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Background The accuracy of multidetector computed tomographic (CT) angiography involving 64 detectors has not been well established.
Methods We conducted a multicenter study to examine the accuracy of 64-row, 0.5-mm multidetector CT angiography as compared with conventional coronary angiography in patients with suspected coronary artery disease. Nine centers enrolled patients who underwent calcium scoring and multidetector CT angiography before conventional coronary angiography. In 291 patients with calcium scores of 600 or less, segments 1.5 mm or more in diameter were analyzed by means of CT and conventional angiography at independent core laboratories. Stenoses of 50% or more were considered obstructive. The area under the receiver-operating-characteristic curve (AUC) was used to evaluate diagnostic accuracy relative to that of conventional angiography and subsequent revascularization status, whereas disease severity was assessed with the use of the modified Duke Coronary Artery Disease Index.
Results A total of 56% of patients had obstructive coronary artery disease. The patient-based diagnostic accuracy of quantitative CT angiography for detecting or ruling out stenoses of 50% or more according to conventional angiography revealed an AUC of 0.93 (95% confidence interval [CI], 0.90 to 0.96), with a sensitivity of 85% (95% CI, 79 to 90), a specificity of 90% (95% CI, 83 to 94), a positive predictive value of 91% (95% CI, 86 to 95), and a negative predictive value of 83% (95% CI, 75 to 89). CT angiography was similar to conventional angiography in its ability to identify patients who subsequently underwent revascularization: the AUC was 0.84 (95% CI, 0.79 to 0.88) for multidetector CT angiography and 0.82 (95% CI, 0.77 to 0.86) for conventional angiography. A per-vessel analysis of 866 vessels yielded an AUC of 0.91 (95% CI, 0.88 to 0.93). Disease severity ascertained by CT and conventional angiography was well correlated (r=0.81; 95% CI, 0.76 to 0.84). Two patients had important reactions to contrast medium after CT angiography.
Conclusions Multidetector CT angiography accurately identifies the presence and severity of obstructive coronary artery disease and subsequent revascularization in symptomatic patients. The negative and positive predictive values indicate that multidetector CT angiography cannot replace conventional coronary angiography at present. (ClinicalTrials.gov number, NCT00738218
[ClinicalTrials.gov]
.)
Multidetector computed tomographic (CT) angiography has been proposed as a noninvasive test to determine the presence of coronary obstruction.12,13,14 However, systematic analysis of published studies to date has shown marked variation in results, which can probably be explained by the limitations of the selection and number of patients, single-center study design, and CT technology.15 In addition, the ability of multidetector CT angiography to predict the need for revascularization in symptomatic patients with suspected coronary artery disease has not been investigated. These inconsistencies and gaps in knowledge reinforce the need for large multicenter studies performed with rigorous control of bias, in which data are analyzed in central core laboratories and standardized protocols are applied in diverse institutions around the world.
We conducted a multicenter, international study using centralized, blinded analysis to determine the diagnostic accuracy of multidetector CT angiography involving 64 detectors and a slice thickness of 0.5 mm for the purpose of identifying symptomatic patients with suspected coronary artery disease who should be referred for conventional coronary angiography. Therefore, the study was designed to determine the presence or absence of obstructive disease in patients already at substantial risk for coronary artery disease who may require coronary revascularization.
Methods
Study Design
The Coronary Artery Evaluation Using 64-Row Multidetector Computed Tomography Angiography (CORE 64) study is a prospective, multicenter diagnostic study performed at nine hospitals in seven countries (three in the United States and one each in Germany, Japan, Brazil, Canada, Singapore, and the Netherlands). All centers received study approval from their local institutional review boards, and all patients gave written informed consent. The study was designed by the CORE 64 Steering Committee; the sponsors had no role in study design, data accrual, data analysis, or manuscript preparation.
Population of Patients
Eligible patients were at least 40 years of age, had suspected symptomatic coronary artery disease, and were referred for conventional coronary angiography. Patients were not eligible if they had history of cardiac surgery, allergy to iodinated contrast dye or contrast dye–induced nephropathy, multiple myeloma, organ transplantation, elevated serum creatinine level (>1.5 mg per deciliter [133 µmol per liter]) or creatinine clearance less than 60 ml per minute, atrial fibrillation, New York Heart Association class III or IV heart failure, aortic stenosis, percutaneous coronary intervention within the past 6 months, intolerance to beta-blockers, or a body-mass index (the weight in kilograms divided by the square of the height in meters) of more than 40. Women of childbearing potential had a negative pregnancy test within 24 hours before undergoing multidetector CT angiography. Patients with Agatston calcium scores over 600 were prespecified to be excluded from the primary analysis and entered into a registry.
Investigators, physicians, and patients were unaware of the results of coronary multidetector CT angiography. Patients were followed for the interim occurrence of death, myocardial infarction, stroke, revascularization (percutaneous or surgical), hospitalization for angina or heart failure, and other serious adverse events at 7 and 30 days after conventional coronary angiography. Multidetector CT images were reviewed locally for noncardiac abnormalities, and abnormal findings were communicated to the patient's physician.
Acquisition and Analysis of Data from Multidetector CT Angiography
Patients underwent two multidetector CT tests (coronary calcium scoring and angiography), before conventional coronary angiography was performed, using 64-row scanners with a slice thickness of 0.5 mm (Aquilion, Toshiba Medical Systems). Technologists completed centralized training to ensure uniform calcium scoring and compliance with the multidetector CT angiography protocol, as monitored throughout the study. Calcium scoring was performed with the use of prospective electrocardiographic (ECG) gating with 400-msec gantry rotation, 120-kV tube voltage, and 300-mA tube current. For multidetector CT angiography, retrospective ECG gating was used, with heart rate–adjusted gantry rotations of 350 to 500 msec to enable adaptive multisegmented reconstruction. Pitch and tube currents of 240 to 400 mA were determined by patients' weight to ensure a sex-specific radiation dose of 12 to 15 mSv, with a maximum effective dose of 20 mSv, for the combination of multidetector CT calcium scoring and angiographic procedures. This was achieved by instituting a cap of 270 mA for women and 400 mA for men. Sublingual nitrates were given before multidetector CT angiography, along with intravenous iopamidol (Isovue 370, Bracco Diagnostics). Beta-blockers were given if the resting heart rate was above 70 beats per minute. If heart rate during acquisition was more than 80 beats per minute, the patient's data were excluded from analysis.
Raw image data sets from all acquisitions were analyzed by an independent core laboratory. Multisegment reconstruction was performed with 0.5-mm slice thickness, 0.3-mm overlap, multiple phases, and ECG editing.16 Images were reconstructed using both standard (FC43) and sharper (FC05) kernels. Two independent observers, using a modified coronary model,17,18 visually graded each of 19 nonstented segments that were 1.5 mm or more in diameter, according to an ordinal scale (no stenosis, 1 to 29% stenosis, 30 to 49% stenosis, 50 to 69% stenosis, 70 to 99% stenosis, or total occlusion). Then, segments with at least one visible stenosis of 30% or more were manually quantified with the use of commercially available software (Vitrea2 version 3.9.0.1, Vital Images), and results for the two readers were averaged. Interreader visual and quantitative differences exceeding 50% were resolved by a third observer. Vessel-based data sets were constructed from the final segment data to create the patient-based data sets used in the primary analysis. In the visual analysis, consensus was required for the determination of segments that could not be evaluated. In the quantitative analysis, only segments that could not be measured by any of the three observers were considered not able to be evaluated and therefore negative in patient-based and vessel-based analyses (see the Supplementary Appendix, available with the full text of this article at www.nejm.org).
Data Acquisition and Analysis of Data from Conventional Coronary Angiography
Conventional coronary angiography was performed within 30 days after multidetector CT angiography using standard techniques made uniform across all centers for quantitative coronary angiography. Intracoronary nitroglycerin was administered (150 to 200 µg), and angiograms in Digital Imaging in Communications in Medicine (DICOM) format were transferred to the angiographic core laboratory. All coronary segments 1.5 mm or more in diameter were analyzed visually and quantitatively using the 29-segment standard model9,18 condensed to 19 segments for comparison with data from multidetector CT angiography.17 Quantitative coronary angiography of the most severe stenosis was performed (CAAS II QCA Research version 2.0.1 software, Pie Medical Imaging) in all nonstented segments. After all measurements from multidetector CT angiography and conventional coronary angiography were finalized, a detailed adjudication process was performed to ensure the correct cross-modality correspondence of segments (i.e., that the same coronary arterial segments imaged by means of each method were compared).
Analysis of Severity of Obstructive Coronary Artery Disease
The ability of multidetector CT angiography, as compared with conventional coronary angiography, to assess disease severity was evaluated using a modified Duke Coronary Artery Disease Index,2 with 50% or more stenosis classified as clinically significant. The number of vessels involved and the location of obstructive lesions (left main and proximal left anterior descending coronary artery) were weighted according to Duke Coronary Artery Disease Index criteria (Table 1).
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Data management and statistical analyses were performed in the statistical core laboratory (Bloomberg School of Public Health) with the use of SAS software version 9.1, Stata software version 9, and S-PLUS software version 8.0. We estimated that a sample of 350 patients would be needed to determine an accuracy of multidetector CT angiography (measured as the area under the receiver-operating-characteristic [ROC] curve [AUC]) of at least 0.85 with a 95% confidence interval of at most ±5%, assuming a 35% disease prevalence and 10% dropout rate.19 Computation of confidence limits for vessel-level data took account of within-patient clustering, through either logistic regression with generalized estimating equations or bootstrap resampling20 for AUC values. Confidence intervals were calculated according to the percentile method, with a beta value of 2000 replicate samples. P values of less than 0.05 were considered to indicate statistical significance. All P values are two-sided, and the 95% confidence intervals are also presented.
Results
Among the 405 patients enrolled in the study from September 2005 through January 2007, 316 were eligible for analysis since they had an Agatston calcium score of 600 or less. Of the 316 patients, 4 were excluded because of major protocol deviations, 11 because conventional coronary angiography was canceled or the results were inappropriate for analysis by quantitative coronary angiography, and 10 due to technical failure of the multidetector CT angiography (Figure 1). Thus, 291 patients were included in the analysis.
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The AUC for quantitative multidetector CT angiography was 0.93 (95% confidence interval [CI], 0.90 to 0.96) for the diagnosis of a patient with at least one coronary stenosis of 50% or more as assessed by quantitative coronary angiography (Figure 2A). The sensitivity for obstructive stenosis of 50% or more was 85% (95% CI, 79 to 90), and the specificity was 90% (95% CI, 83 to 94) (Table 4). The positive and negative predictive values were 91% (95% CI, 86 to 95) and 83% (95% CI, 75 to 89), respectively, for a disease prevalence of 56%. Quantitatively, 3773 of 3782 segments (almost 100%), 864 of 866 vessels (almost 100%), and 290 of 291 patients (almost 100%) could be evaluated by means of multidetector CT angiography, whereas visually, 3763 of 3782 segments (99%), 855 of 868 vessels (99%), and 286 of 291 patients (98%) could be evaluated.
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Vessel-Based Analysis
The diagnostic performance of quantitative multidetector CT angiography on a per-vessel basis, expressed as an AUC, was 0.91 (95% CI, 0.88 to 0.93), with no significant differences among individual AUCs for the right, left anterior descending, and left circumflex coronary arteries (Figure 2D) or between the visual and quantitative methods (Table 4). However, when comparing vessel-based and patient-based analyses, there was a small difference in the respective AUCs (0.02; 95% CI, 0.00 to 0.04). The sensitivity and specificity for the overall vessel-based analysis were 75% (95% CI, 69 to 81) and 93% (95% CI, 90 to 94), respectively, with positive and negative predictive values of 82% (95% CI, 77 to 86) and 89% (95% CI, 86 to 92), respectively (Table 4). Overall vessel disease prevalence (
50% stenosis) was 31% (Table 4). The AUC associated with vessel-specific revascularization was 0.89 (95% CI, 0.86 to 0.91) for quantitative coronary angiography and 0.84 (95% CI, 0.80 to 0.88) for multidetector CT angiography, with a small difference favoring quantitative coronary angiography (0.05; 95% CI, 0.01 to 0.08).
Discussion
In this multicenter, international study of symptomatic patients with suspected coronary artery disease comparing 64-row multidetector CT angiography with conventional coronary angiography, we found that multidetector CT angiography has a reliable accuracy for the diagnosis of obstructive coronary disease. The area under the ROC curve of 0.93 is consistent with robust diagnostic performance and indicates that 64-row multidetector CT angiography has powerful discriminative ability to identify, among symptomatic patients, those with and those without coronary obstruction. However, given the positive predictive value of 91% and the negative predictive value of 83%, multidetector CT angiography cannot replace conventional coronary angiography in this population of patients at present.
Previous studies comparing multidetector CT angiography and conventional coronary angiography have yielded variable results. Underlying these conflicting findings are limitations inherent to single-center designs and the degree of rigor used in controlling for bias in a small study. Although some studies have reported high sensitivity and high negative predictive values, these values were often obtained in selected patients after elimination or imputation of lesions in a substantial number of segments that could not be evaluated. Indeed, in a meta-analysis of primarily single-center studies, Hamon et al.15 found significant statistical heterogeneity among published studies, with smaller studies reporting higher diagnostic accuracy of multidetector CT angiography, which the authors concluded represented indirect evidence of small-study bias.15 However, the only available multicenter study performed with the use of 16-detector technology21 yielded divergent results when segments that could not be evaluated (26%) were taken into account.15,22
Moreover, previous studies performed in populations with a low prevalence of disease21 led to the assumption that multidetector CT angiography should be reserved for use in symptomatic patients with low risk for coronary artery disease.23 In contrast, the CORE 64 results indicate that the test performs well in symptomatic patients with a calcium score of 600 or less and a high prevalence of obstructive coronary artery disease (56% for 50% stenosis on conventional coronary angiography). Patients with calcium scores of more than 600 (22% of our initial cohort) were excluded from the primary analysis because we hypothesized a priori that in these patients multidetector CT angiography would have limited diagnostic utility. The technology as tested in our study population had a positive predictive value of 91% (95% CI, 86 to 95) and a negative predictive value of 83% (95% CI, 75 to 89). These predictive values were not unexpected, given the high prevalence of disease. On the other hand, it is important to highlight that the results of this study should not be used to support the screening of asymptomatic individuals for the presence or absence of coronary artery disease.
Our results for the diagnostic performance of 64-row multidetector CT angiography should be considered in the context of commonly used noninvasive stress tests, coupled with imaging techniques or not. We show that 64-row multidetector CT angiography yields robust diagnostic performance among symptomatic patients with suspected coronary artery disease and calcium scores of 600 or less. However, despite its ability to describe coronary anatomy, multidetector CT angiography misclassified 13% of patients, as compared with quantitative conventional coronary angiography, when the threshold for obstructive stenosis as measured by both techniques was set at 50%. On the other hand, although the concept of severity of coronary artery disease spans the spectrum of disease — from atherosclerotic plaque accumulation to coronary obstruction to ischemic burden and consequent myocardial damage — this work focused on the severity of coronary obstruction (Table 1). For this purpose, 64-row multidetector CT angiography correlates well with conventional coronary angiography. Moreover, because the patient's coronary anatomy as determined by conventional coronary angiography is particularly important for deciding the indication for myocardial revascularization,3,6,7,10 we also compared the ability of multidetector CT angiography and quantitative conventional coronary angiography to predict the need for coronary revascularization. Multidetector CT angiography and quantitative coronary angiography had a similar ability to identify patients who required coronary revascularization procedures (within 30 days after conventional coronary angiography) on the basis of the identification of coronary obstruction.
Exposure to radiation is a major concern in methods involving radiography or nuclear isotopes. The mean effective doses used in the CORE 64 study were 14 mSv for men and 15 mSv for women, which are consistent with those used in previously published trials of 64-row scanners.15 These doses, which included the calcium score and multidetector CT angiography, also compare favorably to those used in stress perfusion imaging involving radioisotopes24 and conventional coronary angiography.25 It has been estimated that the individual risk of radiation can be clinically significant and depends on the patient's age, sex, and expected life span, with younger female patients at increased risk for radiation-induced complications.26,27,28 Thus, 64-row multidetector CT angiography, like radioisotope tests and conventional coronary angiography, should be used with caution in patients with suspected coronary artery disease.
The strengths of our study also include its large number of patients, multicenter design, broad spectrum of clinical characteristics of the patients, and use of centralized core laboratories for data analysis. Moreover, we enrolled a population of patients representative of those with a clinical indication for anatomical coronary imaging.
It has been well established that multidetector CT angiography in highly calcified vessels has historically been difficult because of artifacts caused by high-density calcified lesions. Therefore, most previous studies have limited CT angiography to patients with lesser degrees of coronary calcification. In our study, 22% of patients (89 of 405) with calcium scores of more than 600 were placed in a separate registry and excluded from the primary analysis on the premise that they would be more adequately evaluated through alternative diagnostic strategies. The decision to approach all patients, regardless of the calcium score, was made to limit bias in the selection of patients. In addition, our results do not apply to screening of asymptomatic patients, who were systematically excluded in our study design. We studied patients presenting with a clinical indication for conventional coronary angiography, and therefore our study population had a higher prevalence of disease than is seen in the general outpatient population.
In this international, multicenter study, we have demonstrated that coronary 64-row multidetector CT angiography is accurate in identifying coronary stenoses and characterizing disease severity in symptomatic patients who have coronary calcium scores of 600 or less. However, multidetector CT angiography cannot be used as a simple replacement for conventional coronary angiography, given its negative predictive value of 83% and positive predictive value of 91% in this population of patients. Further studies are needed to define the method's precise role in the diagnostic algorithm for the evaluation of patients with suspected coronary artery disease.
Supported by grants from Toshiba Medical Systems; the Doris Duke Charitable Foundation; the National Heart, Lung, and Blood Institute (RO1-HL66075-01 and HO1-HC95162-01); the National Institute on Aging (RO1-AG021570-01); and the Donald W. Reynolds Foundation.
Drs. Miller, Dewey, Paul, Shapiro, Lardo, and Lima report receiving grant support from Toshiba Medical Systems; Drs. Dewey, Paul, Hoe, Lardo, Bush, and Lima, speakers' fees from Toshiba Medical Systems; Dr. Dewey, speaker's fees from Bayer and Schering and grant support from GE Healthcare and Bracco; and Dr. Paul, advisory fees from Vital Images. Dr. Hoe reports serving as director of the Cardiac CT Training Course sponsored by Toshiba Medical Systems, Asia, and receiving speaker's fees from GE Biosciences. Dr. Lardo reports receiving grant support from CT Core Laboratory; Dr. Bush, speaker's fees from Bristol-Myers Squibb and Sanofi-Aventis; and Dr. Lima, grant support from GE Medical Systems. No other potential conflict of interest relevant to this article was reported.
Source Information
From Johns Hopkins University School of Medicine (J.M.M., A.A.-Z., I.G., E.P.S., A.C.L., D.E.B., J.B., J.A.C.L.) and Johns Hopkins Bloomberg School of Public Health (C.C.) — both in Baltimore; University of São Paulo, InCor São Paulo Heart Institute, São Paulo (C.E.R.); Charité Medical School, Humboldt–Universität zu Berlin and Freie Universität zu Berlin, Berlin (M.D.); Iwate Medical University, Morioka, Japan (H.N.); Toronto General Hospital, Toronto (N.P.); Beth Israel Deaconess Medical Center, Harvard University, Boston (M.E.C.); Mount Elizabeth Hospital, Singapore, Singapore (J.H.); and Leiden University Medical Center, Leiden, the Netherlands (A.R.).
Address reprint requests to Dr. Lima at the Johns Hopkins Hospital, 600 N. Wolfe St., Blalock 524, Baltimore, MD 21287, or at jlima{at}jhmi.edu.
References
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Related Letters:
Coronary Angiography by 64-Row CT
McCulloch A. C., Paulin S., Gerard S. K., Karthikeyan G., Vorobiof G., Fogarty W. M. Jr., Lima J. A.C., Miller J. M., the CORE 64 Investigators , Walsh J., Redberg R. F.
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N Engl J Med 2009;
360:2027-2031, May 7, 2009.
Correspondence
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