coronary computed tomography angiography for the detection of cardiac allograft vasculopathy

Journal of the American College of Cardiology Vol. 63, No. 19, 2014� 2014 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2014.01.071

Cardiac Imaging

Coronary Computed TomographyAngiography for the Detection ofCardiac Allograft Vasculopathy
A Meta-Analysis of Prospective Trials
Omar Wever-Pinzon, MD,* Jorge Romero, MD,y Iosif Kelesidis, MD,y James Wever-Pinzon, MD,*

Carlos Manrique, MD,y Deborah Budge, MD,* Stavros G. Drakos, MD, PHD,*

Ileana L. Piña, MD,MPH,yAbdallah G. Kfoury, MD,*Mario J. Garcia, MD,y Josef Stehlik, MD,MPH*

Salt Lake City, Utah; and Bronx, New York

From the *

Sciences Ce

Salt Lake Ci

Medicine, B

Transplant

they have no

Manuscri

Objectives T

U.T.A.H. Cardiac Tran

nter, Veterans Affairs Me

ty, Utah; and the yMonte

ronx, New York. This

Congress 2012, Boston, M

relationships relevant to

pt received November 27,

his study aimed to evaluate the diagnostic accuracy of coronary computed tomography angiography (CCTA) fordetecting cardiac allograft vasculopathy (CAV) in comparison with conventional coronary angiography (CCAG) aloneor with intravascular ultrasound (IVUS).

Background C
AV limits long-term survival after heart transplantation, and screening for CAV is performed on annual basis. CCTAis currently not recommended for CAV screening due to the limited accuracy reported by early studies. Technologicaladvances, however, might have resulted in improved test performance and might justify re-evaluation of thisrecommendation.
Methods A
systematic review of Medline, Cochrane, and Embase for all prospective trials assessing CAV using CCTA wasperformed using a standard approach for meta-analysis for diagnostic test and a bivariate analysis.
Results T
hirteen studies evaluating 615 patients (mean age 52 years, 83% male) and 9,481 segments fulfilled inclusioncriteria. Patient-based analyses comparing CCTA versus CCAG for the detection of any CAV (> luminal irregularities)and significant CAV (stenosis �50%), showed mean weighted sensitivities of 97% and 94%, specificities of 81%and 92%, a negative predictive value (NPV) of 97% and 99%, a positive predictive value (PPV) of 78% and 67%,and diagnostic accuracies of 88% and 94%, respectively. There was a strong trend toward improved sensitivity(97% vs. 91%, p ¼ 0.06) and NPV (99% vs. 97%, p ¼ 0.06) to detect significant CAV with 64-slice compared with16-slice CCTA. A patient-based analysis of 64-slice CCTA versus IVUS showed a mean weighted sensitivity andspecificity of 81% and 75% to detect CAV (intimal thickening >0.5 mm), whereas the PPV and NPV were 93% and50%, respectively.
Conclusions C
CTA using currently available technology is a reliable noninvasive imaging alternative to coronary angiographywith an excellent sensitivity, specificity, and NPV for the detection of CAV. (J Am Coll Cardiol 2014;63:1992–2004)ª 2014 by the American College of Cardiology Foundation
Long-term survival following heart transplantation is limitedby significant mortality rates (3% to 4%/year) beyond thefirst year after transplant, which have remained constant forthe past 2 decades (1). Timely identification of factorscontributing to the excess mortality observed in this timeperiod is likely to result in decreased morbidity and im-proved survival. Cardiac allograft vasculopathy (CAV)

splant Program, University of Utah Health

dical Center & Intermountain Medical Center,

fiore Medical Center, Albert Einstein College of

work was presented in part at the American

assachusetts. The authors have reported that

the contents of this paper to disclose.

2013; accepted January 14, 2014.

affects over 50% of the recipients by 10 years after transplantand represents an important cause of mortality in recipientswho survive the first year after transplant (1,2). Death orretransplantation 5 years after transplant occurs in 7% of therecipients who develop CAV of any degree and in 50% ofthe recipients who develop severe CAV (3,4).

See page 2005

The diagnosis of CAV has traditionally relied on the useof conventional coronary angiography (CCAG) (4).Although widely available and clinically accepted, it has thedisadvantages of being invasive and only providing visuali-zation of the vessel lumen. The development of intra-vascular ultrasound (IVUS) 2 decades ago brought greater

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Abbreviationsand Acronyms

CAV = cardiac allograft

vasculopathy

CCAG = conventional

coronary angiography

CCTA = coronary computed

tomography angiography

CI = confidence interval

IVUS = intravascular

ultrasound

NPV = negative predictive

value

PPV = positive predictive

value

ROC = receiver-operating

characteristic

JACC Vol. 63, No. 19, 2014 Wever-Pinzon et al.May 20, 2014:1992–2004 CCTA and Cardiac Allograft Vasculopathy

1993

understanding of the coronary wall anatomy and the diseaseprocess in CAV (5). Its high sensitivity and negative pre-dictive value made IVUS valuable for the assessment ofCAV in the investigational field. Nonetheless, the routineclinical use of IVUS as a screening tool for CAV is notcurrently recommended, as it is unclear whether IVUS canprovide clinical incremental value over CCAG and func-tional data. Furthermore, the use of IVUS is invasive,costly, and can be time consuming (4). A technique that hasbeen viewed with enthusiasm in the assessment of CAV iscoronary computed tomography angiography (CCTA). Ithas the advantages of being noninvasive, allows for visuali-zation of all coronary arteries, and provides informationabout the coronary artery wall. A small number of trials,with a limited number of patients, suggested that thediagnostic accuracy of CCTA in detecting CAV may besimilar to that of CCAG (6–10). Prior reviews assessingthe diagnostic accuracy of CCTA to detect CAV arelimited by incomplete data and technical limitations(11,12). As a result of the limited data supporting thediagnostic accuracy of CCTA to detect CAV and concerns

Figure 1 Selection of Studies

Six studies were excluded from the final analysis because they had incomplete data. CA

CCTA ¼ coronary computed tomography; IVUS ¼ intravascular ultrasound.

about radiation exposure, its useis not recommended for routinesurveillance of CAV by theclinical practice guidelines (13).Our aim was to closely examinecontemporary data on the accu-racy of CCTA for the detectionof CAV through a meta-analysisapproach.

Methods

Search strategy. We conductedPubMed, Embase, and CochraneCentral Register of Clinical Trialssearches for prospective studiesin which CCTA was used toassess the presence and/or the
severity of CAV using the terms: (CTA OR CCTA ORcomputed tomography OR coronary computed tomog-raphy angiography OR computed tomography coronary
V ¼ cardiac allograft vasculopathy; CCAG ¼ conventional coronary angiography;

Table 1 Baseline Characteristics of Prospective Studies Evaluating the Diagnostic Accuracy of CCTA in the Assessment of CAV

First Author(Ref. #), Year

Patients(Initial Group) Male (%) Age (yrs)

BMI(kg/m2)

Time AfterTransplant(Months)

Renal Function,Scr (mg/dl)/eGFR(ml/min/1.72 m2)

Use ofb-Blocker

Gold standard: CCAG

Carrascosa et al. (30), 2009 19 (24) 89 53 27 88 Mean Scr: 1.1 � 0.2 No

Iyengar et al. (8), 2006 19 (37) 74 58 NR NR Mean eGFR: 80 � 19 No

Nunoda et al. (26), 2010 13 (22) 77 35 NR NR NR No

Pichler et al. (32), 2008 44 (66) 90 58 27 102 NR(Exclusion if Scr >2.0)

No

Romeo et al. (6), 2005 44 (53) 75 48 NR 91 NR(Exclusion if Scr >2.8)

Yes

Schepis et al. (10), 2009 30 (41) 81 40 26 34 NR(Exclusion if Scr >1.4)

No

Sigurdsson et al. (9), 2006 53 (54) 89 54 28 NR Mean Scr: 1.2 � 0.3 No

Usta et al. (31), 2009 10 (10) 80 52 27 73 Scr: 1.2–1.7: 40% of patients<1.2: 60% of patients

Yes

Von Ziegler et al. (25), 2009 26 (28) 100 53 NR 92 Mean Scr: 1.2 � 0.2 Yes

Kepka et al. (27), 2012 20 (20) 75 48 25 NR Mean eGFR: 67.5 (45–90) Yes

Von Ziegler et al. (28), 2012 46 (51) 84 52 NR 83 Mean Scr: 1.2 � 0.2 Yes

Mittal et al. (29), 2013 130 (138) 78 52 27 144 eGFR: 30–59: 41% of patients�60: 59% of patients

No

Gold standard: IVUS

Carrascosa et al. (30), 2009 19 (24) 89 53 27 88 Mean Scr: 1.1 � 0.2 No

Gregory et al. (7), 2006 20 (20) 80 52 30 70 Mean Scr: 1.2 � 0.2 Yes

Schepis et al. (10), 2009 30 (41) 81 40 26 34 NR(Exclusion if Scr >1.4)

No

Sigurdsson et al. (9), 2006 13 (54) 89 54 28 NR Mean Scr: 1.2 � 0.3 No

Continued on the next page

Wever-Pinzon et al. JACC Vol. 63, No. 19, 2014CCTA and Cardiac Allograft Vasculopathy May 20, 2014:1992–2004

1994

angiography OR cardiac computed tomography angiog-raphy OR coronary CT angiography OR coronarycomputed tomography OR multi-slice computed tomog-raphy OR multi-slice computed tomography angiographyOR multi-detector computed tomography) AND (CAVOR cardiac allograft vasculopathy OR vasculopathy ORtransplant vasculopathy OR graft vasculopathy OR coro-nary allograft vasculopathy OR coronary vasculopathy ORchronic allograft vasculopathy). We limited our search tohumans and adults (>18 years of age) in peer-reviewedjournals from 1966 to 2013. No language restrictionwas applied. The reference lists of bibliographies ofidentified papers were also reviewed. Trials in the abstractform without a published manuscript were excluded fromthis analysis.

Eligibility criteria. Eligible trials had to fulfill thefollowing criteria: 1) prospective study involving hearttransplant recipients who underwent CCTA to assess forthe presence of CAV in comparison to CCAG and/orIVUS; 2) study allowed for sensitivity, specificity, negativepredictive value (NPV), and positive predictive value (PPV)calculations; and 3) there was use of standardized cutoffsfor each test, or enough data were provided to calculatediagnostic and predictive accuracies using these cutoffs.Data extraction and quality assessment. Three inves-tigators (O.W.-P., J.R., C.M.) independently assessed trialeligibility and extracted data using standardized protocoland reporting forms. Disagreements were resolved by con-sensus. Characteristics of each trial, baseline demographics,methods, interval between transplantation and CCTA,

Use ofNitrate CT Slices

Heart Rate(beats/min)

ContrastVolume (ml)

RadiationDose (mSv)

EvaluablePatients or

Segments (%)CAV

Prevalence (%)

Analysis(Patient- vs.

Segment-Based)CAV

Definition

Gold standard: CCAG

No 16 90 100 10–13 98 9 Segment >50% stenosis

No 64 79 100 NR 100 53 (>0% stenosis)5 (�50% stenosis)

Patient >0% stenosis,�50% stenosis

Yes 16 and 64 NR 86–115*0.7 ml/kgy

NR 100 20 (>0% stenosis)6 (>50% stenosis)

Segment >0% stenosis,>50% stenosis

No 16 87 100 NR Patient: 73Segment: 94

Patient: 18Segment: 2

Patient and segment �70% stenosis

No 16 70 70–90 3–8 Patient: 88Segment: 96

Patient:43 (>0% stenosis)14 (�50% stenosis)Segment:16 (>0% stenosis)2 (�50% stenosis)

Patient and segment >0% stenosis,�50% stenosis

No DSCT-64 80 60–80 10 � 2 96 16 Segment >0% stenosis

No 16 90 100 10 � 2 Patient: 100Segment: 95


Patient and segment >50% stenosis

No 16 NR 100 6 100 40 (>0% stenosis)20 (>50% stenosis)

Patient >0% stenosis,>50% stenosis

No 64 86 90 NR Patient: 100Segment: 81


Patient and segment �50% stenosis

Yes DSCT-64 85 68 13 Patient: 100Segment: 84


Patient and segment >50% stenosis

No DSCT-64 88 NR NR Patient: 96Segment: 99


Patient and Segment >50% stenosis

Yes 64 83 70–90 18 Patient: 96Segment: 98

Patient:42 (>0% stenosis)15 (�50% stenosis)Segment:12 (>0% stenosis)3 (�50% stenosis)

Patient and segment >0% stenosis,�50% stenosis

Gold standard: IVUS

No 16 90 100 10–13 100 25 Segment Intimal thickness>0.5 mm

No 64 77 83 � 10 NR Patient: 100Segment: 98


Patient and segment Intimal thickness>0.5 mm

No DSCT-64 80 60–80 10 � 2 96 37 Segment Intimal thickness>0.5 mm

No 16 90 100 10 � 2 100 33 Segment Proliferative changes

*Contrast volume used for 16-slice coronary computed tomography angiography (CCTA). yContrast volume used for 64-slice CCTA.BMI ¼ body mass index; CAV ¼ cardiac allograft vasculopathy; DSCT ¼ dual-source computed tomography; eGFR ¼ estimated glomerular filtration rate; NR ¼ not reported; Scr ¼ serum creatinine.

Table 1 Continued


1995

prevalence of CAV, and data required to evaluate thediagnostic accuracy of CCTA were extracted. In instanceswhere data were not readily available, the main investigatorof that particular trial was approached to supply the relevantinformation. The assessment of quality of each study wasdone by evaluating 14 items considered relevant to the re-view topic, on the basis of the Quality Assessment ofDiagnostic Accuracy Studies instrument (14). Two re-viewers (J.R. and J.W.-P) independently assessed the qualityitems, and discrepancies were resolved by consensus.Statistical analysis. Sensitivities (number of stenotic cor-onary segments estimated by the index test [CCTA]divided by the total number of stenotic segments identifiedby the reference standard [CCAG/IVUS]), specificities(number of normal segments estimated by the index test

divided by the total number of segments without stenosisidentified by the reference standard), PPV (stenotic seg-ments identified by index test confirmed by referencestandard divided by the total number of stenotic segmentsestimated by index test), and NPV (segments withoutstenosis identified by index test confirmed by referencestandard divided by the total of nonstenotic segmentsestimated by index test) were calculated for every study.Summary sensitivity and specificity were estimated usingboth, a standard random effect model and a more recentlydeveloped bivariate random effects model (15,16). Thebivariate approach assumed logit transforms of sensitivityand specificity from individual studies are from a bivariatenormal distribution. The bivariate approach is consideredto be a better approach as compared with the standard


1996

summary receiver operating characteristics (ROC) ap-proach because (17): 1) it assesses heterogeneity acrossstudies and provides a summary estimate of sensitivityand specificity; 2) it models sensitivity and specificity jointlyso that a 95% confidence ellipse around the summary esti-mate can be calculated; 3) it allows a direct comparisonof sensitivity and specificity between methods; and 4) itprovides several choices to obtain a summary ROCcurve (15,16). The summary ROC curve was obtainedby transforming the regression line of logit sensitivity onlogit specificity into ROC space (15). Publication biaswas assessed for each analysis using Peter and Eggermethods. We assessed between-study heterogeneityvisually, by plotting sensitivity and specificity in the ROCcurves. Summary ROC curves and confidence regions forsummary sensitivity and specificity were also drawn(16,18). The analyses were conducted using standardsoftware (Stata 12, Stata Corporation, College Station,Texas).Sensitivity analysis. We further evaluated whether theperformance of each technique depends on features of thetechnique and patient characteristics. A logistic regressionfor each technique was used to model the sensitivity on thesefactors.

Results

Study selection. We identified 2,830 papers, of which1,672 abstracts were retrieved and reviewed for possibleinclusion (Fig. 1). Thirteen studies, enrolling 615 patients(mean age 52 � 8.5 years; 83% male) and a total of 9,481coronary segments fulfilled the inclusion criteria and wereincluded in the analysis (Table 1). These 13 studies allowedfor 34 comparisons. Six studies were excluded from the finalanalysis because they did not meet the inclusion criteria:1 study did not use CCTA and CCAG in all patients,CCAG was used only to confirm abnormal CCTA find-ings (19), another study compared CCTA versus dobut-amine stress echocardiography and only used CCAG inpatients with an abnormal result of either test (20), anotherstudy provided no data to calculate diagnostic accuracies(21), another study did not report demographic data,number of segments and the specific numbers comparedwith CCAG and IVUS (22), another study comparing 64-slice and 256-slice CCTA versus CCAG reported thediagnostic accuracy without differentiation between 64-slice and 256-slice CCTA (23); and the last study wasconducted using 4-slice CCTA (24).Baseline characteristics. Of the 13 studies, 8 studiesanalyzing 410 patients (mean age 49 � 7.6 years; 81%male) and 5,949 coronary segments evaluated CAV using64-slice CCTA (7,8,10,25–29). Seven studies compared64-slice CCTA with CCAG and 2 studies compared64-slice CCTA with IVUS (7,10). Six studies analyzing 205patients (mean age 50 � 8.0 years; 83% male) and 3,532coronary segments evaluated CAV using 16-slice CCTA,

with all of them using CCAG for comparison and 2 of themalso using IVUS for comparison (Table 1) (6,9,26,30–32).Quality assessment. The selected studies showed overallhigh-quality scores in all the 14 items of the QualityAssessment of Diagnostic Accuracy Studies instrument.Reporting was poor in 1 of the studies on item 13: “Wereuninterpretable/intermediate test results reported?” Un-interpretable results are often not reported in diagnosticaccuracy studies. However, this may lead to the biasedassessment of the test characteristics. Bias will arise de-pending on the possible correlation between uninterpretabletest results and the true disease status. If uninterpretableresults occur randomly and are not related to the true diseasestatus, these should have no effect on test performance. Twopapers did not provide sufficient information regarding theexecution of the reference standard, which could affect thereproducibility of the test results or its performance. Threepapers did not explain whether the reference (2 papers) orindex test (1 paper) were interpreted in a blinded fashion(review bias), which might have led to inflated measures ofdiagnostic accuracy (Figs. 2A and 2B).Publication bias. Using Egger’s test, there was no indicationof publication bias for any of the analyzed techniques (p> 0.09for all analyses). Likewise, the Peters test did not suggestpresence of publication bias (p > 0.15 for all analyses).CCTA versus CCAG. Twelve studies evaluated the pres-ence of CAV by CCTA using CCAG as the reference test.CCTA was performed between 34 and 144 months (mean88 months) after transplant. The mean heart rate at the timeof CCTA was 84 beats/min (range 70 to 90 beats/min) and5 studies used beta-blockers for heart rate reduction. The useof contrast media ranged from 60 to 115 ml and the radi-ation dose from 3 to 18 mSv. The incidence of contrastinduced nephropathy was reported in most studies (n ¼ 9),with no cases observed in the enrolled patients. Most studies(n ¼ 10) used a �50% stenosis cutoff to determine thepresence of significant CAV, except for 1 study that useda �70% stenosis cutoff. Six studies used a >0% stenosiscutoff to determine the presence of any CAV (Table 1).Diagnostic accuracy of CCTA for the detection of anyCAV.PATIENT-BASED ANALYSIS. Any CAV was found in 87 pa-tients by means of CCAG, which represents a prevalence of43%. The combined overall weighted mean sensitivity,specificity, PPV, NPV, and accuracy for CCTA (64-sliceand 16-slice CCTA) were 97% (95% confidence interval[CI]: 92% to 100%), 81% (95% CI: 74% to 88%), 78%(95% CI: 71% to 86%), 97% (95% CI: 93% to 100%), and88% (95% CI: 84% to 93%), respectively (Fig. 3). Analysesof the different measures of diagnostic accuracy, stratifiedby the number of CCTA slices are shown in Table 2A.There were no significant differences in these measureswhen 64-slice and 16-slice CCTA were compared.

SEGMENT-BASED ANALYSIS. A total of 384 segments hadevidence of any CAV by CCAG, which represents a prev-alence of 13%. The combined overall weighted mean

Figure 2Quality Assessment of Included CCTA Studies by the Quality Assessment of Diagnostic Accuracy Studies(QUADAS) Instrument

Review authors’ judgment about each methodological quality item for each included study. (A) Methodological quality graph. (B) Methodological quality summary. Good (þ),

indeterminate (?) or poor (�) quality. CCTA ¼ coronary computed tomography angiography.


1997

sensitivity, specificity, PPV, NPV, and accuracy for CCTA(64-slice and 16-slice) were 88% (95% CI: 85% to 92%), 89%(95% CI: 88% to 90%), 55% (95% CI: 51% to 59%), 98%(95% CI: 97% to 98%), and 90% (95% CI: 89% to 91%),respectively (Online Fig. 1). Additional analyses, stratified bythe number of CCTA slices are shown in Table 2B. Therewere no significant differences in the measures of diagnosticaccuracy between 64-slice and 16-slice CCTA.Diagnostic accuracy of CCTA for the detection ofsignificant CAV. PATIENT-BASED ANALYSIS. Sixty-two pa-tients had evidence of significant CAV by CCAG, whichrepresents a prevalence of 16%. The combined overall meanweighted sensitivity, specificity, PPV, NPV, and accuracy forCCTA (64-slice and 16-slice) were 94% (95% CI: 87% to100%), 92% (95% CI: 89% to 95%), 67% (95% CI: 59% to76%), 99% (95% CI: 97% to 100%), and 94% (95% CI: 91%to 96%), respectively (Fig. 4). Analyses of diagnostic accu-racy, stratified by the number of CCTA slices are shownin Table 3A. Although statistically there were no significantdifferences in the evaluated measures between 64-sliceand 16-slice CCTA, there was a trend toward improvedsensitivity (97% vs. 91%, p ¼ 0.06), NPV (99% vs. 97%,p ¼ 0.06), and lower PPV (63% vs. 72%, p ¼ 0.06) with theuse of 64-slice CCTA.

SEGMENT-BASED ANALYSIS. A total of 174 segments hadsignificant CAV by CCAG, which represents a prevalenceof 3%. The combined overall mean weighted sensitivity,specificity, PPV, NPV, and accuracy for CCTA (64-sliceand 16-slice) were 86% (95% CI: 82% to 91%), 99% (95%

CI: 98% to 99%), 73% (95% CI: 68% to 78%), 99% (95%CI: 99% to 100%), and 99% (95% CI: 98% to 99%),respectively (Online Fig. 2). Additional analyses, stratifiedby the number of CCTA slices are shown in Table 3B.There were no significant differences in the measures ofdiagnostic accuracy between 64-slice and 16-slice CCTA.However, there was a trend toward lower PPV with 64-sliceversus 16-slice CCTA (60% vs. 84%, p ¼ 0.06).CCTA versus IVUS. Four studies evaluated the presenceof any CAV by CCTA using IVUS as the reference test.The CCTA was performed between 34 and 88 months(mean 64months) after transplant. Themean heart rate at thetime of testing was 84 beats/min (range 77 to 90 beats/min).The use of contrast media ranged from 60 to 100 ml andthe mean radiation dose was 10 mSv. No cases of contrastinduced nephropathy occurred in the enrolled patients. Threestudies used an intimal thickness >0.5 mm to determine thepresence of CAV, whereas 1 study used the presence of“proliferative changes” to determine the presence of CAV(Table 1).

PATIENT-BASED ANALYSIS. Sixteen patients were found tohave CAV by IVUS, representing a prevalence of 80%. Theweighted mean sensitivity and specificity of 64-slice CCTAwere 81% (95% CI: 57% to 93%) and 75% (95% CI: 30% to95%), whereas the PPV was 93% (95% CI: 68% to 99%) andNPV was 50% (95% CI: 19% to 81%). This technique had amean weighted accuracy of 80% (95% CI: 58% to 92%).There were no studies evaluating the diagnostic accuracy of16-slice CCTA using a patient-based analysis.

Figure 3Diagnostic Accuracy of CCTA for the Evaluation of the Presence of Any CAV Using aPatient-Based Analysis and CCAG as Reference Test

Forest plots of the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy of coronary computed tomography angiography

(CCTA) stratified by number of slices (16-slice and 64-slice CCTA). The size of the square-plotting symbol is proportional to the same size for each study. Horizontal lines are the

95% confidence intervals (CIs). Hierarchical summary receiver operating characteristic (HSROC) plot (CCTA: 64þ16). On the basis of combined sensitivity and specificity

weighted for sample size of each data set reflected by the size of the circles, showing average sensitivity and specificity estimate of the study results (solid square) and 95%

confidence region around it. The 95% prediction region represents the confidence region for a forecast of the true sensitivity and specificity in a future study. CAV ¼ cardiac

allograft vasculopathy; CCAG ¼ conventional coronary angiography; ES ¼ effect size.


1998

Table 2

Summary Estimates for Weighted Mean Sensitivity,Specificity, PPV, NPV, and Accuracy of CCTA forthe Evaluation of the Presence of Any CAV ComparedWith CCAG

Weighted Mean Overall64-SliceCCTA

16-SliceCCTA p Value

A. Patient-basedanalysis

n ¼ 203 n ¼ 149 n ¼ 54

Sensitivity 97 (92–100) 98 (94–100) 91 (78–100) 0.51

Specificity 81 (74–88) 79 (71–87) 84 (72–97) 0.52

PPV 78 (71–86) 78 (69–87) 81 (66–95) 0.43

NPV 97 (92–100) 98 (94–100) 93 (82–100) 0.52

Accuracy 88 (84–93) 87 (82–93) 90 (82–98) 0.45

B. Segment-basedanalysis

n ¼ 2,883 n ¼ 2,424 n ¼ 459

Sensitivity 88 (85–92) 89 (85–92) 88 (81–95) 0.28

Specificity 89 (88–90) 90 (89–91) 85 (82–89) 0.89

PPV 55 (51–59) 55 (51–59) 56 (47–64) 0.71

NPV 98 (97–98) 98 (98–99) 96 (94–98) 0.26

Accuracy 90 (89–91) 90 (89–92) 85 (82–88) 0.22

Values are % (95% confidence interval).CAV ¼ cardiac allograft vasculopathy; CCAG ¼ conventional coronary angiography;

CCTA ¼ coronary computed tomography angiography; NPV ¼ negative predictive value;PPV ¼ positive predictive value.


1999

SEGMENT-BASED ANALYSIS. A total of 204 segments hadCAV by IVUS, representing a prevalence of 34%. Thecombined overall weighted mean sensitivity, specificity,PPV, NPV and accuracy for CCTA (64-slice and 16-slice,n ¼ 836 segments) were 89% (95% CI: 86% to 93%), 89%(95% CI: 87% to 92%), 79% (95% CI: 74% to 83%), 94%(95% CI: 92% to 96%), and 90% (95% CI: 88% to 92%),respectively (Fig. 5). The weighted mean sensitivity andspecificity of 64-slice (n ¼ 229 segments) versus 16-sliceCCTA (n ¼ 607 segments) were 78% (95% CI: 70% to86%) versus 94% (95% CI: 91% to 98%, p ¼ 0.08) and 88%(95% CI: 83% to 94%) versus 90% (95% CI: 87% to 92%,p ¼ 0.90), whereas the PPV was 82% (95% CI: 74% to 90%)versus 77% (95% CI: 71% to 82%, p ¼ 0.43), and NPV was83% (95% CI: 77% to 90%) versus 98% (95% CI: 96% to99%, p ¼ 0.07), respectively. There was no significant dif-ference in mean weighted accuracy between 64-slice 83%(95% CI: 78% to 88%) and 16-slice CCTA 91% (95%CI: 89% to 93%, p ¼ 0.58).

Discussion

In the present meta-analysis, we focused on the diagnosticperformance of the newest generation of CCTA (�16 slices)to assess the extent and severity of CAV compared with theclinical standard of CCAG, and with the highly sensitiveIVUS. The main result of our study is the demonstration ofhigh sensitivity, specificity and NPV of CCTA for thediagnosis of CAV when compared with the clinical standardCCAG. The high sensitivity and NPV suggest that anegative CCTA can accurately exclude CAV in the absolutemajority of heart transplant recipients undergoing this test.As expected, the sensitivity and NPV of CCTA to detect

CAV were lower when the highly sensitive IVUS was usedas the standard reference test.

CAV is a progressive disorder that is characterized bydiffuse concentric intimal hyperplasia involving bothepicardial and intramyocardial arteries (33,34). It is difficultto diagnose in the early stages as it is typically silent inthe denervated transplanted heart, and ischemia or graftdysfunction are usually not evident until the disease isadvanced and manifests as heart failure, arrhythmias orsudden death. Yearly screening to detect CAV before graftinjury results is therefore recommended (13). Noninvasivestress testing such as exercise electrocardiography, stressechocardiography, and single-photon emission computedtomography have been used, however, the modest diagnosticaccuracy is a major limitation of these tests (35), and thusclinical guidelines recommend CCAG as a screening toolfor CAV (13). Although CCAG has an important role inthe clinical assessment of the severity, progression, andclassification of CAV, it often underestimates the extent andseverity of CAV as a consequence of the vascular remodelingprocess (36,37). Histopathologic studies have shown that asmany as 73% of angiographically normal segments have mildto moderate fibrous intimal thickening by light microscopy(38). Addition of coronary IVUS allows for detection andquantification of intimal hyperplasia by imaging of the vesselwall structure, making it the most sensitive test for detectingCAV. At 4 years after transplantation, CCAG detects CAVin one-third of recipients, whereas diagnosis of CAV ismade in 55% by IVUS (37). However, the drawbacks ofIVUS are its invasiveness, limitation to assessment of onlyproximal epicardial arteries, risk of serious complications andcost (39). Although the rate of progression and CAVseverity as assessed by IVUS has been shown to haveprognostic implications as far as the risk of myocardialinfarction, heart failure, retransplantation and death (40,41),the detailed information provided by IVUS does not triggerchanges in clinical care that would alter patient outcomes.Therefore, addition of IVUS to screening CCAG has notbecome the standard approach to CAV screening.

CCTA is a noninvasive technique that permits quantifi-cation of lumen size and wall vessel structure. Its diagnosticaccuracy has been extensively studied in large study groupsof nontransplanted patients (42). However, the smallnumber of studies evaluating the accuracy of CCTA todetect CAV has included only limited number of patients(6–9,25,26,30–32). The aim of our meta-analysis was todetermine whether data pooled from prospectively con-ducted studies could provide a stronger basis for clinicalapplication of CCTA in transplant recipients. Althoughthe results were consistent when analyzed as individualcoronary segments, or when assessed on the basis of anoverall test result in each patient, the main clinical im-plications can be drawn from the patient-based data.Using CCAG as the reference test, CCTA has anexcellent sensitivity and NPV for the diagnosis of CAV,being 94% and 99% for the detection of significant CAV

Figure 4Diagnostic Accuracy of CCTA for the Evaluation of the Presence of Significant CAV Using aPatient-Based Analysis and CCAG as Reference Test

Forest plotsof thesensitivity, specificity, PPV,NPV, anddiagnostic accuracy ofCCTAstratifiedbynumber of slices (16-slice and64-sliceCCTA). The size of thesquare-plotting symbol

is proportional to the samesize for eachstudy.Horizontal linesare the95%CIs. HSROCplot (CCTA:64þ16).On the basis of combined sensitivity andspecificity weighted for sample

size of each data set reflected by the size of the circles, showing average sensitivity and specificity estimate of the study results (solid square) and 95% confidence region around it.

The 95% prediction region represents the confidence region for a forecast of the true sensitivity and specificity in a future study. Abbreviations as in Figure 3.


2000

Table 3Summary Estimates for Weighted Mean Sensitivity,Specificity, PPV, NPV, and Accuracy of CCTA for theEvaluation of Significant CAV Compared With CCAG

Weighted Mean Overall64-SliceCCTA

16-SliceCCTA p Value

A. Patient-basedanalysis

n ¼ 392 n ¼ 241 n ¼ 151

Sensitivity 94 (87–100) 97 (88–100) 91 (81–100) 0.06

Specificity 92 (89–95) 92 (89–96) 92 (86–96) 1.00

PPV 67 (59–76) 63 (52–74) 72 (60–85) 0.06

NPV 99 (97–100) 99 (97–100) 97 (93–100) 0.06

Accuracy 94 (91–96) 94 (91–97) 93 (88–97) 0.37

B. Segment-basedanalysis

n ¼ 5,762 n ¼ 3,296 n ¼ 2,466

Sensitivity 86 (82–91) 89 (82–97) 84 (77–89) 0.87

Specificity 99 (98–99) 99 (98–99) 99 (99–100) 0.97

PPV 73 (68–78) 60 (51–68) 84 (78–90) 0.06

NPV 99 (99–100) 100 (99–100) 99 (99–100) 0.31

Accuracy 99 (98–99) 98 (98–99) 99 (98–99) 0.98

Values are % (95% confidence interval).Abbreviations as in Table 2.


2001

and 97% for the presence of any CAV. Compared with16-slice CCTA, the use of 64-slice CCTA was associatedwith a strong trend toward improved sensitivity and NPVfor the detection of significant CAV, likely the result ofbetter spatial and temporal resolution. These results areclinically important as indicate that CCTA could be usedeffectively as a gatekeeper to CCAG, thus reducing thenumber of downstream tests and procedures, CCAG-related complications and costs, as prior experience inthe general population suggests (43,44). The specificityand PPV of CCTA for the evaluation of the presence ofany CAV were modest, a finding that can be explained bythe low sensitivity of CCAG, related to its inability toevaluate the vessel wall. As expected, the specificity ofCCTA to detect significant CAV was higher than for theevaluation of the presence of any CAV. Although thespecificity of CCTA to detect significant CAV wasexcellent, the PPV remain modest likely as a consequenceof the low prevalence of significant CAV lesions.

The segment-based results are important from the tech-nical perspective. These results showed an excellent sensi-tivity and NPV of CCTA to detect both, the presence of anyCAV and the presence of significant CAV, confirming thehigh diagnostic accuracy of this technique.

The routine use of CCTA for the assessment of CAV isnot supported by current clinical guidelines (13), as a resultof not only the limited data on its diagnostic accuracy, butalso due to limited data evaluating its prognostic value onpost-transplant survival. More recently, Rohnean et al. (19)prospectively evaluated 62 heart transplant recipients bymeans of serial CCTA and showed that this technologyprovides a safe and reliable alternative to CCAG for thelong-term evaluation of CAV. After 5 years, 30% of pa-tients with a normal CCTA at baseline progressed todevelop wall thickening (24%) or significant stenosis (6%),

whereas 22% of patients with wall thickening at baselineprogressed to develop significant stenosis. More impor-tantly, there were no major coronary events during the studyperiod, suggesting that no patients were classified as false-negatives by CCTA and further supporting its high sensi-tivity and NPV (19).

An added diagnostic advantage of CCTA over CCAGis the ability to visualize both the lumen and the vesselwall. In our analysis, CCTA showed a good diagnosticaccuracy in comparison with IVUS, the most sensitive andspecific method for detecting early coronary artery diseaseand CAV. It is possible that these findings might haveimportant clinical implications as use of certain immu-nosuppressant agents (e.g., proliferative signal inhibitors)have been associated with reduced incidence and slowerprogression of CAV (45). Further, vessel wall character-ization may also provide mechanistic insights into thedisease process underlying CAV. Our group has recentlyreported histopathologic differences in vascular remodel-ing between native coronary artery disease and CAV,showing that outward vessel remodeling, a phenotypemore frequently associated with vulnerable lesions, wasreduced in CAV compared with native coronary arterydisease, likely the result of both accelerated intimalingrowth and limited outward remodeling in CAV (46).

The effective radiation dose and total amount of iodin-ated contrast agent administered during CCTA testingcould be of concern if implemented as a repeated annualassessment. In this meta-analysis, the reported dose of ra-diation was 3 to 18 mSv and use of contrast media was 60to 115 ml, which are somewhat higher comparedwith CCAG. The development of newer techniquesincluding acquisition protocols using high-pitch spiral scan(Flash Spiral mode), step and shoot protocols targeting thesystolic phase of the cardiac cycle and reduced-dose lowvoltage CCTA with sonogram-affirmed iterative recon-struction are expected to reduce radiation and contrast doseto approximately 1 mSv and 10 ml per study, respectively(47–49). It is also conceivable that in those patients withnone or minimal vasculopathy, on the basis of the highsensitivity and NPV of CCTA, the interval betweenscreening tests could be increased. In addition, contrastinduced nephropathy was not observed in any of the eval-uated patients, although this might have been the result of aselection bias in the analyzed studies.Study limitations. The results of our study are limited to aselect group of heart transplant recipients. Patients withchronic kidney disease were excluded from the majorityof the studies and no patients with a serum creatinine>2.8 mg/dl were included. Nonetheless, this remains alimitation as well for the reference test CCAG. Patients withcardiac arrhythmias were also excluded. Further, theability of CCTA to evaluate small distant branches islimited. Recognizing this limitation, none of the evaluatedstudies included segments <15 mm in diameter, whereCAV is commonly recognized in its early stages.

Figure 5Diagnostic Accuracy of CCTA for the Evaluation of the Presence of Any CAV Using a Segment-Based Analysis and IVUS asReference Test

Forest plots of the sensitivity, specificity, PPV, NPV, and diagnostic accuracy of CCTA stratified by number of slices (16-slice and 64-slice CCTA). The size of the square-plotting

symbol is proportional to the same size for each study. Horizontal lines are the 95% CIs. HSROC plot (CCTA: 64þ16). On the basis of combined sensitivity and specificity

weighted for sample size of each data set reflected by the size of the circles, showing average sensitivity and specificity estimate of the study results (solid square) and 95%

confidence region around it. The 95% prediction region represents the confidence region for a forecast of the true sensitivity and specificity in a future study. IVUS¼ intravascular

ultrasound; other abbreviations as in Figure 3.


2002


2003

Conclusions

In this meta-analysis, CCTA demonstrated to be a robusttechnique for the diagnosis of CAV. Its excellent sensitivityand NPV suggest that CAV can be accurately excluded withthis noninvasive test, thus avoiding invasive procedures. Inlight of these results, CCTA should be considered as analternative to CCAG for CAV screening in the routine careof heart transplant recipients.

Reprint requests and correspondence: Dr. Josef Stehlik, Uni-versity of Utah Health Sciences Center, Division of Cardiology,30 North Medical Drive, 4A100 SOM, Salt Lake City,Utah 84132. E-mail: [email protected].

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Key Words: accuracy - cardiac allograft vasculopathy -

coronary computed tomography angiography - heart transplantation -

transplant vasculopathy.

APPENDIX

For supplemental figures, please see the online version of this article.

















































coronary computed tomography angiography for the detection of cardiac allograft vasculopathy

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