Clinical trials for carotid stenosis revascularization and relation to methods of stenosis quantification
© Fox and Singh; licensee BioMed Central. 2015
Received: 10 November 2014
Accepted: 7 January 2015
Published: 21 October 2015
Severe carotid stenosis patients in the North American Symptomatic Carotid Endarterectomy Trial (NASCET) were shown to have a high risk of stroke and significant benefit from carotid endarterectomy. More than 20 years after the 1991 NASCET results for severe stenosis, there is a common claim to use the NASCET method to determine % carotid stenosis, but without following the details necessary to properly identify the group most benefitting from carotid endarterectomy. NASCET interpreted for loss of diameter of the cervical ICA, near occlusion, and didn’t calculate % stenosis if present as it is fallacious. NASCET measured the distal ICA for well beyond the tapering ICA bulb where the ICA walls are parallel.
The pitfalls of stenosis quantification and differences between methods are problems of the ratio’s denominator, and may potentially be resolved by the use of absolute measurements for stenosis on CTA or MRA. Furthermore, trials evaluating vessel wall components including intraplaque hemorrhage such as CAIN may add to or replace degree of stenosis for the prediction of cerebrovascular outcomes.
Summary of NASCET’s design, early stop, and surprisingly strong results
Different Methods of Stenosis Measurement and Reconciliation of Stenosis with ECST
NASCET paralleled the European Carotid Surgery Trial (ECST), also stopped for its severe group outcomes, although with notably less strength of outcome data than NASCET’s . Both studies identified the severe group as 70% stenosis or more, yet it was realized that their methods of quantifying % stenosis differed, making the studied groups quite different from each other as well as the strength of the surgical results. NASCET isolated a more severe stenotic group with greater stroke risk and greater surgical benefit. For example, the 70% stenosis cut-off for ECST corresponded to about 40% stenosis for NASCET, while NASCET’s 70% stenosis was about 85% ECST . Given that the NASCET moderate stenosis group, measured as 50-69% stenosis, hardly had slight benefit of surgery , it is easy to understand why ECST’s severe group showed a muted benefit of surgery compared to NASCET, since it contained both NASCET’s severe and moderate groups [3,7].
There had always been different ways to assign % carotid stenosis [1,3]. The blatant differences between NASCET and ECST methods and results were striking [1-7]. A problem is that the multiple ways of calculating % each has its own logic [3,7,8]. NASCET chose a method that effectively quantifies stenosis based on the luminal reduction compared to the internal carotid artery (ICA) distal outflow (Figure 1). ECST’s method measures from luminal reduction of the stenosis and compares it to the unseen ICA bulb width on standard angiography (the stenotic atheroma covers it). This ECST % is derived from a denominator of up to twice the diameter of the distal ICA, with ICA bulb being the largest part of the artery.
NASCET’s method is most commonly used today as it relates to the higher stroke risk group and stronger surgical benefit found in NASCET. In a sense, all methods are arbitrary and anyone can use what they prefer, however, the outcome results of both NASCET and ECST are very specific to the respective methods used. It seems incorrect to use NASCET’s clinical results unless used with NASCET’s stenosis method. Indeed, analysing the results together from both NASCET and ECST  for combined analysis, NASCET’s method was used for all cases.
In effect, NASCET defined its severe group in a way not previously highlighted, and it could be said that NASCET’s “severe” group is really “very severe”, while its moderate group could give the impression of very prominent stenosis if identified just by the eye, without adhering to measurements and calculation of % stenosis [3,4].
Role of stenosis measurement in NASCET’s success
The early NASCET stop by NIH for severe stenosis in 1991 was based on NASCET’s stenosis degree for 70% or more with the 2-year stroke risk being over 20% of cases for 70-79% stenosis, 30% for cases for 80-89% stenosis, and 40% of cases for 90-99% of cases [2,3]. The surgical group showed 2-year stroke risk in the 10% range for all severe stenosis degrees, including peri-operative risks, yielding a two-year stroke prevention benefit of 14%, 18%, and 26% of cases for each of the three deciles of stenosis degree .
While the NASCET group with 50-69% stenosis showed an overall modest benefit to prevent stroke , this was negative for some studied clinical groups, while there was little latitude for surgical complications that could easily erase the muted benefit for all cases in this study group. The 70% stenosis threshold remained a strong criterion for surgery.
Both the incidences of stroke risk and surgical success to prevent stroke were substantially greater than had been predicted in the planning stages for the trial. In effect, NASCET through its % stenosis method (Figure 1) was original to study this group of very severe stenosis that greatly benefited from surgical endarterectomy.
Pitfalls of NASCET measurement
Lack of compliance with NASCET’s stenosis Methods:
Lack of Assessment for Near Occlusion:
Denominator Measurement for % Stenosis:
NASCET chose a denominator to calculate % stenosis using the distal ICA diameter well beyond the bulb where the walls are parallel [1,3,4]. ICA bulb is an anatomical aberration [1,3] where the artery becomes much larger than its inflow parent CCA, and becomes much smaller than its outflow ICA. The transition from wide bulb to narrower outflow ICA is a gradual tapering vessel. To choose a changing diameter structure for % calculation purposes seems both illogical and incorrect  when one can choose a parallel part of the artery, where the walls are parallel. Measuring ICA where it is larger than the distal ICA where walls are parallel falsely increases the calculated % stenosis . Claiming to use NASCET’s approach but failing to measure the distal normal well beyond the bulb where the walls are parallel could result in management decisions that differ from NASCET clinical outcome categories.
Other Methods and New Imaging Methods with Capability for Measurement
Millimetre (mm) Diameter Measurements:
Other Methods for % Stenosis Calculations:
There remain multiple other ways to express % stenosis, using ratios of carotid artery and different basic measurements [3,5,6]. They remain alternatives, each with their own logic of approach, their own following, and all produce % stenosis numbers different from NASCET for the same stenosis [3,6]. All methods are arbitrary, including NASCET’s method. The justification to use NASCET’s method comes from the NASCET outcome results and their statistical strength. Indeed, while ECST initially used a different method, for meta-analysis it converted to NASCET’s approach [6,8] recognizing that NASCET outcome results of stroke risk and surgical benefit was substantially stronger identifying cases with the NASCET method  than results with ECST .
Potential Acceptance of mm Stenosis:
Ultrasound Depiction of % Stenosis:
Vessel Wall Content—“Unstable Plaque”:
The concept of the instability of plaque content as being an important risk factor for carotid stenosis is undergoing study. Intra-plaque haemorrhage (IPH) has long been presumed as such a risk factor, though to identify it was previously difficult. IPH seems to be more prevalent in higher grades of carotid stenosis. However, groups studying IPH appear to focus more on demonstrating that IPH is a risk factor for plaque progression defined by vessel wall or plaque volumes [18,19].
NASCET outcome results for symptomatic carotid stenosis are most accepted to determine surgical or interventional management, yet those results are tied to a particular “severe” way to determine % stenosis degree [2,7,8]. The so-called NASCET approach to carotid stenosis quantification seems to have less than optimal compliance , and it is possible that many patients may be sent to surgical treatment based on NASCET results, yet for which they do not have the indications, because of lack of compliance of % stenosis calculations . Mm stenosis methods  have been suggested as replacements especially because they don’t have the pitfalls of the denominator for ratio calculation. While this is logical and incorporates the mm calibrations inherent in cross-sectional imaging, it may need a new clinical outcome treatment study that uses mm stenosis in order to change user preference of mm over % stenosis. New studies may also find that plaque imaging is an important predictor of stroke from carotid stenosis [18-26], perhaps even as or more important than stenosis degree.
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