(Stroke. 2002;33:2003.)
© 2002 American Heart Association, Inc.
Original Contributions |
From the Julius Center for Patient Oriented Research (P.J.N., E.B., Y. van der G.) and Departments of Radiology (W.P.M., O.E.H.E., P.C.B., A.F.W.), Vascular Surgery (B.C.E.), and Neurology (L.J.K.), University Medical Center Utrecht, Utrecht, Netherlands; Departments of Radiology (M.G.H., A. van der L.) and Epidemiology and Biostatistics (M.G.H.), Erasmus Medical Center Rotterdam, Rotterdam, Netherlands; and Department of Health Policy and Management, Harvard School of Public Health, Boston, Mass (M.G.H.).
Correspondence to Dr Y. van der Graaf, Julius Center for Patient Oriented Research, D.01.335, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, Netherlands. E-mail Y.vanderGraaf{at}jc.azu.nl
| Abstract |
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Methods In a prospective diagnostic study we performed duplex ultrasound (DUS), magnetic resonance angiography (MRA), and DSA on 350 consecutive symptomatic patients. Stenoses were measured with the observers blinded for clinical information and other test results. Separate and combined test results of DUS and MRA were compared with the reference standard DSA. Only the stenosis measurements of the arteries on the symptomatic side were included in the analyses.
Results DUS analyzed with previously defined criteria resulted in a sensitivity of 87.5% (95% CI, 82.1% to 92.9%) and a specificity of 75.7% (95% CI, 69.3% to 82.2%) in identifying severe ICA stenosis (70% to 99%). Stenosis measurements on MRA yielded a sensitivity of 92.2% (95% CI, 86.2% to 96.2%) and a specificity of 75.7% (95% CI, 68.6% to 82.5%). When we combined MRA and DUS results, agreement between these 2 modalities (84% of patients) gave a sensitivity of 96.3% (95% CI, 90.8% to 99.0%) and a specificity of 80.2% (95% CI, 73.1% to 87.3%) for identifying severe stenosis.
Conclusions MRA showed a slightly better accuracy than DUS in the diagnosis of carotid artery stenosis. To achieve the best accuracy, however, both tests should be performed subsequently.
Key Words: angiography, digital subtraction carotid endarterectomy carotid stenosis magnetic resonance angiography ultrasonography, Doppler, duplex
| Introduction |
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Over the last decade many diagnostic studies have been published in which noninvasive diagnostic tests such as duplex ultrasound (DUS) and magnetic resonance angiography (MRA) or combinations of these tests were compared with DSA.919 Two meta-analytic reviews have been published summarizing the literature on the diagnostic performance of DUS and MRA from before 1996. One concluded that the actual sensitivity and specificity for MRA remain unknown but that these are probably lower than reported in the literature because of the presence of verification bias and because frequently both carotid arteries (symptomatic and asymptomatic) were included in the analyses.20 The other meta-analysis reported that noninvasive testing at that point did not appear to be an adequate substitute for DSA for patients about to have carotid endarterectomy.21 Thereafter, the noninvasive imaging techniques have continued to develop. A review of previous publications on this topic published during 19931998, however, criticized the design of the studies and proposed guidelines for diagnostic studies on carotid artery imaging.22 Accordingly, a recent review summarizing publications during 19901999 concluded that MRA seemed accurate for selecting patients for carotid endarterectomy but that evidence was not very robust because of the heterogeneity of the studies included.23 The need for a prospective diagnostic study on noninvasive testing was recently recognized in the literature.13
The objective of this study was to obtain reliable estimates of the diagnostic accuracy of DUS, MRA, and a combination of these tests compared with DSA as reference standard.
| Subjects and Methods |
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Diagnostic Tests
The degree of stenosis on DUS was determined on the basis of the peak systolic velocity (PSV) in the proximal part of the ICA. The PSV is considered the most accurate estimator of the degree of stenosis for DUS.24 We validated DUS results in a pilot series before the present study started. By means of receiver operating characteristic (ROC) curves, we previously defined optimal cutoff criteria for the PSV for different stenosis categories (Table 1). In these criteria the threshold of 70% stenosis is represented by a PSV of 270 cm/s.25
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DSA was performed by selective positioning of an intra-arterial catheter in both common carotid arteries. From each carotid bifurcation, 3 projections (lateral, posteroanterior, and oblique) were acquired. Additional projections of occasionally performed rotational DSA examinations were not used in the context of this study.
In all 3 hospitals, MRA was performed on a 1.5-T MRI system, with the use of a 3-dimensional time-of-flight technique. Postprocessing subvolumes were generated to visualize each carotid bifurcation and to create maximum intensity projection (MIP) images. The DSA and MRA protocols have been described in detail elsewhere.26
Stenosis Measurements
The DSA and MRA test results were read by 1 observer for each hospital (A.F.W. for Utrecht and Enschede, A. van der L. for Rotterdam). The observers were blinded for clinical information and for the results of the other tests. The DSA and MRA images were read independently with a period of at least 1 month between the readings. The observers read the DSA and MRA on printed hard copies. For MRA we only used MIP images. The grade of stenosis on both DSA and MRA was measured according to the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria.1 The degree of stenosis is defined as the remaining lumen at the stenosis as percentage of the normal lumen distal to the stenosis. For a valid comparison with DSA, we used only the percentage of stenosis measured on lateral, posteroanterior, and oblique projections on MRA. The maximum of these 3 measurements, on both DSA and MRA, was used in the analyses.26 To estimate the reproducibility, the percentage of stenosis was measured by 2 independent observers (A.F.W. and P.C.B.) for a representative sample of 170 patients on both DSA and MRA. Figures 1 and 2 show examples of moderate and severe stenoses, respectively.
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Data Analysis
Test results of DUS and MRA were first analyzed separately compared with the reference standard DSA.27 The measured stenoses were divided in categories (0% to 29%, 30% to 49%, 50% to 69%, 70% to 99%, 100%). We included for each patient only the estimate of the stenosis of the carotid artery on the symptomatic side in the analyses. Results were interpreted by calculating sensitivity, specificity, and positive and negative predictive values, defining severe stenosis (70% to 99%) on DSA as a positive test result. Second, DUS and MRA results were combined and considered as a combination test. We analyzed the part in which DUS and MRA were in agreement concerning the diagnosis of severe stenosis (70% to 99%) as a separate group. The combined results of this group were again compared with DSA. We calculated kappa (
) statistics for the DSA and MRA results of the 170 patients read by 2 observers.
| Results |
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From the total of 350 patients included in the 3 hospitals, the following numbers of stenosis measurements from the symptomatic side were interpretable and could be included in the analyses: DSA 323, DUS 330, and MRA 295. Missing values were caused by the following reasons: sometimes it was not feasible to perform all 3 tests before surgery, some patients withdrew from the study after 1 or 2 tests, and the test was not always correctly performed according to our study protocol (see Subjects and Methods). In DUS occasionally the PSV was not measured. Finally, it was impossible to measure stenosis because of poor quality and reliability of the MRA recordings in 10 patients and of the DSA recordings in 7 patients. The complication rate of DSA in our series was 1.4% minor stroke (95% CI, 0.1% to 3.3%), 0.3% major stroke (95% CI, 0.0% to 1.6%), and 0.6% mortality (95% CI, 0.1% to 2.0%). Two hundred twenty patients underwent carotid endarterectomy (63%). The complication rate of surgery (within 4 weeks) was 3.2% minor stroke (95% CI, 1.3% to 6.5%) and 0.5% major stroke (95% CI, 0.0% to 2.5%).
Diagnostic Test Results
In Table 3, the test results of DUS are presented with DSA as reference. DUS analyzed with previously defined PSV criteria resulted in a sensitivity of 87.5% (95% CI, 82.1% to 92.9%) and a specificity of 75.7% (95% CI, 69.3% to 82.2%) in identifying severe ICA stenosis (70% to 99%). Stenosis measurements (NASCET) on MRA compared with DSA yielded a sensitivity of 92.2% (95% CI, 86.2% to 96.2%) and a specificity of 75.7% (95% CI, 68.6% to 82.5%) (Table 4). The positive predictive value was 75.4% (95% CI, 68.9% to 82.0%) for DUS and 76.3% (95% CI, 69.6% to 83.0%) for MRA, and the negative predictive value was 87.7% (95% CI, 82.3% to 93.0%) for DUS and 92.0% (95% CI, 85.8% to 96.1%) for MRA. Both DUS and MRA had a tendency to overestimate the degree of stenosis compared with DSA. In 274 patients, stenosis measurements from all 3 test results (DSA, DUS, and MRA) were available. In 229 of these patients (84%), DUS and MRA were in agreement in regard to diagnosing severe stenosis (70% to 99%). In this subgroup, with agreement between the 2 modalities, the combination of MRA and DUS results (ie, considered as a single test) gave a sensitivity of 96.3% (95% CI, 90.8% to 99.0%) and a specificity of 80.2% (95% CI, 73.1% to 87.3%) for identifying severe stenosis (Table 5). The positive predictive value for the combination was 81.2% (95% CI, 74.5% to 88.0%), and the negative predictive value was 96.0% (95% CI, 90.2% to 98.9%). With the use of this approach, the diagnosis concerning severe stenosis remained unclear in case of disagreement between DUS and MRA (16% of the patients). In this combination strategy there was also a tendency to overestimate the stenosis compared with the reference test DSA. In all 24 cases of overestimation in this combination strategy, on the basis of concordant results, DSA categorized the stenosis only 1 category lower as 50% to 69%. The diagnostic test results of the single tests and combination are listed in Table 6. Interobserver variability for DSA and MRA was very good and was similar for both tests (
=0.79 [95% CI, 0.74 to 0.84] for DSA and
=0.79 [95% CI, 0.73 to 0.84] for MRA).
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| Discussion |
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DUS is commonly used to screen patients with possible carotid artery disease11 but has also been suggested as the sole test to select patients for carotid endarterectomy.12,16 This technique, however, has limitations, such as variability in optimal thresholds,25 possible effect of verification bias,28 and limited morphological information. MRA can also be used as a noninvasive test to diagnose carotid artery stenosis.20,21 MRA provides more morphological information without exposure to the risks of DSA. At the start of our study the time-of-flight technique was the state-of-the-art technique for MRA. MRA techniques, however, have improved during the period of our study. The introduction of contrast-enhanced MRA may add to the development.29,30 Contrast-enhanced MRA provides additional morphological information about the origin of the carotid arteries and intracranial vessels, and the effect of flow-related artifacts occurring with the time-of-flight technique is diminished. To date, however, only a few studies have been published reporting the results of contrast-enhanced MRA validated against DSA in small cohorts, precluding a precise estimate of its accuracy.23 For a valid evaluation of a new imaging technique, an adequately powered study is mandatory.22 However, such a study is likely to be large, expensive, and time consuming, precluding application of the newest imaging protocols. Recently, however, we also introduced contrast-enhanced MRA in our clinical setting supplemental to the time-of-flight protocol, allowing us to estimate its accuracy in a subgroup of patients.
Irrespective of the use of intravenous contrast, very good accuracies have been published for MRA if used in combination with DUS.13,14,17,19 Most of the studies on this subject, however, did not meet all standard criteria for design and reporting of the diagnostic tests.22 The number of patients that underwent MRA in these series was relatively small, and often the data were recorded retrospectively, introducing the risk of observer bias.
Our reported accuracies of DUS and MRA might seem relatively low compared with other studies.1121 However, we believe that our prospective design added to valid and unbiased estimates. Another explanation is the fact that we only included the test results of the carotid artery on the symptomatic side in the analyses, yielding lower accuracies. Furthermore, because the decision of whether to perform endarterectomy needs to be made in regard to the symptomatic artery, excluding the asymptomatic side reflects clinical practice. Previously published reports generally also included the asymptomatic side, which was not suspected of having stenosis on DUS. The majority of the arteries on the asymptomatic side show a stenosis percentage far below the 70% threshold or no stenosis at all, making it more likely for the different tests to agree. In this way the number of true negative results is inflated, and thus specificity may be overestimated in those studies. In our data the specificities increased by 10.7% for DUS and 14.2% for MRA if the stenosis measurements of all arteries were included.
Furthermore, it is important to realize that diagnostic testing is limited by some general methodological limitations. In a diagnostic study a new test by definition never exactly agrees with the reference test.27 Even if readings of the reference test itself were to be repeated, there would always be a certain variability in results. The aim of a diagnostic study should not be to achieve the highest possible accuracy. The more relevant question is to what degree a new test under investigation differs from the reference test and what implications this has for the outcome of clinical decisions for individual patients. For this purpose the most realistic estimate of the accuracy is requested. The results should be the guideline for deciding on diagnostic strategies in the clinical setting. Furthermore, to make the right policy decisions from a societal perspective, in addition to a valid estimate of the accuracy of noninvasive testing, cost-effectiveness should be taken into account.
Both DUS and MRA had a tendency to overestimate the degree of stenosis. In DUS verification bias may have played a role. Verification bias may exist if the decision to perform the gold standard procedure depends on the results of the test under investigation.28 The sensitivity may be lower, and specificity may be higher, after adjustment for this bias. In our study patients were often screened with DUS in the clinical setting before inclusion. On the basis of ethical grounds, inclusion in the study depended on the decision of the clinician to perform DSA if carotid endarterectomy was considered. Accuracy of DUS related to the 70% stenosis threshold was estimated afterward among patients selected for DSA. The tabulations show that all categories of degree of stenosis are present, although the majority have a moderate or severe stenosis. In our opinion, however, it is precisely this selected group of patients, suspected of having ICA stenosis at DUS examination, that constitutes the right domain to answer our study objective, reflecting the population for which the decision on surgery must be made in daily clinical practice.
MRA may also overestimate stenosis in comparison with DSA. Overestimation on MRA may occur when all 12 available projections are used for the stenosis measurements and are subsequently compared with DSA, on which stenosis is often measured in only 3 directions (lateral, posteroanterior, and oblique).26 In our study, with regard to the endarterectomy trials, in all patients we assessed the degree of stenosis on DSA using the 3 standard directions, and therefore we used only the same 3 corresponding projections on MRA. Nevertheless, overestimation still occurred. Although we have interpreted our findings as overestimation on MRA, it is very possible that DSA underestimates the true degree of stenosis and that new (3-dimensional) techniques can estimate the degree of stenosis more precisely.
Using the combination strategy of DUS and MRA yielded the highest accuracy. An important finding was that in all cases in which both DUS and MRA overestimated the stenosis (and agreed that carotid endarterectomy was indicated), the stenosis was classified in the 50% to 69% category according to DSA. On the basis of recently published results from NASCET and the European Carotid Surgery Trial, these patients still have limited benefit from carotid endarterectomy.3,4 It is expected that in the near future additional evidence will become available regarding which patients may expect the most benefit from carotid endarterectomy in the 50% to 69% stenosis category.31,32
In regard to the reported complication rates of DSA and of carotid endarterectomy, in general, the number of complications is relatively small compared with the total population. Moreover, the confidence intervals of the rates in our population of 350 patients are broad. Therefore, a significant difference with complication rates reported in literature cannot be proven. We reported 2 deaths after DSA. One patient experienced a major stroke during the procedure and died 72 hours later. The other patient suffered from generalized embolic disease and cardiac events before and after the DSA procedure and died 5 days after DSA after his symptoms had worsened. It remains unsure whether his death had a direct causal relation to the DSA procedure. The complication rates of carotid endarterectomy were recorded over period of 4 weeks after surgery. We realize that minor events that occurred after the patients were dismissed from the hospital might be underreported.
In conclusion, MRA showed a slightly better accuracy than DUS in the diagnosis of carotid artery stenosis. DUS test results might be influenced by verification bias. Furthermore, both tests have a tendency to overestimate the degree of stenosis compared with the reference test DSA. The best accuracy is achieved in case of agreement between the 2 tests. Therefore, in our opinion, in a noninvasive diagnostic strategy both DUS and MRA should be performed subsequently. To make the right policy decisions, however, in addition to a valid estimate of the accuracy of noninvasive testing, cost-effectiveness should be taken into account.
| Acknowledgments |
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Received February 14, 2002; revision received April 5, 2002; accepted April 22, 2002.
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E. Buskens, P. J. Nederkoorn, T. Buijs-van der Woude, W. P. T. M. Mali, L. J. Kappelle, B. C. Eikelboom, Y. van der Graaf, and M. G. Myriam Hunink Imaging of Carotid Arteries in Symptomatic Patients: Cost-effectiveness of Diagnostic Strategies Radiology, October 1, 2004; 233(1): 101 - 112. [Abstract] [Full Text] [PDF] |
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M. J.W. Koelemay, P. J. Nederkoorn, J. B. Reitsma, and C. B. Majoie Systematic Review of Computed Tomographic Angiography for Assessment of Carotid Artery Disease Stroke, October 1, 2004; 35(10): 2306 - 2312. [Abstract] [Full Text] [PDF] |
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J. K. DeMarco, J. Huston III, and M. A. Bernstein Evaluation of Classic 2D Time-of-Flight MR Angiography in the Depiction of Severe Carotid Stenosis Am. J. Roentgenol., September 1, 2004; 183(3): 787 - 793. [Abstract] [Full Text] [PDF] |
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S. Sabeti, M. Schillinger, W. Mlekusch, A. Willfort, M. Haumer, T. Nachtmann, M. Mullner, W. Lang, R. Ahmadi, and E. Minar Quantification of Internal Carotid Artery Stenosis with Duplex US: Comparative Analysis of Different Flow Velocity Criteria Radiology, August 1, 2004; 232(2): 431 - 439. [Abstract] [Full Text] [PDF] |
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C. H. Wierks and N. Labropoulos Noninvasive Carotid Imaging Perspectives in Vascular Surgery and Endovascular Therapy, June 1, 2004; 16(2): 89 - 99. [Abstract] [PDF] |
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G. Rigatelli, P. J. Nederkoorn, W. P.T.M. Mali, L. J. Kappelle, and Y. van der Graaf Diagnosis of Carotid Artery Occlusive Disease in Patients Scheduled for Cardiac or Vascular Surgery: Is This a Place for Invasive Selective Carotid Angiography? * Response: Combined Testing of Cardiac and Carotid Artery Stenosis? Stroke, May 1, 2004; 35(5): e89 - e90. [Full Text] [PDF] |
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J. M. U-King-Im, R. A. Trivedi, M. J. Graves, N. J. Higgins, J. J. Cross, B. D. Tom, W. Hollingworth, H. Eales, E. A. Warburton, P. J. Kirkpatrick, et al. Contrast-enhanced MR angiography for carotid disease: Diagnostic and potential clinical impact Neurology, April 27, 2004; 62(8): 1282 - 1290. [Abstract] [Full Text] [PDF] |
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M. Nonent, J.-M. Serfaty, N. Nighoghossian, F. Rouhart, L. Derex, C. Rotaru, P. Chirossel, B. Guias, J.-F. Heautot, P. Gouny, et al. Concordance Rate Differences of 3 Noninvasive Imaging Techniques to Measure Carotid Stenosis in Clinical Routine Practice: Results of the CARMEDAS Multicenter Study Stroke, March 1, 2004; 35(3): 682 - 686. [Abstract] [Full Text] [PDF] |
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P. J. Nederkoorn, O. E. H. Elgersma, Y. van der Graaf, B. C. Eikelboom, L. J. Kappelle, and W. P. T. M. Mali Carotid Artery Stenosis: Accuracy of Contrast-enhanced MR Angiography for Diagnosis Radiology, September 1, 2003; 228(3): 677 - 682. [Abstract] [Full Text] [PDF] |
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ADDITIONAL ARTICLES ABSTRACTED IN ACP JOURNAL CLUB Evid. Based Med., March 1, 2003; 8(2): 35 - 35. [Full Text] [PDF] |
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Preoperative Diagnosis of Carotid Stenosis by Noninvasive Testing Journal Watch Neurology, November 21, 2002; 2002(1121): 2 - 2. [Full Text] |
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P. J. Nederkoorn, Y. van der Graaf, B. C. Eikelboom, A. van der Lugt, L. W. Bartels, and W. P.T.M. Mali Time-of-Flight MR Angiography of Carotid Artery Stenosis: Does a Flow Void Represent Severe Stenosis? AJNR Am. J. Neuroradiol., November 1, 2002; 23(10): 1779 - 1784. [Abstract] [Full Text] [PDF] |
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