diagnosis of ischemia-causing coronary stenoses by - qi imaging

Journal of the American College of Cardiology Vol. 58, No. 19, 2011© 2011 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00

Cardiac Imaging

Diagnosis of Ischemia-Causing Coronary Stenosesby Noninvasive Fractional Flow Reserve ComputedFrom Coronary Computed Tomographic AngiogramsResults From the Prospective Multicenter DISCOVER-FLOW(Diagnosis of Ischemia-Causing Stenoses Obtained ViaNoninvasive Fractional Flow Reserve) Study

Bon-Kwon Koo, MD, PHD,* Andrejs Erglis, MD, PHD,† Joon-Hyung Doh, MD, PHD,‡David V. Daniels, MD,§ Sanda Jegere, MD,� Hyo-Soo Kim, MD, PHD,* Allison Dunning, MD,¶Tony DeFrance, MD,# Alexandra Lansky, MD,** Jonathan Leipsic, BSC, MD,†† James K. Min, MD‡‡

Seoul and Goyang, South Korea; Riga, Latvia; Palo Alto, San Francisco, and Los Angeles, California;New York, New York; New Haven, Connecticut; and Vancouver, British Columbia, Canada

Objectives The aim of this study was to determine the diagnostic performance of a new method for quantifying fractionalflow reserve (FFR) with computational fluid dynamics (CFD) applied to coronary computed tomography angiogra-phy (CCTA) data in patients with suspected or known coronary artery disease (CAD).

Background Measurement of FFR during invasive coronary angiography is the gold standard for identifying coronary arterylesions that cause ischemia and improves clinical decision-making for revascularization. Computation of FFRfrom CCTA data (FFRCT) provides a noninvasive method for identifying ischemia-causing stenosis; however, thediagnostic performance of this new method is unknown.

Methods Computation of FFR from CCTA data was performed on 159 vessels in 103 patients undergoing CCTA, inva-sive coronary angiography, and FFR. Independent core laboratories determined FFRCT and CAD stenosis se-verity by CCTA. Ischemia was defined by an FFRCT and FFR �0.80, and anatomically obstructive CAD wasdefined as a CCTA with stenosis �50%. Diagnostic performance of FFRCT and CCTA stenosis was assessedwith invasive FFR as the reference standard.

Results Fifty-six percent of patients had �1 vessel with FFR �0.80. On a per-vessel basis, the accuracy, sensitivity, specificity,positive predictive value, and negative predictive value were 84.3%, 87.9%, 82.2%, 73.9%, 92.2%, respectively, forFFRCT and were 58.5%, 91.4%, 39.6%, 46.5%, 88.9%, respectively, for CCTA stenosis. The area under the receiver-operator characteristics curve was 0.90 for FFRCT and 0.75 for CCTA (p � 0.001). The FFRCT and FFR were well corre-lated (r � 0.717, p � 0.001) with a slight underestimation by FFRCT (0.022 � 0.116, p � 0.016).

Conclusions Noninvasive FFR derived from CCTA is a novel method with high diagnostic performance for the detection andexclusion of coronary lesions that cause ischemia. (The Diagnosis of ISChemia-Causing Stenoses Obtained ViaNoninvasivE FRactional FLOW Reserve; NCT01189331) (J Am Coll Cardiol 2011;58:1989–97) © 2011 by theAmerican College of Cardiology Foundation

Published by Elsevier Inc. doi:10.1016/j.jacc.2011.06.066

From the *Department of Medicine, Seoul National University Hospital, Seoul,South Korea; †Department of Medicine, Pauls Stradins Clinical University Hospital,Riga, Latvia; ‡Department of Medicine, Inje University Ilsan Paik Hospital, Goyang,South Korea; §Department of Medicine, Stanford University School of Medicine,Palo Alto, California; �Division of Cardiology, Pauls Stradins Clinical UniversityHospital, Riga, Latvia; ¶Department of Public Health, Weill Cornell Medical
College, New York, New York; #CVCTA, San Francisco, California; **YaleUniversity School of Medicine, New Haven, Connecticut; ††Department of Radiol-
ogy, St. Paul’s Hospital, Vancouver, British Columbia, Canada; and the ‡‡Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California. Dr.DeFrance is on the Speaker’s Bureau of Toshiba Medical Systems. Dr. Leipsic is onthe Speaker’s Bureau and medical advisory board of GE Healthcare. All other authorshave reported that they have no relationships relevant to the contents of this paper todisclose.

Manuscript received April 20, 2011; revised manuscript received June 21, 2011,accepted June 27, 2011.

http://clinicaltrials.gov/ct2/show/NCT01189331?term=ffr+koo&rank=12

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Large-scale randomized trialshave demonstrated that frac-tional flow reserve (FFR)—orthe ratio of maximal myocardialblood flow through a diseasedartery to the blood flow in thehypothetical case that this arteryis normal—is a useful physiolog-ical test for assessment of lesion-specific ischemia and a valuableadjunct to anatomic assessmentof coronary artery disease (CAD)as determined by invasive coronaryangiography (ICA) (1–4). Thiscombined anatomic-physiologicalevaluation of CAD allows for en-hanced clinical decision-making thatimproves event-free survival, reducesunnecessary revascularization, andlowers healthcare costs (5,6).

Coronary computed tomo-graphic angiography (CCTA) hasemerged as a noninvasive test that

assesses anatomic CAD stenosis severity (7). Although priormulticenter studies have demonstrated favorable diagnosticperformance for CCTA identification and exclusion of ana-tomically obstructive coronary stenoses, CAD stenosis byCCTA demonstrates an unreliable relationship to lesion-specific ischemia, with the majority of high-grade stenosesdetected by CCTA not causal of ischemia (8–11). Thesefindings have raised concerns that widespread use of CCTAmight result in excess referral of patients to ICA and unnec-essary revascularization of nonischemic coronary lesions(12,13).

See page 1998

Computational fluid dynamics (CFD), as applied to CCTAimages, represents a novel method that enables predictionof blood flow and pressure fields in coronary arteries andcalculation of lesion-specific FFR (14–16). The FFR can becomputed from typically acquired CCTA scans (FFRCT)without any modification of CCTA protocols, additionalimage acquisition, or administration of medications.

We performed a prospective multicenter study to com-pare the diagnostic performance of FFRCT with CCTAtenosis for the diagnosis of lesion-specific ischemia, asetermined by FFR performed at the time of ICA.

ethods

tudy design. The DISCOVER-FLOW (Diagnosis ofSChemia-Causing Stenoses Obtained Via NoninvasivERactional FLOW Reserve) study was conducted at 4 sites

Seoul National University Hospital, Seoul, Korea; Pauls

Abbreviationsand Acronyms

AUC � area under thereceiver-operatorcharacteristics curve

CABG � coronary arterybypass surgery

CAD � coronary arterydisease

CCTA � coronarycomputed tomographicangiography

CFD � computational fluiddynamics

FFR � fractional flowreserve

FFRCT � computation offractional flow reserve fromcoronary computedtomographic angiographydata

ICA � invasive coronaryangiography

tradins Clinical University Hospital, Riga, Latvia; Inje

niversity Ilsan Paik Hospital, Goyang, Korea; Stanfordniversity Medical Center, Palo Alto, California). The

tudy protocol was approved by the Institutional Reviewoards of each center. The study was funded by Heartflow,

nc. (Redwood City, California).tudy population. The study population comprised 103table patients with suspected or known CAD who under-ent CCTA, ICA, and FFR between October 13, 2009,

nd January 14, 2011. Inclusion criteria were: adult �18ears of age, CCTA with �50% stenosis in a majororonary artery �2.0 mm diameter (determined by clinicalite), and undergoing clinically indicated ICA with FFR.xclusion criteria included individuals unable to provide

nformed consent; noncardiac illness with life expectancy2 years; pregnant state; allergy to iodinated contrast;

erum creatinine �1.7 mg/dl; significant arrhythmia; heartate �100 beats/min; systolic blood pressure �90 mm Hg;

contraindication to beta blockers, nitroglycerin or adeno-sine; prior coronary artery bypass surgery (CABG); Cana-dian Cardiovascular Society class IV angina; or non-evaluable CCTA as determined by the CCTA corelaboratory. Importantly, every evaluable CCTA as judged bythe CCTA core laboratory was interpreted in independentblinded fashion by the FFRCT core laboratory in an intent-to-diagnose fashion.Protocol for CCTA. Each center performed CCTA inaccordance with the Society of Cardiovascular ComputedTomography Guidelines on Performance of CCTA with avariety of different computed tomography scanner platforms(Lightspeed VCT, GE Healthcare, Milwaukee, Wisconsin;Somatom Sensation and Definition CT, Siemens, Forch-heim, Germany; Brilliance 256 and 64, Philips, Surrey,United Kingdom; Aquilion One and 64, Toshiba, Otawara,Japan) (17). Intravenous or oral metoprolol was adminis-tered for any patient with a heart rate �65 beats/min.Immediately before image acquisition, 0.2 mg sublingualnitroglycerin was administered. During acquisition, 80 to100 cc of contrast (Isovue 370 mg/dl, Bracco, Princeton,New Jersey; Omnipaque 350 mg/dl, GE Healthcare,Princeton, New Jersey; Visipaque 320 mg/dl, GE Health-care) was injected, followed by a saline flush. Helical or axialscan data were obtained with retrospective or prospectiveelectrocardiographic gating, respectively. Image acquisitionwas prescribed to include the coronary arteries, left ventricle,and proximal ascending aorta. The scan parameters were: 64 �0.625/0.750 mm collimation, tube voltage 100 or 120 mV,effective 400 to 650 mA. Radiation dose reduction strategies wereemployed when feasible, and doses ranged from 3 to 15 mSv.

Noninvasive coronary artery analysis by CCTA. TheCCTAs were analyzed in blinded fashion by an independentcore laboratory (CVCTA, San Francisco, California) in accor-dance with the Society of Cardiovascular Computed Tomog-raphy guidelines on CCTA interpretation (18). The CCTAimages were evaluated with 3-dimensional workstations (VitalImages, Minneapolis, Minnesota; Ziosoft, Redwood City,
California). The CCTAs were visualized by any post-

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1991JACC Vol. 58, No. 19, 2011 Koo et al.November 1, 2011:1989–97 Lesion-Specific Ischemia From FFR Computed From CT

processing method, including axial, multiplanar reformat, max-imum intensity projection, and cross-sectional analysis.

Coronary segments were scored in a semi-quantitativemanner with an 18-segment Society of CardiovascularComputed Tomography model. In each segment, athero-sclerosis was defined as tissue structures �1 mm2 thatxisted within the coronary artery lumen or adjacent to theoronary lumen that could be discriminated from pericardialissue, epicardial fat, or vessel lumen itself. Coronary lesionsere quantified for luminal diameter stenosis as none (0%),ild (1% to 49%), moderate (50% to 69%), or severe

�70%). Anatomically obstructive CAD by CCTA wasefined at 2 thresholds (�50% or �70% stenosis severity)n a per-patient and per-vessel basis.CA image acquisition and FFR performance. SelectiveCA was performed by standard catheterization in accor-ance with the American College of Cardiology Guidelinesor Coronary Angiography (19). Two projections werebtained/major epicardial vessel, with angles of projectionptimized on the basis of cardiac position. The FFR waserformed in vessels as clinically indicated but was noterformed for subtotal (99% stenosis) lesions. After admin-stration of nitroglycerin, a pressure-monitoring guidewirePressureWire Certus, St. Jude Medical Systems, Uppsala,weden; ComboWire, Volcano Corporation, San Diego,alifornia) was advanced past the stenosis. Hyperemia was

ttained by administration of intravenous (140 �g/kg/min,n � 90) or intracoronary (50 �g, n � 13) adenosine, withroute of administration at the discretion of the operator(20). The position of the distal pressure sensor was recordedto enable the FFRCT to be calculated from the same points the measured FFR. The FFR was calculated by dividinghe mean distal coronary pressure by the mean aorticressure during hyperemia. The FFR was considered diag-ostic of ischemia at a threshold of �0.80 on a per-patientnd per-vessel basis (3).FRCT interpretation. The FFRCT was performed in

blinded fashion by core laboratory scientists at HeartFlow,Inc. (Redwood City, California). Three-dimensional mod-els of the coronary tree and ventricular myocardium werereconstructed with custom methods applied to blindedCCTA data for simulation of coronary flow and pressure(14). Blood was modeled as a Newtonian fluid with incom-pressible Navier-Stokes equations and solved subject toappropriate initial and boundary conditions with a finiteelement method on a parallel supercomputer. Becausecoronary flow and pressure are unknown a priori, a methodto couple lumped parameter models of the microcirculationto the outflow boundaries of the 3-D model was used (21).The FFRCT analyses required approximately 5 h/exam;iterative improvements in automation are expected to re-duce processing time.

The FFRCT technology is based on 3 key principles.ecause patients with rest angina were excluded, the first is

hat coronary supply meets myocardial demand at rest.
dherence to this principle enabled calculation of total
esting coronary flow relative to ventricular mass. Theecond principle is that resistance of the microcirculation atest is inversely but not linearly proportional to the size ofhe feeding vessel (22–26). The third principle is thaticrocirculation reacts predictably to maximal hyperemic

onditions in patients with normal coronary flow (27). Onhe basis of these principles, a lumped parameter modelepresenting the resistance to flow during simulated hyper-mia was applied to each coronary branch of the segmentedCTA model. The FFRCT was modeled for conditions of

adenosine-induced hyperemia; an FFRCT �0.80 was con-idered diagnostic of lesion-specific ischemia.

The FFRCT core laboratory scientists were instructed as tohe location within a coronary artery where the FFR waseported by an independent scientist who interpreted both theCTA and ICA and who was not involved in the CCTA,

CA, FFRCT, or FFR analyses. The FFRCT core laboratorycientists interpreted all CCTAs judged evaluable by an inde-endent blinded reader in an intent-to-diagnose fashion.ample size calculation and statistical analyses. Theiagnostic accuracy of CCTA stenosis �50% for the detec-ion of lesion-specific ischemia as compared with FFR wasstimated to be 49% (11). To detect a relative improvementn diagnostic accuracy of �25% for FFRCT as comparedith CCTA stenosis, 150 vessels provided 90% power with2-sided alternative hypothesis. For estimation of power,e employed McNemar’s test to account for the pairedature of the data and assumed independence of lesion-pecific ischemia in vessels and a 22% rate of discordanceetween FFRCT and FFR.Categorical variables are presented as frequencies and

percentages, with continuous variables as mean � SD.iagnostic measures on a per-patient and -vessel basis were

alculated, including sensitivity, specificity, positive predic-ive value (PPV), negative predictive value (NPV), accuracy,ositive likelihood ratio, and negative likelihood ratio. Therea under the receiver-operator characteristics curveAUC) was calculated for CCTA stenosis and FFRCT. The

AUCs were compared by the DeLong method. Pearson’sand Spearman’s correlation coefficients were calculated todetermine the relationship between FFRCT and FFR.Bland-Altman analysis was performed with FFR as thestandard of reference. All analyses were performed withSAS Proprietary Software (version 9.2, SAS Institute, Cary,North Carolina).

Results

Patient characteristics. One hundred three patients(100%) who underwent ICA, FFR, CCTA, and blindedCCTA core laboratory evaluation comprised the studypopulation. Baseline characteristics are listed in Table 1.The mean interval between the CCTA and FFR was 2.3days (range 0 to 26 days), with no adverse events orrevascularization between exams. Six vessels were sub-
totally occluded (99% stenosis), and FFR was not measured

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in these vessels. Of the 159 vessels for which FFR wasperformed, maximal stenoses as determined by the CCTAcore lab were: 0% (n � 7); 1% to 25% (n � 20); 26% to 50%n � 18); 50% to 69% (n � 47); and 70% to 98% (n � 67).

Diagnostic performance of FFRCT versus CCTA foriagnosis of ischemia-producing lesions. The FFRCT

applied to coronary vessels resulted in 51 true positives(32.1%), 83 true negatives (52.2%), 18 false positives

Baseline CharacteristicsTable 1 Baseline Characteristics

Mean age, yrs 62.7 (8.5)

Male 74 (72)

Caucasian (%) 34 (33)

Hypertension 67 (65)

Hyperlipidemia 67 (65)

Diabetes 26 (26)

Mean body-mass index 25.8 (3.5)

Current smoker 24 (36)

Cardiovascular history

Prior myocardial infarction 17 (17)

Prior PCI 16 (16)

Prior CABG 0 (0)

Left ventricular ejection fraction, % 62.3 (5.7)

Vital signs*

Systolic blood pressure, mm Hg 139.1 (17.6)

Diastolic blood pressure, mm Hg 80.9 (11.4)

Heart rate, beats/min 63.9 (8.5)

Laboratory measures

Hemoglobin, mg/dl 14 (1.6)

Hematocrit, % 41.2 (4.3)

Creatinine, mg/dl 0.97 (0.18)

Medications

Aspirin 43 (87.8)

Beta-blocker 54 (96.4)

Nitrate 41 (64.1)

Statins 44 (89.8)

ACE inhibitors 39 (86.7)

Calcium-channel blockers 38 (86.7)

Clopidogrel 79 (94.1)

ARBs 5 (10.2)

Other medication 18 (36.7)

Values are n (%). *At time of coronary computed tomographic angiography.ACE � angiotensin-converting enzyme; ARB � angiotensin receptor blocker; CABG � coronary

rtery bypass surgery; PCI � percutaneous coronary intervention.

Diagnostic Performance of FFRCT and CCTA on a Per-Vessel and -PTable 2 Diagnostic Performance of FFRCT and CCTA on a Per-V

Per-Vessel

Measure FFRCT <0.80 (95% CI) CCTA Stenosis >50% (9

Accuracy 84.3 (77.7–90.0) 58.5 (50.4–66.2)

Sensitivity 87.9 (76.7–95.0) 91.4 (81.0–97.1)

Specificity 82.2 (73.3–89.1) 39.6 (30.0–49.8)

PPV 73.9 (61.9–83.7) 46.5 (37.1–56.1)

NPV 92.2 (84.6–96.8) 88.9 (75.9–96.3)

LR (�) 4.94 (3.54–6.89) 1.51 (1.33–1.73)

LR (�) 0.147 (0.097–0.224) 0.22 (0.127–0.370

For this analysis, a fractional flow reserve or computation of fractional flow reserve from coronary
coronary computed tomographic angiography (CCTA ) stenosis �50% was anatomically obstructive.CI � confidence interval; LR(�) � positive likelihood ratio; LR(�) � negative likelihood ratio; NPV � n
(11.3%), and 7 false negatives (4.4%). Diagnostic perfor-mance of FFRCT and CCTA on a patient- and vessel-basedevaluation are listed in Table 2. Representative examples ofanatomically obstructive stenosis with and withoutischemia-producing stenoses are shown in Figures 1 and 2.

pplying FFRCT values and CCTA stenosis ranges re-vealed a higher AUC for FFRCT as compared with CCTA0.90 vs. 0.75, p � 0.001) on a lesion-specific basis (Fig. 3).er-patient performance of FFRCT versus CCTA can beeen in Table 2. A higher AUC for FFRCT was observed,imilar to per-vessel analyses, as compared with CCTA forer-patient discrimination (0.92 vs. 0.70, p � 0.0001)Fig. 3). No improvement in AUC was observed on eitherhe per-vessel and per-patient level when CCTA stenosisas added to FFRCT (p � 0.50 and p � 0.64, respectively).er-vessel diagnostic performance of FFRCT in vesselsith intermediate stenoses by CCTA. Among the 47essels with 50% to 69% stenoses by CCTA, 25.5% (n �2) exhibited ischemia FFR. For these stenoses, FFRCT

demonstrated a diagnostic accuracy, sensitivity, specificity,PPV, and NPV of 83.0%, 66.7%, 88.6%, 66.7%, and 88.6%.All 4 “false negative” vessels, where FFRCT did not dem-onstrate ischemia, had measured FFR values between 0.75and 0.80.Correlation of FFRCT to FFR. There was good correla-tion of per-vessel FFRCT values with FFR values (Spear-

an’s rank correlation � 0.717, p � 0.0001; Pearson’sorrelation coefficient � 0.678, p � 0.0001), with a slightnderestimation of FFRCT as compared with measured FFR

(mean difference 0.022 � 0.116, p � 0.016) (Figs. 4 and 5) at theer-vessel level, with similar values and no systematicifferences at the per-patient level (mean difference 0.019 �.128, p � 0.131).

iscussion

n this prospective multicenter study comparing FFRCTwith CCTA stenosis in patients undergoing ICA and FFR,the diagnostic accuracy of FFRCT was superior and additiveto CCTA stenosis for the diagnosis of ischemia-causinglesions as determined by an invasive FFR reference stan-dard. The FFRCT augmented the discriminatory ability to

t Basisl and -Patient Basis

Per-Patient

I) FFRCT <0.80 (95% CI) CCTA Stenosis >50% (95% CI)

87.4 (79.4–93.1) 61.2 (51.1–70.6)

92.6 (82.1–97.9) 94.4 (84.6–98.8)

81.6 (68.0–91.2) 24.5 (13.3–38.9)

84.7 (73.0–92.8) 58.0 (47.0–68.4)

90.9 (78.3–97.5) 80.0 (51.9–95.7)

5.03 (3.34–7.59) 1.25 (1.11–1.41)

0.091 (0.046–0.181) 0.229 (0.097–0.541)

ted tomographic angiography data (FFRCT) �0.80 was diagnostic of lesion-specific ischemia, and

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identify lesions that cause ischemia, as compared withCCTA stenosis, largely by reducing the rates of falsepositive lesions incorrectly classified by stenosis alone.

To our knowledge, this study represents the first of itskind to evaluate CFD principles applied to CCTA imagesfor derivation of patient-specific measures of coronary arterypressure. Importantly, the calculation of FFRCT required nomodification of CCTA acquisition protocols, no additionalimaging, and no additional administration of medications.The results of the present study establish the feasibility ofCFD modeling for noninvasive determination of the phys-iological consequences of CAD and support a utility forapplication of FFRCT in patients undergoing CCTA.

Coronary computed tomographic angiography is a non-invasive test for anatomic assessment of CAD severity thathas been suggested as an alternative to ICA (8–10,28). PriorCCTA studies employing computed tomography scannerswith �64-detector rows have observed a generally highdiagnostic performance of CCTA, as compared with quan-titative coronary angiography as a reference standard. How-ever, significant false positive rates underscore a generaloverestimation of CAD severity by CCTA, and even amongobstructive CAD lesions identified by CCTA that areconfirmed at ICA, only a minority of such lesions are causalof ischemia (8,10,11). These findings have also been ob-

Figure 1 Anatomically Obstructive Stenosis With No Functiona

(A) Coronary computed tomography angiography demonstrating obstructive (�50%artery. Proximal and distal to the lesion, there are multiple areas of diffuse calcifieraphy confirms the obstructive OM stenosis (red arrow). (C) Computation of fractionstrates no ischemia in the OM, with a computed value of 0.85. (D) Fractional fldemonstrates no ischemia in the OM.

served for ICA, and prior multicenter studies support a i

distinct benefit for adjunctive physiological assessment ofanatomic CAD stenoses by FFR (3,5,6,29). In the FAME(Fractional Flow Reserve versus Angiography for Multives-sel Evaluation) study of 1,005 patients with multivesselCAD, those that underwent FFR-guided revascularization—ascompared with patients undergoing anatomically guided revas-cularization—experienced lower rates of adverse events, place-ment of fewer coronary stents, and lower healthcare costs (3,5).In this regard, the addition of FFRCT to CCTA mightimprove clinical decision-making and promote salutatory out-comes for individuals with CCTA-identified CAD; prospec-tive outcomes studies are warranted.

We employed definitions identical to those used in theFAME study for ischemia by FFR (�0.80) and obstructivestenosis by angiography (�50%) (3). Prior studies havedemonstrated enhanced specificity for detection of ischemiawhen employing an FFR threshold of �0.75 or a stenosisthreshold of �70%, albeit at a penalty of increased falsenegatives (30). We examined the relationship of an FFRCTcutoff of 0.75 and CAD stenosis of 50%, respectively, andfound similar results (data not shown).

One distinction between our study and the FAME studyis how we dealt with subtotal (99%) occlusions. In theFAME study, these lesions were not subjected to FFR forreasons of safety and were assigned a value of 0.50 (3). We

emia

osis (white arrow) in the obtuse marginal (OM) branch of the left circumflexue of intermediate stenosis severity (40% to 69%). (B) Invasive coronary angiog-

ow reserve from coronary computed tomographic angiography data (FFRCT) dem-erve (FFR) of 0.84 at the time of invasive coronary angiography similarly

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dentified 6 vessels with subtotal occlusions in our study and


excluded them from the primary analysis to estimate themost conservative diagnostic performance of FFRCT. As-signment of a value of 0.50 to FFRCT would necessarilyimprove the performance of FFRCT for vessels that wouldrarely be clinically interrogated by FFRCT for ischemia. Posthoc analyses assigning these vessels a value of 0.50 didexpectedly improve diagnostic performance with an accu-

Figure 2 Anatomically Obstructive Stenosis With a Lesion Cau

(A) Multiplanar reformat of coronary computed tomography angiography demonstrarior descending (LAD) artery. (B) Invasive coronary angiography confirms the LAD snary pressure in the first diagonal branch (0.78) and distal LAD (0.58) by FFR. (C)distal LAD (0.57), demonstrating lesion-specific ischemia of the proximal LAD sten

Figure 3 ROC Demonstrating the AUC for FFRCT and CCTA SteDiscrimination of Lesions That Cause Ischemia on a P

Areas under the receiver-operator characteristics curve (AUC) on a per-patient (righcomputed tomography angiography (CCTA) stenosis �50% or computation of fract�0.80. ROC � receiver-operator characteristic.

racy, sensitivity, specificity, PPV, and NPV of 84.8%,89.1%, 82.2%, 76.0%, and 92.2%, respectively.

Interestingly, 12 of 47 (25.5%) lesions judged to be of50% to 69% stenosis severity by CCTA caused ischemia, asdetermined by an FFR �0.80. These results are in agree-ment with prior ICA-FFR studies wherein the magnitudeof stenosis is often discordant with the presence of ischemia

Ischemia

bstructive (�50%) stenosis (white arrow) in the proximal portion of the left ante-is (red arrow) with corresponding hemodynamically significant reductions in coro-vasive computation of FFR from FFRCT of the first diagonal branch (0.79) andAbbreviations as in Figure 1.

for thessel and -Patient Level

per-vessel (left) level for ischemia by fractional flow reserve �0.80 by coronaryow reserve from coronary computed tomographic angiography data (FFRCT)

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(31). These patients do not reach an angiographic thresholdfor revascularization but, nevertheless, experience ischemia(32). In these patients, the diagnostic performance ofFFRCT was maintained (accuracy 83.0%), and all 4 false

egative lesions exhibited an invasive FFR value between.75 and 0.80, suggesting some degree of hemodynamicignificance. The ability to noninvasively identify patientsith ischemia but without high-grade stenoses might allow

Figure 4 Correlation of FFRCT to FFR

A good correlation (R � 0.72) is observed. Abbreviations as in Figure 1.

Figure 5 Bland-Altman Plot of FFR and FFRCT on a Per-Vessel B

A slight systematic underestimation of computation of fractional flow reserve from
CT
or more targeted treatments, and future studies examininghis population should be considered.

We enrolled patients who did as well as did not have a prioristory of CAD. Diagnostic performance of CCTA for ana-omic CAD stenosis for patients with known CAD has beeness robust than for patients with no prior history of CAD8,9). As such, present Appropriate Use Criteria advocate these of CCTA in the low-intermediate likelihood patient withuspected CAD, but the use of CCTA for patients withnown CAD is generally considered uncertain or inappropriate33). The addition of FFRCT to CCTA measures of anatomictenosis might enhance the diagnostic accuracy and expand thetility of CCTA in this population.

The findings of this study are of significant importance.omputation of FFRCT from CCTAs might permit an

“all-in-one” approach, whereby patient-specific stenosis canbe assessed for lesion-specific ischemia. An FFRCT mightllow for enhanced detection of patients who might benefitrom revascularization in a manner more specific thanonventional stress perfusion imaging, which might mani-est abnormalities due to epicardial stenosis or microvascularisease or both. Furthermore, radiation doses from cardiacmaging has recently been a topic of great discussion, andhe computation of FFRCT from typically acquired CCTA

images negates the need for any additional ionizing radia-tion while providing combined physiological assessment ofCAD (34). Finally, future evaluation of FFRCT for predic-tion of hemodynamic improvement after revascularizationor functional assessment of mild diffuse CAD might expandthe clinical indications of this FFRCT technique.

as compared with FFR is observed. Abbreviations as in Figure 1.

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This study is not without limitations. First, our study wasadequately powered to determine the performance ofFFRCT versus CCTA stenosis at the per-vessel rather thanhe per-patient level. Establishment of per-patient perfor-ance of FFRCT versus CCTA will require a greater

number of patients, and we are performing a parallel,prospective study to address this hypothesis (35). Second,this study enrolled patients undergoing clinically indicatedICA and FFR, and thus the ability to assess the diagnosticperformance of FFRCT in all consecutive patients undergo-ing CCTA is not possible. However, ethical considerationsprecluded our performing ICA and FFR in patients forwhom no significant CAD was present. Third, our studyexcluded patients with prior CABG, and thus the utility ofFFRCT in this population remains unknown. The FFRCTshould permit evaluation of CABG stenosis, by using thesame principles applied to native coronary arteries, butfuture studies will be required to determine its diagnosticperformance in this population.

Conclusions

In this prospective multicenter study, noninvasive FFRderived from typically acquired CCTA images offers a novelmethod that demonstrates high diagnostic performance fordetection and exclusion of coronary artery lesions that causeischemia.

Reprint requests and correspondence: Dr. James K. Min, Divi-sion of Cardiology, Department of Medicine, Cedars-Sinai Med-ical Center, 8700 Beverly Boulevard, South Taper Building 1258,Los Angeles, California 90048. E-mail: [email protected].

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Key Words: computational fluid dynamics y coronary CT angiographyy fractional flow reserve.

diagnosis of ischemia-causing coronary stenoses by - qi imaging

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