stratification proffered by CCTA comparedith functional stress testing. Further, whether CCTAlaque characteristics predict future adverse CAD outcomesn a manner that is equivalent to or synergistic with that oferfusion or wall motion findings has also been raised. Toate, only 2 studies have been performed to offer early dataith respect to these issues.In the first of these studies, individuals undergoing

CTA for CAD evaluation (n � 1,132) were comparedith propensity score–matched outpatients (n � 7,849)

eferred for MPS, for a primary end point of all-cause death35). Similar 2-year survival rates after CCTA and MPSere noted (97% for both). In a comparison of CCTAndings as graded by a modified Duke CAD index versushe percentage of ischemic myocardium by single-photonmission CT, the annual mortality rates predicted byCTA were directly proportional to the percentage of

schemic myocardium by MPS, ranging from 0.2% to 11%or CCTA and from 0% to 12% for MPS. These findingsuggest that the prognostic potential of CCTA is similar tohat of perfusion testing. Although the range of values forow to high risk was similar, a more gradual increase in riskas noted for CCTA in patients with less extensive CAD.ecause CCTA is capable of identifying nonobstructiveAD for which functional MPS findings may be expected

o be normal, future prospective studies are necessary toxamine the relationship of nonobstructive plaque identifi-ation to adverse CAD events for further refinement of riskssessment on the lower ends of the risk spectrum.

A more recent study of 541 patients prospectively under-oing both CCTA and MPS examined the relative prog-ostic potential of CCTA CAD detection and MPS per-usion abnormalities in individuals with suspected CAD36). During a 2-year follow-up, annualized mortality andonfatal myocardial infarction rates were higher for patientsith obstructive CAD compared with patients with none orild CAD (4.8% and 1.8%, respectively), findings similar

or patients with abnormal versus normal myocardial per-usion (3.8% vs. 1.1%, respectively). Survival analyses dem-nstrated comparable risk stratification for anatomic CADndings by CCTA and functional perfusion by MPS.natomic and functional measures were synergistic for therediction of death or myocardial infarction. In addition,laque composition seemed to be important for predictingutcomes because individuals with �2 noncalcified plaques,3 mixed plaques, and �4 calcified plaques experienced

igher rates of death and MI than those with none.These proof-of-principle studies will require corrobora-

ion in other centers and in different patient cohorts.urther, direct comparison of CCTA with MPS for prog-ostic risk stratification in individuals undergoing either test

as to date not been performed. Before CCTA is widely

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962 Min et al. JACC Vol. 55, No. 10, 2010Present State of CCTA March 9, 2010:957–65

ccepted as possessing equivalent or superior abilities forisk stratification, head-to-head evaluations will likely beequired using randomized, controlled trials, several ofhich have been proposed but not yet initiated.se of CCTA in the evaluation of acute chest pain. Al-ost 6 million individuals are evaluated each year for acute

hest pain in the emergency department (34). Despitetandardized protocols and high vigilance, between 2% and% of patients are erroneously discharged with missedyocardial infarction (37). Proponents of CCTA advocate

ts potential usefulness in this patient subgroup, highlight-ng the NPV of CCTA to successfully identify individualsn whom no obstructive CAD exists and who have aavorable prognosis.

A single-center, randomized study of 197 individualsresenting with acute chest pain to the emergency depart-ent compared a CCTA-based diagnostic evaluation strat-

gy with standard-of-care algorithms that used MPS (38).n contrast to individuals undergoing standard-of-care as-essment, individuals undergoing CCTA experienced re-uced diagnostic time in the emergency department (3.4nd 15.0 h, respectively; p � 0.01) and fewer repeatvaluations for chest pain. These findings translated toower costs for a CCTA-based evaluation by almost $300er patient. In 6-month and 2-year follow-up, no adverseAD events occurred in discharged individuals by either aCTA- or standard-of-care–based evaluation (G. Raff,ersonal communication, June 2009).In a related study, 368 patients presenting to the emer-

ency department with acute chest pain underwent 64-sliceCTA after initially negative findings on troponin mea-

urements and electrocardiograms (39). The caring physi-ian was blinded to the CCTA results. One half of the studyatients had no evidence of CAD by CCTA, with an NPVf 100% for acute coronary syndrome in a 6-month follow-p. By contrast, the presence of any plaque by CCTA had00% sensitivity for acute coronary syndrome detection,lthough the specificity for acute coronary syndrome detec-ion was low (54%). Specificity for acute coronary syndromeetection was improved by restriction of CAD to those with50% stenosis by CCTA, findings, which were incremental

o thrombolysis in myocardial infarction risk scores.In aggregate, the current data on CCTA for acute chest

ain suggest that in appropriate populations, CCTA may beseful as a successful triage tool that may allow safe earlyischarge of low-risk patients. On the other hand, theresence of nonobstructive coronary artery plaque portendslow but nonzero risk, congruent with the data observed in

he stable chest pain population, and is therefore an imper-ect stand-alone instrument for triaging individuals withossible acute coronary syndrome. Although these early datare favorable, further study is still needed in larger cohorts toerify the safety and effectiveness of a CCTA-based evalu-tion of acute chest pain patients.ost-efficiency and resource utilization after CCTA. At

resent, the potential clinical utility of CCTA is not i

niformly recognized by third-party payers, with privateayer coverage of CCTA for CAD evaluation existing inpproximately 50% of U.S. plans. Concerns of uncheckedrowth for CCTA have also been expressed by the Centersor Medicare and Medicaid Services in a proposed Nationaloverage Determination for CCTA that called for the

nswer to 3 questions to appraise the value of CCTA (40).hese 3 questions, which deal with diagnostic test accuracy,

esource utilization, and improvement in patient-centeredealth outcomes, were reinforced by the Medicare Evidenceevelopment and Coverage Advisory Committee, with

nput from the National Heart, Lung, and Blood Institute,hich prioritized the need to answer the question: how

ost-effective is CCTA (41)?Given the shorter clinical experience with CCTA com-

ared with other modalities such as MPS, relatively littlevidence is as yet available to describe the cost-effectivenessf CCTA. Early evaluations of the economic implicationsf a CCTA-based strategy have relied primarily on single-enter “back-of-the-envelope” calculations of costs or deci-ion analytic models whose findings are largely driven byeasures of test sensitivity and specificity.One recent multicenter study related total health care and

AD-related costs to downstream CAD hospitalizationutpatient visits, acute myocardial infarction and new-onsetngina in 8,235 matched low-risk individuals undergoingCTA or MPS (42). In a 1-year follow-up, adjusted CAD

osts were 25.9% lower in individuals undergoing CCTAompared with MPS, by an average of $1,075 per patient.hese differences were driven, in part, by the lower likeli-ood of undergoing coronary revascularization. Despitehis, rates of myocardial infarction and CAD-related hos-italization were similar, and rates of new-onset angina inndividuals undergoing CCTA were lower than those re-orted for MPS. These findings were extended in a similartudy of 9,690 matched intermediate-risk individuals un-ergoing CCTA or MPS (43). In a 9-month follow-up,djusted total and CAD-related costs were one third loweror individuals after CCTA compared with MPS by anverage of $467 per patient. Rates of new CAD medicationsnd coronary revascularization were similar in CCTA and

PS patients, and the cost differences were explained inart due to methods of downstream testing. Individualsvaluated by CCTA were more likely to undergo follow-upesting with MPS, whereas MPS individuals were moreikely to undergo downstream testing by ICA. Despiteower costs for CCTA, no differences were observed forAD events, including CAD hospitalizations, CAD out-atient visits, myocardial infarction, or new-onset angina.Although these findings are provocative, they are far from

efinitive. The aforementioned studies used administrativelaims data, and, thus, clinical results of CCTA or MPS asell as symptom data are lacking. The deficiency of this

mportant clinical information prevents ascertainment ofhether the increased costs noted in the MPS group were,

n fact, appropriate. In addition, the nonrandomized nature

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963JACC Vol. 55, No. 10, 2010 Min et al.March 9, 2010:957–65 Present State of CCTA

f the individuals undergoing CCTA or MPS, despiteareful statistical matching techniques, may be beset byesidual confounders. Further, these analyses were per-ormed using 2005 and 2006 claims data, at a time whenlinical use of 64-detector row CCTA was in its inception.he increased rates of ICA after MPS may simply reflect

he unavailability of CCTA to those patients at that time.afety. Performance of CCTA results in non-negligibleoses of ionizing radiation, and this has been a criticism of

ts use. Traditional measures of radiation dosimetry bylectrocardiogram-gated CCTA have used the use of anverage conversion coefficient (0.014 mSv·mGy�1·cm�1) tostimate the effective radiation dose from the scanner-eported dose–length product; the millisievert (mSv) unit isypically used for doses (44). Although radiation doses from

PS, ICA, and nonelectrocardiogram-gated noncardiacT are generally straightforward in their measurements, the

adiation dose of CCTA is highly variable and substantiallyepends on the image acquisition parameters.Among the numerous methods of performing CCTA,

adiation doses can vary by an order of magnitude, and inractice, these variations are similarly observed. In PRO-ECTION I (Prospective Multicenter Study on Radiationose Estimates of Cardiac CT Angiography in Dailyractice), 120 sites reported radiation dose estimates fromCTA (45). The average radiation dose conferred byCTA was 12 mSv, or approximately 4 times that derived

rom the annual background radiation from radon. Al-hough this dose compares favorably with MPS, it isevertheless twice the amount of radiation associated with aiagnostic ICA. Further, the variation of dose at sitesxperienced in performing CCTA in PROTECTION Ias wide, and ranged from 4 to nearly 30 mSv.In an effort to minimize radiation dose from CCTA,

umerous methods for dose reduction have been developed.hese include automated tube current modulation, electro-

ardiographic modulation, prospective axial triggering, re-uced tube voltage, and iterative reconstruction techniques.

CTA-Related Issue and Pro and Con ArgumentTable 2 CCTA-Related Issue and Pro and Con Argument

CCTA Diagnostic TestCharacteristic Pro

Diagnosis ofobstructive CAD

CCTA possesses a high NPV for identification of indwhom no further testing is warranted.

Anatomic diagnosis ofCAD

Most individuals undergoing imaging do not have sCAD and, thus, a test with high NPV is most use

Detection of subclinicalatherosclerosis

CCTA diagnoses individuals with subclinical atheroswhich offers the opportunity to initiate primary pfuture CAD events.

Prognosis CCTA plaque characterization for prognostic risk asas effective and is synergistic to stress imaging

Resource utilization CCTA can act as an effective gatekeeper to cardiaccatheterization, thereby reducing costs.

Safety CCTA exposes a patient to less radiation than otherincluding nuclear stress testing and invasive ang

AD � coronary artery disease; CCTA � cardiac computed tomography angiography; NPV � negative pre

he combination of these techniques can result in morehan a 90% radiation dose reduction to �1 mSv (46).evertheless, the penetration of these techniques into wide-

pread clinical practice outside of specialized centers has notet occurred, and radiation dose associated with CCTAemains excessively high. A recent multicenter, single-stateegistry, reflecting real-world practice, reported unaffectedoses of 25 mSv with CCTA (47). Educational interven-ions to these sites reduced radiation by almost 50%,uggesting that instruction and implementation of radiationechniques can effectively lower the radiation dose andotentially improve patient safety.eneralizability. Although study of CCTA has been

bundant since the introduction of 64-detector row CCTAcanners in 2005, the generalized applicability of thesebservations remains to be seen. CCTA studies have, toate, been largely performed by centers with expertise inmage acquisition, reconstruction, and interpretation. Fur-her, studies of CCTA have generally limited inclusion ofatients for whom CCTA performance would be most

ikely successful. The ability of CCTA to be commonlypplied in subjects with high CACS, irregular hearthythms, or obese individuals can result in significantrtifacts related to beam hardening, misregistration, andmage noise, respectively. Whether CCTA can be rou-inely performed in such subjects remains to be deter-ined, but diagnostic performance will likely be less

obust than that previously reported for individuals with-ut these characteristics.

onclusions

he Irish playwright George Bernard Shaw once wrote,New opinions often appear first as jokes and fancies, thens blasphemies and treason, then as questions open toiscussion, and finally as established truths” (48). Primarilyver the past 3 years, the profusion of scientific evidenceelated to CCTA has permitted evolution of the field to the

Con

ls in CCTA possesses high rates of false positive findings, which will leadto unnecessary catheterization and revascularization.

nt Ischemia-guided management is more proven than anatomy-guidedmanagement.

is,ion of

Most individuals diagnosed by CCTA with subclinical atherosclerosisshould already be receiving medical therapy. Further CCTAdiagnosis may simply represent lead-time bias for which nointervention is necessary or useful.

ent iss.

Functional stress testing with or without imaging is robust forrisk stratification.

CCTA will simply serve as an add-on test rather than as astand-alone test, thereby increasing costs.

hy.CCTA exposes a patient to excessive radiation.

ividua

ignificaful.

clerosrevent

sessmfinding

tests,iograp

dictive value.

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964 Min et al. JACC Vol. 55, No. 10, 2010Present State of CCTA March 9, 2010:957–65

oint of raising questions, most of which remain open toiscussion. In the past year alone, considerable discussionccurred regarding the widespread use of CCTA in thevaluation of patients with suspected CAD. Interestingly,he same available evidence often evokes directly contrarynterpretations from proponents and critics of CCTATable 2).

The reasons underlying this debate stem not only fromifferences in scientific opinion, but also under a backdropf spiraling health care costs and disproportionate growth inoninvasive imaging. In this regard, newly introducedechnologies such as CCTA have experienced a “raising ofhe bar” of medical evidence required to either prove orisprove their clinical and economic effectiveness. Althoughhis standard of evidence development has not been aistorical mandate for other imaging methods, it will never-heless be required for CCTA in the current budget-neutralealth care environment that stresses comparative effective-ess against established methods of CAD evaluation.What, then, is the current and future state of CCTA? In

ur opinion, the diagnostic accuracy of CCTA has alreadyeen definitively established. By well-performed prospec-ive, multicenter studies, CCTA is an accurate diagnosticodality with superior diagnostic accuracy to detect and

xclude anatomically obstructive CAD. The exclusion ofAD seems to offer immediate clinical usefulness and is

ikely to reduce the need for subsequent resource utilization.owever, improvements are still necessary to reduce over-

stimation of CAD severity. With newer generation CTcanners, this will be a process of evolution.

Nevertheless, the ability of CCTA, beyond conventionalethods of CAD evaluation, to predict patient-centered

utcomes and to invoke appropriate medical or invasivereatment and do so safely and in a cost-effective manner haset to be determined. The future of CCTA will lie in thenswers to these questions, which will depend on the type ofigh-quality evidence typically only derived from large,ell-designed, randomized, controlled trials.

eprint requests and correspondence: Dr. Daniel S. Berman,epartment of Imaging, Cedars-Sinai Medical Center, 8700everly Boulevard, Room 1258, Los Angeles, California 90048.-mail: bermand@cshs.org.

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ey Words: cardiac computed tomography angiography y coronary

rtery disease y diagnosis.