US Wingspan Registry
12-Month Follow-Up Results
Background and Purpose—The purpose of this study is to present 12-month follow-up results for a series of patients undergoing percutaneous transluminal angioplasty and stenting with the Gateway-Wingspan stenting system (Boston Scientific) for the treatment of symptomatic intracranial atherostenosis.
Methods—Clinical and angiographic follow-up results were recorded for patients from 5 participating institutions. Primary end points were stroke or death within 30 days of the stenting procedure or ipsilateral stroke after 30 days.
Results—During a 21-month study period, 158 patients with 168 intracranial atherostenotic lesions (50% to 99%) were treated with the Gateway-Wingspan system. The average follow-up duration was 14.2 months with 143 patients having at least 3 months of clinical follow-up and 110 having at least 12 months. The cumulative rate of the primary end point was 15.7% for all patients and 13.9% for patients with high-grade (70% to 99%) stenosis. Of 13 ipsilateral strokes occurring after 30 days, 3 resulted in death. Of these strokes, 76.9% (10 of 13) occurred within the first 6 months of the stenting procedure and no events were recorded after 12 months. An additional 9 patients experienced ipsilateral transient ischemic attack after 30 days. Most postprocedural events (86%) could be attributed to interruption of antiplatelet medications (n=6), in-stent restenosis (n=12), or both (n=1). In 3 patients, the events were of uncertain etiology.
Conclusions—After successful Wingspan percutaneous transluminal angioplasty and stenting, some patients continued to experience ipsilateral ischemic events. Most of these ischemic events occurred within 6 months of the procedure and were associated with the interruption of antiplatelet therapy or in-stent restenosis.
The Gateway balloon-Wingspan stent system (Boston Scientific, Fremont, CA), a stenting system specifically designed for the cerebrovasculature, became commercially available in the United States in 2005. The US Wingspan Registry is a 5-center collaboration in which data were prospectively collected from 158 consecutively treated patients with symptomatic intracranial atherostenosis.1 Procedural success was defined as completion of Gateway balloon angioplasty and Wingspan stent placement across the target lesion despite the degree of residual stenosis or any complications related to the procedure. Primary end points were stroke or death within 30 days of the stenting procedure or ipsilateral stroke after 30 days. Although in selected patients, the periprocedural safety of the treatment compared favorably to the documented natural history of the disease treated medically, angiographic follow-up revealed significant rates of in-stent restenosis (ISR) and occlusion.2 These findings raised a question regarding the durability of the procedure and the susceptibility of treated patients to experience continued ipsilateral ischemic events after successful treatment.
In the present study, we report the longer-term outcomes of patients treated with the Gateway-Wingspan system. Clinical data from patients meeting primary end points were evaluated in an attempt to determine a probable cause for treatment failure.
Patients and Methods
Patient and Institutional Enrollment
Patients with symptomatic intracranial atherostenosis undergoing attempted treatment with the Wingspan system were prospectively enrolled into a multicenter intention-to-treat registry (US Wingspan Registry) that included the Barrow Neurological Institute, Cleveland Clinic, State University of New York at Buffalo, University of Texas Southwestern, and University of Wisconsin. The Institutional Review Board at each institution approved the use of the Wingspan system under a Humanitarian Device Exemption as well as the collection and sharing of registry data among the participating centers.
Clinical and angiographic data were typically collected at the time of the initial procedure and at 3 to 6 months and 12 to 15 months. Clinical data were also collected at discharge and between 2 and 6 weeks after the original procedure.
Percutaneous transluminal angioplasty and stenting (PTAS) was performed using the Wingspan system as described previously.1 In brief, access was typically achieved through the common femoral artery. Most cases were performed through a 6-Fr guiding catheter or long sheath system. Heparinization was instituted to a targeted activated coagulation time of 250 to 300 seconds. In most cases, after conventional catheter-based angiography, an SL-10 (Boston Scientific, Natick, MA), Prowler-10 (Cordis), or Echelon-10 (Microtherapeutics, Irvine, CA) microcatheter was manipulated across the target lesion using a 0.014-inch Synchro (Boston Scientific) or Transcend EX Soft Tip (Boston Scientific) microwire. The microcatheter was then exchanged over a 0.014-inch exchange microwire for a Gateway angioplasty balloon. The remaining lesions were primarily crossed with the Gateway angioplasty balloon and 0.014-inch exchange-length microwire. In each case, the balloon diameter was sized to 80% of the “normal” parent vessel diameter. The balloon length was selected to match the lesion length. Angioplasty was typically performed with a slow, graded inflation of the balloon to a pressure of between 6 and 12 atmospheres for approximately 120 seconds. After angioplasty, the balloon was removed and conventional angiography was repeated.
Next, the Wingspan delivery system was prepared and advanced over the exchange wire across the target lesion. The stent diameter was sized to exceed the diameter of the normal parent vessel by 0.5 to 1.0 mm. The stent length was selected to equal or exceed the length of the angioplasty balloon and to completely cover the entire diseased segment. The diameter of the stenotic lesion was measured using biplane angiography and compared with a reference diameter of the normal vessel (usually proximal to the lesion) per the technique used in the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) study.3
All patients were pretreated with antiplatelet agents (aspirin and clopidogrel); most were discharged on both aspirin (325 mg daily) and clopidogrel (75 mg daily). The dual antiplatelet regimen was usually maintained until follow-up angiography was performed. Provided that no ISR had developed, clopidogrel was usually discontinued after follow-up angiography. All patients remained on aspirin therapy (325 mg daily) indefinitely after treatment.
Imaging follow-up was available for 138 lesions. Most of the lesions (n=109) were evaluated with conventional catheter-based angiography. In some cases, lesions were evaluated with CT angiography (n=28). If the entire stented segment as well as the proximal and distal parent vessel was well visualized and widely patent on CT angiography, these stents were designated as demonstrating “no ISR.” If a region of the stented segment or adjacent parent vessel could not be adequately visualized, catheter angiography was performed. In cases in which the findings on the cross-sectional imaging were ambiguous or suggestive of ISR, conventional angiography was performed. In 1 case, only MR angiography was available as a follow-up examination.
At angiographic follow-up, the minimum luminal diameter was identified and measured. The percentage of residual or recurrent stenosis was calculated using the WASID technique.3 ISR was defined as a lesion demonstrating (1) >50% stenosis (ie, within or immediately adjacent [within 5 mm] to the stent); and (2) >20% of absolute luminal loss. The measurements were made by the authors at each institution and then adjudicated by 1 investigator (D.J.F.). Lesion retreatment was performed at the discretion of the primary operator.
Clinical Event Adjudication
Scheduled clinical follow-up occurred at the time of discharge and at 2 to 6 weeks, 3 to 6 months, and 12 to 15 months after the Wingspan procedure. Any stroke or death occurring during or within 30 days of the procedure or any stroke within the ipsilateral vascular distribution after 30 days was counted as a primary neurological end point. For the purpose of the present analysis, any hemorrhagic or ischemic event resulting in a new neurological deficit lasting >24 hours was considered a stroke. Any ischemic event resulting in a transient neurological deficit that resolved within 24 hours was considered a transient ischemic attack (TIA) regardless of the neuroimaging findings. The distribution of the stroke (ipsilateral or other) was adjudicated on the basis of the neurological findings evaluated within the context of any available neuroimaging study. End point adjudication was determined by investigators at the individual sites.
During a 21-month study period, 158 patients with 168 intracranial atherostenotic lesions (50% to 99% severity) were treated with the Gateway-Wingspan system. Patients (95 men, 63 women) ranged in age from 33 to 86 years (average age, 62.7 years). Ninety patients presented with a qualifying event of stroke (57%). The average stenosis treated measured 75.2%, and 115 of the treated lesions (69%) were in the 70% to 99% stenosis range at presentation. Periprocedural stroke was encountered in 9 patients (5.7%). In 4 patients (2.5%), these strokes ultimately resulted in death.
Of the initial group of 158 patients, 147 were eligible for 3-month follow-up evaluation allowing for loss to periprocedural primary end points (n=9) or nonneurological death occurring after 30 days (n=2). A total of 143 of these patients (97.3%) had at least 3 months of clinical follow-up. One hundred ten of 127 eligible patients (86.6%) had at least 12 months of follow-up. The average length of clinical follow-up for the registry patients was 14.2 months.
The cumulative rate of the primary end point was 15.7% for all patients and 13.9% for patients with high-grade (70% to 99%) stenosis. Of 13 ipsilateral strokes occurring after 30 days, 3 resulted in death. Ten of 13 (76.9%) of the ipsilateral strokes that occurred after the 30-day periprocedural period occurred within 6 months of the procedure, and no events were recorded after 12 months. An additional 9 patients experienced an ipsilateral TIA after 30 days. The composite rate of either stroke or TIA between 30 days and 12 months was 20% (22 total events in 110 patients with 12-month clinical follow-up).
Most postprocedural events (86%) were associated with interruption of antiplatelet medications (n=6), ISR (n=12), or both (1). In 3 patients, the events were of uncertain etiology. Specifically, for the 13 patients meeting the primary end point with ipsilateral ischemic stroke after 30 days, 5 were believed to be due to ISR and 5 to the interruption of antiplatelet medication; and in 3, a specific cause was not determined. Patients experiencing stroke from interruption of antiplatelet medications presented between 2 and 9.5 months (average, 4.4 months) postprocedure (Figure 1 through 3). Patients experiencing stroke as a result of ISR presented between 3.5 and 11.5 months (average, 6.9 months) postprocedure (Figure 4). Two patients who experienced stroke at 10.5 and 11.5 months, respectively, skewed the average time of presentation for stroke associated with ISR. These patients had been transiently symptomatic with ISR at earlier time points and had undergone ≥1 repeat angioplasties before ultimately presenting with stroke from recurrent ISR. The average time of presentation for patients with an unknown cause of stroke was 3.2 months (range, 1.5 to 5 months). In the 9 patients experiencing an ipsilateral TIA after 30 days, 7 events were associated with ISR, 1 to the interruption of antiplatelet medication; and in 1 patient, both factors were present.
The most important findings derived from the present analysis of the US Wingspan Registry are (1) some patients continue to experience ipsilateral ischemic events after initial successful PTAS with the Gateway-Wingspan system; (2) most of these delayed events can be attributed to defined factors, either early interruption of antiplatelet medication or ISR; and (3) these delayed ischemic events most frequently occurred within the first 6 months after treatment.
The Gateway-Wingspan system was introduced in 2005 as a novel strategy for the treatment of symptomatic intracranial atherosclerosis. The initial experience with the system indicated that the angioplasty and stenting procedure could be achieved with rates of periprocedural stroke (approximately 5%) that compared very favorably with event rates in selected high-risk patients treated medically.1,3–5 However, midterm angiographic follow-up results from 2 independently conducted single-arm registries revealed rates of ISR or complete stent occlusion that ranged between 25 and 35%.2,6–8 These rates of late luminal loss were considerably higher than those reported in the initial Eurasian Humanitarian Device Exemption study.7 Although the majority of patients with ISR were asymptomatic, approximately one third presented with ipsilateral ischemic symptoms.2,6,8 These findings provoked questions about the durability of the treatment modality and the potential for ongoing ischemic events after initially successful treatment. The goal of the present analysis was to address this issue.
Event Rates After the Periprocedural Period
In the present study, some patients continued to accrue ipsilateral ischemic events after initially successful PTAS. These delayed events accounted for almost two thirds of the total number of cumulative events, exceeding those incurred during the actual PTAS procedure. The National Institutes of Health Wingspan Registry reported a 5% to 6% rate of delayed ipsilateral stroke after the periprocedural period in patients with high-grade (70% to 99%) symptomatic stenosis.5 However, although this study provides an excellent assessment of the periprocedural risk of the procedure in >100 patients, 12-month follow-up results were available for very few patients (n=15). As such, these data are probably not sufficient to allow an accurate estimation of postprocedural event rates.5 In the present study, there was no difference observed in either the periprocedural or postprocedural event rates between the overall group (50% to 99% stenosis) and those patients presenting with high-grade (70% to 99%) stenosis.
Thus, although the periprocedural stroke risk associated with the PTAS procedure itself (approximately 5%) appears far lower than the risk associated with high-grade (70% to 99%) symptomatic stenosis treated medically (20% to 25% over the first year), the ischemic events occurring beyond the periprocedural period in patients undergoing stenting make the risk profile of the 2 treatment strategies appear far more comparable.3,9,10 As such, a direct comparison between the stenting procedure and medical therapy, as is currently underway in the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) trial, will be necessary to definitively determine whether stenting can provide a meaningful additional benefit to medical therapy in high-risk patients.11
Etiology of Delayed Events
In addition to better defining the overall risks related to Wingspan PTAS, it is critical to make an attempt to ascertain the circumstances under which the Wingspan stenting procedure might fail beyond the periprocedural period. In the present study, 2 predictable factors seemed to be associated with the majority (86%) of delayed ischemic events, the interruption of antiplatelet therapy and the development of ISR.
Approximately 40% of delayed strokes were associated with the interruption of antiplatelet medications. Early discontinuation of antiplatelet medications typically results from patient nonadherence, discontinuation in response to hemorrhage or a perceived risk of hemorrhage, in preparation for an upcoming invasive/surgical procedure, or at the discretion of the patient's primary physician. Conceivably, these events could be largely overcome by more aggressive and proactive education of patients, their families, and all their managing physicians. Dual antiplatelet therapy was typically continued during the present study for 3 to 6 months with discontinuation of clopidogrel contingent on angiographic follow-up confirming the absence of ISR. Thus, intensive clinical follow-up and assurance of adherence to the recommended antiplatelet regimen is most critical during this initial 90- to 180-day period. In the present series, only 1 delayed ipsilateral stroke could be attributed to the interruption of antiplatelet medications after 6 months and this patient had stopped taking all antiplatelet medications.
ISR represents a potential limitation of any stenting procedure. In the present series, ISR was associated with almost 40% of postprocedural stroke events. In addition, the majority of patients within the registry underwent scheduled imaging surveillance of their stents as part of routine clinical follow-up. When identified at follow-up, ISR was typically managed with the continuation of dual antiplatelet therapy. When patients experienced new neurological symptoms or late luminal loss to the extent that the recurrent stenosis was of a severity greater than or equivalent to the presenting lesion before treatment, repeat angioplasty was typically performed. As such, the reported recurrent stroke risk attributable to ISR was observed in the setting of a fairly proactive program of imaging surveillance, medical management, and interventional retreatment. Thus, it seems that measures to reduce the delayed morbidity associated with ISR may be limited to strategies designed to improve the existing devices such as the development of drug-eluting balloons, a drug-eluting version of the current self-expanding stent platform, or an optimization of the degree of chronic outward force exerted by the device on the vessel wall.12,13
Timing of Delayed Events
The vast majority (80%) of delayed ischemic symptoms (both TIAs and strokes) occurred within 6 months of treatment. The timing of these events correlates well with the “risk period” of the 2 major factors responsible for recurrent ischemia. The discontinuation of antiplatelet medications is likely to become less of a risk with time as the implanted stent becomes fully “endothelialized” and incorporated into the parent artery. Similarly, the risk associated with ISR is almost exclusively incurred during the first 3 to 6 months after the stenting procedure. Those patients who experienced stroke attributable to ISR at later time points had been symptomatic earlier with TIAs and then represented with stroke after developing recurrent ISR months after angioplasty. The available literature suggests that after this initial 3- to 6-month postprocedural period, the tissue ingrowth along the stented segment stabilizes and, in some cases, actually undergoes a process of reorganization to become somewhat more compact, resulting in partial regression of the angiographic stenosis. This process of stabilization and/or spontaneous regression of ISR has been documented for both coronary and intracranial stents.14,15 The present data suggest that if patients with ISR do not become symptomatic during this initial 3- to 6-month period after the procedure and an appropriate medication regimen is maintained, it is unlikely that they will ultimately become symptomatic in follow-up.
Although the present report represents the longest follow-up of a large series of patients with intracranial atherosclerosis treated with the Wingspan-Gateway system, it is important to acknowledge that the present data set has some significant limitations. Most importantly, not all eligible patients were available for follow-up at the 12-month time period (13% were lost to follow-up by 1 year). Because there is no guarantee that the patients who were lost to follow-up had event rates that were similar to those who were followed to (and beyond) 12 months, it is important to acknowledge that this represents a potential source of bias with respect to the reported 1-year event rates.
After successful PTAS, some patients may continue to experience ipsilateral ischemic events. Most of these events occur within 6 months of the procedure. These ischemic events can largely be attributed to premature interruption of antiplatelet medications or ISR.
Sources of Funding
The US Wingspan Registry was supported by a research grant from Boston Scientific; however, all data collection, analysis, and interpretation were performed by the authors independent of Boston Scientific's input or interpretation.
B.A.-K. received research support (<$10 000) from Micrus Registry (co-Principal Investigator) and other (unpaid) from the Matrix And Platinum Science (MAPS) trial (Prinicipal Investigator). F.C.A. is a consultant/Advisory Board (<$10 000) of Codman-Micrus and ev3/Covidien. D.J.F. received a research grant (>$10 000) from SAMMPRIS (National Institutes of Health) and Wingspan Registry (Boston Scientific); other research support (>$10 000) from MicroIntervention (terminated 2009) and Siemens Medical; honoraria (>$10 000) from MicroVention (terminated in 2010) and Micrus-JNJ; has ownership interest (>$10 000) in Micrus-JNJ; is a consultant/Advisory Board (>$10 000) Micrus-JNJ; and is a consultant/Proctor (unpaid) for ev3/Covidien and NFocus. L.N.H. received research grants (>$10 000) from Abbott, Boston Scientific, Cordis, ev3/Covidien Vascular Therapies, and Toshiba; owns stock/shareholder (>$10 000) in AccessClosure, Boston Scientific, Cordis, Micrus, and Valor Medical; receives royalties (>$10 000) from Cordis; is on the Speakers' Bureau (<$10 000) of Abbott Vascular; receives honoraria (<$10 000) from Bard, Boston Scientific, Complete Conference Management, Cordis, Cleveland Clinic, and SCAI; was an expert witness in various cases (each >$10 000); is a consultant/advisory board for Abbott (<$10 000), AccessClosure (>$10 000), Bard (<$10 000), Boston Scientific (>$10 000), Cordis (>$10 000), Gore (<$10 000), Lumen Biomedical (>$10 000), Micrus (until July 2010), and Toshiba (unpaid); other (>$10 000); and was Conference Director, Nurcon Conferences/Strategic Medical Seminars. E.I.L. received a research grant (>$10 000) from Boston Scientific; other research support (>$10 000) from Boston Scientific (Wingspan stents), Codman & Shurtleff (>$10 000), and ev3/Covidien Vascular Therapies (<$10 000); owns stock/shareholder in Intratech Medical (<$10 000) and Mynx/Access Closure (>$10 000); is a consultant for Codman & Shurtleff (>$10 000), TheraSyn Sensors, and ev3/Covidien Vascular Therapies (<$10 000); and received honoraria (<$10 000) from Boston Scientific, Carotid Stent Training (>$10 000) from Abbott Vascular and ev3/Covidien Vascular Therapies. G.L.P. received other research support/honorarium (<$10 000) from the SAMMPRIS trial steering committee. P.A.R. received a research grant (<$10 000) from Boston Scientific; honoraria (<$10 000) from Boston Scientific and Micrus Endovascular (terminated in 2010); and has ownership interest (>$10 000) in ev3/Covidien Vascular. A.S.T. received research grants from Biomerix (<$10 000), Boston Scientific (<$10 000), General Electric (GE; <$10 000), NFocus Neuromedical (>$10 000), and Pulsar Vascular (>$10 000); and is a consultant/Advisory Board/ownership interest (<$10 000) in Biomerix, Boston Scientific, Codman/Micrus, Penumbra, and Pulsar Vascular. H.H.W. received a research grant and other support (>$10 000) from Siemens; and is a consultant/Advisory Board (>$10 000) from Codman-Micrus Endovascular.
We thank Paul H. Dressel, BFA, for illustration preparation and Debra J. Zimmer for editorial assistance.
- Received January 14, 2011.
- Revision received February 1, 2011.
- Accepted February 16, 2011.
- © 2011 American Heart Association, Inc.
- Fiorella D,
- Levy EI,
- Turk AS,
- Albuquerque FC,
- Niemann DB,
- Aagaard-Kienitz B,
- et al
- Fiorella D,
- Woo HH
- Zaidat OO,
- Klucznik R,
- Alexander MJ,
- Chaloupka J,
- Lutsep H,
- Barnwell S,
- et al
- Bose A,
- Hartmann M,
- Henkes H,
- Liu HM,
- Teng MM,
- Szikora I,
- et al
- Fiorella DJ,
- Levy EI,
- Turk AS,
- Albuquerque FC,
- Pride GL Jr.,
- Woo HH,
- et al
- Kasner SE,
- Chimowitz MI,
- Lynn MJ,
- Howlett-Smith H,
- Stern BJ,
- Hertzberg VS,
- et al
- Kasner SE,
- Lynn MJ,
- Chimowitz MI,
- Frankel MR,
- Howlett-Smith H,
- Hertzberg VS,
- et al
- Turan TN,
- Derdeyn CP,
- Fiorella D,
- Chimowitz MI
- Posa A,
- Nyolczas N,
- Hemetsberger R,
- Pavo N,
- Petnehazy O,
- Petrasi Z,
- et al