Clinical trials for carotid stenosis revascularization and relation to methods of stenosis quantification

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 [5]. 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 [6]. Given that the NASCET moderate stenosis group, measured as 50-69% stenosis, hardly had slight benefit of surgery [7], 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 [8] 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].

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 [2].

While the NASCET group with 50-69% stenosis showed an overall modest benefit to prevent stroke [7], 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.

The nearly complete collapse of ICA lumen beyond a very severe stenosis is (Figure 2) known by with a variety of names, called near occlusion in NASCET [1,3,9-12]. Less well identified is a lesser physiological loss of diameter of ICA beyond severe stenosis (Figures 3, 4) that can be considered “normal-looking” but otherwise shows partial collapse [11,12]. Both categories are called near occlusion in NASCET [1,3,9-12], representing complete and partial collapse. They can’t be correctly measured and calculated for % stenosis because the distal ICA diameter is too small and not truly normal. NASCET understood that no measurements could be correctly taken for near occlusion [1,3,9-12] because to do so would be fallacious. Yet many still do not recognize partial collapse as near occlusion and go ahead to fallaciously calculate % stenosis. As such the yielded % can be substantially less than severe stenosis [4]. To avert this lack of compliance, NASCET suggested that before any stenosis be measured it should be first interpreted for presence or not of the subtle near occlusion [1,3,4].

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 [4] 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 [4]. 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.

NASCET outcome results [2,7] are considered a “bible” of stroke prevention management for symptomatic patients with carotid stenosis. Misuse of NASCET % stenosis calculations [4] exists. There is reluctance by many to abandon NASCET % stenosis because NASCET outcomes derived from % stenosis. In the days of standard angiography, % calculation made sense: old film angiography had uncertainty of magnification factors for real measurements, while digital subtraction angiography (DSA) was basically expressed in pixels and not real mm. The pitfalls of NASCET % stenosis arise mainly from the denominator; yet the numerator essentially expresses the lumen [3]. Now in an era when real mm are part of CTA (Figure 5) and MRA, it seems appropriate and logical to eliminate the problem denominator and consider the quantification of stenosis based on mm diameter of the residual lumen. That has been done in a series of experiments using a CTA stenosis database [12-16] and comparing mm stenosis with other derived stenosis methods. The CTA method shown in Figure 5 [13] uses measurements from thin axial source images which have highest spatial resolution, guided by reformats in other directions. Today we get accurate mm diameters; why persist with a % method that was useful when DSA did could not give accurate mm when now CTA gives mm, especially since problems with compliance with the NASCET approach are due to variable and inconsistent ways to determine the denominator for % ratio?

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 [2] than results with ECST [5].

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].

Now the ability to image plaque hematoma in the methemoglobin phase [20] has brought in a new era (Figure 6) [21]. IPH may further risk stratify within stenosis degree groups. IPH has been shown to predict cerebrovascular outcomes within various specific stenosis groups [22-25]. IPH, in conjunction with stenosis, may provide precise cerebrovascular risk stratification. Larger and/or more systematic trials are now underway that should be able to shed light including CAIN [26]. CAIN is a multi-centre, pan-national serial imaging trial of the carotids and brain that includes investigation of clinical and imaging cerebrovascular outcomes [26].

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 [4], 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 [4]. Mm stenosis methods [13] 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.