Multiple predictors of in-stent restenosis after stent implantation in symptomatic intracranial atherosclerotic stenosis

Ying YuDepartments of Interventional Neuroradiology and
China National Clinical Research Center for Neurological Diseases;
Neurology, Beijing Tiantan Hospital, Capital Medical University;

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Long YanDepartments of Interventional Neuroradiology and
China National Clinical Research Center for Neurological Diseases;

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Yake LouDepartment of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases; and

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Rongrong CuiDepartments of Interventional Neuroradiology and
China National Clinical Research Center for Neurological Diseases;
Neurology, Beijing Tiantan Hospital, Capital Medical University;

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Kaijiang KangChina National Clinical Research Center for Neurological Diseases;
Neurology, Beijing Tiantan Hospital, Capital Medical University;

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Lingxian JiangDepartments of Interventional Neuroradiology and
China National Clinical Research Center for Neurological Diseases;
Neurology, Beijing Tiantan Hospital, Capital Medical University;

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Dapeng MoDepartments of Interventional Neuroradiology and
China National Clinical Research Center for Neurological Diseases;

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Feng GaoDepartments of Interventional Neuroradiology and
China National Clinical Research Center for Neurological Diseases;

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Yongjun WangChina National Clinical Research Center for Neurological Diseases;
Neurology, Beijing Tiantan Hospital, Capital Medical University;

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Xin LouDepartment of Radiology, Chinese People’s Liberation Army General Hospital, Beijing, China

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Zhongrong MiaoDepartments of Interventional Neuroradiology and
China National Clinical Research Center for Neurological Diseases;

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Ning MaDepartments of Interventional Neuroradiology and
China National Clinical Research Center for Neurological Diseases;

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Free access

OBJECTIVE

This study aimed to identify predictors of intracranial in-stent restenosis (ISR) after stent placement in symptomatic intracranial atherosclerotic stenosis (ICAS).

METHODS

The authors retrospectively collected data from consecutive patients who suffered from symptomatic ICAS and underwent successful stent placement in Beijing Tiantan hospital. Eligible patients were classified into “ISR,” “indeterminate ISR,” or “no-ISR” groups by follow-up digital subtraction angiography or CT angiography. A multivariate logistic regression model was used to explore the predictors of intracranial ISR after adjustments for age and sex. In addition, ISR and no-ISR patients were divided into two groups based on the strongest predictor, and the incidence of ISR, recurrent stroke, and symptomatic ISR was compared between the two groups.

RESULTS

A total of 511 eligible patients were included in the study: 80 ISR, 232 indeterminate ISR, and 199 no-ISR patients. Elevated high-sensitivity C-reactive protein (hs-CRP; odds ratio [OR] 4.747, 95% confidence interval [CI] 2.253–10.01, p < 0.001), Mori type B and C (Mori type B vs Mori type A, OR 3.119, 95% CI 1.093–8.896, p = 0.033; Mori type C vs Mori type A, OR 4.780, 95% CI 1.244–18.37, p = 0.023), coronary artery disease (CAD; OR 2.721, 95% CI 1.192–6.212, p = 0.017), neutrophil/lymphocyte ratio (NLR; OR 1.474 95% CI 1.064–2.042, p = 0.020), residual stenosis (OR 1.050, 95% CI 1.022–1.080, p = 0.001) and concurrent intracranial tandem stenosis (OR 2.276, 95% CI 1.039–4.986, p = 0.040) synergistically contributed to the occurrence of intracranial ISR. Elevated hs-CRP (hs-CRP ≥ 3 mg/L) was the strongest predictor for ISR, and the incidence of ISR in the elevated hs-CRP group and normal hs-CRP group (hs-CRP < 3 mg/L) was 57.14% versus 21.52%, respectively, with recurrent stroke 44.64% versus 16.59%, and symptomatic ISR 41.07% versus 8.52%.

CONCLUSIONS

Elevated hs-CRP level, NLR, residual stenosis, Mori type B and C, CAD, and concurrent intracranial tandem stenosis are the main predictors of intracranial ISR, and elevated hs-CRP is crucially associated with recurrent stroke in patients with symptomatic ICAS after intracranial stent implantation.

ABBREVIATIONS

BA = basilar artery; BMS = bare-metal stent; CAD = coronary artery disease; CI = confidence interval; CTA = CT angiography; DAPT = dual antiplatelet therapy; DES = drug-eluting stent; DSA = digital subtraction angiography; ESR = erythrocyte sedimentation rate; hs-CRP = high-sensitivity C-reactive protein; ICA = internal carotid artery; ICAS = intracranial atherosclerotic stenosis; ISR = in-stent restenosis; LDL = low-density lipoprotein; MCA = middle cerebral artery; mRS = modified Rankin Scale; NIHSS = National Institutes of Health Stroke Scale; NLR = neutrophil/lymphocyte ratio; OR = odds ratio; PLR = platelet/lymphocyte ratio; TIA = transient ischemic attack; VA = vertebral artery; WEAVE = Wingspan Stent System Post Market Surveillance; WOVEN = Wingspan One-year Vascular Events and Neurologic Outcomes.

OBJECTIVE

This study aimed to identify predictors of intracranial in-stent restenosis (ISR) after stent placement in symptomatic intracranial atherosclerotic stenosis (ICAS).

METHODS

The authors retrospectively collected data from consecutive patients who suffered from symptomatic ICAS and underwent successful stent placement in Beijing Tiantan hospital. Eligible patients were classified into “ISR,” “indeterminate ISR,” or “no-ISR” groups by follow-up digital subtraction angiography or CT angiography. A multivariate logistic regression model was used to explore the predictors of intracranial ISR after adjustments for age and sex. In addition, ISR and no-ISR patients were divided into two groups based on the strongest predictor, and the incidence of ISR, recurrent stroke, and symptomatic ISR was compared between the two groups.

RESULTS

A total of 511 eligible patients were included in the study: 80 ISR, 232 indeterminate ISR, and 199 no-ISR patients. Elevated high-sensitivity C-reactive protein (hs-CRP; odds ratio [OR] 4.747, 95% confidence interval [CI] 2.253–10.01, p < 0.001), Mori type B and C (Mori type B vs Mori type A, OR 3.119, 95% CI 1.093–8.896, p = 0.033; Mori type C vs Mori type A, OR 4.780, 95% CI 1.244–18.37, p = 0.023), coronary artery disease (CAD; OR 2.721, 95% CI 1.192–6.212, p = 0.017), neutrophil/lymphocyte ratio (NLR; OR 1.474 95% CI 1.064–2.042, p = 0.020), residual stenosis (OR 1.050, 95% CI 1.022–1.080, p = 0.001) and concurrent intracranial tandem stenosis (OR 2.276, 95% CI 1.039–4.986, p = 0.040) synergistically contributed to the occurrence of intracranial ISR. Elevated hs-CRP (hs-CRP ≥ 3 mg/L) was the strongest predictor for ISR, and the incidence of ISR in the elevated hs-CRP group and normal hs-CRP group (hs-CRP < 3 mg/L) was 57.14% versus 21.52%, respectively, with recurrent stroke 44.64% versus 16.59%, and symptomatic ISR 41.07% versus 8.52%.

CONCLUSIONS

Elevated hs-CRP level, NLR, residual stenosis, Mori type B and C, CAD, and concurrent intracranial tandem stenosis are the main predictors of intracranial ISR, and elevated hs-CRP is crucially associated with recurrent stroke in patients with symptomatic ICAS after intracranial stent implantation.

In Brief

Researchers studied the predictors of intracranial in-stent restenosis (ISR) in symptomatic intracranial atherosclerotic artery stenosis. Multiple factors including high-sensitivity C-reactive protein, neutrophil/lymphocyte ratio, residual stenosis, Mori type B and C, coronary artery disease, and concurrent intracranial tandem stenosis were found to predict intracranial ISR. Identifying a high risk of intracranial ISR before the procedure is helpful for the prevention of ISR.

Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of ischemic stroke worldwide, especially in Asian populations.1,2 The recent WEAVE (Wingspan Stent System Post Market Surveillance)/WOVEN (Wingspan One-year Vascular Events and Neurologic Outcomes) trial3,4 showed intracranial stent implantation is an effective approach to decrease stroke recurrence for patients with symptomatic ICAS who have not responded to aggressive medical management. However, in-stent restenosis (ISR) affects the long-term outcome in these patients by increasing the risk of recurrent stroke.5,6 Although the WEAVE/WOVEN trial reported a low periprocedural complication rate (2.6%) and 1-year stroke and death rate (8.5%), the 1-year ISR rate (stenosis rate ≥ 70%) was still as high as 17.6%, with 9.6% (95% confidence interval [CI] 6.1%–14.9%) symptomatic ISR (stenosis rate ≥ 50%) at 1 year follow-up in the post hoc analysis of the SAMMPRIS (Stenting and Aggressive Medical Management for the Prevention of Recurrent Stroke in Intracranial Stenosis) trial5 and 10.9% in the US Wingspan Registry trial.6

Identifying risk factors for intracranial ISR is particularly important for the prevention of intracranial ISR. Previous studies have shown that ISR is related to multiple factors such as age, stenosis location, and stent diameter.7,8 Inflammation plays an important role in the process of ISR, and the mechanism of inflammation is neointimal hyperplasia.9 Recently, high-sensitivity C-reactive protein (hs-CRP), one of the most representative inflammatory markers,10 has been preliminarily found to be associated with intracranial ISR.11 However, the predictive value of hs-CRP in intracranial ISR remains unclear. Therefore, we investigated the predictors of intracranial ISR from the perspectives of inflammatory markers, demographic profile, features of the responsible lesion, and technical characteristics in patients with symptomatic ICAS undergoing intracranial stent implantation.

Methods

Study Design and Population

This was a retrospective study conducted in a high-volume stroke center (Beijing Tiantan Hospital) performed in accordance with the Declaration of Helsinki and approved by the institutional ethics committee. Written informed consent was obtained from all patients or their relatives. Baseline data and study endpoints were collected and evaluated by a central adjudication committee that consisted of neurologists, interventionists, and radiologists who were blinded to the study design. An independent data and safety monitoring board supervised the conduction, safety, and efficacy of the study.

Inclusion and Exclusion Criteria

We collected data from consecutive patients who suffered from symptomatic ICAS and underwent successful stent placement in Beijing Tiantan Hospital from June 2012 to September 2019. Study inclusion criteria were: 1) age 18–85 years old; 2) 70%–99% of arterial stenosis in the intracranial internal carotid artery (ICA), middle cerebral artery (MCA), intracranial vertebral artery (VA), or basilar artery (BA), as defined by the warfarin–aspirin symptomatic intracranial disease method with normal distal vessels as the reference on digital subtraction angiography (DSA);12 3) transient ischemic attacks (TIAs) or nondisabling ischemic stroke within the past 90 days that were attributable to hypoperfusion in the territory of the target lesion, in which ischemic stroke referred to a new focal neurological deficit lasting ≥ 24 hours, or < 24 hours with new infarction on imaging, and TIA was defined as acute onset of a focal neurological deficit lasting < 24 hours without new infarction on imaging; 4) preprocedural serum detection of inflammatory markers was conducted (including hs-CRP); and 5) vascular imaging follow-up using DSA or CT angiography (CTA) was performed after stent placement. Study exclusion criteria were as follows: 1) acute cerebral infarction within 2 weeks; 2) nonatherosclerotic stenosis including moyamoya disease, muscle fiber dysplasia, or arterial dissection; 3) ischemic mechanisms entirely explained as an embolic phenomenon or perforator occlusion; 4) a baseline modified Rankin Scale (mRS) score > 3; 5) concurrent intracranial tumor, aneurysm, and cerebral arteriovenous malformation; or 6) concurrent pneumonia, urinary tract infection, and autoimmune disease.

Laboratory Analysis

Erythrocyte sedimentation rate (ESR), hs-CRP, neutrophil, monocyte, platelet count, fibrinogen, and low-density lipoprotein (LDL) were measured before intracranial stent implantation. High-sensitivity CRP was centrally measured on a Roche Modular P800 analyzer (Roche) using a turbidimetric immunoassay (Ji’en Technique Co. Ltd.) in the clinical laboratory in Tiantan Hospital. The intra- and interassay coefficients of variation were 2.5% and 2.0%, respectively. Common hematology parameters, including total counts of white blood cells, neutrophils, lymphocytes, and platelets, were determined with automatic particle counters at hematology laboratories in Tiantan Hospital. Antecubital venous blood collection and sample analysis were performed by professionals blinded to the study design and outcome.

Interventional Procedure and Device Selection

The anesthesiologist gives patients either local or general anesthesia based on preoperative assessment, and all stent implantation procedures were performed by experienced neurointerventionists, who perform more than 240 intracranial endovascular procedures per year. An intravenous heparin bolus (75 U/kg) was administered after the placement of vascular access and followed by half of the dose 1 hour later. A 6-Fr guide catheter was used after right femoral artery puncture, and a Transcend 0.014-inch microwire was sent through the narrow segment under the road map. The Gateway balloon is pre-expanded at the stenosis as appropriate before the stent is placed. Operators selected devices based on their experience and preference, as well as lesion characteristics. For patients with smooth arterial access and a Mori type A lesion,13 the Apollo balloon-mounted stent was chosen. For patients with tortuous arterial access, or Mori type C lesion, or a lesion with a significant mismatch in the diameter between the proximal and distal segments, balloon pre-dilation in addition to a self-expanding stent (Gateway balloon plus Wingspan stent system [Stryker]) was preferred. It is difficult to deploy Wingspan stents for long lesions with an extremely tortuous path and curved lesions with a tiny vessel diameter, therefore the Enterprise stent (Codman Neurovascular) or Neuroform EZ stent (Boston Scientific) was used for its excellent conformability, lower radial force, and good wall apposition.14

Periprocedural Management

All patients fasted for more than 12 hours before surgery, and a head CT scan was performed to exclude intracranial hemorrhage after the procedure. Systolic blood pressure was managed, ranging from 100 to 120 mm Hg.

Medical Treatment

All patients received either dual antiplatelet therapy (DAPT) of aspirin (100 mg/day) plus clopidogrel (75 mg/day) for at least 5 days, or a loading dose of DAPT (300 mg clopidogrel + 300 mg aspirin) before stent placement. Aspirin (100 mg/day) plus clopidogrel (75 mg/day) was prescribed after stenting, and either aspirin or clopidogrel would be discontinued 90 days after the procedure according to the resistance testing for antiplatelet drugs. Other risk factor management included lowering blood pressure, lowering LDL, quitting smoking, and improving lifestyle.

Radiological and Clinical Follow-Up

For CTA follow-up, if the entire stented segment as well as the proximal and distal parent vessel was well-visualized and widely patent on CTA, it would be designated as “no-ISR.”6 If a region of the stented segment or adjacent parent vessel could not be adequately visualized on CTA, it would be designated as “indeterminate ISR.” For DSA follow-up, ISR was defined as > 50% stenosis within or immediately adjacent (within 5 mm) of the implanted stent and > 20% absolute luminal loss. If the previous conditions were not met on DSA it would be defined as “no-ISR.” Indeterminate ISR would be regarded as a state between no-ISR and ISR. ISR was evaluated by two professional radiologists, and disagreements were resolved by a third expert.

Complications within 30 days were recorded including hyperperfusion syndrome, perforator stroke, and acute thrombosis. All of the patients were followed up after hospital discharge, and recurrent stroke, death, and regular drug management were recorded. Most of the follow-up was performed via face-to-face interview, with a few via telephone. Follow-up evaluations were performed by trained personnel who were blinded to study design. MRI or CT was performed for patients with new ischemic symptoms.

Statistical Analysis

All eligible patients were classified into ISR, indeterminate ISR, or no-ISR groups. Statistical analyses were performed using SPSS for Windows (version 26.0, IBM-SPSS). Continuous variables are presented as median or mean (± standard deviation), and compared using one-way ANOVA test for normal distribution variables or the Kruskal-Wallis H test for nonnormal distribution variables. The Kolmogorov-Smirnov test was used to test distribution normality. The difference in each of the categorical variables between the two groups was tested with chi-square or Fisher’s exact tests. For variables with statistical difference (p < 0.10), age and gender would be added to the multivariate logistic regression analysis. The results of regression analysis are presented as odds ratios (ORs) and 95% CIs. A two-tailed p value < 0.05 was considered statistically significant. The Kaplan-Meier method was used to evaluate the cumulative incidence of ISR and recurrent stroke between the no-ISR and ISR groups.

Results

Baseline Characteristics

A total of 2023 consecutive patients with symptomatic ICAS who underwent stent implantation in Beijing Tiantan Hospital from June 2012 to September 2019 were screened, and 511 cases (mean age 57.73 ± 8.73 years, 80.63% men) were ultimately eligible for our study (Fig. 1), including 167 (32.68%) followed up using DSA and 344 (67.32%) by CTA. Among them, 80 cases were identified as ISR, 232 cases as indeterminate ISR, and 199 cases as no-ISR. The median imaging follow-up period was 11 months (IQR 6–14.5 months), and median time until occurrence of ISR was 9 months (IQR 6–13 months). Baseline characteristics between groups are displayed in Table 1. The ISR group had a higher proportion of coronary artery disease (CAD; 20% vs 13.36% vs 8.54%, p = 0.029) than those in the indeterminate ISR and no-ISR groups. In the ISR group, 62.5% were admitted to the hospital because of stroke and 37.5% due to TIA; these values were 65.52% and 34.48% in the indeterminate ISR group, and 63.82% and 36.18% in the no-ISR group. In terms of blood parameters, patients in the ISR group had a higher level of baseline hs-CRP (median 1.95 vs 1.40 vs 1.10 mg/L, p < 0.001), neutrophil count (median 4.37 vs 4.05 vs 3.75 ×109/L, p = 0.001), and neutrophil/lymphocyte ratio (NLR; median 2.31 vs 2.27 vs 2.07, p = 0.006) than those in the indeterminate ISR and no-ISR groups. Differences were not statistically significant in BMI, fasting plasma glucose, platelet/lymphocyte ratio (PLR), fibrinogen, LDL, and ESR among the three groups, nor in qualifying ischemic events, target artery distribution, baseline National Institutes of Health Stroke Scale (NIHSS) score, or baseline mRS score.

FIG. 1.
FIG. 1.

Flow chart of study.

TABLE 1.

Comparison of demographic and blood parameters among the ISR, indeterminate ISR, and no-ISR groups

VariableISR, n = 80Indeterminate ISR, n = 232No ISR, n = 199p Value
Mean age ± SD, yrs58.2 ± 8.7457.59 ± 9.0957.72 ± 8.330.863
Males, n (%)63 (78.75)194 (83.62)155 (77.89)0.291
Median BMI (IQR)26.21 (23.70–29.06)25.95 (24.15–27.90)25.65 (23.89–27.34)0.074
Smoking, n (%)0.850
 Current smoker28 (35.00)68 (29.31)61 (30.65)
 Previous smoker23 (28.75)74 (31.90)67 (33.67)
 Never smoked29 (36.25)90 (38.79)71 (35.68)
Hypertension, n (%)62 (77.50)178 (76.72)164 (82.41)0.327
Diabetes mellitus, n (%)34 (42.50)86 (37.07)65 (32.66)0.282
Hyperlipidemia, n (%)64 (80.00)157 (67.67)135 (67.84)0.091
CAD, n (%)16 (20.00)31 (13.36)17 (8.54)0.029
Qualifying ischemic events, n (%)0.869
 Ischemic stroke50 (62.5)152 (65.52)127 (63.82)
 TIA30 (37.5)80 (34.48)72 (36.18)
Target artery distribution, n (%)0.217
 ICA12 (15.00)40 (17.24)23 (11.56)
 MCA8 (10.00)21 (9.05)33 (16.58)
 VA32 (40.00)94 (40.52)73 (36.68)
 BA28 (35.00)77 (33.19)70 (35.18)
Baseline NIHSS score, n (%)0.594
 052 (65.00)160 (68.96)122 (61.31)
 1–321 (26.25)56 (24.14)60 (30.15)
 >37 (8.75)16 (6.90)17 (8.54)
Baseline mRS score, n (%)0.929
 044 (55)135 (58.19)116 (58.29)
 127 (33.75)73 (31.47)60 (30.15)
 27 (8.75)20 (8.62)21 (10.55)
 32 (2.5)4 (1.72)2 (1.01)
Blood parameters, median (IQR)
 Neutrophil count, ×109/L4.37 (3.64–5.26)4.05 (3.35–5.22)3.75 (3.13–4.63)0.001
 Monocyte count, ×109/L0.47 (0.34–0.57)0.46 (0.35–0.55)0.44 (0.35–0.55)0.704
 Lymphocyte count, ×109/L1.81 (1.33–2.07)1.85 (1.47–2.24)1.84 (1.48–2.25)0.219
 NLR2.31 (1.89–3.50)2.27 (1.72–2.91)2.07 (1.63–2.68)0.006
 Platelet count, ×109/L210.5 (181–251.75)213 (179–256)212.00 (183–243)0.960
 PLR125.60 (94.15–167.37)117.70 (94.83–147.38)119.57 (94.93–141.67)0.456
 Fibrinogen, mg/dl3.01 (2.52–3.50)2.83 (2.34–3.34)2.79 (2.34–3.32)0.078
 Fasting plasma glucose, mmol/l5.31 (4.81–6.63)5.22 (4.51–6.40)5.01 (4.58–5.94)0.065
 LDL, mmol/L1.86 (1.50–2.24)1.81 (1.45–2.26)1.86 (1.45–2.36)0.424
 HDL, mmol/L0.97 (0.80–1.16)0.99 (0.84–1.11)0.98 (0.84–1.14)0.852
 ESR, mm/hr7.00 (3.25–14.75)7.00 (2.00–12.00)7.00 (3.25–14.75)0.388
 hs-CRP, mg/L1.95 (0.93–6.18)1.40 (0.61–3.54)1.10 (0.50–2.10)<0.001

HDL = high-density lipoprotein.

Periprocedural Characteristics

Of the 511 patients, general anesthesia was used in 90% (72/80) of ISR patients, 91.38% (212/232) of indeterminate ISR patients, and 86.93% (173/199) in no-ISR patients, respectively (Table 2). Compared with the indeterminate ISR and no-ISR groups, the ISR group had a lower proportion of Mori type A lesions (7.50% vs 15.09% vs 20.60%), which was statistically significant (p = 0.023). In the univariate analysis, length of lesion (p = 0.021), concurrent intracranial tandem stenosis (p = 0.017), and residual stenosis (p = 0.005) were statistically significant between groups, but there was no obvious difference in age, diabetes status, and stent diameter. The incidence of recurrent stroke in the ISR group was higher than that in the indeterminate ISR and no-ISR groups (52.5% vs 15.09% vs 10.05%, p < 0.001), but the incidence of death (1.25% vs 3.45 vs 2.01%, p = 0.554) and proportion of regular drug management (88.75% vs 89.22% vs 92.96%, p = 0.342) were not significantly different.

TABLE 2.

Comparison of periprocedural and technical characteristics and prognosis among the ISR, indeterminate ISR, and no-ISR groups

VariableISR, n = 80Indeterminate ISR, n = 232No ISR, n = 199p Value
Type of anesthesia, n (%)0.321
 General anesthesia72 (90.00)212 (91.38)173 (86.93)
 Local anesthesia8 (10.00)20 (8.62)26 (13.07)
Mori types, n (%)0.051
 Mori A6 (7.50)35 (15.09)41 (20.60)0.023
 Mori B46 (57.50)132 (56.90)112 (56.28)0.981
 Mori C28 (35.00)65 (28.02)46 (23.12)0.122
Median arterial stenosis % (IQR)80.00 (75.25–90.00)80.00 (74.25–90.00)80.00 (75.00–90.00)0.617
Median lesion length (IQR), mm8 (6–12)8 (6–10.88)7 (5–10)0.021
Concurrent intracranial tandem stenosis, n (%)18 (22.50)34 (14.66)19 (9.55)0.017
Concurrent extracranial tandem stenosis, n (%)2 (2.50)11 (4.74)7 (3.52)0.711
Type of stent, n (%)0.756
 Apollo47 (56.63)136 (57.14)121 (60.20)
 Wingspan25 (30.12)80 (33.61)61 (30.35)
 Enterprise8 (9.64)15 (6.30)16 (7.96)
 Neuroform EZ 3 (3.61)7 (2.94)3 (1.49)
No. of stents, n (%)0.242
 177 (96.25)226 (97.41)197 (98.99)
 23 (3.75)6 (2.59)2 (1.01)
Median stent diameter (IQR), mm3 (2.5-3.5)3 (2.5–3.5)3 (2.5–3.5)0.606
Median stent length (IQR), mm13 (8-15)13 (8–15)13 (8–15)0.284
Residual stenosis %
 Median (IQR)10 (10–20)10 (5–20)10 (5–15)0.005
 Mean ± SD15.93 ± 12.1713.12 ± 9.3211.63 ± 10.090.004
Periop complications, n (%)0.783
 Hyperperfusion syndrome2 (2.50)2 (0.86)5 (2.51)
 Occlusion of perforating artery2 (2.50)7 (3.02)4 (2.01)
 Acute cerebral thrombosis02 (0.86)1 (0.50)
Regular drug management, n (%)71 (88.75)207 (89.22)185 (92.96)0.342
Recurrent stroke, n (%)42 (52.5)35 (15.09)20 (10.05)<0.001
Death, n (%)1 (1.25)8 (3.45)4 (2.01)0.554

ISR Predictors

Variables with p values < 0.1 were added to the multivariate logistic regression model for analysis, and gender, age, and diabetes would also be added for error adjustment. The following variables were independent predictors for intracranial ISR (Table 3): hs-CRP ≥ 3 mg/L (OR 4.747, 95% CI 2.253–10.01, p < 0.001), NLR (OR 1.474, 95% CI 1.064–2.042, p = 0.020), residual stenosis (OR 1.050, 95% CI 1.022–1.080, p = 0.001), Mori type B and C (Mori type B vs Mori type A, OR 3.119, 95% CI 1.093–8.896, p = 0.033; Mori type C vs Mori type A, OR 4.780, 95% CI 1.244–18.37, p = 0.023), CAD (OR 2.721, 95% CI 1.192–6.212, p = 0.017), and concurrent intracranial tandem stenosis (OR 2.276, 95% CI 1.039–4.986, p = 0.040). In addition, we found that higher hs-CRP was the strongest predictor for ISR in the multivariate logistic regression model.

TABLE 3.

Factors predicting ISR used by multivariate logistic regression analysis

VariableIndeterminate ISRISR
OR95% CIp ValueOR95% CIp Value
Sex (male)0.8250.490–1.3880.4681.3160.635–2.7250.460
Age1.0020.979–1.0260.8651.0010.968–1.0360.955
BMI1.0440.980–1.1120.1851.0630.974–1.1600.168
Hyperlipidemia0.8820.572–1.3590.5681.4340.724–2.8380.301
CAD1.8000.942–3.4360.0752.7211.192–6.2120.017
Diabetes mellitus0.8100.486–1.3500.4201.0710.509–2.2520.856
Neutrophil1.1350.927–1.3880.2201.0350.780–1.3740.809
NLR1.0940.844–1.4170.4981.4741.064–2.0420.020
Fibrinogen1.0100.864–1.1810.8990.9190.651–1.2980.632
Fasting plasma glucose1.0010.873–1.1470.9891.1780.991–1.4000.064
hs-CRP (≥ 3 mg/L)2.3891.360–4.1950.0024.7472.253–10.01<0.001
Lesion length1.0140.950–1.0830.6750.9810.893–1.0770.685
Residual stenosis1.0211.000–1.0430.0531.0501.022–1.0800.001
Concurrent intracranial tandem stenosis1.3260.706–2.4910.3802.2761.039–4.9860.040
Mori types (w/ reference to Mori A)
 Type B1.4100.773–2.5710.2623.1191.093–8.8960.033
 Type C1.5300.643–3.6380.3364.7801.244–18.3760.023

The no-ISR group was used as the reference group.

Clinical Follow-Up Outcomes

All cases completed clinical follow-up and the median follow-up period was 48 months. Ninety-seven patients (18.98%, 97/511) had recurrent stroke and 2.54% (13/511) died. To better assess the impact of the strongest predictor (hs-CRP) on follow-up clinical outcomes, the determinate ISR and no-ISR patients (n = 279) were dichotomized according to hs-CRP levels: 56 cases were in the elevated hs-CRP group (hs-CRP ≥ 3 mg/L) and 223 cases in the normal hs-CRP group (hs-CRP < 3 mg/L; Table 4). Compared with the normal hs-CRP group, the incidence of ISR (57.14% vs 21.52%, p < 0.001), recurrent stroke (44.64% vs 16.59%, p < 0.001), and symptomatic ISR (41.07% vs 8.52%, p < 0.001) are higher in the elevated hs-CRP group. Median time to recurrent stroke was 13.5 months and 18.0 months (p = 0.914) in the elevated hs-CRP group and normal hs-CRP group, respectively. The Kaplan-Meier curves indicate that the cumulative incidence of ISR or recurrent ischemic stroke in the elevated hs-CRP group is statistically higher than that in the normal group (p = 0.001, p < 0.001), and the incidence difference between the two groups gradually increases over time (Fig. 2).

TABLE 4.

Binary classification of hs-CRP among determinate ISR and no-ISR patients

VariableTotal, n = 279hs-CRPp Value
≥ 3 mg/L, n = 56 < 3 mg/L, n = 223
Periop complications14 (5.02%)2 (3.57%)12 (5.38%)0.743
ISR80 (28.67%)32 (57.14%)48 (21.52%)<0.001
Median time to ISR (IQR), mos9 (6–13)10.75 (6.63–16)8 (4.63–12.88)0.341
Recurrent of stroke62 (22.22%)25 (44.64%)37 (16.59%)<0.001
Median time to recurrent stroke (IQR), mos17.25 (6.88–37.88)13.5 (6.75–27.5)18 (6–44)0.914
Symptomatic ISR42 (15.05%)23 (41.07%)19 (8.52%)<0.001
Death5 (1.79%)1 (1.79%)4 (1.79%)>0.99
FIG. 2.
FIG. 2.

A: Kaplan-Meier ISR curves. B: Kaplan-Meier ischemic stroke curves. Elevated hs-CRP indicates hs-CRP ≥ 3 mg/L, and normal hs-CRP indicates hs-CRP < 3 mg/L. Figure is available in color online only.

Discussion

Our study investigating the predictors of intracranial ISR mainly found that multiple factors such as hs-CRP level, NLR, residual stenosis, Mori type B and C, CAD, and concurrent intracranial tandem stenosis synergistically contribute to the occurrence of intracranial ISR in patients with symptomatic ICAS who underwent intracranial stent implantation. In addition, we innovatively found that preprocedural elevated hs-CRP is the strongest predictor for intracranial ISR and significantly correlated with recurrent ischemic stroke.

The first important finding in our study is that many factors were associated with the occurrence of ISR. There have been many studies on the effects of technical characteristics and lesion morphology on intracranial ISR, and residual stenosis is one of the factors. We found that every 1% increase of residual stenosis would lead to a 5% increase for ISR risk, which was almost consistent with a previous study demonstrating that inadequate stent dilation is more likely to achieve poor angiographic results.15 Conversely, a meta-analysis16 showed a close relationship between lower residual stenosis and higher incidence of symptomatic ISR, which may be true because lower residual stenosis implies greater arterial and endothelial injury that promotes ISR and plaque progression.9 The optimal immediate residual stenosis rate needs investigating in the future. Our results indicate that Mori type B and C lesions are more likely to develop ISR than Mori type A lesions, highlighting that long and tortuous lesions increase the risk of ISR by limiting the stent to navigating through tortuous vascular access and attaching adequately to the vessel wall.13,16 Our study findings were consistent with the finding of Kang et al.17 that Mori type C lesions (53.8%) have a higher rate of ISR than that Mori type A (15.8%) and B (15.6%) lesions in balloon-mounted stents for symptomatic ICAS, and confirmed that Mori type (angulation and length) of lesions can provide a basis for the preprocedural selection of stents.

CAD and concurrent intracranial tandem stenosis as predictors of intracranial ISR have not been previously reported. In fact, CAD and ICAS share the same pathology, which is atherosclerosis of vascular walls, and the rupture or instability of atherosclerotic plaques can cause both cardiovascular and cerebrovascular events.18,19 In essence, atherosclerosis is also an inflammatory disease, and inflammation plays a crucial role in the progression of atherosclerosis.20 The severity of atherosclerosis may partly reflect the intensity of inflammatory activity in the systemic vessel walls. ICAS patients with CAD or concurrent intracranial tandem stenosis may have more severe atherosclerosis in vessels throughout the body, and the plaques may be more prone to rupture and to instability, which means a more active systemic inflammatory response in vessel walls and a greater chance of ISR.

ISR is a complicated healing process of the vascular wall’s overreaction to stent placement or foreign body stimulation, and it is also a vigorous neointimal hyperplasia process.21 The pathophysiological mechanisms of restenosis are currently being explored. Farb et al.22 noted that inflammatory responses contribute to in-stent neointimal growth following arterial injury, and the number of inflammatory cells around stent struts was significantly higher in restenosis compared with no restenosis. The activated inflammatory response induces the secretion of various growth factors and proinflammatory cytokines, including platelet-derived growth factor, transforming growth factor-β, and especially interleukin-6.23 Interleukin-6 stimulates the production of acute-phase proteins, primarily CRP, and the latter can activate the complement system by binding to the ligands.24 Subsequently, inflammatory cells migrate to and infiltrate around stent struts mediated by adhesion molecules,9,25 further leading to a series of proliferating reactions including vascular smooth muscle cell proliferation and migration, extracellular matrix formation, and neointimal hyperplasia.26 This healing process of overreaction happening only in some people may be associated with regulatory and coding imbalances between inflammatory and antiinflammatory genes in these people.27,28

As a representative inflammatory marker produced principally by hepatocytes, hs-CRP plays an important role in the ISR process.29 Our study first found that preprocedural hs-CRP is a strong predictor for intracranial ISR. Earlier studies suggested that CRP strongly predicts recurrent coronary ISR.30,31 Interestingly, many studies demonstrated that a higher baseline CRP serum level was a significant predictor of angiographic coronary restenosis only in patients undergoing bare-metal stent (BMS) implantation, instead of in those undergoing drug-eluting stent (DES) deployment.31 The underlying reason for this inconsistency may be that the effects of systemic hyperinflammation on the local vascular wall were offset by the antiinflammation and antiproliferation effect of drugs eluted by DES. In this case, the systemic hyperinflammation failed to take effect in the development of ISR, so CRP failed to predict ISR of DESs,32 while the systemic hyperinflammation activated local inflammatory cells around stent struts that play an essential role in the ISR process of BMSs. The pathogenesis of ISR in BMSs and DESs may be different: the formation of neointima in BMSs is the traditional inflammation-mediated mode, while in DESs, it may be dominated by atherosclerosis and lipid deposition.33 In our study, all cases were treated with different types of BMSs, accordingly lesions bear more vascular inflammation burden, so that we had positive results. Our findings confirmed a previous study involving only 16 intracranial stents, in which preprocedural hs-CRP predicted extra- and intracranial midterm ISR (OR 2.2, 95% CI 1.29–6.66, p = 0.018).34 The difference is that our study had a larger sample size, and only intracranial lesions were included in our study. We hypothesize that a higher preprocedural inflammatory status in patients with elevated hs-CRP may cause more active intimal hyperplasia in response to the intimal injury caused by stent invasion, and thus a higher risk of ISR.

Similar to hs-CRP, NLR, as a potential inflammatory marker, can also be used to predict intracranial ISR in our study. In contrast to CRP, NLR is a good predictor of coronary ISR after DES implantation.35 At present, the application of DESs in patients with ICAS is under preliminary exploration, and the prediction of NLR and hs-CRP on ISR still needs further study.

We also found that patients with preprocedural elevated hs-CRP had a higher incidence of recurrent stroke. In a subanalysis of the CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events),36 Li et al. found elevated hs-CRP (hs-CRP ≥ 3 mg/L) independently predicted recurrent stroke (hazard ratio 1.40, 95% CI 1.07–1.83, p = 0.013) during the 1-year follow up in patients with minor stroke or TIA, which may be because inflammation could lead to poor response to antiplatelet therapy in patients with symptomatic ICAS.37 In addition, patients with increased hs-CRP have a tendency to have earlier recurrent stroke, which has never been reported previously. It is desirable to consider hs-CRP as a prognostic factor of risk stratification for stroke recurrence in cerebrovascular diseases in the future. Our results also suggest that elevated hs-CRP is associated with symptomatic ISR. Currently, endovascular recanalization is justified in symptomatic ISR patients,38 but it remains unclear whether high inflammatory status affects safety and long-term efficacy of target lesion revascularization for symptomatic ISR with elevated hs-CRP, and more rigorous prospective studies are needed.

The negative predictive value of CTA in intracranial ISR is reliable. However, compared with invasive intraarterial DSA, CTA, although a noninvasive follow-up examination, may overestimate ISR because the accuracy of CTA quantifying stenosis is affected by artifacts caused by an exaggerated thickening or blooming of the stent struts, especially in small-type stents with diameters < 4 mm.39,40 To maximize the accurateness of ISR detection in our study, cases that could not be determined by CTA for ISR were classified as the “indetermined ISR” group and were also included in the statistical calculation to minimize potential bias. It was found that parameter values in this group were between those of the no-ISR group and ISR group, which was our expectation.

Before the procedure, identifying a high risk of intracranial ISR is helpful for the prevention of ISR. For mori type A/B lesions, the balloon-mounted stent should be preferable, while for Mori type C lesions, the self-expanding stent may be a better option. For patients at high inflammatory risks, a drug-coated balloon may facilitate a lower risk of restenosis by antiproliferation and inhibiting neointimal hyperplasia,41,42 and postoperative high-dose statins or antiinflammatory drugs (such as canakinumab) may lower hs-CRP levels to decrease the ISR risk.43,44 For patients with CAD or intracranial tandem stenosis, more aggressive control of atherosclerosis may be considered. More prospective studies are warranted to lower the ISR incidence.

Limitations

Our study has several limitations. First, this study is a retrospective study, lacking data on potentially significant biomarkers, such as interleukin-6 and serum amyloid A. Second, this study is a single-center study, so it may not be generalized in a wide range. And third, inflammatory markers such as hs-CRP and NLR were tested only once before the procedure, which cannot be avoided in a retrospective study.

Conclusions

Elevated hs-CRP, NLR, residual stenosis, Mori type B and C, CAD, and concurrent intracranial tandem stenosis are the main predictors of intracranial ISR, and elevated hs-CRP is crucially associated with recurrent stroke in patients with symptomatic ICAS after intracranial stent implantation.

Acknowledgments

We thank all of the patients and healthcare providers who participated in this study. This work was supported by the National Natural Science Foundation of China (contract grant no. 81471390 to N.M.), the Beijing Yangfan Plan (contract grant no. XMlX201844 to N.M.), and National Natural Science Foundation of China (contract grant no. 81825012 and 81730048 to X.L.).

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Ma, Yu. Acquisition of data: Yu, Yan, Cui, Kang, Jiang. Analysis and interpretation of data: Yu, Yan, Y Lou. Drafting the article: Yu, Yan, Y Lou. Critically revising the article: Ma, Cui. Reviewed submitted version of manuscript: Ma, Yu, X Lou. Approved the final version of the manuscript on behalf of all authors: Ma. Statistical analysis: Y Lou. Administrative/technical/material support: Ma, Wang, Miao. Study supervision: Mo, Gao, Wang.

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  • Collapse
  • Expand
Illustration from Houk et al. (pp 1796–1803). Image by Lydia Gregg © 2020 JHU. Published with permission.
  • View in gallery
    FIG. 1.

    Flow chart of study.

  • View in gallery
    FIG. 2.

    A: Kaplan-Meier ISR curves. B: Kaplan-Meier ischemic stroke curves. Elevated hs-CRP indicates hs-CRP ≥ 3 mg/L, and normal hs-CRP indicates hs-CRP < 3 mg/L. Figure is available in color online only.

  • 1

    Banerjee C, Chimowitz MI. Stroke caused by atherosclerosis of the major intracranial arteries. Circ Res. 2017;120(3):502513.

  • 2

    Zhou M, Wang H, Zeng X, Yin P, Zhu J, Chen W, et al. Mortality, morbidity, and risk factors in China and its provinces, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2019;394(10204):11451158.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Alexander MJ, Zauner A, Chaloupka JC, Baxter B, Callison RC, Gupta R, et al. WEAVE trial: final results in 152 on-label patients. Stroke. 2019;50(4):889894.

  • 4

    Alexander MJ, Zauner A, Gupta R, Alshekhlee A, Fraser JF, Toth G, et al. The WOVEN trial: Wingspan One-year Vascular Events and Neurologic Outcomes. J Neurointerv Surg. 2020;13(4):307310.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Derdeyn CP, Fiorella D, Lynn MJ, Turan TN, Cotsonis GA, Lane BF, et al. Nonprocedural symptomatic infarction and in-stent restenosis after intracranial angioplasty and stenting in the SAMMPRIS trial (Stenting and Aggressive Medical Management for the Prevention of Recurrent Stroke in Intracranial Stenosis). Stroke. 2017;48(6):15011506.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Fiorella DJ, Turk AS, Levy EI, Pride GL Jr, Woo HH, Albuquerque FC, et al. U.S. Wingspan Registry: 12-month follow-up results. Stroke. 2011;42(7):19761981.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Turk AS, Levy EI, Albuquerque FC, Pride GL Jr, Woo H, Welch BG, et al. Influence of patient age and stenosis location on wingspan in-stent restenosis. AJNR Am J Neuroradiol. 2008;29(1):2327.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Yu J, Wang L, Deng JP, Gao L, Zhang T, Zhao ZW, Gao GD. Treatment of symptomatic intracranial atherosclerotic stenosis with a normal-sized Gateway(™) balloon and Wingspan(™) stent. J Int Med Res. 2010;38(6):19681974.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Kornowski R, Hong MK, Tio FO, Bramwell O, Wu H, Leon MB. In-stent restenosis: contributions of inflammatory responses and arterial injury to neointimal hyperplasia. J Am Coll Cardiol. 1998;31(1):224230.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Fortmann SP, Ford E, Criqui MH, Folsom AR, Harris TB, Hong Y, et al. CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: report from the population science discussion group. Circulation. 2004;110(25):e554e559.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Guo X, Ma N, Gao F, Mo DP, Luo G, Miao ZR. Corrigendum: Long-term risk factors for intracranial in-stent restenosis from a multicenter trial of stenting for symptomatic intracranial artery stenosis registry in China. Front Neurol. 2021;12:673264.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ, Hertzberg VS, Frankel MR, et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med. 2005;352(13):13051316.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Mori T, Mori K, Fukuoka M, Arisawa M, Honda S. Percutaneous transluminal cerebral angioplasty: serial angiographic follow-up after successful dilatation. Neuroradiology. 1997;39(2):111116.

    • Crossref
    • PubMed
    • Search Google Scholar
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