Predictors of midterm high-grade restenosis after carotid revascularization in a multicenter national database

From the Society for Vascular Surgery

Predictors of midterm high-grade restenosis after carotid revascularization in a multicenter national database Hanaa Dakour-Aridi, MD,a Asma Mathlouthi, MD,a Satinderjit Locham, MD,a Philip Goodney, MD,b Marc L. Schermerhorn, MD,c and Mahmoud B. Malas, MD,a La Jolla, Calif; Lebanon, NH; and Boston, Mass

ABSTRACT Background: Restenosis after carotid revascularization is clinically challenging. Several studies have looked into the management of recurrent restenosis; however, studies looking into factors associated with restenosis are limited. This study evaluated the predictors of restenosis after carotid artery stenting (CAS) and carotid endarterectomy (CEA) using a large national database. Methods: Patients undergoing CEA or CAS in the Vascular Quality Initiative data set (2003-2016) were analyzed. Patients with no follow-up (33%) and those who had prior ipsilateral CEA or CAS were excluded. Significant restenosis was defined as $70% diameter-reducing stenosis, target artery occlusion or peak systolic velocity $300 cm/s, or repeated revascularization. Kaplan-Meier survival analysis and bootstrapped Cox regression models with stepwise forward and backward selection were used. Results: A total of 35,720 procedures were included (CEA, 31,329; CAS, 4391). No significant difference in restenosis rates was seen between CEA and CAS at 2 years (7.7% vs 9.4% [P ¼ .09]; hazard ratio [HR], 0.99; 95% confidence interval [CI], 0.79-1.25; P ¼ .97). However, after adjustment for age, sex, and symptomatic status at the time of the index operation, CAS patients who had postoperative restenosis were more likely to have a symptomatic presentation (odds ratio, 2.2; 95% CI, 1.2-4.0; P ¼ .01) and to undergo repeated revascularization at 2 years (HR, 1.75; 95% CI, 1.3-2.4; P < .001) compared with patients who had restenosis after CEA. Predictors of restenosis after CAS included a common carotid artery lesion (HR, 1.65; 95% CI,1.06-2.57; P ¼ .03), whereas age (HR, 0.91; 95% CI, 0.84-0.99; P ¼ .03) and dilation after stent placement (HR, 0.53; 95% CI, 0.39-0.72; P < .001) were associated with decreased restenosis at 2 years. Predictors of restenosis after CEA included female sex (HR, 1.55; 95% CI, 1.38-1.74; P < .001), prior neck irradiation (HR, 2.35; 95% CI, 1.66-3.30; P < .001), and prior bypass surgery (HR, 1.29; 95% CI, 1.01-1.65; P ¼ .04). On the other hand, factors associated with decreased restenosis after CEA included age (HR, 0.95; 95% CI, 0.92-0.98; P < .001), black race (HR, 0.57; 95% CI, 0.37-0.89; P ¼ .01), patching (HR, 0.61; 95% CI, 0.47-0.79; P < .001), and completion imaging (HR, 0.70; 95% CI, 0.52-0.95; P ¼ .02). Conclusions: Our results show no significant difference in restenosis rates at 2 years between CEA and CAS. Restenosis after CAS is more likely to be manifested with symptoms and to undergo repeated revascularization compared with that after CEA. Poststent ballooning after CAS and completion imaging and patching after CEA are associated with decreased hazard of restenosis; however, further research is needed to assess longer term outcomes and to balance the risks vs benefits of certain practices, such as poststent ballooning. (J Vasc Surg 2019;-:1-11.) Keywords: Carotid artery stenting; Carotid endarterectomy; Restenosis; Predictors

Carotid endarterectomy (CEA) is the “gold standard” procedure for the treatment of symptomatic and asymptomatic carotid artery stenosis, whereas carotid artery stenting (CAS) is reserved for patients who are at high risk for surgery.1,2 However, a major drawback of both procedures is the potential for restenosis due to

neointimal hyperplasia or recurrent atherosclerotic lesions.3,4 Restenosis after carotid revascularization is clinically challenging and can lead to recurrent ipsilateral stroke. The occurrence of restenosis after CAS and CEA ranges from 5% to 20%, depending on the definition of

From the Division of Vascular and Endovascular Surgery, University of California

Correspondence: Mahmoud B. Malas, MD, MHS, RPVI, FACS, Vice Chair of Sur-

San Diego, La Jollaa; the Section of Vascular Surgery and The Dartmouth Insti-

gery for Clinical Research, Chief, Vascular and Endovascular Surgery, Univer-

tute, Dartmouth-Hitchcock Medical Center, Lebanonb; and the Division of

sity of California San Diego Health System, 9300 Campus Point Dr, MC

Vascular and Endovascular Surgery, Beth Israel Deaconess Medical Center, Boston.c Author conflict of interest: M.B.M. is a site principal investigator for the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2) and the Safety and Efficacy Study for Reverse Flow Used During Carotid Artery Stenting Procedure (ROADSTER) trial. Presented at the Third Annual Meeting of the Vascular Quality Initiative at the

7403, La Jolla, CA 92037 (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214 Copyright Ó 2019 by the Society for Vascular Surgery. Published by Elsevier Inc. https://doi.org/10.1016/j.jvs.2019.07.100

2018 Vascular Annual Meeting of the Society for Vascular Surgery, Boston, Mass, June 20-23, 2018.

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restenosis and the duration of follow-up.5,6 The Endarterectomy vs Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial showed significantly higher recurrent carotid stenosis (>70%) by ultrasound at 2 years after CAS vs CEA (11.1% vs 4.6%; P ¼ .001).5 However, the degree of in-stent stenosis is slightly overestimated by conventional ultrasound criteria. On the other hand, a secondary analysis of the Carotid Revascularization Endarterectomy vs Stenting Trial (CREST) showed no significant difference between the two procedures in the percentage of patients who had restenosis or underwent revascularization. In 2 years, restenosis occurred or revascularization was performed in 6.0% of the patients treated with stenting and in 6.3% of those treated with endarterectomy (P ¼ .58).7 Female sex, diabetes, and dyslipidemia were independent predictors of restenosis or occlusion after the two procedures. Smoking predicted an increased rate of restenosis after CEA but not after CAS.7 Our group has previously looked into the management of patients with recurrent stenosis after CAS and CEA and showed no significant difference in perioperative and 1-year outcomes between different revascularization procedures after prior CAS.8 However, in patients with prior ipsilateral CEA, redo CEA was associated with increased mortality and cranial nerve injury compared with CAS, which appeared to be a safer revascularization approach when the need to intervene arose.9-12 This study builds on our previous research and aims to assess high-grade restenosis (>70%) and to identify the predictors of restenosis after CEA and CAS using a nationally representative sample of patients.

METHODS Patients undergoing carotid revascularization (CEA or CAS) in the Vascular Quality Initiative (VQI) data set (2003-2016) were included. Patients with no follow-up (33%) and those who had prior ipsilateral CEA or CAS were excluded (2.2% of CEA cases and 26.7% of CAS cases). We also excluded eversion CEA cases (12.4% of CEA cohort) and concomitant procedures during CEA (2.9%) as well as dissection, trauma, and tandem lesions in CAS (23.6% of CAS cohort). The VQI is a prospectively maintained database containing data on preoperative and intraprocedural variables and postprocedural outcomes from multiple sites across all regions of the United States and Canada. This study included data from 239 participating centers in the VQI data set. CEA data were retrieved from 185 centers (77.4% of participating centers), whereas CAS cases were entered from 177 centers (74%). An annual validation process is carried out to ensure consecutive procedure entry of appropriate cases into the VQI and to eliminate inconsistencies between claims data and procedures entered.13 The VQI Research Advisory Committee approved this study. The Institutional Review Board waived the need

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ARTICLE HIGHLIGHTS d

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Type of Research: Multicenter retrospective analysis of prospectively collected registry data (Vascular Quality Initiative) Key Findings: Analysis of 31,329 carotid endarterectomy (CEA) and 4391 carotid artery stenting (CAS) procedures in the Vascular Quality Initiative data set demonstrated no significant difference in restenosis rates between the two procedures. Restenosis after CAS was more likely to be present with neurologic symptoms and to necessitate repeated revascularization. Young age, common carotid artery lesion, and lack of dilation after stent placement were significantly associated with increased restenosis after CAS. Young age, female sex, white race, prior neck irradiation, prior bypass surgery, and lack of patching and completion imaging after CEA were associated with restenosis after CEA. Take Home Message: There is no significant difference in restenosis rates at 2 years between CEA and CAS. However, restenosis after CAS is more likely to be manifested with symptoms and to require repeated revascularization. Poststent ballooning after CAS and completion imaging and patching after CEA might decrease restenosis after these procedures. However, a careful weighing of the risks vs benefits of certain practices, such as poststent ballooning, should be done.

for individual patient consent under the provisions for deidentified human subject data and quality improvement research. Significant restenosis was defined as $70% diameterreducing stenosis, target artery occlusion or peak systolic velocity $300 cm/s, or repeated revascularization. This definition was also used in CREST and was chosen because many surgeons consider a stenosis of $70% to warrant intervention even if it is asymptomatic. The degree of stenosis was determined from the follow-up data in the VQI data set, which provide information on the percentage of stenosis on the follow-up duplex ultrasound scan at the carotid bifurcation or internal or common carotid artery, depending on lesion location. The variable is labeled as follows: 1, #50%; 2, >50%; 3, >60%; 4, >70%; 5, >80%; 6, occluded; 7, not done; and 8, unknown. Univariate analysis was performed to compare the baseline characteristics of patients with and without recurrent restenosis at up to 2 years of follow-up including baseline demographics, medical comorbidities, and operative factors. Symptomatic status was defined as occurrence of ipsilateral cortical or ocular symptoms within 6 months before surgery.

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Fig 1. Kaplan-Meier survival estimates of high-grade restenosis after carotid endarterectomy (CEA) and carotid artery stenting (CAS). CI, Confidence interval; HR, hazard ratio.

Statistical analysis. Continuous variables were reported as mean (standard deviation) or median (interquartile range) and were compared using Student t-test or Wilcoxon rank sum test. Categorical variables were presented as counts (percentages) and compared using Fisher exact and Pearson c2 tests. Kaplan-Meier survival analysis and Cox regression models with stepwise forward and backward selection were used to identify baseline characteristics and perioperative factors associated with increased risk of restenosis. The models were initially fit on all baseline and procedure-specific variables that were significantly associated with recurrent restenosis on univariable analysis. Afterward, the most parsimonious models were selected. Observations were clustered in each center to reduce bias from hospital-level unmeasurable factors and to account for intragroup correlations. Models were internally validated by bootstrapping of 1000 replications and were tested for concordance using Harrell’s C and Gönen and Heller’s K concordance coefficients. All analyses were performed using Stata version 14.1 statistical software (StataCorp LP, College Station, Tex). Statistical significance was accepted at a P value of <.05.

RESULTS Restenosis rates. The final cohort included 4391 CAS and 31,329 CEA procedures performed between 2003 and 2016. Median follow-up was 391 days (interquartile range, 322-459 days). Restenosis rates were 2.5% (CAS 2.8% vs CEA 2.5%; P ¼ .26) and 7.8% (9.4% vs 7.7%; P ¼ .09) at 1 year and 2 years, respectively (Fig 1). After adjustment for age, sex, race, medical comorbidities (congestive heart failure, chronic kidney disease),

American Society of Anesthesiologists class, smoking status, statin and beta-blocker use, history of any noncardiac arterial bypass, contralateral CEA or CAS, contralateral occlusion, and degree of ipsilateral stenosis, no significant difference in restenosis rates was observed between CAS and CEA (hazard ratio [HR], 0.99; 95% confidence interval [CI], 0.79-1.25; P ¼ .97). The distribution of baseline characteristics in our cohort and their association with recurrent restenosis at 2 years are shown in Table I. In CEA patients, restenosis was more likely to occur in patients with a history of prior irradiation (12.7% vs 7.6%; P < .001) and those without patching (9.7% vs 7.6%; P < .001) or completion imaging (8.3% vs 5.9%; P < .001). On the other hand, in CAS patients, restenosis was less likely to occur in medically high-risk patients (12.5% vs 5.9%; P < .001), those without angioplasty before stenting (12.8% vs 7.8%; P ¼ .04) or after stenting (16.0% vs 8.0%; P < .001), and those with lesions in the bifurcation or internal carotid artery compared with the common carotid artery (20.1% vs 8.0%; P < .001; Table II). According to the VQI, a common carotid artery lesion is reported if the treatment did not extend into the internal carotid artery. Poststent angioplasty was performed for 3449 (79.2%) CAS patients and was more common among asymptomatic patients compared with symptomatic patients (83.1% vs 73.6%; P < .001). Outcomes of patients with restenosis. Patients presenting with recurrent stenosis after CAS within the first 2 years of follow-up (n ¼ 176) were more likely to have symptoms (11.3% vs 4.5%; P < .001) compared with those with recurrent stenosis after CEA (n ¼ 1166). They were

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Table I. Association of baseline characteristics and high-grade restenosis at 2 years Restenosis at 2 years (n ¼ 1342 [3.8%]) Distribution, frequency (%)

Kaplan-Meier estimates, % (95% CI)

Unadjusted HR (95% CI)

Type

.09

CAS

4391 (12.3)

9.4 (7.7-11.5)

Reference

CEA

31,329 (87.7)

7.7 (7.1-8.2)

0.87 (0.74-1.02)

e

0.94 (0.91-0.97)

Age, years, median (IQR)

P value

70 (64-77)

<.001 <.001

Sex Male

22,017 (61.6)

6.9 (6.2-7.5)

Reference

Female

13,702 (38.4)

9.5 (8.6-10.4)

White

33,369 (93.5)

8.0 (7.4-8.5)

Black

1351 (3.8)

6.1 (3.9-9.6)

0.77 (0.56-1.07)

.13

Others

984 (2.8)

6.3 (4.2-9.6)

0.82 (0.58-1.17)

.28

7.6 (7.1-8.2)

Reference

1.40 (1.26-1.57)

Race Reference

Symptomatic

.17

No

28,589 (80.1)

Yes

7120 (19.9)

9.5 (7.9-11.4)

No

3990 (11.2)

9.2 (7.4-11.4)

Yes

31,711 (88.8)

7.7 (7.2-8.3)

1.10 (0.96-26)

Hypertension

.45 Reference 1.07 (0.90-1.28)

Diabetes

.52

No

23,458 (65.7)

8.0 (7.4-8.7)

Reference

Yes

12,230 (34.3)

7.5 (6.7-8.4)

0.96 (0.86-1.08)

No

25,562 (71.7)

8.4 (7.7-9.1)

Reference

Yes

10,112 (28.4)

6.7 (5.9-7.6)

0.88 (0.78-0.99)

No

32,115 (90.0)

8.1 (7.5-8.7)

Reference

Yes

3580 (10.0)

5.9 (4.8-7.4)

0.81 (0.67-0.98)

Coronary artery disease

.04

Congestive heart failure

.03

Chronic kidney disease

.89

No

22,478 (64.5)

8.2 (7.5-8.9)

Yes

12,368 (35.5)

7.5 (6.7-8.3)

No

33,522 (93.9)

7.8 (7.2-8.3)

Yes

2185 (6.1)

9.2 (7.3-11.5)

Reference 1.01 (0.90-1.13)

Prior noncardiac bypassa

.01 Reference 1.31 (1.07-1.59)

Prior endovascular intervention (PTA or stent)

.04

No

32,493 (91.0)

7.8 (7.3-8.4)

Yes

3198 (9.0)

8.4 (6.8-10.3)

Reference 1.20 (1.01-1.43)

Smoking history Never

8406 (23.6)

7.8 (6.7-9.1)

Prior

17,454 (48.9)

8.3 (7.6-9.1)

9817 (27.5)

7.1 (6.2-8.2)

0.94 (0.81-1.10)

No

24,133 (67.6)

7.5 (6.9-8.1)

Reference

Yes

11,558 (32.4)

8.7 (7.7-9.9)

No

5531 (15.5)

9.2 (7.8-10.8)

Reference

Yes

30,173 (84.5)

7.6 (7.1-8.2)

0.90 (0.78-1.04)

Current

Reference 1.12 (0.98-1.28)

.11 .46

Preoperative medication P2Y12 inhibitors

.03 1.13 (1.01-1.27)

Aspirin

.16

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Table I. Continued. Restenosis at 2 years (n ¼ 1342 [3.8%]) Distribution, frequency (%)

Kaplan-Meier estimates, % (95% CI)

Unadjusted HR (95% CI)

Statin

P value .01

No

7102 (19.9)

6.5 (5.6-7.6)

Yes

28,602 (80.1)

8.2 (7.6-8.9)

Reference

No

13,562 (38.0)

9.3 (8.3-10.5)

Reference

Yes

22,132 (62.0)

7.2 (6.6-7.8)

0.88 (0.79-0.98)

No

22,112 (90.7)

10.6 (9.6-11.8)

Yes

2278 (9.3)

7.8 (6.0-10.0)

0.92 (0.74-1.14)

No

11,999 (49.1)

9.5 (8.3-10.9)

Reference

Yes

12,458 (50.9)

11.2 (9.7-12.8)

1.20 (1.05-1.39)

Beta blockers

.02

Anticoagulants

.43 Reference

ACE inhibitors

.04 1.14 (1.01-1.29)

Ipsilateral stenosis 0%-49%

833 (2.4)

5.4 (3.2-9.1)

50%-69%

3478 (9.9)

8.8 (6.8-11.4)

Reference 1.42 (0.89-2.29)

.14

70%-79%

9740 (27.7)

8.1 (7.1-9.3)

1.61 (1.02-2.52)

.04

80%-99%

20,615 (58.7)

7.6 (7.0-8.3)

1.52 (0.98-2.37)

.06

Occluded

462 (1.3)

12.6 (7.5-20.5)

2.11 (1.16-3.82)

.01

ACE, Angiotensin-converting enzyme; CAS, carotid artery stenting; CEA, carotid endarterectomy; CI, confidence interval; HR, hazard ratio; IQR, interquartile range; PTA, percutaneous transluminal angioplasty. a Any noncardiac arterial bypass for occlusive disease.

also more likely to undergo repeated revascularization (83.3% vs 51.8%; P < .001). Repeated surgical interventions (redo CEA, patch, or interposition graft) occurred in 32.4% (95% CI, 13.4-65.4) of patients with restenosis after CAS and in 27.5% (95% CI, 18.0-40.6) of patients with restenosis after CEA. On the other hand, repeated endovascular interventions (angioplasty or stent) were seen in 75.8% (95% CI, 56.8-91.0) of CAS patients and 34.9% (95% CI, 27.1- 44.3) of CEA patients at 2 years. After adjustment for age, sex, and symptomatic status at the time of the index operation, restenosis after CAS was associated with twice the odds of symptomatic presentation secondary to the restenosis (odds ratio, 2.2; 95% CI, 1.2-4.0; P ¼ .01), and patients were 75% more likely to have repeated revascularization within 2 years compared with restenosis after CEA (HR, 1.75; 95% CI, 1.28-2.40; P < .001; Table III). In patients with untreated restenosis $70% after CAS, the incidence of ipsilateral stroke was 2.4% compared with 1.0% in patients without significant restenosis (P ¼ .12). On the other hand, for patients with untreated restenosis after CEA, ipsilateral stroke occurred in 1.0% compared with 0.6% in patients without restenosis at 2 years (P ¼ .01). The results did not change after adjustment for age, sex, and symptomatic status for CAS (HR, 2.78, 95% CI, 0.66-11.6; P ¼ .16) and CEA (HR, 2.86; 95% CI, 1.32-6.20; P ¼ .01). The increase in the estimates of

ipsilateral stroke in patients with untreated restenosis was not significantly different between CEA and CAS (2.4% vs 1.0%; P ¼ .17). Predictors of restenosis after CEA and CAS. Multivariable Cox regression analysis with stepwise forward and backward selection showed an independent association between young age and high-grade restenosis after both CEA and CAS; for each 5-year increase in age, the hazards of restenosis at 2 years significantly decreased after CEA (HR, 0.95; 95% CI, 0.92-0.98; P < .001) and CAS (HR, 0.91; 95% CI, 0.84-0.99; P ¼ .03). Female sex (HR, 1.55; 95% CI, 1.38-1.74; P < .001), history of prior neck irradiation (HR, 2.35; 95% CI, 1.66-3.30; P < .001), and prior peripheral bypass surgery (HR, 1.29; 95% CI, 1.01-1.64; P ¼ .04) were associated with increased restenosis after CEA (Table IV). On the other hand, black race (HR, 0.57; 95% CI, 0.37-0.89; P ¼ .01), patching (HR, 0.61; 95% CI, 0.47-0.79; P < .001), and the use of completion imaging (HR, 0.70; 95% CI, 0.52-0.95; P ¼ .02) were associated with a decrease in restenosis at 2 years. As for CAS, a common carotid artery lesion was associated with higher restenosis rates at 2 years (HR, 1.65; 95% CI, 1.06-2.57; P ¼ .03), whereas poststent dilation decreased restenosis rates by 47% (HR, 0.53; 95% CI, 0.39-0.72; P < .001; Table V).

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Table II. Association of procedure-specific variables and high-grade restenosis at 2 years Restenosis at 2 years (n ¼ 1342 [3.8%]) Distribution, frequency (%)

Kaplan-Meier estimates, % (95% CI)

Unadjusted HR (95% CI)

P value

CEA-specific variables Prior irradiation No

30,841 (98.7)

7.6 (7.0-8.2)

Yes

414 (1.3)

12.7 (8.8-18.2)

Reference

No

1502 (4.8)

9.7 (7.7-12.3)

Reference

Yes

29,803 (95.2)

7.6 (7.0-8.2)

0.66 (0.52-0.82)

No

13,877 (44.4)

7.1 (6.4-7.9)

Reference

Yes

17.412 (55.7)

8.1 (7.4-8.9)

<.001

2.1 (1.5-3.0)

Patch

Shunting

<.001 .62

1.03 (0.92-1.16) <.001

Completion imaging (duplex ultrasound or angiography) No

22.355 (71.4)

8.3 (7.7-9.1)

Reference

Yes

8942 (28.6)

5.9 (5.1-6.9)

0.72 (0.63-0.83)

No

2377 (54.3)

12.5 (9.7-16.0)

Yes

1999 (45.7)

5.9 (4.2-8.3)

445 (10.2)

20.1 (12.8-30.7)

3930 (89.8)

8.0 (6.4-10.1)

0.53 (0.36-0.77)

<.001

e

0.99 (0.97-1.00)

.09

CAS-specific variables <.001

Medical high riska Reference 0.55 (0.40-0.76)

Treated lesion CCA only Bifurcation or ICA only Lesion length, mm, median (IQR)

23 (15-30)

Reference

Angioplasty before stenting

.04

No

1552 (35.6)

Yes

2811 (64.4)

12.8 (9.1-17.8) 7.8 (6.0-10.0)

Reference 0.73 (0.54-0.98) <.001

Angioplasty after stenting No

908 (20.8)

16.0 (10.6-23.9)

Yes

3449 (79.2)

8.0 (6.2-10.2)

Reference 0.47 (0.34-0.65)

CAS, Carotid artery stenting; CCA, common carotid artery; CEA, carotid endarterectomy; CI, confidence interval; HR, hazard ratio; ICA, internal carotid artery; IQR, interquartile range. a Defined on the basis of Centers for Medicare and Medicaid Services criteria for surgical high risk that have been used in carotid stent trials.

DISCUSSION This population-based study of >35,000 patients who had CEA or CAS for carotid artery disease highlighted several findings. First, there was no significant difference in restenosis rates between CEA and CAS. The rate of restenosis at 2 years was 7.7% after CEA and 9.4% after CAS (logrank test, P ¼ .09).14 This is in line with results from CREST, which revealed similar rates of restenosis after CEA (6.3%) and CAS (6%) at 2 years.7 In contrast, a study conducted by Heo et al15 showed significantly higher restenosis rates after CAS vs CEA. The Stent-Protected Angioplasty vs Carotid Endarterectomy (SPACE) trial also showed higher carotid restenosis rates after CAS than after CEA.16 There are several potential explanations for the discrepancy in the results of different studies. In the latter study, all patients were symptomatic with severe carotid artery

stenosis. Moreover, evidence from more recent studies suggests that well-established duplex ultrasound criteria for the diagnosis of an atherosclerotic stenosis of the carotid artery cannot easily be applied to in-stent restenosis.5 The incidence of carotid in-stent stenosis has been reported to vary between 1% and 30% and might be slightly overestimated by conventional ultrasound criteria.5,17 Although most recurrent stenosis is secondary to intimal hyperplasia in the early postoperative period, the data do not offer information on whether lesions are due to intimal hyperplasia, recurrent atherosclerosis, or residual stenosis of >50%. It has previously been reported that lesions detectable on completion angiography are associated with significant morbidity and restenosis after CEA, with residual disease being a contributing factor in 23% of all restenosis and in 12%

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Table III. Presentation and outcomes of patients with high-grade restenosis after carotid endarterectomy (CEA) vs carotid artery stenting (CAS)

Symptomatic presentation

Repeated revascularization Ipsilateral stroke for untreated lesions

Restenosis after

Restenosis after

CEA

CAS

CAS vs CEAa

No. (%)

No. (%)

P value

OR (95% CI)

P value

51 (4.5)

18 (11.3)

<.001

2.2 (1.2-4.0)

.01

Kaplan-Meier estimates, % (95% CI)

Kaplan-Meier estimates, % (95% CI)

P value

51.8 (42.5-61.9)

83.3 (67.3-94.3)

1.0 (0.5-2.1)

2.4 (0.6-9.4)

HR (95% CI)

P value

<.001

1.75 (1.28-2.40)

<.001

.17

1.70 (0.33-8.9)

.53

CI, Confidence interval; HR, hazard ratio; OR, odds ratio. a Analysis adjusted for age, sex, and symptomatic status at the time of the index operation.

of restenosis of >80%.16,18,19 On the other hand, true restenosis in arteries without residual disease is related largely to myointimal hyperplasia during the first 2 years and to progressive atherosclerosis thereafter.19 Standardizing completion assessments or obtaining a baseline duplex ultrasound scan in the first month after the procedure can help distinguish these lesions and correct significant residual defects that might warrant surgical revisions, especially for less experienced surgeons. Compared with patients with restenosis after CEA, those with restenosis after CAS were more likely to be symptomatic and to undergo repeated revascularization. This might be explained by the likelihood of stent fractures after CAS, which are often associated with restenosis. In a study by Chang et al,20 the authors showed that stent fractures are not uncommon after CAS and are usually associated with heavy calcification. However, the clinical relevance of carotid stent fractures in association with restenosis and stroke has not yet been clarified. 21,22 In CEA patients, the estimates of ipsilateral stroke for untreated restenotic lesions were higher compared with patients without recurrent stenosis (HR, 2.86; 95% CI, 1.32-6.20; P ¼ .01). In CAS patients, ipsilateral stroke was also more likely to occur in patients with untreated restenosis $70% compared with patients without significant restenosis (HR, 2.78; 95% CI, 0.66-11.6; P ¼ .16); however, the difference did not reach statistical significance, which might be due to the small sample size in the CAS cohort. In a meta-analysis of 11 randomized controlled trials (RCTs) by Kumar et al23 during a mean follow-up of 50 months after CAS, the prevalence of late ipsilateral stroke was 0.8% in patients with a restenosis >70% (or occlusion) vs 2.0% in patients with no significant restenosis. On the other hand, the presence of a restenosis >70% or occlusion after CEA was associated with a significant increase in the rate of late ipsilateral stroke (odds ratio, 9.02; 95% CI, 4.70-17.28).23 However, the findings of this meta-analysis should be taken in light of certain limitations. First, the follow-up period varied among the analyzed RCTs, and the mean follow-up in

the CAS RCTs was longer than in the CEA RCTs. Moreover, given that the included studies did not account for preoperative and postoperative medication, the lower rate of ipsilateral stroke after CAS can be due to the preferential use of dual antiplatelet therapy after CAS in most of the centers. In addition, most of the large RCTs combined all CEA patients together and did not distinguish the method of CEA (eversion vs traditional) or the mode of arteriotomy closure (primary vs patched) and did not account for the patient’s preoperative symptom status, which might have influenced the likelihood for development of a significant restenosis after CEA.21 Our analysis was restricted to 2 years of follow up, included traditional CEA, and accounted for patch use, preoperative symptomatic status, and medication use. Our results are in line with CREST, which used a stricter criterion for defining restenosis using duplex ultrasound in CREST-certified laboratories that was interpreted at the ultrasound core laboratory (University of Washington). In CREST, participants who had restenosis or occlusion within 2 years were at greater risk for ipsilateral stroke after the periprocedural period up to the end of follow-up than were those who did not have restenosis (HR, 4.37; 95% CI, 1.91-10.03; P ¼ .001, adjusted for age, sex, and symptomatic status).7 However, because of the retrospective nature and limited follow-up of our study, these results need to be revisited. Among patients who underwent CEA, predictors of high-grade restenosis were younger age, female sex, prior neck irradiation, history of peripheral bypass surgery, primary closure, and absence of completion imaging, which includes completion duplex ultrasound and angiography (Fig 2). Previous studies determined female sex and younger age as independent predictors of restenosis after CEA.3,24,25 This may reflect more severe atherosclerotic disease in this subset of patients who develop carotid artery stenosis. On the other hand, a history of neck irradiation has been considered an anatomic risk factor for poor outcomes after CEA because of the increased risk of cranial nerve palsies, poor cutaneous

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Table IV. Multivariable Cox regression analysis of the predictors of high-grade restenosis at 2 years after carotid endarterectomy (CEA)

Table V. Multivariable Cox regression analysis of the predictors of high-grade restenosis at 2 years after carotid artery stenting (CAS)

CEA Adjusted HR Age (5-year increase) Female sex

0.95 1.55

95% CI

CAS

P value

0.92-0.98 <.001 1.38-1.74

<.001

Race White

Reference

Black

0.57

0.37-0.89

.01

Others

0.87

0.58-1.30

.50

Congestive heart failure

0.85

0.68-1.05

.14

Chronic kidney disease

1.03

0.91-1.17

.59

Prior neck irradiation

2.35

1.66-3.30

<.001

Prior bypass

1.29

1.01-1.64

.04

Symptomatic status

1.03

0.83-1.29

.77

Adjusted HR

95% CI

P value

Age (5-year increase)

0.91

0.84-0.99

.03

History of endovascular intervention

0.58

0.31-1.09

.09

1.42

0.82-2.45

.21

Prior contralateral CEA or CAS

0.53

0.39-0.72

<.001

ACE inhibitors

1.13

0.82-1.80

.52

Beta blockers

0.80

0.79-1.61

.21

1.06-2.57

.03

Dilation after stenting

Lesion treated Bifurcation or ICA only Common carotid only

Reference 1.65

ACE, Angiotensin-converting enzyme; CEA, carotid endarterectomy; CI, confidence interval; HR, hazard ratio; ICA, internal carotid artery.

Degree of ipsilateral stenosis <50%

2019

Reference

50%-69%

1.27

0.67-2.43

.46

70%-79%

1.56

0.82-2.96

.18

80%-99%

1.48

0.78-2.79

.23

Occluded

.05

2.21

0.99-4.91

Statin use

1.24

0.98-1.56

.07

Patching

0.61

0.47-0.79

<.001

Completion imaging (duplex ultrasound or angiography)

0.70

0.52-0.95

.02

CI, Confidence interval; HR, hazard ratio.

healing, anastomotic rupture, and arterial infections.26-28 In our study, patients with a history of prior neck irradiation (n ¼ 414) had a restenosis incidence of 12.7% compared with 7.6% in patients with no prior irradiation (P < .001). On adjusted analysis, a history of prior irradiation was associated with 2.35 times the hazard of restenosis compared with patients without prior neck irradiation (HR, 2.35; 95% CI, 1.66-3.30; P < .001). On the other hand, the optimal technique for arteriotomy closure is one of the most extensively researched aspects of CEA. Both the European Society for Vascular Surgery and the American Society for Vascular Surgery recommended patch closure in their latest guidelines on CEA.29,30 A subset analysis of CREST showed a reduction in the risk of restenosis similar to our study in patients who underwent patch closure.31 Many authors have shown that detection by completion imaging and correction of any significant technical defect lower the risk of postoperative stroke and restenosis.32,33 The defects discovered during intraoperative imaging are usually flaps and retained atheroma. Barnes et al34 detected 10 cases of restenosis after 125 CEAs (8.0%) using intraoperative Doppler ultrasound and suggested that restenosis may actually be residual carotid artery stenosis. However,

even when residual plaque and thrombus do not produce perioperative complications, they may contribute to the perception of recurrent disease on early postoperative surveillance. In CAS patients, poststent balloon dilation significantly reduced the risk of restenosis (Fig 2). Postdilation is performed to achieve maximum stent expansion. Thus, it reduces the risk of restenosis and in-stent thrombosis. A study including 169 patients who underwent CAS without postdilation concluded that the rate of restenosis was significantly higher in the patient group with >30% residual stenosis.35 Nonetheless, a retrospective analysis of all patients who had CAS between 2005 and 2014 in the VQI database demonstrated that the use of ballooning after stenting increases the chances of perioperative hemodynamic depression and stroke and death rate compared with ballooning before stenting alone.36 Transcranial Doppler ultrasound studies have also demonstrated that the highest potential for embolization occurs during postdilation when the balloon crushes friable plaque against the metal stent.37 Thus, poststent ballooning should be used only in cases with severe residual stenosis, and surgeons should carefully weigh the risk of stroke vs the benefit of reducing restenosis associated with this practice. Although information about prior neck irradiation in patients undergoing CAS is not available in our study, several studies have demonstrated radiation-induced carotid stenosis to be an independent predictor of recurrent restenosis after CAS.27,38,39 A systematic review of eight trials reported that irradiated patients who underwent CEA had a 9.7% restenosis rate compared with 18.1% in CAS interventions.40 Another prospective study that compared freedom from restenosis in patients who underwent CAS with a positive history of irradiation vs patients at high

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Females (vs. males) Black (vs. White) Race Prior neck radiation Prior bypass surgery

CEA

Patch Angioplasty Completion imaging (duplex/angiography)

Age (5−year increase)

CAS

Post−stent dilatation CCA lesion 0

1

2 Hazard Ratio

3

4

Fig 2. Predictors of high-grade restenosis after carotid endarterectomy (CEA) and carotid artery stenting (CAS) after multivariable analysis. CCA, Common carotid artery.

risk for surgery without irradiation history showed that patients with a history of irradiation were at a significantly higher risk for restenosis (freedom from restenosis, 20% vs 79%).41 This study has several shortcomings that deserve highlighting. Because of the observational nature of our study, unmeasured confounders remain a possible explanation for our study results. There is inherent selection bias by indication in comparing two procedures that were not randomly assigned. Another limitation is that our definition of restenosis did not distinguish between recurrent stenosis and residual stenosis present immediately after treatment because of the lack of information on completion assessments or early postoperative surveillance studies and the potential differences in assessment and reporting for degree of stenosis on follow-up across the multiple centers that contribute to the VQI. Moreover, the median time of follow-up in our study was 391 days (322-459 days); however, because we wanted to include all potential causes of restenosis (intimal hyperplasia, progressive atherosclerosis, and residual restenosis), we elected to identify predictors of restenosis for patients within 2 years after the procedure. Despite these limitations, the study identifies a subpopulation of high-risk patients that might benefit from routine Doppler ultrasound surveillance, although its value may be limited and not cost-effective, particularly if the finding on immediate postoperative duplex ultrasound is normal or shows minimal disease.42

CONCLUSIONS In this nationally representative study, we have shown no significant difference in restenosis rates at 2 years between CEA and CAS. However, restenosis after CAS is

more likely to be manifested with symptoms and to have repeated revascularization compared with that after CEA. Poststent ballooning after CAS and completion neuroimaging and patching after CEA are associated with decreased hazard of restenosis. Longer follow-up is needed to confirm the findings of this study and to balance the risks vs benefits of certain practices, such as poststent ballooning.

AUTHOR CONTRIBUTIONS Conception and design: HDA, MM Analysis and interpretation: HDA, AM, SL, PG, MS Data collection: HDA, SL Writing the article: HDA, AM Critical revision of the article: HDA, SL, PG, MS, MM Final approval of the article: HDA, AM, SL, PG, MS, MM Statistical analysis: HDA, MM Obtained funding: Not applicable Overall responsibility: MM

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Submitted Feb 8, 2019; accepted Jul 25, 2019.