- Review
- Open Access
Clinical trials for carotid stenosis revascularization and relation to methods of stenosis quantification
- Allan J Fox1, 2Email author and
- Navneet Singh1
https://doi.org/10.1186/s40809-015-0002-1
© Fox and Singh; licensee BioMed Central. 2015
- Received: 10 November 2014
- Accepted: 7 January 2015
- Published: 21 October 2015
Abstract
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.
Keywords
- Internal Carotid Artery
- Stroke Risk
- Carotid Stenosis
- Severe Stenosis
- North American Symptomatic Carotid Endarterectomy Trial
Summary of NASCET’s design, early stop, and surprisingly strong results
Shows a conceptualized drawing of the calculation of % stenosis = (1 – N/D)100, with N as the narrowest observed diameter and D as the diameter of the “normal” internal carotid diameter well beyond the bulb where the walls are parallel. Reproduced with permission from Radiology [3].
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 [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].
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 [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.
Pitfalls of NASCET measurement
- 1)
Lack of compliance with NASCET’s stenosis Methods:
- 2)
Lack of Assessment for Near Occlusion:
Shows a conceptualized drawing of “near occlusion” as a collapsed lumen beyond very severe stenosis with flow reduction associated with presumed physiological loss of diameter of the distal ICA. NASCET recognized that any % stenosis calculation from such a reduced distal ICA lumen was flawed. Figure 2 is a reproduced part of a figure in Stroke (1). “Promotional and commercial use of the material in print, digital or mobile device format is prohibited without the permission from the publisher Lippincott Williams & Wilkins. Please contact journalpermissions@lww.com for further information”.
Shows less profound near occlusion with an angiogram of the “normal-appearing” internal carotid well beyond a prominent ICA bulb stenosis, with its diameter (large arrow) narrower that the external carotid diameter nearby, implying partial collapse of the distal ICA. The ICA diameter should be substantially larger than ECA diameter. Picture reproduced with permission from AJNR [11].
Shows a reformatted image from a CTA “normal-appearing” internal carotid well beyond a prominent ICA bulb stenosis, with its diameter (large arrow) narrower that the external carotid diameter nearby, implying partial collapse of the distal ICA. ICA diameter should be substantially larger than ECA diameter. Picture reproduced with permission from AJNR [12].
- 3)
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 [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.
Other Methods and New Imaging Methods with Capability for Measurement
- 1)
Millimetre (mm) Diameter Measurements:
shows axial (A) and sagittal (B) reformatting of a right ICA bulb stenosis with large plaque ulcer/uplifted plaque. The larger solid arrow shows the reduced ICA lumen at the stenosis, readily measured by CT caliper tool, more accurate from the axial source image. The dashed arrow indicates the ulcerated plaque and small arrow the ECA. Picture reproduced with permission from AJNR [13]. The thin axial source images are used for measurement as they have the highest spatial resolution.
- 2)
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 [2] than results with ECST [5].
- 3)
Potential Acceptance of mm Stenosis:
- 4)
Ultrasound Depiction of % Stenosis:
- 5)
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].
shows multiplanar images (coronal (A), axial (B) and sagittal (C) demonstrating MR-depicted intraplaque hemorrhage (IPH) (arrowheads). IPH is indicated by the high signal intensity of methemoglobin on this T1-weighted gradient echo MRI technique. Figure reproduced with permission from the International Journal of Cardiovascular Imaging [26].
Conclusions
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.
Declarations
Authors’ Affiliations
References
- North American Symptomatic Carotid Endarterectomy Trial (NASCET) Steering Committee. North American symptomatic carotid endarterectomy trial: methods, patient characteristics, and progress. Stroke. 1991;22:711–20.View ArticleGoogle Scholar
- North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high grade carotid stenosis. N EnglJ Med. 1991;325:445–53.View ArticleGoogle Scholar
- Fox AJ. How to measure carotid stenosis. Radiology. 1993;186:316–8.View ArticlePubMedGoogle Scholar
- Fox AJ, Symons SP, Aviv RI, Howard P, Yeung R, Bartlett ES. Falsely claiming use of NASCET percentage stenosis method. Radiology. 2009;253:574–5.View ArticlePubMedGoogle Scholar
- European Carotid Surgery Trialists’ Collaborative Group. MRC European carotid surgery trial: interim results for symptomatic patients with severe (70-99%) or with mild (0-29%) carotid stenosis. Lancet. 1991;337:1235–43.View ArticleGoogle Scholar
- Rothwell PM, Gibson RJ, Slattery J, Warlow CP. Prognostic value and reproducibility of measurements of carotid stenosis. A comparison of three methods on 1001 angiograms. European Carotid Surgery Trialists’ Collaborative Group. Stroke. 1994;25:2440–4.View ArticlePubMedGoogle Scholar
- Barnett HJM, Taylor DW, Eliasziw M, Fox AJ, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med. 1998;339:1415–25.View ArticlePubMedGoogle Scholar
- Rothwell PM, Eliasziw M, Gutnikov SA, Fox AJ, Taylor DW, Mayberg MR, et al. Analysis of pooled data from the randomised controlled trials of endarterectomy for symptomatic carotid stenosis. Lancet. 2003;361:107–16.View ArticlePubMedGoogle Scholar
- Morgenstern LB, Fox AJ, Sharpe B, Eliasziw M, Barnett HJM, Grotta JC. The risks and benefits of carotid endarterectomy in patients with near-occlusion of the carotid artery. Neurology. 1997;48:911–5.View ArticlePubMedGoogle Scholar
- Henderson RD, Eliasziw M, Fox AJ, Rothwell PM, Barnett HJM, for the NASCET group. Angiographically-Defined Collateral Circulation and the Risk of Stroke in Patients with Severe Carotid Artery Stenosis. Stroke. 2000;31:128–32.View ArticlePubMedGoogle Scholar
- Fox AJ, Eliasziw M, Rothwell PM, Schmidt MH, Warlow CP, Barnett HJM. Identification, Prognosis, and Management of Patients with Carotid Artery Near Occlusion. AJNR. 2005;26:2086–94.PubMedGoogle Scholar
- Bartlett ES, Walters TD, Symons SP, Fox AJ. Diagnosing Carotid Stenosis Near-Occlusion by Using CT Angiography. AJNR. 2006;27:632–7.PubMedGoogle Scholar
- Bartlett ES, Walters TD, Symons SP, Fox AJ. Quantification of Carotid Stenosis on CT Angiography. AJNR. 2006;27:13–9.PubMedGoogle Scholar
- Bartlett ES, Symons SP, Fox AJ. Correlation of Carotid Stenosis and Cross-Sectional Areas with CT Angiography. AJNR. 2006;27:638–42.PubMedGoogle Scholar
- Bartlett ES, Walters TD, Symons SP, Fox AJ. Carotid Stenosis Index Revisited With Direct CT Angiography Measurements of Carotid Arteries to Quantify Carotid Stenosis. Stroke. 2007;38:286–91.View ArticlePubMedGoogle Scholar
- Bartlett ES, Walters TD, Symons SP, Aviv AJ, Fox AJ. Classification of carotid stenosis by millimeter CT angiography measures: effects of prevalence and gender. AJNR. 2008;29:1677–83.View ArticlePubMedGoogle Scholar
- Dreisbach JN, Seibert CE, Smazal SF, et al. Duplex sonography in the evaluation of carotid artery disease. AJNR. 1983;4:678–80.PubMedGoogle Scholar
- Takaya N, Yuan C, Chu B, Saam T, Polissar NL, Jarvik GP, et al. Presence of intraplaque hemorrhage stimulates progression of carotid atherosclerotic plaques: a high-resolution magnetic resonance imaging study. Circulation. 2005;111:2768–75.View ArticlePubMedGoogle Scholar
- Boussel L, Arora S, Rapp J, Rutt B, Huston J, Parker D, et al. Atherosclerotic plaque progression in carotid arteries: monitoring with high-spatial-resolution MR imaging–multicenter trial. Radiology. 2009;252:789–96.PubMed CentralView ArticlePubMedGoogle Scholar
- Moody AR, Murphy RE, Morgan PS, Martel AL, Delay GS, Allder S, et al. Characterization of complicated carotid plaque with magnetic resonance direct thrombus imaging in patients with cerebral ischemia. Circulation. 2003;107:3047–52.View ArticlePubMedGoogle Scholar
- Singh N, Moody AR, Rochon-Terry G, Kiss A, Zavodni A. Identifying a high risk cardiovascular phenotype by carotid MRI-depicted intraplaque hemorrhage. Int J Cardiovasc Imaging. 2013;29(7):1477–83.View ArticlePubMedGoogle Scholar
- Lindsay AC, Biasiolli L, Lee JM, Kylintireas I, MacIntosh BJ, Watt H, et al. Plaque features associated with increased cerebral infarction after minor stroke and TIA: a prospective, case–control, 3-T carotid artery MR imaging study. JACC Cardiovasc Imaging. 2012;5:388–96.View ArticlePubMedGoogle Scholar
- Gupta A, Baradaran H, Schweitzer AD, Kamel H, Pandya A, Delgado D, et al. Carotid plaque MRI and stroke risk: a systematic review and meta-analysis. Stroke. 2013;44:3071–7.View ArticlePubMedGoogle Scholar
- Singh N, Moody AR, Gladstone DJ, Leung G, Ravikumar R, Zhan J, et al. Moderate carotid artery stenosis: MR imaging-depicted intraplaque hemorrhage predicts risk of cerebrovascular ischemic events in asymptomatic men. Radiology. 2009;252:502–8.View ArticlePubMedGoogle Scholar
- Singh N, Moody AR, Zavodni AE. Magnetic Resonance Imaging of Carotid Atherosclerosis and the Risk of Stroke. Current Cardiovascular Imaging Reports. 2012;6:25–33.View ArticleGoogle Scholar
- Tardif JC, Spence JD, Heinonen TM, Moody A, Pressacco J, Frayne R, et al. Atherosclerosis imaging and the Canadian Atherosclerosis Imaging Network. Can J Cardiol. 2013;29:297–303.View ArticlePubMedGoogle Scholar
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