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Incidence and Predictors of the In-stent Restenosis after Vertebral Artery Ostium Stenting
ARTICLE IN PRESS
Incidence and Predictors of the In-stent Restenosis after Vertebral Artery Ostium Stenting Wanhong Chen, MD,*,† Fang Huang, MD,* Min Li, MD,* Yongjun Jiang, MD, PHD,‡ Jianbo He, MD,† Huiqi Li, MD,† Zheng Dai, MD,§ Wei Shi, MD,║ Mingyue Zhu, MD,{ Guanghui Chen, MD, PHD,* Fang Yang, MD, PHD,* and Renliang Zhang, MD, PHD* Background: The incidence and predictors for in-stent restenosis (ISR) was not fully explored. We aim to investigate the incidence and predictors of ISR after stenting at the origin of vertebral artery. Materials and Methods: Two hundred and six patients with 229 stents implantation between July 1, 2005 and July 31, 2015 were included in the study. All patients underwent conventional clinical and angiographic (digital subtraction angiography) follow-up at around 6 months post procedure. ISR was defined as greater than 50% stenosis within or immediately (within 5 mm) adjacent to the stent. Multivariate Cox regression analyses were utilized to investigate the predictors for ISR. Results: The ISR was found in 30 patients (30/206, 14.6%) with 31 lesions (31/229, 13.5%) with the mean follow-up duration of 11.1-month (range: 3 - 92 months). Stent diameter (hazard ratio 0.504, 95% confidence interval 0.294 - 0.864) was an independent predictor for ISR. Conclusion: ISR rate after Vertebral artery ostium stent placement is acceptable, which was conversely associated with the stent diameter. Key Words: In-stent restenosis—Vertebral artery ostium—Ischemic stroke— Atherosclerotic stenosis © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.
Introduction
From the *Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province 210002; †Department of Neurology, Xi'an XD group hospital, Xi'an, Shanxi Province 710077, China; ‡Department of Neurology, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province 510260; §Department of Neurology, Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu Province 214023; ║Department of Intensive Care Unit, The Affiliated Brain Hospital with Nanjing Medical University, Nanjing, Jiangsu Province 210009; and {Department of Intensive Care Unit, The Third Affiliated Hospitial of Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province 210001, China. Received January 28, 2018; revision received May 27, 2018; accepted June 24, 2018. Conflicts of Interest: None. Address Correspondence to Renliang Zhang, MD PHD, and Fang Yang, MD PHD, Department of Neurology, Jinling Hospital, Medical School of Nanjing University, 305#East Zhongshan Road, Nanjing, Jiangsu Province 210002, China. E-mail: [email protected]; [email protected] 1052-3057/$ - see front matter © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2018.06.031
Vertebral artery ostium (VAO) is regarded as the most common stenotic position in posterior circulation ischemic stroke.1 Patients with atherosclerotic stenosis of 50% or more in VAO might exert a higher risk on the occurrence and recurrence of stroke or death.2-4 However, the treatment of posterior circulation stroke remains a great challenge. In addition to intensive medical therapy, stenting in VAO was safe and effective for preventing stroke.5,6 Although the primary endpoint (any stroke during follow-up) of Vertebral artery Ischemic Stenting Trial showed no statistical deference between stenting and medical treatment arms,7 the study would lend a perspective to the benefit from extracranial vertebral artery stenting which might reduce recurrent stroke.7-9 One of the problems for stenting in VAO is in-stent restenosis (ISR), which is induced by the excessive neointimal hyperplasia in the lumen of stent and the thrombosis in the stent. Lin et al study10 found that CYP2C19 mutations might be a risk factor of ISR in patients with
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vertebral artery stent placement. However, the incidence and predictors for ISR was not fully investigated. Therefore, our study aims to explore the incidence and predictors of ISR after VAO stent implantation in Chinese patients.
Materials and Methods Patient Information Between July 1, 2005 and July 31, 2015, all the patients were retrieved from the Nanjing stroke registry that was an ongoing single center prospective database on stroke in Jinling Hospital in Nanjing. In the study, patients were included if they met the following criteria: (1) symptomatic stenosis greater than or equal to 50% in VAO (defined as transient ischemic attack [TIA] or stroke in the territory of vertebral artery); (2) asymptomatic stenosis greater than or equal to 70% in the VAO; (3) successful stent implantation and residual stenosis Less than or equal to 30%; (4) the imaging and clinical data were available. Patients were excluded if (1) non-atherosclerosis; (2) poor quality of the imaging.
Stent Implantation Protocol Dual antiplatelet drugs (aspirin 100 mg and clopidogrel 75 mg) were prepared for at least 3 days prior to the stent placement. The procedure was performed under local anesthesia by the senior neuroradiologists. A 6-French sheath was placed in the femoral artery and systemic heparinization with activated clotting time of 2-3 times the baseline was maintained during the procedure. Then, A 6-French guiding catheter (Cordis, Miami Lakes, FL) was placed in the subclavian artery over a .035-in. guide wire. Next, stenotic lesions were crossed with .014-in. guidewires (Cordis) under road-map fluoroscopy. The appropriate stent was subsequently used to the lesion. The diameter of the deployed stent was based on the diameter of the distal normal vessel and the length of the stent had to cover 3-5 mm of normal lumen on either side of the lesion. Balloonexpandable bare-metal stents (BMS) (Express Vascular SD; Boston Scientific Corporation, Natick, MA) were deployed as the first choice. Drug-eluting stents (DES) (sirolimus-eluting stent [SES] Firebird2 stent; MicroPort Medical, Shanghai, China) as coronary stents were used only when BMS implantation was predicted to be challenging due to the tortuosity of the proximal vertebral artery. Finally, angiography was performed to evaluate the residual stenosis. Dual antiplatelet drugs (aspirin and clopidogrel) were continued for at least 6 months and then switched to aspirin for lifelong. All patients were given a standardized prevention program, including smoking cessation, alcohol restriction, management of blood pressure, blood glucose, and serum lipid.
post procedure. The clinical events including TIA, stroke (both anterior and posterior circulation), myocardial infarction or any death were recorded as clinical outcomes. The digital subtraction angiography (DSA) follow-up was performed usually at 6 months after the surgery. The angiographic assessment was performed according to the decision of the physicians once the patient had recurrent stroke or TIA. ISR was defined as greater than 50% stenosis within or immediately (within 5 mm) adjacent to the stent11. Patients with ISR but no occlusion were treated with balloon angioplasty alone or stent re intervention.
Statistical Analysis The data analysis was performed using SPSS version 22.0 (SPSS Inc., Chicago, IL). ISR and clinical events during follow-up were evaluated using Kaplan-Meier analysis. To evaluate the differences between the ISR group and no ISR group, categorical data were compared using Pearson's chisquare or Fisher exact tests; continuous variables were analyzed by student t tests for normal distributed data or MannWhitney U tests for skewed data. Significant variables in the univariate analyses were further put into a multivariate Cox regression analysis with backward elimination modeling. P less than .05 was considered statistically significant.
Results A total of 206 patients (age range, 42-82 years) who had undergone 229 stents implantation were included in the analysis. Table 1 summarizes the baseline characteristics.
Clinical and Angiographic Outcomes during Follow-up With mean clinical follow-up of 32.7-month (range: 4-29 months), 23 patients (23/206, 11.2%) had clinical events. Of those, 4 patients died of nonstroke related diseases; 1 patient had TIA; 5 patients suffered from cerebral hemorrhage; and the other 13 patients experienced cerebral infarction. Kaplan-Meier curve for clinical event was constructed (Fig. 1), which showed that the cumulative clinical event-free survival was 98% at 12 months and 94% at 24 months after stent placement. The ISR was identified in the 30 patients (30/206, 14.6%) with 31 lesions (31/ 229, 13.5%) with the mean follow-up duration of 11.1-month (range: 3-92 months). In our study, Kaplan-Meier curve for ISR (Fig. 2) showed that the cumulative ISR rate was 7%, 21% and 34% at 6, 12 and 24 months after the procedure, respectively. Among 30 patients with ISR, three (10.0%) had clinical events. Of those, 1 patient died of stroke; 1 patient died of nonstroke related diseases; and 1 patient experienced cerebral infarction.
Predictors for ISR Clinical and Angiographic Follow-up The clinical follow-up was performed by telephone interview or clinic visits at 1, 3, 6, 12 months and yearly thereafter
Table 2 shows the comparisons of clinical, demographic, and procedure characteristics between the two groups. Stent diameter, stent type, smoking, and diabetes
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Table 1. Baseline characteristics N (%)/mean § SD Male Age (years) Risk factors Coronary artery disease Hypertension Diabetes Smokers History of alcohol use TG (mM) TC (mM) HDL (mM) LDL (mM) Symptoms Transient ischemic attack Stroke Medication situation Lipid modulating therapy Hypoglycemic therapy Location of stenting LVAO RVAO Stent diameter (mm) Stent length (mm) Lesion length (mm) Stent type BMS SES Residual stenosis (%) Clinical events
182 (88.3) 64.45 § 8.38 17 (8.3) 157 (76.2) 48 (23.3) 109 (52.9) 56 (27.2) 1.46 § .76 4.09 § 1.06 1.05 § .27 2.45 § .90 8 (3.9) 48 (23.3) 193 (93.7) 44 (21.4) 108 (47.2) 121 (52.8) 4.16 § .83 15.15 § 2.57 8.18 § 3.16 198 (86.5) 31 (13.5) 2.84 § 7.84 23 (11.2)
Abbreviations: SD, Standard deviation; TG, Triglyceride; TC, total cholesterol; HDL, High density lipoprotein; LDL, Low density lipoprotein; TIA, Transient ischemic attack; LVAO, Left vertebral artery ostium; RVAO, Right vertebral artery ostium; BMS, Balloon-expandable bare-metal stent; SES, Sirolimus-eluting stent Risk factors represent the medical history before the procedure and blood lipids in the first few days before the operation, and medication situation represent the use of the drugs after the surgery. Symptoms, TIA and stroke represent manifestations of posterior circulation ischemia.
Figure 1. Kaplan-Meier estimates of cumulative clinical event (TIA, stroke [both anterior and posterior circulation], myocardial infarction or any death) rate among patients with stenting in VAO.
Figure 2. Kaplan-Meier estimates of cumulative ISR rate among patients with stenting in VAO.
were analyzed in a multivariate Cox regression model. The results showed that stent diameter (hazard ratio = .504, 95% confidence interval: .294-.864) was an independent predictor with stent type, smoking, and diabetes as covariates.
Discussion Our study found that the rate of ISR after VAO stenting was acceptable, and the main risk factor of ISR in VAO in China might be the stent diameter. The stent implantation of posterior circulation remains controversial. Vertebral artery Ischemic Stenting Trial shows that medical treatment is favored for intracranial vertebral stenosis because of higher operative risk.7,9 In contrast, the stent implantation of extracranial symptomatic vertebral stenosis has been acknowledged as a safe option for reducing long term stroke risk.7,9 Nevertheless, ISR remains an important issue after the stent placement. However, there has been a huge difference on the ISR rate after VAO stenting due to the diversity of included case series, the disparity in the experience and technology of interventional neuroradiologists, the discrepancy on diagnosis of ISR, the difference of management of patient after the procedure and durations of follow-up, and so forth. A prospective multicenter study12 showed that the rate of restenosis occurred in VAO lesions after 1 year (50%) can be as high as 67%, but Tsutsumi et al13 found that the restenosis rate (>70%) was 0% (0/12) and 8% (1/12) after the mean follow-up duration of 12-month and 31.5month, respectively. In contrast to ISR in VAO (27.0%, 17/63) after the mean follow-up duration of 12.5-month in our center in 2009,14 the observed ISR rate (13.5%, 31/ 229) after the mean follow-up duration of 11.1-month in the study was significantly reduced. During the latest 5 years, we emphasized on the standard medical management of the ISR (antiplatelets, statins, antihypertensive drugs, etc.), which eventually leading to overall reduced ISR rate. In general, ISR occured at around 6 months after BMS implantation.15 Owing to the invasion of DSA and difficulty of follow-up, the average follow-up period for
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Table 2. Comparisons of clinical, demographic, and procedure characteristics between the two groups Predictor
ISR 50% (n = 176)
ISR > 50% (n = 30)
P
Age Male Hypertension Diabetes Coronary artery disease Smokers History of alcohol use TG TC HDL LDL Medication situation Lipid modulating therapy Hypoglycemic therapy Symptoms TIA Stroke Stent diameter (mm) Stent length (mm) Lesion length (mm) Location of stenting LVAO RVAO Stent type BMS SES Residual stenosis (%)
64.22 § 8.40 154 (87.5) 136 (77.3) 40 (22.7) 13 (7.4) 92 (52.3) 45 (25.6) 1.44 § .71 4.12 § 1.09 1.06 § .27 2.48 § .93
65.80 § 8.27 28 (93.3) 21 (70.0) 8 (26.7) 4 (13.3) 17 (56.7) 11 (36.7) 1.56 § 1.03 3.89 § .90 .98 § .27 2.33 § .73
.340 .540 .387 .644 .282 .656 .207 .563 .278 .175 .429
164 (93.2) 36 (20.5)
29 (96.7) 8 (26.7)
.697 .443
6 (3.4) 41 (23.3) 4.21 § .88 15.13 § 2.64 8.12 § 3.43
2 (6.7) 7 (23.3) 3.87 § .29 15.29 § 2.12 8.58 § 2.87
.329 .996 <.001 .753 .478
90 (45.5) 108 (54.5)
18 (58.1) 13 (41.9)
.191
171 (86.4) 27 (13.6) 2.78 § 7.65
27 (87.1) 4 (12.9) 3.23 § 9.01
.999 .768
Abbreviations: ISR, In-stent restenosis; TG, Triglyceride; TC, Total cholesterol; HDL, High density lipoprotein; LDL, Low density lipoprotein; TIA, Transient ischemic attack; LVAO, Left vertebral artery ostium; RVAO, Right vertebral artery ostium; BMS, Balloon-expandable bare-metal stent; SES, Sirolimus-eluting stent
the most research on ISR assessed by DSA was around 6 months to 2 years. In order to explore the ISR rate after 3 years, 5 years or even further, longer follow-up periods are needed. Our data indicated that smaller diameter of stent was at higher risk of ISR after stent placement in VAO, which was consistent with the conclusion of the previous study in our center.14 The previous published studies16,17 on restenosis in percutaneous coronary interventions had provided us with a definitive insight into the role of vessel caliber on restenosis, namely, smaller artery size was probably a contributing factor for restenosis. Lederman et al18 indicated that ISR in renal artery interventions might be related to the diameter of the artery, moreover, the ISR rate (36%) in smaller than 4.5 mm in diameter was higher compared with ISR rate (12%) in larger than 4.5 mm. Therefore, we presume that stenting in smaller artery in VAO might lead to stagnation and produce microscopic injuries of the segment more easily, then ISR occurs. This will provide an insight into the choice of patients who might be beneficial from stenting in VAO for the interventional neuroradiologists. Different types of stents were successfully developed for clinical application with the progress of science and
technology. A multicenter randomized study19 showed that SES restenosis rate was significantly lower than BMS after coronary stenting. Nevertheless, Raghuram et al20 showed no superiority of DES in preventing ISR in VAO, which was consistent with our results. This might be explained by the difference of BMS in coronary artery and VAO. However, the BMS (Express Vascular SD) that were used in our study were approved for renal arteries.21 Nonetheless, Albuquerque et al22 pointed out that VAO was rich in elastin and smooth muscle, and always had large movement as well as subclavian artery, which most likely lead to ISR after stenting. Nevertheless, the occurrence of ISR was not entirely explained by the anatomy and histology of the vessel per se. Moreover, Hatano et al23 described that coronary stents were easy to deploy, but might not withstand high recoil force and large movement at VAO, leading to stent fracture and deformity with restenosis, compared with Palmaz stent. Thus, we surmise that the use of SES as the coronary stents might be a possible risk factor of ISR in VAO. Nevertheless, the previous studies24,25 indicated that DES outperformed BMS in preventing ISR in VAO. Hence, the randomized controlled studies are needed to explore whether or not DES could reduce ISR in VAO. In the last decades,
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bioabsorbable stent was used in the patients with coronary lesions.26 However, it has not been applied to the patients with vertebral artery lesions at present. This maybe the direction of further exploration. Based on data from our study, history of smoking, diabetes, dyslipidaemia before the procedure, and female sex were not independent risk factors of ISR after stenting in VAO. However, the previous trials27,28 highlighted that smoking was involved in high rate of restenosis (50%) in VAO. The different conclusion might be due to the difference of included case series and diverse ethnic background, and so forth. Zhou et al14 described that diabetes was also a risk factor of ISR in VAO, but could not predict future restenosis. After coronary stenting, Kornowski et al29 proposed that diabetes could lead to exaggerated intimal hyperplasia, nevertheless, Kubo et al30 showed that the significant distinction of intimal hyperplasia was not observed at 8-month follow-up between the diabetes and non-diabetes. Furthermore, Sakata et al31 reported that smaller lumen at postprocedure might be responsible for the follow-up lumen after coronary DES placement in diabetes, rather than enhancement of neointimal hyperplasia. These differences highlighted the need for standardized prevention program after the procedure. That is, smoking cessation, alcohol restriction and the standard managements of blood pressure, blood glucose, and serum lipid are essential. The previous studies32,33 identified that smoking, diabetes, dyslipidaemia, and female sex were concerned with high rate of restenosis after carotid artery stenting. This may be due to the anatomic and physiological differences between the anterior and posterior circulation. Additionally, Wang et al34 put forth an independent risk factor of ISR in intracranial vertebral artery that was residual stenosis. From our data, residual stenosis was not an independent risk factor. The difference could be due to residual stenosis less than or equal to 30% in our study. Of those patients had clinical events, 17.4% (4/23) patients with mean age 71.5 years old had death due to nonstroke related diseases during mean clinical follow-up duration of 20 months in our study, which demonstrated that an adequate evaluation was essential before stenting for the patients with no long life expectancy. The rate of clinical events occurred in patients with ISR was even slightly lower than overall incidence in our investigation, which made us surmise that smooth neointimal hyperplasia of some degree might not be completely bad, even relatively benign23 or active interventions were applied to the patients with ISR when restenosis was first discovered. In order to further explore the relation between the clinical events and ISR, larger sample size of randomized controlled studies are warranted in the future. Strengths of our study lie on detailed evaluation of the stents. However, the limited event rate did not allow powerful analysis on the predictors for ISR and the clinical effect of ISR. Longitudinal studies with larger sample size are warranted.
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Conclusion The ISR after VAO stent implantation was acceptable, and the stent diameter was the independent predictor. Larger sample sized studies are needed.
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Incidence and Predictors of the In-stent Restenosis after Vertebral Artery Ostium Stenting Wanhong Chen, MD,*,† Fang Huang, MD,* Min Li, MD,* Yongjun Jiang, MD, PHD,‡ Jianbo He, MD,† Huiqi Li, MD,† Zheng Dai, MD,§ Wei Shi, MD,║ Mingyue Zhu, MD,{ Guanghui Chen, MD, PHD,* Fang Yang, MD, PHD,* and Renliang Zhang, MD, PHD* Background: The incidence and predictors for in-stent restenosis (ISR) was not fully explored. We aim to investigate the incidence and predictors of ISR after stenting at the origin of vertebral artery. Materials and Methods: Two hundred and six patients with 229 stents implantation between July 1, 2005 and July 31, 2015 were included in the study. All patients underwent conventional clinical and angiographic (digital subtraction angiography) follow-up at around 6 months post procedure. ISR was defined as greater than 50% stenosis within or immediately (within 5 mm) adjacent to the stent. Multivariate Cox regression analyses were utilized to investigate the predictors for ISR. Results: The ISR was found in 30 patients (30/206, 14.6%) with 31 lesions (31/229, 13.5%) with the mean follow-up duration of 11.1-month (range: 3 - 92 months). Stent diameter (hazard ratio 0.504, 95% confidence interval 0.294 - 0.864) was an independent predictor for ISR. Conclusion: ISR rate after Vertebral artery ostium stent placement is acceptable, which was conversely associated with the stent diameter. Key Words: In-stent restenosis—Vertebral artery ostium—Ischemic stroke— Atherosclerotic stenosis © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.
Introduction
From the *Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province 210002; †Department of Neurology, Xi'an XD group hospital, Xi'an, Shanxi Province 710077, China; ‡Department of Neurology, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province 510260; §Department of Neurology, Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu Province 214023; ║Department of Intensive Care Unit, The Affiliated Brain Hospital with Nanjing Medical University, Nanjing, Jiangsu Province 210009; and {Department of Intensive Care Unit, The Third Affiliated Hospitial of Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province 210001, China. Received January 28, 2018; revision received May 27, 2018; accepted June 24, 2018. Conflicts of Interest: None. Address Correspondence to Renliang Zhang, MD PHD, and Fang Yang, MD PHD, Department of Neurology, Jinling Hospital, Medical School of Nanjing University, 305#East Zhongshan Road, Nanjing, Jiangsu Province 210002, China. E-mail: [email protected]; [email protected] 1052-3057/$ - see front matter © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2018.06.031
Vertebral artery ostium (VAO) is regarded as the most common stenotic position in posterior circulation ischemic stroke.1 Patients with atherosclerotic stenosis of 50% or more in VAO might exert a higher risk on the occurrence and recurrence of stroke or death.2-4 However, the treatment of posterior circulation stroke remains a great challenge. In addition to intensive medical therapy, stenting in VAO was safe and effective for preventing stroke.5,6 Although the primary endpoint (any stroke during follow-up) of Vertebral artery Ischemic Stenting Trial showed no statistical deference between stenting and medical treatment arms,7 the study would lend a perspective to the benefit from extracranial vertebral artery stenting which might reduce recurrent stroke.7-9 One of the problems for stenting in VAO is in-stent restenosis (ISR), which is induced by the excessive neointimal hyperplasia in the lumen of stent and the thrombosis in the stent. Lin et al study10 found that CYP2C19 mutations might be a risk factor of ISR in patients with
Journal of Stroke and Cerebrovascular Diseases, Vol. &&, No. && (&&), 2018: pp 16
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vertebral artery stent placement. However, the incidence and predictors for ISR was not fully investigated. Therefore, our study aims to explore the incidence and predictors of ISR after VAO stent implantation in Chinese patients.
Materials and Methods Patient Information Between July 1, 2005 and July 31, 2015, all the patients were retrieved from the Nanjing stroke registry that was an ongoing single center prospective database on stroke in Jinling Hospital in Nanjing. In the study, patients were included if they met the following criteria: (1) symptomatic stenosis greater than or equal to 50% in VAO (defined as transient ischemic attack [TIA] or stroke in the territory of vertebral artery); (2) asymptomatic stenosis greater than or equal to 70% in the VAO; (3) successful stent implantation and residual stenosis Less than or equal to 30%; (4) the imaging and clinical data were available. Patients were excluded if (1) non-atherosclerosis; (2) poor quality of the imaging.
Stent Implantation Protocol Dual antiplatelet drugs (aspirin 100 mg and clopidogrel 75 mg) were prepared for at least 3 days prior to the stent placement. The procedure was performed under local anesthesia by the senior neuroradiologists. A 6-French sheath was placed in the femoral artery and systemic heparinization with activated clotting time of 2-3 times the baseline was maintained during the procedure. Then, A 6-French guiding catheter (Cordis, Miami Lakes, FL) was placed in the subclavian artery over a .035-in. guide wire. Next, stenotic lesions were crossed with .014-in. guidewires (Cordis) under road-map fluoroscopy. The appropriate stent was subsequently used to the lesion. The diameter of the deployed stent was based on the diameter of the distal normal vessel and the length of the stent had to cover 3-5 mm of normal lumen on either side of the lesion. Balloonexpandable bare-metal stents (BMS) (Express Vascular SD; Boston Scientific Corporation, Natick, MA) were deployed as the first choice. Drug-eluting stents (DES) (sirolimus-eluting stent [SES] Firebird2 stent; MicroPort Medical, Shanghai, China) as coronary stents were used only when BMS implantation was predicted to be challenging due to the tortuosity of the proximal vertebral artery. Finally, angiography was performed to evaluate the residual stenosis. Dual antiplatelet drugs (aspirin and clopidogrel) were continued for at least 6 months and then switched to aspirin for lifelong. All patients were given a standardized prevention program, including smoking cessation, alcohol restriction, management of blood pressure, blood glucose, and serum lipid.
post procedure. The clinical events including TIA, stroke (both anterior and posterior circulation), myocardial infarction or any death were recorded as clinical outcomes. The digital subtraction angiography (DSA) follow-up was performed usually at 6 months after the surgery. The angiographic assessment was performed according to the decision of the physicians once the patient had recurrent stroke or TIA. ISR was defined as greater than 50% stenosis within or immediately (within 5 mm) adjacent to the stent11. Patients with ISR but no occlusion were treated with balloon angioplasty alone or stent re intervention.
Statistical Analysis The data analysis was performed using SPSS version 22.0 (SPSS Inc., Chicago, IL). ISR and clinical events during follow-up were evaluated using Kaplan-Meier analysis. To evaluate the differences between the ISR group and no ISR group, categorical data were compared using Pearson's chisquare or Fisher exact tests; continuous variables were analyzed by student t tests for normal distributed data or MannWhitney U tests for skewed data. Significant variables in the univariate analyses were further put into a multivariate Cox regression analysis with backward elimination modeling. P less than .05 was considered statistically significant.
Results A total of 206 patients (age range, 42-82 years) who had undergone 229 stents implantation were included in the analysis. Table 1 summarizes the baseline characteristics.
Clinical and Angiographic Outcomes during Follow-up With mean clinical follow-up of 32.7-month (range: 4-29 months), 23 patients (23/206, 11.2%) had clinical events. Of those, 4 patients died of nonstroke related diseases; 1 patient had TIA; 5 patients suffered from cerebral hemorrhage; and the other 13 patients experienced cerebral infarction. Kaplan-Meier curve for clinical event was constructed (Fig. 1), which showed that the cumulative clinical event-free survival was 98% at 12 months and 94% at 24 months after stent placement. The ISR was identified in the 30 patients (30/206, 14.6%) with 31 lesions (31/ 229, 13.5%) with the mean follow-up duration of 11.1-month (range: 3-92 months). In our study, Kaplan-Meier curve for ISR (Fig. 2) showed that the cumulative ISR rate was 7%, 21% and 34% at 6, 12 and 24 months after the procedure, respectively. Among 30 patients with ISR, three (10.0%) had clinical events. Of those, 1 patient died of stroke; 1 patient died of nonstroke related diseases; and 1 patient experienced cerebral infarction.
Predictors for ISR Clinical and Angiographic Follow-up The clinical follow-up was performed by telephone interview or clinic visits at 1, 3, 6, 12 months and yearly thereafter
Table 2 shows the comparisons of clinical, demographic, and procedure characteristics between the two groups. Stent diameter, stent type, smoking, and diabetes
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Table 1. Baseline characteristics N (%)/mean § SD Male Age (years) Risk factors Coronary artery disease Hypertension Diabetes Smokers History of alcohol use TG (mM) TC (mM) HDL (mM) LDL (mM) Symptoms Transient ischemic attack Stroke Medication situation Lipid modulating therapy Hypoglycemic therapy Location of stenting LVAO RVAO Stent diameter (mm) Stent length (mm) Lesion length (mm) Stent type BMS SES Residual stenosis (%) Clinical events
182 (88.3) 64.45 § 8.38 17 (8.3) 157 (76.2) 48 (23.3) 109 (52.9) 56 (27.2) 1.46 § .76 4.09 § 1.06 1.05 § .27 2.45 § .90 8 (3.9) 48 (23.3) 193 (93.7) 44 (21.4) 108 (47.2) 121 (52.8) 4.16 § .83 15.15 § 2.57 8.18 § 3.16 198 (86.5) 31 (13.5) 2.84 § 7.84 23 (11.2)
Abbreviations: SD, Standard deviation; TG, Triglyceride; TC, total cholesterol; HDL, High density lipoprotein; LDL, Low density lipoprotein; TIA, Transient ischemic attack; LVAO, Left vertebral artery ostium; RVAO, Right vertebral artery ostium; BMS, Balloon-expandable bare-metal stent; SES, Sirolimus-eluting stent Risk factors represent the medical history before the procedure and blood lipids in the first few days before the operation, and medication situation represent the use of the drugs after the surgery. Symptoms, TIA and stroke represent manifestations of posterior circulation ischemia.
Figure 1. Kaplan-Meier estimates of cumulative clinical event (TIA, stroke [both anterior and posterior circulation], myocardial infarction or any death) rate among patients with stenting in VAO.
Figure 2. Kaplan-Meier estimates of cumulative ISR rate among patients with stenting in VAO.
were analyzed in a multivariate Cox regression model. The results showed that stent diameter (hazard ratio = .504, 95% confidence interval: .294-.864) was an independent predictor with stent type, smoking, and diabetes as covariates.
Discussion Our study found that the rate of ISR after VAO stenting was acceptable, and the main risk factor of ISR in VAO in China might be the stent diameter. The stent implantation of posterior circulation remains controversial. Vertebral artery Ischemic Stenting Trial shows that medical treatment is favored for intracranial vertebral stenosis because of higher operative risk.7,9 In contrast, the stent implantation of extracranial symptomatic vertebral stenosis has been acknowledged as a safe option for reducing long term stroke risk.7,9 Nevertheless, ISR remains an important issue after the stent placement. However, there has been a huge difference on the ISR rate after VAO stenting due to the diversity of included case series, the disparity in the experience and technology of interventional neuroradiologists, the discrepancy on diagnosis of ISR, the difference of management of patient after the procedure and durations of follow-up, and so forth. A prospective multicenter study12 showed that the rate of restenosis occurred in VAO lesions after 1 year (50%) can be as high as 67%, but Tsutsumi et al13 found that the restenosis rate (>70%) was 0% (0/12) and 8% (1/12) after the mean follow-up duration of 12-month and 31.5month, respectively. In contrast to ISR in VAO (27.0%, 17/63) after the mean follow-up duration of 12.5-month in our center in 2009,14 the observed ISR rate (13.5%, 31/ 229) after the mean follow-up duration of 11.1-month in the study was significantly reduced. During the latest 5 years, we emphasized on the standard medical management of the ISR (antiplatelets, statins, antihypertensive drugs, etc.), which eventually leading to overall reduced ISR rate. In general, ISR occured at around 6 months after BMS implantation.15 Owing to the invasion of DSA and difficulty of follow-up, the average follow-up period for
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Table 2. Comparisons of clinical, demographic, and procedure characteristics between the two groups Predictor
ISR 50% (n = 176)
ISR > 50% (n = 30)
P
Age Male Hypertension Diabetes Coronary artery disease Smokers History of alcohol use TG TC HDL LDL Medication situation Lipid modulating therapy Hypoglycemic therapy Symptoms TIA Stroke Stent diameter (mm) Stent length (mm) Lesion length (mm) Location of stenting LVAO RVAO Stent type BMS SES Residual stenosis (%)
64.22 § 8.40 154 (87.5) 136 (77.3) 40 (22.7) 13 (7.4) 92 (52.3) 45 (25.6) 1.44 § .71 4.12 § 1.09 1.06 § .27 2.48 § .93
65.80 § 8.27 28 (93.3) 21 (70.0) 8 (26.7) 4 (13.3) 17 (56.7) 11 (36.7) 1.56 § 1.03 3.89 § .90 .98 § .27 2.33 § .73
.340 .540 .387 .644 .282 .656 .207 .563 .278 .175 .429
164 (93.2) 36 (20.5)
29 (96.7) 8 (26.7)
.697 .443
6 (3.4) 41 (23.3) 4.21 § .88 15.13 § 2.64 8.12 § 3.43
2 (6.7) 7 (23.3) 3.87 § .29 15.29 § 2.12 8.58 § 2.87
.329 .996 <.001 .753 .478
90 (45.5) 108 (54.5)
18 (58.1) 13 (41.9)
.191
171 (86.4) 27 (13.6) 2.78 § 7.65
27 (87.1) 4 (12.9) 3.23 § 9.01
.999 .768
Abbreviations: ISR, In-stent restenosis; TG, Triglyceride; TC, Total cholesterol; HDL, High density lipoprotein; LDL, Low density lipoprotein; TIA, Transient ischemic attack; LVAO, Left vertebral artery ostium; RVAO, Right vertebral artery ostium; BMS, Balloon-expandable bare-metal stent; SES, Sirolimus-eluting stent
the most research on ISR assessed by DSA was around 6 months to 2 years. In order to explore the ISR rate after 3 years, 5 years or even further, longer follow-up periods are needed. Our data indicated that smaller diameter of stent was at higher risk of ISR after stent placement in VAO, which was consistent with the conclusion of the previous study in our center.14 The previous published studies16,17 on restenosis in percutaneous coronary interventions had provided us with a definitive insight into the role of vessel caliber on restenosis, namely, smaller artery size was probably a contributing factor for restenosis. Lederman et al18 indicated that ISR in renal artery interventions might be related to the diameter of the artery, moreover, the ISR rate (36%) in smaller than 4.5 mm in diameter was higher compared with ISR rate (12%) in larger than 4.5 mm. Therefore, we presume that stenting in smaller artery in VAO might lead to stagnation and produce microscopic injuries of the segment more easily, then ISR occurs. This will provide an insight into the choice of patients who might be beneficial from stenting in VAO for the interventional neuroradiologists. Different types of stents were successfully developed for clinical application with the progress of science and
technology. A multicenter randomized study19 showed that SES restenosis rate was significantly lower than BMS after coronary stenting. Nevertheless, Raghuram et al20 showed no superiority of DES in preventing ISR in VAO, which was consistent with our results. This might be explained by the difference of BMS in coronary artery and VAO. However, the BMS (Express Vascular SD) that were used in our study were approved for renal arteries.21 Nonetheless, Albuquerque et al22 pointed out that VAO was rich in elastin and smooth muscle, and always had large movement as well as subclavian artery, which most likely lead to ISR after stenting. Nevertheless, the occurrence of ISR was not entirely explained by the anatomy and histology of the vessel per se. Moreover, Hatano et al23 described that coronary stents were easy to deploy, but might not withstand high recoil force and large movement at VAO, leading to stent fracture and deformity with restenosis, compared with Palmaz stent. Thus, we surmise that the use of SES as the coronary stents might be a possible risk factor of ISR in VAO. Nevertheless, the previous studies24,25 indicated that DES outperformed BMS in preventing ISR in VAO. Hence, the randomized controlled studies are needed to explore whether or not DES could reduce ISR in VAO. In the last decades,
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bioabsorbable stent was used in the patients with coronary lesions.26 However, it has not been applied to the patients with vertebral artery lesions at present. This maybe the direction of further exploration. Based on data from our study, history of smoking, diabetes, dyslipidaemia before the procedure, and female sex were not independent risk factors of ISR after stenting in VAO. However, the previous trials27,28 highlighted that smoking was involved in high rate of restenosis (50%) in VAO. The different conclusion might be due to the difference of included case series and diverse ethnic background, and so forth. Zhou et al14 described that diabetes was also a risk factor of ISR in VAO, but could not predict future restenosis. After coronary stenting, Kornowski et al29 proposed that diabetes could lead to exaggerated intimal hyperplasia, nevertheless, Kubo et al30 showed that the significant distinction of intimal hyperplasia was not observed at 8-month follow-up between the diabetes and non-diabetes. Furthermore, Sakata et al31 reported that smaller lumen at postprocedure might be responsible for the follow-up lumen after coronary DES placement in diabetes, rather than enhancement of neointimal hyperplasia. These differences highlighted the need for standardized prevention program after the procedure. That is, smoking cessation, alcohol restriction and the standard managements of blood pressure, blood glucose, and serum lipid are essential. The previous studies32,33 identified that smoking, diabetes, dyslipidaemia, and female sex were concerned with high rate of restenosis after carotid artery stenting. This may be due to the anatomic and physiological differences between the anterior and posterior circulation. Additionally, Wang et al34 put forth an independent risk factor of ISR in intracranial vertebral artery that was residual stenosis. From our data, residual stenosis was not an independent risk factor. The difference could be due to residual stenosis less than or equal to 30% in our study. Of those patients had clinical events, 17.4% (4/23) patients with mean age 71.5 years old had death due to nonstroke related diseases during mean clinical follow-up duration of 20 months in our study, which demonstrated that an adequate evaluation was essential before stenting for the patients with no long life expectancy. The rate of clinical events occurred in patients with ISR was even slightly lower than overall incidence in our investigation, which made us surmise that smooth neointimal hyperplasia of some degree might not be completely bad, even relatively benign23 or active interventions were applied to the patients with ISR when restenosis was first discovered. In order to further explore the relation between the clinical events and ISR, larger sample size of randomized controlled studies are warranted in the future. Strengths of our study lie on detailed evaluation of the stents. However, the limited event rate did not allow powerful analysis on the predictors for ISR and the clinical effect of ISR. Longitudinal studies with larger sample size are warranted.
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Conclusion The ISR after VAO stent implantation was acceptable, and the stent diameter was the independent predictor. Larger sample sized studies are needed.
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