How to Reduce Unnecessary Invasive Angiograms When Patients Are Initially Evaluated by Coronary Computed Tomography?

doi:10.4236/act.2013.21003

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Advances in Computed Tomography, 2013, 2, 13-19

http://dx.doi.org/10.4236/act.2013.21003 Published Online March 2013 (http://www.scirp.org/journal/act)

How to Reduce Unnecessary Invasive Angiograms When

Patients Are Initially Evaluated by Coronary Computed

Tomography?

Edouard Cheneau1, Bruno Vahdat1, Noémie Resseguier2, Laurent Bernard1, Annamaria Molon1,

Roch Giorgi2, Dimitri Panagides1

1Service de Cardiologie, Clinique Bouchard, Marseille, France

2Service de Santé Publique et d’Information Médicale, Hôpital de la Timone, Marseille, France

Email: edouard.c[email protected]

Received November 5, 2012; revised December 16, 2012; accepted December 26, 2012

ABSTRACT

Purpose: When Coronary Computed Tomography (CCT) detects coronary obstruction, patients are regularly referred to

invasive angiogram. With higher sensitivity than specificity, CCT might induce unnecessary angiograms (“false posi-

tive CCT”). We sought to determine the patients and CCT findings associated with false positive CCT. Methods: Pa-

tients were prospectively referred to CCT with a 64-slice CT scan for suspected CAD. Inclusion criteria were: 1) clini-

cally suspected angina pectoris; or 2) suspected silent ischemia on resting EKG. Exclusion criteria were acute coronary

syndrome and non sinus rhythm. Invasive coronary angiogram (ICA) was performed on the basis of CCT findings

(stenosis >50%). Analysis was performed on a per patient basis. Results: Out of 702 patients, 228 had suspected sig-

nificant stenosis by CCT and ICA was performed in 176 patients. Coronary stenosis >50% was not confirmed by ICA

in 44 (25%). In multivariate analysis, we observed that atypical angina (OR 3.63, CI 1.43 - 9.66), silent ischemia (OR

5.11, CI 1.89 - 14.6) and number of suspected stenosed arteries by CCT (OR 1.81, CI 1.15 - 2.94) were independently

predictive of false positive CCT (p < 0.05). Lesion location and coronary plaque characteristics did not impact on CCT

accuracy. Conclusions: Performing CCT for atypical angina or silent ischemia is associated with higher rate of unnec-

essary invasive coronary angiograms. We failed to identify lesions characteristics prone to be “false positive” of CCT.

Keywords: Angina; Coronary Disease; Diagnosis; CCT

1. Introduction

Coronary computed tomography (CCT) is a rapidly de-

veloping technique and plays a rising role in angina di-

agnosis [1,2]. CCT has shown high sensibility for de-

tecting obstructive coronary disease in a non-invasive

manner [3,4]. Despite CCT can adequately rule out ob-

structive coronary artery disease (CAD), its high sensi-

tivity is associated with a lower positive predictive value

and a number of coronary stenosis on CCT are not con-

firmed on invasive coronary angiograms. Since CCT has

a growing role as first line work-up for angina pectoris

diagnosis, referring patients with a positive CCT to inva-

sive coronary angiography might induce numerous un-

necessary invasive angiograms [5]. From retrospective

analysis, CCT usefulness appears to be dependent on

pre-test probability for having CAD and might be most

advantageous in subsets of patients, especially those with

an intermediate risk [6]. Consequently, patient selection

prior to CCT enables to increase CCT accuracy.

A complementary approach would be to individualize

subset of patients or CCT findings that are more likely to

be false positive of CCT after they were screened by this

technique. In these patients, a positive CCT would not

justify to directly undergo cardiac catheterization and al-

ternative work-up might be developed. In this study, we

sought to determine the patient characteristics and CCT

findings associated with false positive CCT.

2. Material and Method

2.1. Patients

We included all patients referred to our center for CT

scan as initial work up test to evaluate possible obstruc-

tive coronary heart disease. Patients presenting with ty-

pical or atypical angina pectoris or suspected silent

ischemia on resting EKG were referred for CCT and

prospectively included into the study. CCT is the front-

line test routinely used in our institution for CAD diag-

nosis. Inclusion criteria were patients referred for CCT

without previous myocardial stress imaging or treadmill

E. CHENEAU ET AL.

test and patients with preceding equivocal stress test dur-

ing a six month period.

A dedicated information sheet and database was used

for data collection. Inclusions were opened from January

2009 to December 2010. Typical angina was defined as

having three characteristics: 1) substernal discomfort; 2)

that is precipitated by physical exertion or emotion; and 3)

relieved with rest or sublingual nitroglycerin. Atypical

angina pectoris was defined as having 2 of 3 of the defi-

nition characteristics. Suspected silent ischemia was de-

fined as Q wave or negative T wave on resting EKG in at

least in two derivations in patients with at least one risk

factor. Inclusion criteria were patients referred for CCT

as initial work up test and patients with preceding equi-

vocal stress test. Exclusion criteria were non sinus rhy-

thm, acute coronary syndromes, impaired renal function

(serum creatinine >120 µmol/l) and known allergy to io-

dinated contrast material. The estimated pretest prob-

ability for obstructive CAD was estimated using the

Duke Clinical Score, which includes type of chest dis-

comfort, age, gender, and traditional risk factors [7]. The

protocol was reviewed and accepted by the ethic com-

mittee of our Board of Cardiology.

2.2. Scan Protocol

Patients with a heart rate exceeding 70 beats/min re-

ceived IV beta-blockers (Atenolol 5 to 15 mg) before CT

examination. All scans were performed with a 64-slice

CT scanner (Lightspeed VCT, General Electric Health-

care) that features a gantry rotation time of 350 ms, a

temporal resolution of 175 ms, and a spatial resolution of

0.54 mm3. Tube voltage was 120 kV( 100 kV for patients

weight <70 kg), X-ray tube current was prospectively

modulated on EKG (250 to 650 mA). CT was acquired in

a breath-hold and ECG-gated. Rotation speed and pitch

were adjusted to the acquisition protocols and the heart

rate. Calcium scoring was not performed. A bolus of con-

trast media (Ioxaglate 320 mG I/mL, Guerbet) was in-

fused in an antebrachial vein with use of a dual-barrel

injector (70 cc of contrast media at 5 cc/s washed out by

30 cc of isotonic solution at 3.5 cc/s). CT data were ana-

lyzed by the use of an offline Advantage Workstation

(General Electric) using (curved) multiplanar reconstruc-

tion. Phases from 0 to 90% every 10% were systemati-

cally reconstructed to allow for imaging coronary arteries.

Segments were scored positive for significant CAD if

there was ≥50% diameter reduction of the lumen (at least

2 mm) by visual assessment. Three experienced (more

than 500 CT coronary angiograms) observers blinded

about previous medical history and symptoms partici-

pated in the study. Optimal quality CT scan was defined

as lumen visual assessment available in all >2 mm di-

ameter coronary arteries. Patients with non-optimal qual-

ity CT (including heavy calcification without lumen as-

sessment) were scored positive for significant CAD. All

patients with significant stenosis by CCT were suggested

to undergo to ICA.

2.3. Angiographic Analysis

Baseline quantitative angiography was performed using

the contrast-filled injection catheter for image calibration.

Cine Angiographic stenosis was defined as stenosis grea-

ter than 50%. Quantitative coronary angiographic (QCA)

analysis was performed using the Integris H5000C soft-

ware (Philips, The Netherlands). Patients were classified

as positive for significant CAD if at least one (>2 mm

diameter) coronary artery showed a significant stenosis

(>50%). Patients were classified as true positive CCT if

they were classified as positive for CAD by both CCT

and ICA and false positive CCT if significant stenosis by

CCT was not confirmed by ICA.

2.4. Statistics

All statistical analyses were realized using the R software,

version 2.12.0 (R Foundation for Statistical Computing,

Vienna, Austria). First, a descriptive analysis of all re-

corded data was performed among the overall study po-

pulation. Bivariate analysis was then performed by com-

paring the patients and lesions characteristics of the two

groups, i.e. true positive CCT and false positive CCT.

Continuous variables were expressed as mean ± standard

deviation, and were compared using t-test after graphi-

cally checking of the conditions of the test. Categorical

variables were expressed as number of patients and per-

centages, and were compared using chi-square test or

Fisher test, when appropriate. Variables were retained for

the multivariate analysis when their effect had a p-value

less than 0.25 for the bivariate analysis.

A multivariate logistic regression model was built. A

backward stepwise selection procedure was applied to

retain the significant (p < 0.05) independent variables

and their interactions in the final model. Significance was

determined using likelihood ratio test. The accuracy of

the final model was assessed by Hosmer-Lemeshow test

(HLgof.test R package).

3. Results

We evaluated 702 patients (male 66%) by CCT. Age was

61 ± 11 years. CCT image quality was inadequate in 74

patients (10.5%). Significant obstruction was suspected

in 228 patients (32%) by CCT and invasive coronary

angiogram was performed in 176 patients. Coronary

stenosis was >50% in 132 patients (75%) by ICA. False

positive CCT were observed in 44 patients (25%).

Patients’ characteristics were compared between true

E. CHENEAU ET AL.

positive CCT and false positive CCT and Table 1 shows

a higher rate of false positive CCT in women as com-

pared to men, in atypical angina and silent ischemia as

compared to typical angina symptoms. Lesion location

and characteristics detected by CCT were also compared

between the two groups (Table 2). We observed that

false positive CCT was less likely when more coronary

plaques and segment with obstruction were detected by

CCT.

In multivariate analysis, atypical angina (OR 3.63, CI

1.43 - 9.66, p = 0.008), silent ischemia (OR 5.11, CI 1.89 -

14.6, p = 0.002) and number of suspected stenosed ar-

teries by CCT (OR 1.81, CI 1.15 - 2.94, p = 0.010) were

predictive of false positive CCT (Table 3).

Table 1. Indicating patients characteristics.

Stenosis by ICA

(True positive CCT)

N = 132

No stenosis by ICA

(False positive CCT)

N = 44

Age (years) 64 ± 12 64 ± 12 0.96

Male 105 (80%) 28 (20%) 0.03

Female 27 (64%) 16 (36%)

Previous CAD 39 (30%) 7 (16%) 0.07

Pretest likelihood for CAD (%) 59 ± 29 53 ± 32 0.20

Angina typical 69 (52%) 13 (30%) 0.03

Atypical 37 (28%) 17 (39%)

Silent ischemia 26 (20%) 14 (32%)

Hypercholesterolemia 62 (47%) 26 (59%) 0.16

Diabetics 35 (26%) 9 (20%) 0.42

Hypertension 63 (48%) 19 (43%) 0.60

Smokers 43 (33%) 10 (23%) 0.22

ST changes by rest EKG 10 (7.6%) 3 (6.8%) >0.99

Q waves 8 (6.1%) 0 (0%) 0.20

Table 2. Indicating lesion characteristics observed by coronary computed tomography.

Stenosis by ICA

(True positive CCT)

N = 132

No stenosis by ICA

(False positive CCT)

N = 44

Number of atherosclerotic plaques 1.9 ± 0.8 1.6 ± 0.9 0.047

Number of plaques with stenosis >50% 1.5 ± 1.0 1.1 ± 0.9 0.036

Ostial lesions 12 (10%) 8 (22%) 0.08

Calcified lesions 93 (73%) 31 (79%) 0.43

Left Main 6 (5%) 3 (7%) 0.69

LAD 76 (62%) 19 (53%) 0.31

Diagonal 14 (11%) 6 (17%) 0.40

LCX 31 (25%) 4 (11%) 0.07

Obtuse marginal 12 (10%) 2 (6%) 0.73

RCA 50 (41%) 14 (39%) 0.82

Graft 4 (3%) 0 (0%) 0.57

E. CHENEAU ET AL.

Table 3. Indicating predictive factors for true positive corornary computed tomography by multivariate analysis.

OR Lower CI OR Upper CI OR P

Angina

Typical 1

Atypical 3.63 1.43 9.66 0.0076

Silent 5.11 1.89 14.63 0.0016

Number of plaques with stenosis >50% 1.81 1.15 2.94 0.0130

Explanations for false positive CCT were retrospec-

tively analyzed in view of ICA (some patients with more

than one explanation). They were related to stenosis

overestimation (N = 28), inadequate lumen measurement

flanking calcified plaque (N = 17) or ulcerated plaque (N

= 3), myocardial bridge (N = 2), abnormal origin of the

artery (N = 1), and instent lumen assessment (N = 4).

Poor CCT imaging acquisition contributed to eleven

cases of false positive CCT: supraventricular arrhythmia

during acquisition (N = 3), heart rate > 75/min (N = 2),

breathing artifact (N = 2).

Off note, 31 patients out of 144 patients correctly clas-

sified as significant CAD in the true positive CCT group

had one lesion false positive by CCT.

4. Discussion

In this unselected group of patients with suspected CAD,

a positive CCT followed by invasive coronary angiogram

resulted in 25% of unnecessary invasive procedures. The

lowest diagnostic yield of CCT was observed in patients

with atypical angina and suspected silent ischemia. Sec-

ondary, we searched to establish whether some CCT

findings were more likely to be false positive but we

failed to individualize lesion patterns or localization in

which CCT was more imprecise.

Risk stratification and diagnostic strategies are re-

quired for efficient utilization of ICA. However, the di-

agnostic yield of ICA remains low and recent studies

suggest that one fourth to one half of patients who un-

dergo ICA are found to have no obstructive CAD [8,9].

CCT has been compared with invasive coronary an-

giography for the detection of significant coronary artery

lesions in several studies [10]. These studies demon-

strated that significant coronary artery lesions can be

identified with high sensitivity, especially since introduc-

tion of newer imaging modalities of 64 or more detectors

tomography. Appropriate use criteria of CCT are grow-

ing and CCT is increasingly performed for CAD diagno-

sis [5]. When CCT detects coronary obstruction, patients

are usually referred to invasive angiography to confirm

coronary findings and establish treatment. Since CCT

positive predictive value ranges from 80% to 95%, a step

by step approach with upstream CCT will likely be asso-

ciated to unnecessary invasive angiograms [11,12]. In

our study, we included unselected patients with sus-

pected CAD and also observed that 25% of patients did

not have obstructive CAD despite initial positive CCT

finding. This result is encouraging and support findings

that estimate a decrease in normal rate of ICA when car-

diac CT programs are implemented [13]. CCT prevents

to perform invasive angiography more frequently than it

indicates the need for an ‘unnecessary’ invasive testing

[14].

Since CCT is not a perfect “gatekeeper” to ICA, we

investigated the patients characteristics associated to

false positive CCT. We observed that patients with aty-

pical angina and silent ischemia were not good candi-

date for CCT in this regard. These findings are also ob-

served when functional testing is performed before ICA:

a positive stress test has minimal effect on the predictive

ability of diagnosis model of obstructive coronary artery

disease [8]. Therefore, the diagnostic yield of CCT likely

won’t outperform functional tests in suspected silent

ischemia.

Female gender is a consistent predictor of failed strat-

egy for CAD diagnosis with functional tests and women

have more frequently non obstructive invasive angio-

grams [9]. In our study, we did not show a lack of per-

formance of CCT in women. Meijboom et al. found that

positive predictive value of CCT was lower in women

[15]. They attributed the difference to women having

smaller arteries. Since CCT accuracy decreases with

vessel size, higher rate of false positive findings are ob-

served in women on a per-vessel analysis. In our study

that included 240 women, we did not observe that wo-

men had a higher rate of normal angiogram in the multi-

variate analysis. Theoretical limitations of CCT in wo-

man are not translated in large scale analysis on a per-

patient basis. This encouraging finding suggests that a

strategy with CCT as first line test might be useful to take

over difficulties in evaluating chest pain in women [16].

Among patients characteristics, we also confirmed that

age does not impact on CCT accuracy despite older age

is associated with more calcified arteries [17]. This sug-

gests that patients can undergo CCT imaging, independently

E. CHENEAU ET AL. 17

from their age.

Once CCT detects coronary obstruction in epicardial

coronary vessel, patients are commonly referred for ca-

theterization. The goal is to confirm CCT findings and

decision-making for potential revascularization. However,

a greater focus should be placed on CCT findings and

evaluate the likelihood of false positive CCT. That strat-

egy might avoid unnecessary catheterization. In studies

evaluating 64-slice CT to invasive coronary angiogra-

phy, positive predictive value differed between vessels: it

was lower in left circumflex and right coronary arteries

as compared to left descending and left main arteries as

well as in stent and distal segments as compared to native

and proximal segments [18]. However, positive predic-

tive value of CCT remained constantly high in a narrow

range (85% to 93%). As a result, lesion location im-

pacted so slightly on CCT accuracy that anatomical fea-

tures could not be predictive of false positive CCT.

When we compared patients with or without confirmed

coronary obstruction by ICA, we did not see difference

in lesion characteristics or location. No anatomical sub-

group can be identified as “prone to be false positive

CCT”. Though, we logically found that risk for false

positive decreased when more plaques and more signifi-

cant lesions were detected by CCT. Our per-patient ana-

lysis emphasizes the impact of the number of diseased

vessels. Thus, patients with one vessel disease justify con-

sideration before referring to catheterization although

patients with more than one stenosed vessel by CCT can

be more evidently directed to ICA. Performance of CCT

was equivalent in calcified versus non-calcified plaques

and lesion location did not impact on CCT accuracy. At a

patient level, the CORE—64 trials did not find calcium

score as a predictor of diagnostic accuracy of CCT [12].

Even if calcified lesions remain challenging in a per le-

sion analysis, this suggests that calcium does not de-

crease diagnosis accuracy on a per patient basis since the

introduction of 64 detectors scans [18,19].

Overall, we observed that image quality had the great-

est impact on false positive CCT. Our data sustain the

previously described influence of heart rate and rhythm

on image reconstruction [19-21]. In addition, we have

faced overestimation in stenosis measurement. This oc-

currence of stenosis overestimation is likely the most

common mechanism leading to perform non obstructive

invasive angiograms, especially in intermediate stenosis

and complex lesions [22,23]. The definition of positive

CCT we utilized was “50% diameter reduction of the

lumen by visual assessment” to determine significant

stenosis by CCT. Even if this definition is commonly

accepted, it might be insufficient to quantify CAD ob-

struction. New tools are developed to better evaluate lu-

men stenosis with automated quantification [24]. Thus,

predictive value of CCT might increase with computed

quantification, especially in high-quality image recon-

struction [25]. Overall, we utilized best acquisition and

reconstruction methods available at the time of the study

inclusion. However, we didn’t anticipate false positive

CCT and did not implement our strategy in order to de-

crease those occurrences throughout the study. We can-

not state that a higher lumen percent stenosis threshold

might have impacted on “false positive” CCT rate.

This study had limited exclusion criteria. Therefore, it

reflects a “real life” study evaluating coronary artery

disease in a wide spectrum of patients. No functional

testing was requested in the inclusion criteria and the

impact of such test on CCT accuracy has not been evalu-

ated. Secondly, the negative predictive value of CCT has

not been established in this study. Definition for positive

CCT might have been too restrictive and increase posi-

tive predictive value and lower negative predictive value

of CCT. Nevertheless, we observed a negative predictive

value of 99% in a previous study with same inclusion

criteria, CCT methods and analysis criteria [26]. This

suggests that definitions we utilized in the current study

were adequately set in order to preserve high negative

predictive value of CCT.

5. Conclusion

Performing CCT for atypical angina or silent ischemia is

associated with higher rate of unnecessary invasive

coronary angiograms. We failed to identify lesions char-

acteristics prone to be “false positive” of CCT. Improv-

ing CCT imaging and lumen stenosis measurement ap-

pear the best means to reduce the rate of unnecessary an-

giogram following CCT.

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