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Carotid Stenting Using Tapered and Nontapered Stents: Associated Neurological Complications and Restenosis Rates
Carotid Stenting Using Tapered and Nontapered Stents: Associated Neurological Complications and Restenosis Rates Katherine E. Brown,1 Asad Usman,1 Melina R. Kibbe,1 Mark D. Morasch,1 Jon S. Matsumura,1 William H. Pearce,1 Daniel J. Amaranto,1 and Mark K. Eskandari,1,2 Chicago, Illinois
Self-expanding stent design systems for carotid artery stenting (CAS) have morphed from nontapered (NTS) to tapered (TS); however, the impact of this change is unknown. We reviewed the outcomes of CAS with these two broad categories of stents in a single-center retrospective review of 308 CAS procedures from May 2001 to July 2007. Nitinol self-expanding TS or NTS coupled with cerebral embolic protection devices were used to treat extracranial carotid occlusive disease. Data analysis included demographics, procedural records, duplex exams, and conventional arteriography. Mean follow-up was 18 months (range 1e69). Restenosis was defined as 80% in-stent carotid artery stenosis by angiography. The mean age of the entire cohort was 71.3 years (75% men, 25% women). Of the 308 cases, 233 were de novo lesions and 75 had a prior ipsilateral carotid endarterectomy (n ¼ 44) or external beam radiation exposure (n ¼ 31). Preprocedure neurological symptoms were present in 30% of patients. TS were used in 156 procedures and NTS in 152 procedures. The 30-day ipsilateral stroke and death rates were 1.3% and 0.3%, respectively. An additional three (1.0%) posterior circulation strokes occurred. There was no statistically significant difference in the 30-day total stroke rates between TS (3.2%, n ¼ 5) and NTS (1.3%, n ¼ 2) ( p ¼ 0.5). At midterm follow-up, restenosis or asymptomatic occlusion was detected in eight cases (2.6%). All occurred in arteries treated with NTS, and this was statistically different when compared to arteries treated with TS ( p ¼ 0.03). Furthermore, a post-hoc subgroup analysis revealed significant correlation (c2 ¼ 0.02) for restenosis in ‘‘hostile necks’’ when separated by TS vs. NTS. Early CAS outcomes between TS and NTS are comparable. In contrast, self-expanding nitinol TS may have a lower incidence of significant restenosis or asymptomatic occlusion when compared to NTS.
INTRODUCTION
Presented at the 31st Annual Midwestern Vascular Surgical Society Meeting, September 7, 2007, Chicago, IL. Mark K. Eskandari serves as a consultant for Cook, Cordis, Abbott Vascular Devices, Medtronic, Boston Scientific, Terumo, and W. L. Gore & Associates, Inc. 1
Division of Vascular Surgery, Northwestern University, Chicago,
IL. 2 Department of Radiology, Northwestern University, Chicago, IL. Correspondence to: Mark K. Eskandari, MD, 676 North St. Clair, Suite 650, Chicago, IL 60611, USA, E-mail: [email protected]
Ann Vasc Surg 2009; 23: 439-445 DOI: 10.1016/j.avsg.2008.11.007 Ó Annals of Vascular Surgery Inc. Published online: January 6, 2009
Outcomes of carotid artery stenting (CAS) are highly dependent on experience, judgment, and equipment as well as patient risk factors and plaque characteristics.1-5 In particular, self-expanding stent configuration is increasingly recognized as a possible predictor of both early and late outcomes following CAS.1-3 Cell structure, extent of scaffolding, and composition of the stents are part of the equation, yet changes from a straight to tapered stent to accommodate the anatomic carotid bifurcation might also have clinical consequences. This becomes important since, in the majority of cases, stent placement crosses the external carotid artery (ECA) orifice and needs to be well apposed to both the common carotid artery (CCA) and the internal 439
440 Brown et al.
carotid artery (ICA) lumens. Many nontapered stents (NTS) are promoted as ‘‘self-tapering,’’ yet due to the natural size mismatch between the ICA and CCA, extreme oversizing in the ICA is a frequent occurrence after CAS. The unfavorable effects of excessive oversizing in the ICA are increased chronic outward radial force and decreased free cell area in the ICA. Tapered stent (TS) design systems attempt to minimize these factors. Although the development of TS is aesthetically appealing, the clinical impact of this change remains to be determined. The aim of this study is to retrospectively analyze the outcomes of CAS using TS and NTS, with regard to neurological events and restenosis.
METHODS Patients From May 2001 to July 2007 a total of 308 primary CAS procedures were performed on a total of 295 patients at Northwestern Memorial Hospital and the Jesse Brown or Lakeside Veteran Administration Medical Centers. All data were collected and retrospectively reviewed under institutional review board protocols for these institutions. Carotid revascularization was performed on patients presenting to our institution with either asymptomatic carotid stenosis 80% or symptomatic carotid stenosis 50% as measured by conventional angiography. Preoperative imaging in the form of duplex ultrasonography was performed on all patients. Additional imaging such as computed tomography angiogram (CTA) or magnetic resonance angiography (MRA) was also performed preoperatively in the majority of patients. CAS Procedure All procedures were performed in an operating room angiosuite with either a fixed (V5000; Philips, Eindhoven, The Netherlands) or a mobile (9800 OEC; General Electric, Milwaukee, WI) C-arm fluoroscopy unit. The complete procedural details have been described previously.6,7 Local anesthetic was used in all patients prior to obtaining percutaneous femoral arterial access. Aspirin and clopidogrel were given to patients at least 24 hr prior to the procedure and continued into the 30-day postoperative period. The degree of stenosis was confirmed during the procedure according to the North American Carotid Endarterectomy Trial (NASCET) criteria.8 Systemic heparinization was administered prior to crossing the target lesion to achieve an activated clotting time (ACT) of 250-350 sec.
Annals of Vascular Surgery
Cerebral embolic protection devices (EPDs) were utilized in 95% (292/308) of cases. EPDs were not used in 5% of cases due to lack of device availability early in our experience or an inability to safely deliver the device in subsequent cases. The types of EPDs used included PercuSurge Guardwire (Medtronic Vascular, Santa Rosa, CA), Angioguard (Cordis, Warren, NJ), AccuNet (Guidant, Santa Clara, CA), Filterwire (Boston Scientific, Maple Grove, MN), Emboshield (Abbott Vascular, Redwood City, CA), and Gore Neuro Protection System (W. L. Gore, Flagstaff, AZ). Predilatation and poststent angioplasty were performed with a 4.0 mm and 5.0 mm balloon inflated to nominal pressure, respectively (Gazelle, Boston Scientific). The selfexpanding stents used are listed in Table I. The choice of stents in the patient population was largely dictated by the investigational study in which the patient was enrolled rather than by the patient’s arterial anatomy. However, in the veteran population treated, where the patients are not enrolled in clinical trials, stent choice was dictated by surgeon preference. Follow-Up In the majority of cases, neurological evaluation was performed by a stroke neurologist pre- and postprocedure. Any death or major adverse event occurring within 30 days of the CAS procedure was recorded. A major stroke was defined as a new neurological deficit discovered in the postoperative period that persisted beyond 24 hr and/or increasing the National Institutes of Health Stroke Scale (NIHSS) by 3 points, whereas a minor stroke was defined as a deficit beyond 24 hr without increasing the NIHSS by more than 3 points. Computed tomography (CT) and/or magnetic resonance imaging were performed on all patients with a presumed stroke event. A transient ischemic attack (TIA) was defined as any neurological deficit that resolved within 24 hr after presentation. Permanent neurological deficits were also investigated and confirmed with either follow-up magnetic resonance diffusion-weighted imaging and/or CT of the brain. Duplex ultrasonography (DUS) was performed within 1 month of the procedure and at 6 months, 12 months, and yearly intervals thereafter. Our institutional duplex criteria for significant restenosis have been described.6 All patients with DUS findings consistent with 80% underwent angiography for confirmation and reintervention. The mean follow-up was 18 months (range 1-69). Mean follow-up was 24 and 12 months for the NTS and TS groups, respectively. A total of 22 patients were lost to follow-up.
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Carotid stenting using tapered and nontapered stents
Table I. Carotid stents deployed Stent type
Stent name
n (%)
Nontapered (n ¼ 152)
Precise S.M.A.R.T. Acculink X-Act Vivexx Acculink X-Act Vivexx
130 10 9 2 1 108 33 15
Tapered (n ¼ 156)
(85.5) (6.6) (5.9) (1.3) (0.7) (69.2) (21.2) (9.6)
Statistical Analysis Student’s t-test was used to compare baseline demographics within the patient population. The Fischer exact test was used to compare the 30-day major adverse events of death, stroke, and TIA. The Breslow (Wilcoxon) test was used to evaluate for statistical significance in the incidence of restenosis or occlusion between patients receiving NTS and TS. This test favored early incidence of restenosis and, thus, was more appropriate to examining the data with differing follow-up periods. A Cox regression analysis was performed to evaluate variables other than stent type that may have contributed to the incidence of restenosis. A Martingale-Schoenfeld residuals table was extracted from the data, and a global test for proportional hazard was done to determine if the proportional hazard ratio assumption was not violated. p 0.05 was considered statistically significant for all tests. All statistical tests were performed using STATA 9.2 (StataCorp, College Station, TX).
RESULTS Patients A total of 295 patients were treated with 308 CAS procedures over approximately a 6-year period. A total of 92 (30%) cases were performed for symptomatic carotid occlusive disease. The mean age for the entire group was 71.3 years (±9). A total of 64 patients (21%) were age 80 years or older. Seventy-five percent of the patients were male. The baseline characteristics of the patients are detailed in Table II. Of the total cases, TS were placed in 156 patients and NTS in 152 patients. Overall, the comorbidities of the two cohorts were equally distributed. The only demographic that approached statistical significance was the number of patients treated with ‘‘hostile necks’’ compared to de novo lesions. The hostile neck group included patients who had undergone previous ipsilateral carotid
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endarterectomy (CEA) or external beam neck irradiation (TS 20% [n ¼ 31] vs. NTS 29% [n ¼ 44], p ¼ 0.07) (Table III). Procedural Outcomes The 30-day ipsilateral stroke and death rates were 1.3% and 0.32%, respectively. Included in this number is one patient who experienced bilateral hemispheric strokes. An additional three (1.0%) posterior circulation strokes occurred. There was no statistically significant difference in the 30-day total stroke rates between the TS (3.2%, n ¼ 5) and NTS (1.3%, n ¼ 2) groups ( p ¼ 0.5). Of the total strokes that occurred, four were categorized as major and three were minor. In-Stent Restenosis or Occlusion Mean follow-up for all patients was 18 months. Mean follow-up for the NTS and TS groups was 24 months and 12 months, respectively. The total restenosis or stent occlusion rate was 2.6% (n ¼ 8); all of these events occurred in patients with NTS ( p ¼ 0.03). The assumption of constant hazard proportion was not violated, with the c2 p ¼ 0.276. The average time to restenosis or occlusion was 17.6 months. Two cases of asymptomatic stent occlusion occurred within 6 months of the original CAS procedure; both patients were originally treated for de novo carotid lesions. Six patients developed in-stent stenosis of 80% during follow-up; one patient was symptomatic with a TIA. Of the six restenosis patients, four were categorized as ‘‘hostile neck patients’’ (ipsilateral CEA [n ¼ 1], neck irradiation [n ¼ 2], saphenous vein CCA-to-ICA bypass after previous CEA [n ¼ 1]). Repeat interventions (carotid angioplasty alone [n ¼ 3], angioplasty with stent [n ¼ 3]) were successfully performed on all five patients without any complications. These patients have had no further evidence of restenosis during follow-up.9 Additionally, a post-hoc subgroup analysis revealed significant correlation (c2 ¼ 0.02) for restenosis in hostile necks when separated by TS vs. NTS. However, when looking at de novo lesions, there was no correlation to restenosis by TS vs. NTS. Edge Stenosis Two patients developed discrete stenosis either proximal or distal to the original ICA stent; both of these patients had a history of previous neck irradiation. One patient was found on her 1-year surveillance DUS to have an asymptomatic 90% stenosis proximal to the original NTS. This patient
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Table II. Demographics Variable
Total,n (%)
Tapered,n (%)
Nontapered,n (%)
p
Total procedures Age 80 years Male gender Asymptomatic Symptomatic Hostile neck Hypertension DM COPD ESRD Previous CABG/PTCA Hyperlipidemia Contralateral ICA occlusion Tobacco use
308 64 232 216 92 75 271 90 54 1 111 213 28
156 30 117 108 48 31 136 46 22 1 54 109 10
152 34 115 108 44 44 135 44 32 0 57 104 18
0.5 0.8 0.8 0.8 0.07 0.7 1.0 0.1 1.0 0.6 0.7 0.1
(21) (75) (70) (30) (24) (88) (29) (18) (0.3) (36) (69) (9)
131 (43)
(19) (75) (69) (31) (20) (87) (29) (14) (0.6) (35) (70) (6)
64 (41)
(22) (76) (71) (29) (29) (89) (29) (21) (0) (38) (68) (12)
67 (44)
0.6
DM, diabetes mellitus; COPD, chronic obstructive pulmonary disease; ESRD, end-stage renal disease; CABG/PTCA, coronary artery bypass graft/percutaneous transluminal coronary angioplasty; ICA, internal carotid artery.
Table III. Major adverse events Variable
Total (308),n (%)
Tapered,n (%)
Nontapered,n (%)
p
Death Total stroke
1 7 3 1 3 7 8
1 5 3 1 2 3 0
0 2 0 0 1 4 8
1.0 0.5 0.3 1.0 1.0 0.7 0.03*
Ipsilateral hemisphere Bilateral hemisphere Posterior circulation Total TIA Restenosis or occlusion
(0.3) (2.3) (1) (0.3) (1) (2.3) (2.6)
(0.6) (3.2) (1.9) (0.6) (1.3) (1.9) (0)
(0) (1.3) (0) (0) (0.7) (2.6) (5.3)
*Based on incidence of risk difference from Breslow (Wilcoxon) test.
underwent repeat angioplasty and proximal stent extension without any complications. The other patient was found to have a symptomatic 99% stenosis distal to the original TS at 18 months; he had a known contralateral ICA occlusion and presented with syncopal episodes. On CTA imaging there was evidence of recurrent squamous cell carcinoma encasing the distal ICA resulting in severe stenosis immediately distal to the previously placed stent. This patient underwent repeat angioplasty and stent placement with a good angiographic result and resolution of his syncope.10 He died 7 months after his secondary intervention of metastatic carcinoma.
DISCUSSION Self-expanding stent configuration is increasingly recognized as a possible predictor of both early and late outcomes following CAS.1-3 While cell structure, extent of scaffolding, and composition of the stents have been partially addressed in other studies,
the effects of tapering to accommodate the natural carotid bifurcation have not been analyzed.1-5 Our retrospective review of CAS performed with TS and NTS shows that the early neurological event rates are nearly equivalent between the two groups, yet the incidence of significant restenosis or occlusion is lower after placement of a TS, particularly among patients with prior CEA or external beam neck irradiation. Two primary configurations of nitinol TS are available: (1) conical, represented by Acculink and X-Act (Abbott Vascular), and (2) shouldered, represented by Protege (ev3, Plymouth, MN). In the conical TS there is a gradual increase in the diameter of the stent from distal to proximal, whereas in the shouldered TS there exists a short transition point in the midsegment. On the other hand, NTS configurations are purported to ‘‘self-taper’’ in the transition zone between the ICA and the CCA. To date, it is unknown which is best suited for the natural carotid bifurcation.
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The true incidence of in-stent restenosis following CAS in the long term has yet to be determined. Part of the difficulty in better understanding recurrent stenosis is the lack of a cohesive definition of ‘‘restenosis.’’ Some suggest a definition of 50% narrowing, others 80%, and still others any lesion requiring reintervention for target lesion revacularization.5,9,11 In this report we used the definition of 80%. When taking into account this definition along with asymptomatic occlusions, we discovered a restenosis rate of 2.6% in our entire cohort, and all of these occurred in patients in which NTS were placed. Previous reports have attempted to identify clinical and technical risk factors that put patients at risk for developing restenosis following CAS. Patients with radiation-induced arterial occlusive disease or previous ipsilateral CEA have been reported to be at an increased risk for restenosis following carotid stenting.5,12,13 We have previously compared hostile neck patients to patients with de novo lesions in our series and found no significant difference in restenosis rates during midterm follow-up.9 Within our cohort of patients, our Cox regression model did not reveal any predictor variable that, when combined with stent type, correlated with a higher incidence of restenosis. In fact, the only variable that was significant in relation to incidence of restenosis or occlusion was stent type. Recently, Lal et al.14 found a higher incidence of restenosis among diabetic patients treated with carotid stents. In addition, this group provided a classification system of CAS restenosis which correlates with the long-term prognosis for recurrent narrowing. The pattern of restenosis within the stent may help predict those patients who will require repeat interventions. The mechanism behind restenosis within stented arteries has been investigated extensively in human coronary arteries following percutaneous transluminal coronary angioplasty.6,15 Neointimal hyperplasia is the mechanism attributed to the development of in-stent restenosis.15 The inciting factor for intimal hyperplasia is postulated to be secondary to stretch injury from angioplasty as well as the injury to the internal elastic lamina from stent struts and during stent placement.16,17 Several series that experimented in animal models using stents oversized for the artery or stents with different strut designs found that it was not the oversized stents that incited a hyperplastic response but, rather, injury to the vessel wall during stent placement.15-20 Whether NTS may cause more intimal injury during implantation in the lumen of the ICA due to fracture of the internal elastic lamina in the smaller portion of the distal artery due to excessive oversizing has not
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been elucidated by current human studies in carotid stenting. In order to adequately accommodate CCA vessel wall apposition, NTS are largely oversized for the normal diameter of the ICA. There is nearly a 50% reduction in luminal diameter from the natural taper of the CCA to the ICA. Therefore, with placement of an 8 mm NTS there would be a significant size discrepancy within a normal 5 mm ICA. These types of wall stress forces have been studied in coronary arteries where small arterial diameters necessitate stent overexpansion and aggressive angioplasty to prevent in-stent thrombosis and acute occlusion. The carotid arteries are larger in diameter, and the same requirement of stent overexpansion with angioplasty may not be as essential to prevent postimplantation thrombosis. This arterial overexpansion required with balloon-expandable stents has been eliminated with the advent of nitinol selfexpanding stents. During the placement of all stent types we routinely perform pre- and postdilation with angioplasty balloons to an approximately nominal pressure of 6-8 atmospheres; excessive poststent angioplasty may cause intimal injury, contributing to the higher incidence of restenosis, and is another factor that may contribute to restenosis. However, aggressive poststent angioplasty was not employed in our series of patients, thereby implicating stent stretch as a prominent factor responsible for inciting late neointimal proliferation. In the setting of intimal injury and hyperplasia, the artery also undergoes a remodeling process. There is DUS evidence that luminal diameters increase over time after carotid stent placement and can actually lead to an increasing luminal diameter over time, particularly at the point of plaque burden.21,22 Restenosis from neointimal hyperplasia balanced by this positive arterial remodeling is required to prevent luminal narrowing with CAS. Similar findings of stent oversizing and its effect on luminal diameter have revealed that stent oversizing may not lead to neointimal hyperplasia in larger-caliber arteries.20,23 The next logical step is to identify which stent type and shape is best utilized with certain types of atherosclerotic carotid plaques. Further pre- and poststent imaging, clinical evaluation, and DUS surveillance are required to determine the fate of the carotid artery in the long term after stent placement. In addition, correlating the pattern of in-stent stenosis as it relates to stent design may predict what stent morphology is best suited to carotid lesions. The occurrence of stent edge stenosis in our series suggests that the original stent placement either did not exclude the entirety of the atherosclerotic lesion or accelerated the progression of remaining disease secondary to changes in wall stress and arterial
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luminal flow velocities.24 Interestingly, both instances of stent edge lesions occurred in patients with previous neck irradiation. Radiation arteritis is known to affect long segments of the artery, and the disease progress affects the periadvential tissues, resulting in fibrosis and stenosis that continue to progress over time. It is in these patients that CEA is discouraged for the reasons of postoperative wound complications and the potential for nerve injury; however, repeat endovascular interventions may be required for the treatment of additional lesions or, as some suggest, for in-stent restenosis. In addition, on angiographic imaging the extent of the disease within the artery may not be clear or whether multiple stents at the initial procedure may be required to treat this patient population. The major limitations of this retrospective review are a paucity of long-term follow-up among the TS group, resulting in a potential for lead time bias and perhaps the weighting of hostile neck patients in the NTS group. However, even with these considerations, no restenosis has been seen in the TS group over a mean follow-up period of 12 months. While this may seem short, the highest incidence of CAS restenosis typically occurs within the first 12-18 months following stent placement. In addition, when analyzing the follow-up data in relation to the incidence of restenosis, we found a statistically significant difference between TS and NTS. In regard to the weighting of hostile neck patients in the NTS group, we have previously reported on the lack of significant CAS restenosis between de novo lesions and hostile lesions.9 Despite these shortcomings, these early findings are compelling enough to warrant a more thorough examination of the late effects of stent design as it relates to extreme oversizing and restenosis.
CONCLUSIONS Use of TS or NTS designs for CAS in this group of patients did not result in a difference in periprocedural neurological events but brings forth the question of whether differing stent designs alter the outcomes of in-stent restenosis with nitinol self-expanding stents following CAS. The development of in-stent stenosis is related to intimal hyperplasia, which is caused by stretching and damage to the arterial intima with insertion and angioplasty, and is not necessarily related to stent oversizing. There may be factors associated with stent placement, as well as stent configuration within the artery, that stimulate a neointimal hyperplastic response, leading to restenosis over time. Tandem lesions may develop in
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follow-up and are likely to be caused by progression of atherosclerotic disease or lack of adequate treatment at the time of the original intervention. Surveillance DUS is required to monitor for evidence of restenosis. Further follow-up and research is required to determine the long-term durability of the use of differing stent types for the treatment of carotid occlusive disease. REFERENCES 1. Bosiers M, de Donato G, Deloose K, et al. Does free cell area influence the outcome in carotid artery stenting? Eur. J Vasc Endovasc Surg 2007;33:135-142. 2. Hart JP, Peeters P, Verbist J, Deloose K, Bosiers M. Do device characteristics impact outcome in carotid artery stenting? J Vasc Surg 2006;44:725-730. 3. Ischinger TA. Carotid stenting: which stent for which lesion? J Interv Cardiol 2001;14:617-623. 4. Lal BK, Hobson RW, 2nd, Goldstein J, et al. In-stent recurrent stenosis after carotid artery stenting: life table analysis and clinical relevance. J Vasc Surg 2003;38:1162-1169. 5. Skelly CL, Gallagher K, Fairman RM, et al. Risk factors for restenosis after carotid artery angioplasty and stenting. J Vasc Surg 2006;44:1010-1015. 6. Eskandari MK, Longo GM, Matsumura JS, et al. Carotid stenting done exclusively by vascular surgeons: first 175 cases. Ann Surg 2005;242:431-438. 7. Peterson BG, Longo GM, Kibbe MR, et al. Duplex ultrasound remains a reliable test even after carotid stenting. Ann Vasc Surg 2005;19:793-797. 8. Barnett HJ, Taylor DW, Eliasziw M, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N. Engl. J Med 1998;339: 1415-1425. 9. Eskandari MK, Brown KE, Kibbe MR, Morasch MD, Matsumura JS, Pearce WH. Restenosis after carotid stent placement in patients with prior neck irradiation or endarterectomy. J Vasc Interv Radiol 2007;18:1368-1374. 10. Adel JG, Morasch MD, Eskandari MK. An uncommon cause for carotid artery stenosis after carotid stenting. Ann. Vasc. Surg 2008;13. doi:10.1016/j.avsg.2008.05.017. 11. Groschel K, Riecker A, Schulz JB, Ernemann U, Kastrup A. Systematic review of early recurrent stenosis after carotid angioplasty and stenting. Stroke 2005;36:367-373. 12. Setacci C, Pula G, Baldi I, et al. Determinants of in-stent restenosis after carotid angioplasty: a case-control study. J Endovasc Ther 2003;10:1031-1038. 13. Zhou W, Lin PH, Bush RL, et al. Management of in-stent restenosis after carotid artery stenting in high-risk patients. J Vasc Surg 2006;43:305-312. 14. Lal BK, Kaperonis EA, Cuadra S, Kapadia I, Hobson RW, 2nd. Patterns of in-stent restenosis after carotid artery stenting: classification and implications for long-term outcome. J Vasc Surg 2007;46:833-840. 15. Schwartz RS, Huber KC, Murphy JG, et al. Restenosis and the proportional neointimal response to coronary artery injury: results in a porcine model. J Am Coll Cardiol 1992;19:267-274. 16. Hoffmann R, Mintz GS, Mehran R, et al. Tissue proliferation within and surrounding Palmaz-Schatz stents is dependent on the aggressiveness of stent implantation technique. Am J Cardiol 1999;83:1170-1174.
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17. Sullivan TM, Ainsworth SD, Langan EM, et al. Effect of endovascular stent strut geometry on vascular injury, myointimal hyperplasia, and restenosis. J Vasc Surg 2002;36:143-149. 18. Ballyk PD. Intramural stress increases exponentially with stent diameter: a stress threshold for neointimal hyperplasia. J Vasc Interv Radiol 2006;17:1139-1145. 19. Kirsch EC, Khangure MS, Morling P, York TJ, McAuliffe W. Oversizing of self-expanding stents: influence on the development of neointimal hyperplasia of the carotid artery in a canine model. A.J.N.R. Am J Neuroradiol 2002;23:121-127. 20. Piamsomboon C, Roubin GS, Liu MW, et al. Relationship between oversizing of self-expanding stents and late loss index in carotid stenting. Cathet Cardiovasc Diagn 1998;45: 139-143.
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21. Clark DJ, Lessio S, O’Donoghue M, Tsalamandris C, Schainfeld R, Rosenfield K. Mechanisms and predictors of carotid artery stent restenosis: a serial intravascular ultrasound study. J Am Coll Cardiol 2006;47:2390-2396. 22. Willfort-Ehringer A, Ahmadi R, Gruber D, et al. Arterial remodeling and hemodynamics in carotid stents: a prospective duplex ultrasound study over 2 years. J Vasc Surg 2004;39:728-734. 23. Puato M, Piergentili C, Zanardo M, et al. Vascular remodeling after carotid artery stenting. Angiology 2007;58: 565-571. 24. Liu MW, Roubin GS, King SB, 3rd. Restenosis after coronary angioplasty. Potential biologic determinants and role of intimal hyperplasia. Circulation 1989;79: 1374-1387.
Self-expanding stent design systems for carotid artery stenting (CAS) have morphed from nontapered (NTS) to tapered (TS); however, the impact of this change is unknown. We reviewed the outcomes of CAS with these two broad categories of stents in a single-center retrospective review of 308 CAS procedures from May 2001 to July 2007. Nitinol self-expanding TS or NTS coupled with cerebral embolic protection devices were used to treat extracranial carotid occlusive disease. Data analysis included demographics, procedural records, duplex exams, and conventional arteriography. Mean follow-up was 18 months (range 1e69). Restenosis was defined as 80% in-stent carotid artery stenosis by angiography. The mean age of the entire cohort was 71.3 years (75% men, 25% women). Of the 308 cases, 233 were de novo lesions and 75 had a prior ipsilateral carotid endarterectomy (n ¼ 44) or external beam radiation exposure (n ¼ 31). Preprocedure neurological symptoms were present in 30% of patients. TS were used in 156 procedures and NTS in 152 procedures. The 30-day ipsilateral stroke and death rates were 1.3% and 0.3%, respectively. An additional three (1.0%) posterior circulation strokes occurred. There was no statistically significant difference in the 30-day total stroke rates between TS (3.2%, n ¼ 5) and NTS (1.3%, n ¼ 2) ( p ¼ 0.5). At midterm follow-up, restenosis or asymptomatic occlusion was detected in eight cases (2.6%). All occurred in arteries treated with NTS, and this was statistically different when compared to arteries treated with TS ( p ¼ 0.03). Furthermore, a post-hoc subgroup analysis revealed significant correlation (c2 ¼ 0.02) for restenosis in ‘‘hostile necks’’ when separated by TS vs. NTS. Early CAS outcomes between TS and NTS are comparable. In contrast, self-expanding nitinol TS may have a lower incidence of significant restenosis or asymptomatic occlusion when compared to NTS.
INTRODUCTION
Presented at the 31st Annual Midwestern Vascular Surgical Society Meeting, September 7, 2007, Chicago, IL. Mark K. Eskandari serves as a consultant for Cook, Cordis, Abbott Vascular Devices, Medtronic, Boston Scientific, Terumo, and W. L. Gore & Associates, Inc. 1
Division of Vascular Surgery, Northwestern University, Chicago,
IL. 2 Department of Radiology, Northwestern University, Chicago, IL. Correspondence to: Mark K. Eskandari, MD, 676 North St. Clair, Suite 650, Chicago, IL 60611, USA, E-mail: [email protected]
Ann Vasc Surg 2009; 23: 439-445 DOI: 10.1016/j.avsg.2008.11.007 Ó Annals of Vascular Surgery Inc. Published online: January 6, 2009
Outcomes of carotid artery stenting (CAS) are highly dependent on experience, judgment, and equipment as well as patient risk factors and plaque characteristics.1-5 In particular, self-expanding stent configuration is increasingly recognized as a possible predictor of both early and late outcomes following CAS.1-3 Cell structure, extent of scaffolding, and composition of the stents are part of the equation, yet changes from a straight to tapered stent to accommodate the anatomic carotid bifurcation might also have clinical consequences. This becomes important since, in the majority of cases, stent placement crosses the external carotid artery (ECA) orifice and needs to be well apposed to both the common carotid artery (CCA) and the internal 439
440 Brown et al.
carotid artery (ICA) lumens. Many nontapered stents (NTS) are promoted as ‘‘self-tapering,’’ yet due to the natural size mismatch between the ICA and CCA, extreme oversizing in the ICA is a frequent occurrence after CAS. The unfavorable effects of excessive oversizing in the ICA are increased chronic outward radial force and decreased free cell area in the ICA. Tapered stent (TS) design systems attempt to minimize these factors. Although the development of TS is aesthetically appealing, the clinical impact of this change remains to be determined. The aim of this study is to retrospectively analyze the outcomes of CAS using TS and NTS, with regard to neurological events and restenosis.
METHODS Patients From May 2001 to July 2007 a total of 308 primary CAS procedures were performed on a total of 295 patients at Northwestern Memorial Hospital and the Jesse Brown or Lakeside Veteran Administration Medical Centers. All data were collected and retrospectively reviewed under institutional review board protocols for these institutions. Carotid revascularization was performed on patients presenting to our institution with either asymptomatic carotid stenosis 80% or symptomatic carotid stenosis 50% as measured by conventional angiography. Preoperative imaging in the form of duplex ultrasonography was performed on all patients. Additional imaging such as computed tomography angiogram (CTA) or magnetic resonance angiography (MRA) was also performed preoperatively in the majority of patients. CAS Procedure All procedures were performed in an operating room angiosuite with either a fixed (V5000; Philips, Eindhoven, The Netherlands) or a mobile (9800 OEC; General Electric, Milwaukee, WI) C-arm fluoroscopy unit. The complete procedural details have been described previously.6,7 Local anesthetic was used in all patients prior to obtaining percutaneous femoral arterial access. Aspirin and clopidogrel were given to patients at least 24 hr prior to the procedure and continued into the 30-day postoperative period. The degree of stenosis was confirmed during the procedure according to the North American Carotid Endarterectomy Trial (NASCET) criteria.8 Systemic heparinization was administered prior to crossing the target lesion to achieve an activated clotting time (ACT) of 250-350 sec.
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Cerebral embolic protection devices (EPDs) were utilized in 95% (292/308) of cases. EPDs were not used in 5% of cases due to lack of device availability early in our experience or an inability to safely deliver the device in subsequent cases. The types of EPDs used included PercuSurge Guardwire (Medtronic Vascular, Santa Rosa, CA), Angioguard (Cordis, Warren, NJ), AccuNet (Guidant, Santa Clara, CA), Filterwire (Boston Scientific, Maple Grove, MN), Emboshield (Abbott Vascular, Redwood City, CA), and Gore Neuro Protection System (W. L. Gore, Flagstaff, AZ). Predilatation and poststent angioplasty were performed with a 4.0 mm and 5.0 mm balloon inflated to nominal pressure, respectively (Gazelle, Boston Scientific). The selfexpanding stents used are listed in Table I. The choice of stents in the patient population was largely dictated by the investigational study in which the patient was enrolled rather than by the patient’s arterial anatomy. However, in the veteran population treated, where the patients are not enrolled in clinical trials, stent choice was dictated by surgeon preference. Follow-Up In the majority of cases, neurological evaluation was performed by a stroke neurologist pre- and postprocedure. Any death or major adverse event occurring within 30 days of the CAS procedure was recorded. A major stroke was defined as a new neurological deficit discovered in the postoperative period that persisted beyond 24 hr and/or increasing the National Institutes of Health Stroke Scale (NIHSS) by 3 points, whereas a minor stroke was defined as a deficit beyond 24 hr without increasing the NIHSS by more than 3 points. Computed tomography (CT) and/or magnetic resonance imaging were performed on all patients with a presumed stroke event. A transient ischemic attack (TIA) was defined as any neurological deficit that resolved within 24 hr after presentation. Permanent neurological deficits were also investigated and confirmed with either follow-up magnetic resonance diffusion-weighted imaging and/or CT of the brain. Duplex ultrasonography (DUS) was performed within 1 month of the procedure and at 6 months, 12 months, and yearly intervals thereafter. Our institutional duplex criteria for significant restenosis have been described.6 All patients with DUS findings consistent with 80% underwent angiography for confirmation and reintervention. The mean follow-up was 18 months (range 1-69). Mean follow-up was 24 and 12 months for the NTS and TS groups, respectively. A total of 22 patients were lost to follow-up.
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Carotid stenting using tapered and nontapered stents
Table I. Carotid stents deployed Stent type
Stent name
n (%)
Nontapered (n ¼ 152)
Precise S.M.A.R.T. Acculink X-Act Vivexx Acculink X-Act Vivexx
130 10 9 2 1 108 33 15
Tapered (n ¼ 156)
(85.5) (6.6) (5.9) (1.3) (0.7) (69.2) (21.2) (9.6)
Statistical Analysis Student’s t-test was used to compare baseline demographics within the patient population. The Fischer exact test was used to compare the 30-day major adverse events of death, stroke, and TIA. The Breslow (Wilcoxon) test was used to evaluate for statistical significance in the incidence of restenosis or occlusion between patients receiving NTS and TS. This test favored early incidence of restenosis and, thus, was more appropriate to examining the data with differing follow-up periods. A Cox regression analysis was performed to evaluate variables other than stent type that may have contributed to the incidence of restenosis. A Martingale-Schoenfeld residuals table was extracted from the data, and a global test for proportional hazard was done to determine if the proportional hazard ratio assumption was not violated. p 0.05 was considered statistically significant for all tests. All statistical tests were performed using STATA 9.2 (StataCorp, College Station, TX).
RESULTS Patients A total of 295 patients were treated with 308 CAS procedures over approximately a 6-year period. A total of 92 (30%) cases were performed for symptomatic carotid occlusive disease. The mean age for the entire group was 71.3 years (±9). A total of 64 patients (21%) were age 80 years or older. Seventy-five percent of the patients were male. The baseline characteristics of the patients are detailed in Table II. Of the total cases, TS were placed in 156 patients and NTS in 152 patients. Overall, the comorbidities of the two cohorts were equally distributed. The only demographic that approached statistical significance was the number of patients treated with ‘‘hostile necks’’ compared to de novo lesions. The hostile neck group included patients who had undergone previous ipsilateral carotid
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endarterectomy (CEA) or external beam neck irradiation (TS 20% [n ¼ 31] vs. NTS 29% [n ¼ 44], p ¼ 0.07) (Table III). Procedural Outcomes The 30-day ipsilateral stroke and death rates were 1.3% and 0.32%, respectively. Included in this number is one patient who experienced bilateral hemispheric strokes. An additional three (1.0%) posterior circulation strokes occurred. There was no statistically significant difference in the 30-day total stroke rates between the TS (3.2%, n ¼ 5) and NTS (1.3%, n ¼ 2) groups ( p ¼ 0.5). Of the total strokes that occurred, four were categorized as major and three were minor. In-Stent Restenosis or Occlusion Mean follow-up for all patients was 18 months. Mean follow-up for the NTS and TS groups was 24 months and 12 months, respectively. The total restenosis or stent occlusion rate was 2.6% (n ¼ 8); all of these events occurred in patients with NTS ( p ¼ 0.03). The assumption of constant hazard proportion was not violated, with the c2 p ¼ 0.276. The average time to restenosis or occlusion was 17.6 months. Two cases of asymptomatic stent occlusion occurred within 6 months of the original CAS procedure; both patients were originally treated for de novo carotid lesions. Six patients developed in-stent stenosis of 80% during follow-up; one patient was symptomatic with a TIA. Of the six restenosis patients, four were categorized as ‘‘hostile neck patients’’ (ipsilateral CEA [n ¼ 1], neck irradiation [n ¼ 2], saphenous vein CCA-to-ICA bypass after previous CEA [n ¼ 1]). Repeat interventions (carotid angioplasty alone [n ¼ 3], angioplasty with stent [n ¼ 3]) were successfully performed on all five patients without any complications. These patients have had no further evidence of restenosis during follow-up.9 Additionally, a post-hoc subgroup analysis revealed significant correlation (c2 ¼ 0.02) for restenosis in hostile necks when separated by TS vs. NTS. However, when looking at de novo lesions, there was no correlation to restenosis by TS vs. NTS. Edge Stenosis Two patients developed discrete stenosis either proximal or distal to the original ICA stent; both of these patients had a history of previous neck irradiation. One patient was found on her 1-year surveillance DUS to have an asymptomatic 90% stenosis proximal to the original NTS. This patient
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Table II. Demographics Variable
Total,n (%)
Tapered,n (%)
Nontapered,n (%)
p
Total procedures Age 80 years Male gender Asymptomatic Symptomatic Hostile neck Hypertension DM COPD ESRD Previous CABG/PTCA Hyperlipidemia Contralateral ICA occlusion Tobacco use
308 64 232 216 92 75 271 90 54 1 111 213 28
156 30 117 108 48 31 136 46 22 1 54 109 10
152 34 115 108 44 44 135 44 32 0 57 104 18
0.5 0.8 0.8 0.8 0.07 0.7 1.0 0.1 1.0 0.6 0.7 0.1
(21) (75) (70) (30) (24) (88) (29) (18) (0.3) (36) (69) (9)
131 (43)
(19) (75) (69) (31) (20) (87) (29) (14) (0.6) (35) (70) (6)
64 (41)
(22) (76) (71) (29) (29) (89) (29) (21) (0) (38) (68) (12)
67 (44)
0.6
DM, diabetes mellitus; COPD, chronic obstructive pulmonary disease; ESRD, end-stage renal disease; CABG/PTCA, coronary artery bypass graft/percutaneous transluminal coronary angioplasty; ICA, internal carotid artery.
Table III. Major adverse events Variable
Total (308),n (%)
Tapered,n (%)
Nontapered,n (%)
p
Death Total stroke
1 7 3 1 3 7 8
1 5 3 1 2 3 0
0 2 0 0 1 4 8
1.0 0.5 0.3 1.0 1.0 0.7 0.03*
Ipsilateral hemisphere Bilateral hemisphere Posterior circulation Total TIA Restenosis or occlusion
(0.3) (2.3) (1) (0.3) (1) (2.3) (2.6)
(0.6) (3.2) (1.9) (0.6) (1.3) (1.9) (0)
(0) (1.3) (0) (0) (0.7) (2.6) (5.3)
*Based on incidence of risk difference from Breslow (Wilcoxon) test.
underwent repeat angioplasty and proximal stent extension without any complications. The other patient was found to have a symptomatic 99% stenosis distal to the original TS at 18 months; he had a known contralateral ICA occlusion and presented with syncopal episodes. On CTA imaging there was evidence of recurrent squamous cell carcinoma encasing the distal ICA resulting in severe stenosis immediately distal to the previously placed stent. This patient underwent repeat angioplasty and stent placement with a good angiographic result and resolution of his syncope.10 He died 7 months after his secondary intervention of metastatic carcinoma.
DISCUSSION Self-expanding stent configuration is increasingly recognized as a possible predictor of both early and late outcomes following CAS.1-3 While cell structure, extent of scaffolding, and composition of the stents have been partially addressed in other studies,
the effects of tapering to accommodate the natural carotid bifurcation have not been analyzed.1-5 Our retrospective review of CAS performed with TS and NTS shows that the early neurological event rates are nearly equivalent between the two groups, yet the incidence of significant restenosis or occlusion is lower after placement of a TS, particularly among patients with prior CEA or external beam neck irradiation. Two primary configurations of nitinol TS are available: (1) conical, represented by Acculink and X-Act (Abbott Vascular), and (2) shouldered, represented by Protege (ev3, Plymouth, MN). In the conical TS there is a gradual increase in the diameter of the stent from distal to proximal, whereas in the shouldered TS there exists a short transition point in the midsegment. On the other hand, NTS configurations are purported to ‘‘self-taper’’ in the transition zone between the ICA and the CCA. To date, it is unknown which is best suited for the natural carotid bifurcation.
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The true incidence of in-stent restenosis following CAS in the long term has yet to be determined. Part of the difficulty in better understanding recurrent stenosis is the lack of a cohesive definition of ‘‘restenosis.’’ Some suggest a definition of 50% narrowing, others 80%, and still others any lesion requiring reintervention for target lesion revacularization.5,9,11 In this report we used the definition of 80%. When taking into account this definition along with asymptomatic occlusions, we discovered a restenosis rate of 2.6% in our entire cohort, and all of these occurred in patients in which NTS were placed. Previous reports have attempted to identify clinical and technical risk factors that put patients at risk for developing restenosis following CAS. Patients with radiation-induced arterial occlusive disease or previous ipsilateral CEA have been reported to be at an increased risk for restenosis following carotid stenting.5,12,13 We have previously compared hostile neck patients to patients with de novo lesions in our series and found no significant difference in restenosis rates during midterm follow-up.9 Within our cohort of patients, our Cox regression model did not reveal any predictor variable that, when combined with stent type, correlated with a higher incidence of restenosis. In fact, the only variable that was significant in relation to incidence of restenosis or occlusion was stent type. Recently, Lal et al.14 found a higher incidence of restenosis among diabetic patients treated with carotid stents. In addition, this group provided a classification system of CAS restenosis which correlates with the long-term prognosis for recurrent narrowing. The pattern of restenosis within the stent may help predict those patients who will require repeat interventions. The mechanism behind restenosis within stented arteries has been investigated extensively in human coronary arteries following percutaneous transluminal coronary angioplasty.6,15 Neointimal hyperplasia is the mechanism attributed to the development of in-stent restenosis.15 The inciting factor for intimal hyperplasia is postulated to be secondary to stretch injury from angioplasty as well as the injury to the internal elastic lamina from stent struts and during stent placement.16,17 Several series that experimented in animal models using stents oversized for the artery or stents with different strut designs found that it was not the oversized stents that incited a hyperplastic response but, rather, injury to the vessel wall during stent placement.15-20 Whether NTS may cause more intimal injury during implantation in the lumen of the ICA due to fracture of the internal elastic lamina in the smaller portion of the distal artery due to excessive oversizing has not
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been elucidated by current human studies in carotid stenting. In order to adequately accommodate CCA vessel wall apposition, NTS are largely oversized for the normal diameter of the ICA. There is nearly a 50% reduction in luminal diameter from the natural taper of the CCA to the ICA. Therefore, with placement of an 8 mm NTS there would be a significant size discrepancy within a normal 5 mm ICA. These types of wall stress forces have been studied in coronary arteries where small arterial diameters necessitate stent overexpansion and aggressive angioplasty to prevent in-stent thrombosis and acute occlusion. The carotid arteries are larger in diameter, and the same requirement of stent overexpansion with angioplasty may not be as essential to prevent postimplantation thrombosis. This arterial overexpansion required with balloon-expandable stents has been eliminated with the advent of nitinol selfexpanding stents. During the placement of all stent types we routinely perform pre- and postdilation with angioplasty balloons to an approximately nominal pressure of 6-8 atmospheres; excessive poststent angioplasty may cause intimal injury, contributing to the higher incidence of restenosis, and is another factor that may contribute to restenosis. However, aggressive poststent angioplasty was not employed in our series of patients, thereby implicating stent stretch as a prominent factor responsible for inciting late neointimal proliferation. In the setting of intimal injury and hyperplasia, the artery also undergoes a remodeling process. There is DUS evidence that luminal diameters increase over time after carotid stent placement and can actually lead to an increasing luminal diameter over time, particularly at the point of plaque burden.21,22 Restenosis from neointimal hyperplasia balanced by this positive arterial remodeling is required to prevent luminal narrowing with CAS. Similar findings of stent oversizing and its effect on luminal diameter have revealed that stent oversizing may not lead to neointimal hyperplasia in larger-caliber arteries.20,23 The next logical step is to identify which stent type and shape is best utilized with certain types of atherosclerotic carotid plaques. Further pre- and poststent imaging, clinical evaluation, and DUS surveillance are required to determine the fate of the carotid artery in the long term after stent placement. In addition, correlating the pattern of in-stent stenosis as it relates to stent design may predict what stent morphology is best suited to carotid lesions. The occurrence of stent edge stenosis in our series suggests that the original stent placement either did not exclude the entirety of the atherosclerotic lesion or accelerated the progression of remaining disease secondary to changes in wall stress and arterial
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luminal flow velocities.24 Interestingly, both instances of stent edge lesions occurred in patients with previous neck irradiation. Radiation arteritis is known to affect long segments of the artery, and the disease progress affects the periadvential tissues, resulting in fibrosis and stenosis that continue to progress over time. It is in these patients that CEA is discouraged for the reasons of postoperative wound complications and the potential for nerve injury; however, repeat endovascular interventions may be required for the treatment of additional lesions or, as some suggest, for in-stent restenosis. In addition, on angiographic imaging the extent of the disease within the artery may not be clear or whether multiple stents at the initial procedure may be required to treat this patient population. The major limitations of this retrospective review are a paucity of long-term follow-up among the TS group, resulting in a potential for lead time bias and perhaps the weighting of hostile neck patients in the NTS group. However, even with these considerations, no restenosis has been seen in the TS group over a mean follow-up period of 12 months. While this may seem short, the highest incidence of CAS restenosis typically occurs within the first 12-18 months following stent placement. In addition, when analyzing the follow-up data in relation to the incidence of restenosis, we found a statistically significant difference between TS and NTS. In regard to the weighting of hostile neck patients in the NTS group, we have previously reported on the lack of significant CAS restenosis between de novo lesions and hostile lesions.9 Despite these shortcomings, these early findings are compelling enough to warrant a more thorough examination of the late effects of stent design as it relates to extreme oversizing and restenosis.
CONCLUSIONS Use of TS or NTS designs for CAS in this group of patients did not result in a difference in periprocedural neurological events but brings forth the question of whether differing stent designs alter the outcomes of in-stent restenosis with nitinol self-expanding stents following CAS. The development of in-stent stenosis is related to intimal hyperplasia, which is caused by stretching and damage to the arterial intima with insertion and angioplasty, and is not necessarily related to stent oversizing. There may be factors associated with stent placement, as well as stent configuration within the artery, that stimulate a neointimal hyperplastic response, leading to restenosis over time. Tandem lesions may develop in
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follow-up and are likely to be caused by progression of atherosclerotic disease or lack of adequate treatment at the time of the original intervention. Surveillance DUS is required to monitor for evidence of restenosis. Further follow-up and research is required to determine the long-term durability of the use of differing stent types for the treatment of carotid occlusive disease. REFERENCES 1. Bosiers M, de Donato G, Deloose K, et al. Does free cell area influence the outcome in carotid artery stenting? Eur. J Vasc Endovasc Surg 2007;33:135-142. 2. Hart JP, Peeters P, Verbist J, Deloose K, Bosiers M. Do device characteristics impact outcome in carotid artery stenting? J Vasc Surg 2006;44:725-730. 3. Ischinger TA. Carotid stenting: which stent for which lesion? J Interv Cardiol 2001;14:617-623. 4. Lal BK, Hobson RW, 2nd, Goldstein J, et al. In-stent recurrent stenosis after carotid artery stenting: life table analysis and clinical relevance. J Vasc Surg 2003;38:1162-1169. 5. Skelly CL, Gallagher K, Fairman RM, et al. Risk factors for restenosis after carotid artery angioplasty and stenting. J Vasc Surg 2006;44:1010-1015. 6. Eskandari MK, Longo GM, Matsumura JS, et al. Carotid stenting done exclusively by vascular surgeons: first 175 cases. Ann Surg 2005;242:431-438. 7. Peterson BG, Longo GM, Kibbe MR, et al. Duplex ultrasound remains a reliable test even after carotid stenting. Ann Vasc Surg 2005;19:793-797. 8. Barnett HJ, Taylor DW, Eliasziw M, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N. Engl. J Med 1998;339: 1415-1425. 9. Eskandari MK, Brown KE, Kibbe MR, Morasch MD, Matsumura JS, Pearce WH. Restenosis after carotid stent placement in patients with prior neck irradiation or endarterectomy. J Vasc Interv Radiol 2007;18:1368-1374. 10. Adel JG, Morasch MD, Eskandari MK. An uncommon cause for carotid artery stenosis after carotid stenting. Ann. Vasc. Surg 2008;13. doi:10.1016/j.avsg.2008.05.017. 11. Groschel K, Riecker A, Schulz JB, Ernemann U, Kastrup A. Systematic review of early recurrent stenosis after carotid angioplasty and stenting. Stroke 2005;36:367-373. 12. Setacci C, Pula G, Baldi I, et al. Determinants of in-stent restenosis after carotid angioplasty: a case-control study. J Endovasc Ther 2003;10:1031-1038. 13. Zhou W, Lin PH, Bush RL, et al. Management of in-stent restenosis after carotid artery stenting in high-risk patients. J Vasc Surg 2006;43:305-312. 14. Lal BK, Kaperonis EA, Cuadra S, Kapadia I, Hobson RW, 2nd. Patterns of in-stent restenosis after carotid artery stenting: classification and implications for long-term outcome. J Vasc Surg 2007;46:833-840. 15. Schwartz RS, Huber KC, Murphy JG, et al. Restenosis and the proportional neointimal response to coronary artery injury: results in a porcine model. J Am Coll Cardiol 1992;19:267-274. 16. Hoffmann R, Mintz GS, Mehran R, et al. Tissue proliferation within and surrounding Palmaz-Schatz stents is dependent on the aggressiveness of stent implantation technique. Am J Cardiol 1999;83:1170-1174.
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17. Sullivan TM, Ainsworth SD, Langan EM, et al. Effect of endovascular stent strut geometry on vascular injury, myointimal hyperplasia, and restenosis. J Vasc Surg 2002;36:143-149. 18. Ballyk PD. Intramural stress increases exponentially with stent diameter: a stress threshold for neointimal hyperplasia. J Vasc Interv Radiol 2006;17:1139-1145. 19. Kirsch EC, Khangure MS, Morling P, York TJ, McAuliffe W. Oversizing of self-expanding stents: influence on the development of neointimal hyperplasia of the carotid artery in a canine model. A.J.N.R. Am J Neuroradiol 2002;23:121-127. 20. Piamsomboon C, Roubin GS, Liu MW, et al. Relationship between oversizing of self-expanding stents and late loss index in carotid stenting. Cathet Cardiovasc Diagn 1998;45: 139-143.
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21. Clark DJ, Lessio S, O’Donoghue M, Tsalamandris C, Schainfeld R, Rosenfield K. Mechanisms and predictors of carotid artery stent restenosis: a serial intravascular ultrasound study. J Am Coll Cardiol 2006;47:2390-2396. 22. Willfort-Ehringer A, Ahmadi R, Gruber D, et al. Arterial remodeling and hemodynamics in carotid stents: a prospective duplex ultrasound study over 2 years. J Vasc Surg 2004;39:728-734. 23. Puato M, Piergentili C, Zanardo M, et al. Vascular remodeling after carotid artery stenting. Angiology 2007;58: 565-571. 24. Liu MW, Roubin GS, King SB, 3rd. Restenosis after coronary angioplasty. Potential biologic determinants and role of intimal hyperplasia. Circulation 1989;79: 1374-1387.