Restenosis Rates following Vertebral Artery Origin Stenting: Does Stent Type Make a Difference?

ABSTRACT: Objectives. To compare our experience with sirolimus- and paclitaxel-eluting stents (drug-eluting stents [DES]) and non-drug-eluting stents (NDES) for treatment of vertebral artery (VA) origin stenosis and review the literature. Methods. A retrospective review of our prospectively collected database was performed. Clinical and radiologic follow up was obtained by reviewing office records and radiology. Data collected included demographics, comorbidities, presenting symptoms, stenosis severity, contralateral VA stenosis and/or carotid stenosis, type of stent used, angioplasty before or after stenting, post-treatment residual stenosis, clinical and radiological follow up and retreatment. Patients with symptomatic > 60% stenosis or asymptomatic > 70% stenosis and/or a hypoplastic or occluded contralateral VA or significant carotid occlusion were chosen for revascularization. Results. Thirty-five patients treated with NDES and 15 treated with DES for management of VA origin stenosis were identified. The technical success rate of the procedure was 100%. There were no procedural complications. There were 7 asymptomatic patients (NDES Group-4, DES Group-3). In the NDES Group, 9 patients had prestent angioplasty; 2 had post-stent angioplasty. In the DES group, 4 patients had post-stent angioplasty. Symptoms resolved in 30/31 (96.8%) patients treated with NDES and 11/12 (91.7%) treated with DES. Thirty-six patients had radiologic follow up (median 21.3 months); in-stent restenosis was documented in 11 patients (NDES 9/24 [38%], DES 2/12 [17%]). Among patients receiving NDES, restenotic lesions required angioplasty in 7 patients. No patients in the DES group required angioplasty. Conclusions. DES for treatment of VA origin stenosis may decrease the incidence of restenosis when compared to NDES. Validation in prospective, randomized, multicenter trials is necessary. J INVASIVE CARDIOL 2010;22:119–124 Key words: sirolimus- and paclitaxel-eluting stents, endovascular treatment, extracranial atherosclerotic disease, vertebral artery origin stenosis, restenosis The prevalence of vertebral artery (VA) origin stenosis varies from 20–40% in patients who have cerebrovascular disease.1–7 Posterior circulation atherosclerotic disease is a condition with a known potential for poor outcome as a result of stroke and related disability.2 Of patients experiencing posterior circulation transient ischemic attack, 22–35% will suffer an infarct within 5 years of the transient ischemic attack, with a mortality rate of 20–30%.1,7 The first line of therapy for patients with atherosclerotic VA origin stenosis has traditionally been antiplatelet medications or anticoagulation based on published carotid data, although the efficacy of this approach has not been established definitively.5 Failure of medical management prompts intervention, either open surgery or endovascular treatment. Surgery is usually successful technically, however, it is associated with high rates of procedural and periprocedural complications.8–10 Utilization of intravascular stents for the treatment of VA origin stenosis has been described in several small series and case reports in the literature.1,11–13 Although technical success rates have been reported as high, follow-up radiologic studies have documented in-stent restenosis to be a significant issue.1,14 Despite this, a large majority of the patients reported have had improvement in symptoms. The promising initial technical success rates with bare-metal stents, coupled with concerns over in-stent restenosis, have elicited a growing interest in the use of drug-eluting stents (DES) for the treatment of VA origin atherosclerotic disease.15–20 These stents have been used in the coronary circulation to minimize restenosis.21–23 DES utilize a strategy of coating a stent with an immunomodulatory (sirolimus) or antiproliferative (paclitaxel) medication that slowly releases the drug in vivo after deployment. The purpose of the present study is to compare our experience with sirolimus- and paclitaxel-eluting stents (DES) and stents not eluting sirolimus or paclitaxel (NDES) in the treatment of VA origin disease, and to review the literature.

Materials and Methods

A retrospective review of a prospectively collected database for endovascular procedures at a single center was performed to identify patients receiving stent treatment for VA origin stenosis. Clinical and radiologic follow up was obtained by review of office records and computed tomographic (CT) angiograms or digital subtraction angiograms. The study was approved by the institutional review board at our center. The data collected include patient demographics (age, sex), comorbidities (smoking, cardiovascular disease), presenting symptoms, degree of stenosis, presence of contralateral VA stenosis and/or carotid stenosis, type of stent used, angioplasty (before or after stenting), residual stenosis after treatment, clinical and radiological follow up and retreatment. Indication for treatment. Patients with symptomatic > 60% VA origin stenosis or asymptomatic patients with > 70% VA origin stenosis and/or a hypoplastic or occluded contralateral VA or significant carotid occlusion that could lead to an isolated hypoperfused territory were chosen for revascularization. The degree of stenosis was graded after catheterization of the subclavian artery and by comparison with the distal, nonstenosed segment of the VA. The choice of stent was simply operator-dependent. DES were not available at our center until 2003. Technique. Patients were given aspirin (325 mg per day) and clopidogrel (75 mg per day) for several days before treatment. If dual antiplatelet therapy had not been initiated 1 week or more prior to treatment, patients were given a loading dose of aspirin (650 mg) and clopidogrel (600 mg) on the day of the procedure. Most of the procedures were performed under conscious sedation to allow neurological examination during the procedure. Access to the subclavian artery was attained using a transfemoral or transradial approach, as dictated by the patient’s anatomy. After access, full heparinization was achieved with an activated coagulation time between 250 and 300 seconds. A standard hydrophilic guidewire and a guide catheter were normally used for access. In cases with marked tortuosity in the supra-aortic vessels, an 80 cm 6 French (Fr) shuttle sheath (Cook, Inc., Bloomington, Indiana) was used to provide a stable platform. For further stability and better control, a 0.014 inch or 0.018 inch guidewire may be placed in the ipsilateral axillary artery through the side port to support the guide catheter and prevent it from moving. Distal protection devices were not used because the smallest device available is smaller than the average VA diameter, and the use of the device might cause spasm or dissection. In our clinical experience with VA intervention, we have not found distal embolization to be a significant problem. Once the guide catheter was in position near the lesion to be treated, the lesion was crossed with a curved tip 0.014 inch or 0.018 inch microwire. The microwire was advanced in the distal VA and the stent was advanced across the VA origin lesion. Great care was taken to deploy the stent in such a position that very little of the stent protruded into the subclavian vessel. Coronary balloon-mounted stents are preferred, as they allow precise positioning of the stent in these patients. The maximum available diameter of the sirolimus-eluting stents was 3.5 mm, whereas the paclitaxel-eluting stents were available in diameters of up to 4.5 mm. Once the stent was deployed, post-deployment angioplasty was performed. In cases in which severe stenosis was present and a stent could not be advanced across the lesion, pre-stenting angioplasty was performed. Angiography was obtained after deployment of the stent (Figure 1). Patients were placed in the intensive care unit for 1 night after the procedure and maintained on aspirin and clopidogrel antiplatelet therapy for 3–6 months. Follow up. Symptom improvement was recorded at follow-up office visits, and CT angiograms were used to screen for in-stent restenosis. If there was a suggestion of restenosis (of > 50%), a digital subtraction angiogram was obtained. Angioplasty was performed at the time of follow up if there was > 50% in-stent restenosis. In patients in whom no in-stent restenosis was evident on CT angiography, this study alone was used for the follow-up radiologic image. The degree of stenosis before and after stenting was assessed by manual quantitative measures on imaging in which the stenotic region was compared with the normal vessel diameter distal to the poststenotic dilatation, if any.

Results

Thirty-five patients treated with NDES (between January 2001 and October 2008), and 15 patients treated with DES (2003–2008) for the management of VA origin stenosis were identified. Table 1 delineates the demographics of the patients treated. There were 4 asymptomatic patients in the NDES group, and 3 in the DES group. All asymptomatic patients had > 80% VA origin stenosis along with contralateral VA occlusion or ipsilateral carotid occlusion, except for 1 patient with 70% stenosis and a significant bilateral common carotid artery occlusion. In the NDES group, 9 patients had pre-stenting angioplasty and 2 underwent direct stenting and post-stent angioplasty. In the DES group, 4 patients underwent direct stenting and post-stent angioplasty. All the remaining patients in both groups underwent direct stenting. Symptoms resolved in 30 of 31 patients (96.8%) treated with NDES and 11 of 12 patients (91.7%) treated with DES (Table 1). Types of stents used. For patients receiving DES, 8 were treated with Cypher (Cordis Corp., Bridgewater, New Jersey) and 7 with Taxus Express2 (Boston Scientific Corp., Natick, Massachusetts) stents. The following NDES were used: AVE S7 (Medtronic, Inc., Sunnyvale, California), 1 patient; Express2 (Boston Scientific), 11 patients; Bx Velocity Hepacoat (Cordis), 9 patients; Herculink Elite (Abbott, Abbott Park, Illinois), 1 patient; Palmaz (Cordis), 1 patient; Penta (Guidant Corp., Santa Clara, California), 1 patient; Racer (Medtronic), 1 patient; Ultra (Guidant), 3 patients; Vision (Guidant), 6 patients; and Xact (Abbott), 1 patient. One patient included in the present series has been reported in a series of patients who received heparin-coated Bx Velocity stents in cervical and intracranial vessels.24 Technical success (successful stent deployment across the stenotic lesion) was achieved in all 50 patients treated for VA origin stenosis (Table 1). After deployment of the stent, less than 5% of patients in each treatment group had any degree of residual stenosis. Clinical follow up was available from 1–77 months for 30 of 35 patients treated with NDES and 1–28 months for 14 of 15 patients treated with DES. Radiological follow up was available for 24 patients in the NDES group and 12 patients in the DES group. Eleven patients (9 in the NDES group and 2 in the DES group) demonstrated restenosis. None of the recurrent VA stenoses progressed to complete occlusion. Two patients in the DES group had approximately 50% asymptomatic restenosis and were not treated with angioplasty. Of the 9 patients who had restenosis in the NDES group, 7 patients had > 50% symptomatic restenosis and were treated with angioplasty, whereas 2 patients had approximately 50% asymptomatic restenosis and were not treated with angioplasty.

Discussion

The use of intravascular stents to treat atherosclerotic disease at the VA origin is a natural extension of the treatment of atherosclerotic disease in other vascular beds.21–23,25,26 However, previous reports in which NDES stents were used for the treatment of VA origin stenosis1,3–5,11,12,15,27–32 have documented a fairly high incidence of restenosis. As in our series and previous reports (Table 2), the technical success rate for placing a stent at the VA origin is high, with a very low complication rate. In our series, pre-stenting angioplasty was required more often in the NDES group and more between 2001 and 2004. The reason is most probably that earlier versions of the NDES have a higher profile and require angioplasty before the stent system can be positioned in the VA. Refinements in engineering of these stents have rendered them low-profile and easier for the operator to position without angioplasty. Post-dilatation angioplasty was mainly used to flare open the orifice of the VA when it was found to be narrow after stent deployment. Follow-up data regarding the treatment of VA origin stenosis with NDES are more difficult to acquire. Table 2 documents a total of 304 such patients (including our series) reported in the literature. In this group of patients, follow-up angiography and radiologic studies were available for 194 patients, of whom 77 demonstrated significant restenosis (40%). This is consistent with what we found in the 35 patients we treated. In 24 of these patients in whom radiologic follow up was available, 9 had in-stent restenosis (38%). Albuquerque et al1 reported similar results, with a restenosis rate of 43.3%. These authors have raised the concept that there might be better options for the treatment of this disease. Interestingly, although most reports to date demonstrate a fairly significant restenosis rate, symptom improvement occurred in a high percentage of patients using NDES (83–100%) (Table 2). The high incidence of VA origin restenosis calls into question the difference between ostial atherosclerotic disease and that at other locations in the vessel. Albuquerque et al1 highlight the fact that there is increased elastin and smooth muscle at the orifice of vessels in other circulations (coronary and renal). This may set the stage for a poorer response to angioplasty and stenting, with increased recoil. In addition, the VA origin is a more mobile location, and increased mobility may raise a problem with an increased inflammatory response to the placement of a stent. If this is the case, DES would be ideal for the treatment of ostial lesions. Ostial lesions in the coronary bed are known to be associated with a higher incidence of restenosis than elsewhere.1,33 As DES were developed, utilization in the cardiac and peripheral vascular beds has been reported.21–23,34 DES utilize an immunomodulatory agent (sirolimus) or an antiproliferative agent (paclitaxel) in an attempt to minimize the inflammatory response to injury at the cellular level in atherosclerotic disease.35–37 In the coronary literature, there have been conflicting data regarding the utility of DES in large, > 3–3.5 mm coronary vessels.38–44 The theory behind this confusion is that for large arteries, the superiority of the DES is diminished because the same degree of neointimal hyperplasia develops, and the large arteries can more easily accommodate intimal hyperplasia than the small arteries.45 There is an evolving literature on the use of DES for the treatment of VA origin disease15–20,46,47 (Table 3). We identified 104 patients in the literature, including our series, who were treated with DES for VA origin stenosis. In this group of patients, follow-up angiography was available in 54 patients, with a documented incidence of significant in-stent restenosis in 6 patients (11%) (Table 3). Note should be made of the 2 instances from case reports of in-stent stenosis included in these 6, although we do not know the total number of cases performed by this team.47 This rate is substantially lower than the rate of 40% reported for NDES (Table 2). As with patients treated with NDES, those treated with DES had a low incidence of symptom recurrence. No patients with DES required angioplasty, whereas 7 patients with NDES required angioplasty during follow up. Study limitations. This retrospective chart review has the inherent bias associated with any retrospective study. The clinical and radiological follow-up period is short and incomplete. CT angiograms were used to assess the in-stent stenosis in most cases, and this is not the gold standard for assessing in-stent stenosis. The patients in the DES and NDES groups were not matched, had procedures at different time-points, and the indication for the selection of a stent was operator-dependent. Measurements of inflation pressures and minimal lumen diameters were not collected during chart review, and these factors might have partly accounted for differences in results in the DES and NDES groups. The analysis of previous reports to compare the restenosis rate may not be correct, as there is a bias in reporting only patients who had restenosis in case reports. Advances in stent technology over the years have led to stents with a lower profile that can be used without predilatation and distal protection devices that make this procedure safer. Despite these limitations, this series and review establishes and confirms the substantial difference in restenosis rates between the two groups. A randomized, controlled trial comparing DES, NDES and surgery with rigorous follow up is necessary.

Conclusion

In the present study and after review of the literature, substantially lower restenosis rates have been reported after DES implantation in comparison with NDES implantation for treatment of VA origin stenosis. Although restenosis remains a problem with VA origin disease, DES may help minimize this problem. Randomized, multicenter trials are needed to validate previous results. It is of interest that the symptoms improved in patients treated with either stent type, despite progression of stenosis. This may be a result of lesion stabilization, giving time for collateral circulation to develop. With continued advances in stent technology, it is hoped that success rates with VA origin stenosis using an endovascular approach will continue to improve. Acknowledgments. We thank Paul H. Dressel, BFA, for preparation of the illustrations and Joyce Davis and Debra J. Zimmer, AAS CMA-A, for editorial assistance.

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From ^aNeurovascular Service, Massachusetts General Hospital, Boston, Massachusetts; ^bDepartment of Neurosurgery and Toshiba Stroke Research Center; and ^cDepartment of Radiology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York; ^dDepartment of Neurosurgery, Millard Fillmore Gates Hospital, Kaleida Health, Buffalo, New York; and the ^eDepartment of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China. The authors report no financial or material support related to the content herein. Financial disclosures: Dr. Hopkins receives research study grants from Abbott (ACT 1 Choice), Boston Scientific (CABANA), Cordis (SAPPHIRE WW), and ev3 (CREATE) and a research grant from Toshiba (for the Toshiba Stroke Research Center); has an ownership/financial interest in AccessClosure, Boston Scientific, and Micrus; serves on the Abbott Vascular Speakers’ Bureau; receives honoraria from Bard, Boston Scientific, Cordis, and from the following for speaking at conferences – Complete Conference Management, Cleveland Clinic, and SCAI; serves as a consultant to or on the advisory board for Abbott, AccessClosure, Bard, Boston Scientific, Cordis, Gore, Lumen Biomedical, Micrus, and Toshiba; and serves as the conference director for Nurcon Conferences/Strategic Medical Seminars LLC. Dr. Levy receives research grant support (principal investigator: Stent-Assisted Recanalization in acute Ischemic Stroke, SARIS), other research support (devices), and honoraria from Boston Scientific and research support from Micrus Endovascular and ev3; has ownership interests in Intratech Medical Ltd. and Mynx/Access Closure; serves as a consultant on the board of Scientific Advisors to Codman Neurovascular/Cordis Corporation; serves as a consultant per project and/or per hour for Micrus Endovascular, ev3, and TheraSyn Sensors, Inc.; and receives fees for carotid stent training from Abbott Vascular and ev3. Dr. Levy receives no consulting salary arrangements. All consulting is per project and/or per hour. Dr. Ogilvy serves as a consultant to Mizuho America. Dr. Siddiqui has received research grants from the University at Buffalo and from the National Institutes of Health (NINDS 1R01NS064592-01A1, Hemodynamic induction of pathologic remodeling leading to intracranial aneurysms); is a consultant to Codman Neurovascular/Cordis Corporation, Concentric Medical, ev3, and Micrus Endovascular; serves on speakers’ bureaus for Codman Neurovascular/Cordis Corporation and Genentech; and has received honoraria from Genentech, Neocure Group LLC, American Association of Neurological Surgeons’ course, and an Emergency Medicine Conference and from Codman Neurovascular/Cordis Corporation for training other neurointerventionists. Dr. Siddiqui receives no consulting salary arrangements. All consulting is per project and/or per hour. Dr. Hauck, Ms. Lewis-Mason, Dr. Natarajan, Ms. Sun, and Dr. Yang have no financial relationships to disclose. Manuscript submitted July 6, 2009, provisional acceptance given August 18, 2009, final version accepted November 23, 2009. Address for correspondence: Christopher S. Ogilvy, MD, Neurosurgery, Wang 745, 55 Fruit Street, Boston, MA 02114. E-mail: cogilvy@partners.org

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