Diagnostic accuracy of contrast-enhanced MR angiography in severe carotid stenosis: meta-analysis with metaregression of different techniques

In symptomatic patients with recent transient ischaemic attacks or ischaemic stroke within the last 6 months and ipsilateral severe (70–99%) extracranial carotid stenosis, carotid endarterectomy or angioplasty with carotid artery stenting is recommended according to current guidelines to reduce the stroke risk [18, 21]. Additionally, endarterectomy may be considered in selected asymptomatic patients with severe carotid stenosis for the primary prevention of ischemic stroke [18, 22]. To apply these guidelines it is necessary to distinguish severe carotid stenosis from moderate stenosis and from occlusion. Currently digital subtraction angiography (DSA) is the diagnostic gold standard that offers angiographic images with high spatial resolution and high contrast between vessels and surrounding tissues [18]. However, DSA is invasive and has complications in about 1% of cases [1, 5, 18]. For diagnostic purposes carotid CE-MRA has become a well-established noninvasive alternative [5, 18].

In appropriate patients carotid MRA has a high sensitivity and specificity for diagnosing or ruling out severe carotid stenosis [18, 23, 24]. The presented bivariate random effects meta-analysis found a pooled sensitivity (with 95% confidence interval) of 94.3% (92.0–96.0%) and a pooled specificity of 93.0% (89.8–95.3%) based on 17 primary studies. These results are similar to two other current meta-analyses: Wardlaw et al. used a random effects model and found a pooled sensitivity of 94% (88–97%) and specificity of 93% (89–96%) [23]. Debrey et al. used a fixed effects model and found a pooled sensitivity of 94.6% (92.4–96.4%) and specificity of 91.9% (90.3–93.4%) [24]. In this case the results from random effects and fixed effects meta-analytic models were relatively similar.

Both of the previously mentioned meta-analyses found a homogeneous distribution of sensitivities, but a heterogeneous distribution of specificities among the primary studies, similar to the meta-analysis presented here [23, 24]. Wardlaw et al. focused on comparing several noninvasive carotid imaging techniques in general and, therefore, did not explore sources of heterogeneity in more detail [23]. Debrey et al. focused on comparing CE-MRA with time-of-flight MRA and studied sources of heterogeneity predominantly for time-of-flight MRA [24]. The presented meta-analysis focused on carotid CE-MRA and analysed possible sources of heterogeneity that have not been studied by either of the other meta-analyses [23, 24]. This was done by bivariate random effects metaregressions of sensitivity and specificity with six different covariates. The results are discussed below.

The 17 studies included had a high prevalence of severe carotid stenosis and occlusions, ranging from 21 to 59%. In the metaregression, sensitivity slightly increased with disease prevalence (Fig. 4a–c and Table 4). This has also been empirically observed in other situations, although there is no mathematical relationship between sensitivity and specificity on the one hand and prevalence on the other hand [38, 39]. Here, not only sensitivity but also specificity slightly increased. However, these trends were not significant. This qualifies sensitivity and specificity to be suitable diagnostic accuracy parameters across a wide range of prevalence percentages.

Within the isotropic voxel size range of 0.8 to 1.8 mm under study, the metaregression found no significance change in sensitivity with voxel size (Fig. 4d–e and Table 4). There was a trend for specificity to increase with larger voxels, but this trend was not significant either. These meta-analysis findings are consistent with the empirical findings of Cosottini et al., who studied the diagnostic accuracy of carotid CE-MRA by sequences with different voxel sizes [10]. They found that smaller voxels with a volume of 0.8 mm³ did not cause a significant improvement in diagnostic accuracy compared with larger voxels with a volume of 2.15 mm³. With reference to Fig. 4d–e, these voxel volumes correspond to a normalised isotropic voxel size of (0.8)^1/3 = 0.5 mm and (2.15)^1/3 = 1.3 mm. However, their findings and this study’s metaregression findings are limited to the techniques applied. With other carotid CE-MRA techniques smaller voxel sizes may allow for increased diagnostic accuracy, for instance when using 3-T magnets, parallel imaging or blood pool contrast agents with their prolonged vessel enhancement [40‐44].

The metaregression showed a slight increase in diagnostic accuracy with smaller acquisition times, although this trend was not significant (Fig. 4g–i and Table 4). Generally, in MRA a better temporal resolution comes at the expense of spatial resolution [1]. In carotid CE-MRA this trade-off between temporal and spatial resolution seems to be slightly in favour of temporal resolution. This may explain why time-resolved CE-MRA with its inherently low spatial resolution provides a high diagnostic accuracy, and thus remains concurrent with bolus-timed and fluoroscopically triggered sequences with their longer acquisition times and higher spatial resolution. A further explanation in favour of shorter acquisition times may be that the risk of slight motion artefacts increases with measurement time, perhaps not only in noncompliant patients [13].

In the literature there is currently no evidence that any of the three MRA timing techniques (bolus-timed, fluoroscopically triggered, time-resolved) has a higher diagnostic accuracy than the others. Only one primary study compared fluoroscopically triggered versus time-resolved CE-MRA intraindividually in a small number of 21 patients [15]. This study found sensitivities of 100% (11/11 carotids) with both timing techniques. The observed specificity was 80.6% (25/31 carotids) with fluoroscopically triggered CE-MRA and elliptic acquisition. The specificity was 83.9% (26/31 carotids) with time-resolved CE-MRA, and thus slightly but not significantly higher. In their discussion the authors favoured fluoroscopically triggered CE-MRA because of its higher spatial resolution, which allowed for greater diagnostic confidence and interobserver agreement [15]. Another study used time-resolved CE-MRA in 19 patients and examined the next 20 patients with bolus-timed CE-MRA [45]. However, the authors found no significant differences between the two timing techniques regarding the diagnostic accuracy in severe carotid stenosis [45]. Currently, there are no other studies that compare the different CE-MRA timing techniques at the person-level. At the study-level the metaregression presented here found a trend in favour of bolus-timed CE-MRA, but the differences in diagnostic accuracy observed among the three CE-MRA timing techniques did not reach significance (Fig. 5a–c, Tables 5 and 6). Therefore, it seems justified to apply and to further develop all three different CE-MRA timing techniques equally.

There are no primary studies that compare the use of hardcopy films versus electronic monitor images in carotid CE-MRA at the person-level. At the study-level the metaregression showed a significant improvement in sensitivity with electronic monitor images (P = 0.02) (Fig. 5d–e, Tables 5 and 6). This gives evidence of the trend in clinical practice, where conventional film systems are subsequently replaced by electronic viewing facilities and electronic picture archive and communication systems (PACS). This requires sufficiently suitable monitors not only for the radiologist, but also for the admitting clinician. However, the net costs of electronic systems are generally smaller than those of hardcopy films, and the fast image access is a further advantage.

In the metaregression of two different MRA reading modes the pooled specificity was 88.8% with (1) using solely MIP images; with (2) using MIP plus 3D images the pooled specificity was 95.8% and thus significantly higher (P = 0.01) (Fig. 5g–i, Tables 5 and 6). This can be explained by the maximum intensity projection (MIP) algorithm, which generates the MIP images from the original 3D images [46]. In MIP images it easier to detect vessels with large diameters than those with small diameters. A small vessel may be hidden in the MIP image, although it is visible in the original 3D data [46]. The same applies to a vessel stenosis, which also has a small diameter. Therefore, a vessel stenosis may be overestimated on the MIP image, although being less severe on the 3D source images. This increases the rate of false-positives and thus reduces the specificity of method (1) compared with method (2), which explains the metaregression findings. However, according to the metaregression, the sensitivity with method (1) was nearly similar to that with method (2). These findings give statistical evidence to support the following reading algorithm that has naturally developed in clinical practice: first, the MIP images are viewed to search for severe carotid stenoses; then, the 3D images are assessed, paying specific attention to the suspected stenoses to reduce the rate of false-positives. This image-reading algorithm is consistent with the findings of Huston et al., who compared the diagnostic accuracy of MIP images and 3D source images in 50 patients [3]. They found that MIP images have the highest sensitivity (93.3%) for the detection of severe carotid stenosis, whereas 3D images have the highest specificity (97.0%) for ruling out severe carotid stenosis.

The metaregression findings presented here are limited to carotid CE-MRA. Transfer of these findings to other imaging techniques like carotid computed tomographic angiography would mean an extrapolation of results and is perhaps invalid. It will be better to study the possible sources of heterogeneity directly for the other noninvasive carotid imaging techniques.

The metaregressions were limited to analysing the six covariates at the study-level. In the literature there are only a few primary studies that studied these covariates at the person-level. Future diagnostic accuracy studies might, for example, compare the different MRA timing techniques intraindividually [15, 45]. Another limitation of this meta-analysis results from analysing only six covariates. It is possible that the diagnostic accuracy of carotid CE-MRA is influenced by further factors. To some degree such factors are statistically considered by the random effects component of this meta-analysis.

The 17 primary studies applied DSA as their gold standard for the grading of carotid stenosis. However, DSA has its own measurement errors and may additionally underestimate noncircular carotid stenoses because of the angle-dependent projection. This has, for example, been illustrated by Serfaty et al. (Fig. 5 in ref. [1]). Rotational angiography, with its multiple projections at different angles, overcomes this problem and may thus become a more accurate gold standard than DSA [16]. However, for a meta-analysis there are currently not enough studies that compare carotid CE-MRA with rotational angiography [16]. In summary, the true diagnostic accuracy of CE-MRA may be somewhat higher than when assessed by DSA.

The populations of the 17 primary studies consisted of preselected patients with a high probability for severe carotid artery disease. Thus, there is no major selection bias, when applying the meta-analysis results in similar, clinically high-risk collectives. However, extrapolation of the meta-analysis results to asymptomatic screening populations with less than 20% disease prevalence might produce such selection bias. Currently, this is not relevant, because Doppler sonography, not CE-MRA, is the first-line technique in the general population. Furthermore, the net benefit of such screening for carotid artery disease is unclear [47‐49].

This meta-analysis is limited to primary CE-MRA studies with 1.0- or 1.5-T magnets. In principle, CE-MRA with 3-T magnets allows for higher spatial resolution and image contrast [40, 41]. It may be hypothesised that the diagnostic accuracy of carotid CE-MRA at 3-T might be somewhat higher than with 1.5-T magnets. However, currently, there are not many publications on the sensitivity and specificity of carotid CE-MRA at 3-T [41, 50]. Perhaps such studies could be conducted with rotational angiography as the reference standard [16].