Korean Journal of Cerebrovascular Surgery 2005;7(2):135-142.
Published online June 1, 2005.
Usefulness of Drug-Eluting Stents in Angioplasty and Stenting of the Vertebral Artery Origin : Comparison with Bare Stents: Clinical Research.
Kim, Jin Sung , You, Seung Hoon , Kim, Seong Rim , Kim, Sang Don , Kim, Young Woo , Park, Ik Seong , Baik, Min Woo , Kim, Moon Chan
1Department of Neurosurgery, Holly Family Hospital, Catholic University of Korea, Bucheon, Korea. minwookr@hfh.cuk.ac.kr
2Department of Neurosurgery, Kangnam St. Mary's Hospital, Catholic University of Korea, Seoul, Korea.
Abstract
OBJECT: In the treatment of coronary atherosclerosis, drug-eluting stents are effective in decreasing the rate of major adverse cardiac events and angiographic restenosis compared with bare metal stents. However, the benefits and safety of using these new devices in the cerebral vasculature have not been evaluated. To assess the effectiveness of drug-eluting stents in the cerebral vasculature, the authors analyzed clinical and angiographic results after percutaneous transluminal angioplasty and stenting in patients with vertebral artery origin stenosis. METHODS: Ninety-one patients with 99 vertebral origin stenoses treated with percutaneous endovascular balloon angioplasty and stent placement during a period of 5.1 years (September 1999-October 2004). Follow-up angiograms were obtained from 38 patients with 42 lesions (24 men, 14 women ; mean age, 61.9 yrs ; mean follow-up period, 9.1 months). We reviewed the clinical and radiological records of these patients. RESULTS: Bare stents were implanted in 30 lesions, while drug-eluting stents were implanted in 12 lesions, with a mean residual stenosis of 5.1 %. The overall rate of moderate-to-severe restenosis (> or =50%) was 31.0 % (13 of 42 cases). The restenosis rate in the bare stent group was 36.7 %, compared with 16.7 % in the drug-eluting stent group (p=0.282). Comparing the restenosis rate in stented lesions with reference diameters less than 3.5 mm (11 with bare stents, 12 with drug-eluting stents), the restenosis rates were 63.6 % in the bare stent-group and 16.7 % in the drug-eluting stent-group (p=0.029). CONCLUSION: Drug-eluting stents placed in vertebral artery origin stenosis have lower restenosis rate than bare stents, particularly in small-sized vessels.
Key Words: Bare stent, Drug-eluting stent, Restenosis, Vertebral artery origin

Introduction


  
Atherosclerotic stenosis of the vertebral artery most commonly occurs at its origin, and embolization from such lesions is an important cause of posterior circulation stroke, which accounts for one-fourth of all ischemic strokes.3)6)8)16)22)31) While initial management with platelet inhibitors and anticoagulants is warranted, arch and four vessel angiographic studies are needed if symptoms continue despite appropriate medical management. Since Sundt et al.37) reported the first successful treatment of the vertebrobasilar system by intraoperative percutaneous transluminal angioplasty(PTA) in 1980, multiple case reports and clinical studies have described the successful use of PTA.10)16)17)18)21)28)34)38) In a recent study, Albuquerque et al.1) reported that vertebral origin angioplasty and stenting(VOAS) is prone to moderate-to-severe restenosis despite a technical success rate of 97% and low incidence of complications. 
   Improving on the VOAS techniques, drug-eluting stents have been shown to reduce the incidence of restenosis in coronary artery lesions.4)12)27)41)42) However, there are few reports about the effectiveness and complications of these new devices in the cerebral vasculature.24)
   We assessed the rate of restenosis after VOAS by comparing the angiographic follow-up of patients receiving bare stents and drug-eluting stents.

Clinical Material and Methods

1. Patient characteristics and stent selection
  
From September 1999 to October 2004, 91 patients(60 men, 31 women) underwent VOAS in 99 vessels. Patients ranged from 38 to 78 years of age(mean 63.0±8 years). We typically require that candidates for VOAS have persistent posterior circulation ischemic symptoms despite appropriate medical therapy or demonstrate angiographic risk factors that predispose them to stroke. About two-thirds of the patients met both criteria, while the other one-third of the patients presented with anterior circulation transient ischemic attacks(TIAs) and/or stroke, and demonstrated vertebral artery origin stenosis that predispose them to posterior circulation stroke.
   Until September 2003, only bare stents were implanted. Since then, drug-eluting stents(Cypher stent, Cordis Corp, a Johnson & Johnson Company, Miami Lakes, FL) were implanted in most cases where the diameter of the vertebral artery was less than 3.5 mm. Because of the limitation in diameter of the Cypher stent, only a bare stent was used in cases where the vertebral artery measured more than 3.5 mm. Follow-up angiograms were obtained from 38 patients with 42 lesions(24 men, 14 women; mean age, 61.9 yrs;mean follow-up period, 9.1 months). Of 38 patients, 24 patients presented with posterior circulation TIAs or stroke while the other 14 patients presented with anterior circulation TIAs or stroke. Among the latter 14 patients, 7 patients had posterior circulation infarct lesions on magnetic resonance imaging without symptoms, and the other 7 patients had only angiographic risk factors. Bare stents were implanted in 30 lesions and drug-eluting stents in 12 lesions, with a mean residual stenosis of 5.1%(Table 1). We reviewed the clinical and radiological records of these patients, and compared the restenosis rate between the bare stent group and the drugeluting stent group. 

2. Endovascular technique
  
All patients undergoing elective angioplasty and stenting were given dual antiplatelet therapy for at least 7 days preoperatively, which consisted of aspirin(300 mg/d orally) and clopidogrel(Plavix;Bristol-Myers Squibb/Sanofi Pharmaceuticals, New York, NY)(75 mg/d orally). Dual therapy was continued indefinitely or switched to monotherapy after at least 12 weeks(aspirin 200 mg/d orally). All endovascular procedures were performed under local anesthesia by a single neurosurgeon. A 6 F sheath was inserted percutaneously under local anesthesia into the right or left femoral artery. A 6 F guiding catheter was then inserted into the subclavian artery over an exchange wire. A balloon-expandable stent loaded over a 0.014 inch(0.35 mm) wire was introduced through the guiding catheter. After guiding the wire through the stenosis by roadmapping, the stent was placed across the stenosis with the proximal end positioned at the origin of the vertebral artery from the subclavian artery. The stent was deployed at the same time the stenosis was dilated by inflation of the angioplasty balloon. This procedure was performed under anticoagulation treatment with intravenous heparin, which was followed by nadroparin calcium(Fraxiparin; 2850 IU anti-Factor Xa, Sanofi Winthrop Industrie, Ambares, France) dosed at 0.3 ml SC q 12 hours for three days following the procedure.

3. Measurement of vertebral restenosis
  
All digital subtraction angiograms were analyzed by a neurosurgeon who was not involved in the stenting procedures. The angiographic view that best demonstrated the origin of the diseased vertebral artery was identified during the pre-stenting angiography. This optimal view was used as the working view for stent placement and immediate post-stenting angiography. The angle of the chosen working view was recorded and reproduced during follow-up angiography. The degree of vertebral orifice stenosis was calculated as the percent stenosis from the catheter angiogram using the following formula:
   Percent stenosis(%)=100×(1-S/N), where S is the diameter of the residual lumen at the point of maximum stenosis and N is the width of the disease-free distal vertebral artery at the point where the walls were approximately parallel. Restenosis was quantified according to the vessel diameter achieved immediately after the patient's original angioplasty and stenting. The percent of vertebral artery restenosis was categorized into two groups: insignificant to mild restenosis (0-49%), and moderate to severe restenosis (50-100%).1)

4. Statistical analysis
  
Between-group comparisons were made for age, sex, diameter of the disease-free distal vertebral artery, length of stenosis, preoperative percent stenosis, angulation of the proximal vertebral artery, follow-up interval, concomitant tandem arterial diseases, type of stent used, and clinical data such as hypertension, diabetes mellitus, smoking history, and familial history of cardiovascular diseases and/or stroke. We compared continuous variables by using Student's t-tests and compared categorical variables by using Chi-Square tests. Comparisons were made according to confidence intervals of 95%. All statistical tests were two-sided and all analyses were performed using statistical software(SPSS for Win-dows, 11.0 standard version). A probability value less than 0.05 was considered statistically significant.

Results

1. Angiographic findings
  
The origin of the left vertebral artery was stented 27 times while the right was stented 15 times. All of the stents were coronary premounted balloon-expandable stents (Table 1). VOAS were successful in all 42 lesions and no complications were associated with the procedure. The mean diameter of the vertebral artery distal to the lesion was 3.4±0.7 mm. The mean percent stenosis before procedure was 62.4±12.2%, whereas the residual stenosis was 5.1±7.4 % immediately after stent deployment. Follow-up angiograms were obtained in 42 lesions at a mean of 9.1±12.0 months after procedure. The mean percent of restenosis was 38.3±21.7% on the follow-up angiograms. Each of the documented restenoses occurred as "in-stent" restenoses, as a sequela of recurrent atheromastous plaque formation and/or intimal hyperplasia. In two cases, restenosis occurred as a result of the stent fracture. However, in no cases was the vessel lumen stenotic as a result of stent recoil or stent kinking. On the other hand, the overall rate of moderate-to-severe restenosis(≥50%) was 31.0%(13 of 42 cases). The data comparison between the group of insignificant-to-mild restenosis and that of the moderate-to-severe restenosis group is shown in Table 2. There were more concomitant tandem artery stenoses in the moderate-to-severe restenosis group than in the insignificant-to-mild restenosis group(Chi-square test, 61.5% vs. 7.0%, p=0.021). All other factors, such as the mean age of the patients, reference diameter of the diseased vertebral artery, preoperative percent stenosis, length of the lesion, angulation of the proximal vertebral artery, follow-up interval, and the type of stent deployed were not significantly different between the two groups (Table 2). There was no association between the development of restenosis and past medical disease history including hypertension, diabetes mellitus, familial history of cardiovascular disease or stroke, and smoking history.
  
The angiographic data was reassessed according to the type of stent(bare stent vs. drug-eluting stent, Table 3). There was no significant correlation between the type of stents and the restenosis rate. However, the follow-up interval and the diameter of the vertebral artery were significantly different (10.9±13.8 months vs. 4.6±1.4 months, p=0.020;3.6±0.6 mm vs. 2.8±0.3, p=0.000). As shown in Table 4, there was no association between the follow-up interval and the restenosis rate, especially in cases with a follow-up interval within 6 months. Because the diameter of the Cypher stent was 3.5 mm or less, we compared the restenosis rate in lesions with a reference diameter less than 3.5 mm(11 with bare stents, 12 with drug-eluting stents). The restenosis rates were 63.6 % in the bare stent group and 16.7 % in the drugeluting stent group (p=0.036)(Table 5). There was no significant difference between these two groups in any other characteristics measured.
   In the bare stent group, we specified the standard vertebral artery diameter as 3.5 mm and found a significant difference between the smaller diameter and larger diameter groups in development of moderate-to-severe restenosis(Chi-square test, 63.6 % vs. 21.1 %, p=0.047;Table 6). There was also a linear relationship between the diameter of the vertebral artery and the percent restenosis in the bare stent group (p=0.002), and a linear regression plot of the reference diameter of the vertebral artery versus the percent restenosis is shown in Fig. 1. However, there was no correlation in the drug-eluting stent group (Fig. 1).

2. Clinical findings
  
Results of clinical follow up were available for 38 patients with 42 lesions at a mean follow-up period of 9.1±12.0 months. We specifically assessed the impact of VOAS on posterior circulation TIA or stroke. Twenty-four patients that presented with posterior circulation TIA or stroke improved or were cured of their symptoms after VOAS regardless of restenosis. The remaining fourteen patients had no change in their symptoms after the procedure. No correlation between the persistence or recurrence of symptoms and severity of restenosis was identified. 
   There were no complications associated with the sirolimus-eluting stent such as infection, hypersensitivity reaction, or other unexplained but suspicious phenomena.2)12)39)

Discussion

   The introduction of stenting to angioplasty for the treatment of carotid and peripheral arterial stenoses has improved long-term patency rates.11)13)20)28)33)36) Typically, VOAS is associated with a low morbidity rate and a high technical success rate.9)20)25)30)32)36) In a recent report, however, the combined rate of moderate-to-severe restenosis was much higher than previously expected.1) In that report, the higher rate of concomitant brachiocephalic stenoses(94%) and longer follow up periods(16.2 months) were regarded as the causes for the higher rate of restenosis than that reported in previous studies.1) In our study, the restenosis rate was 31.0%, which is more favorable than the observations of these investigators. However, in our study, patients received either bare stents or drug-eluting stents, especially in the small vertebral artery, which is within the diameter limitations of the Cypher stent. The drug-eluting stent has been known to have anti-proliferative and anti-inflammatory actions on the vascular wall, and many authors have reported its effectiveness in the prevention of restenosis in coronary stenting.4)12)24)27)40)41) Considering the suspected mechanisms of restenosis after vertebral artery origin angioplasty and stenting, such as intimal hyperplasia and/or atheromastous plaque formation, drug-eluting stents may be effective in preventing restenosis in VOAS.1) However there have been few reports about its usefulness in the cerebral vasculature.24) We first compared the results between the bare stent and drug-eluting stent in the origin of the vertebral artery. 
  
In the bare stent group, degree of restenosis after VOAS seemed to be influenced by the caliber of the disease-free vertebral artery just distal to the ostial lesion, and concomitant arterial disease such as brachial artery stenosis and/or atheroma near the orifice of the vertebral artery(Fig. 2). A comparison may be made with renal ostial stenting, which is associated with a higher rate of restenosis than treatment of more distal arterial segments.7)14)23)35) In a review of 363 procedures for renal artery orifice stenosis, Lederman et al.23) documented an overall angiographic restenosis rate of 21%. When this population is analyzed on the basis of the treated segment size, patients with treated vessels smaller than 4.5 mm had a 36% restenosis rate, compared with 12% in patients with arteries larger than 4.5 mm.23) In our study, there was a significant difference in restenosis rates between the cases with a vertebral arterial size of less than 3.5 mm and those of a larger caliber in the bare stent group(Table 6). On the other hand, a much lower rate of restenosis was observed in the drug-eluting stent group, in which all of the vertebral arteries measured less than 3.5 mm in diameter.
   Of the thirty cases in which a bare stent was used, five cases had tandem arterial disease and the others did not. Four of those five cases(80%) developed moderate or severe restenosis, while 7 of the other 25 cases(28%) did(p=0.047). However, the restenosis rate did not seem to be influenced by the presence of tandem arterial disease in those cases where a drug-eluting stent was used, though the number of cases was small. Concomitant arterial disease is suspected to be an important factor contributing to restenosis in the bare stent group. This seems to be associated with simultaneous disease progression within the vertebral artery orifice, though this association has not been substantiated by pathological or epidemiological studies.
  
The suspected causes of restenosis after VOAS must be considered, including pathological and technical factors. Specifically, the anatomy and histology of the vertebral artery origin most likely contribute to a higher rate of restenosis.11)12)19)29) The ostial segment of the artery, much like the coronary and renal ostia, is characterized by a large amount of elastin and smooth muscle, both of which could produce high recoil forces after angioplasty and stenting.11)12)19)29) If this were the case,



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