Current status of stenting in intracranial atherosclerotic disease: The story thus far and the way ahead
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.82744
Source of Support: None, Conflict of Interest: None
Despite medical management, symptomatic intracranial atherosclerotic disease has a high risk of stroke and death. This unacceptably high rate has provided the impetus for development and continuous advancements in the field of endovascular revascularization. From early attempts at angioplasty alone to state-of-the art stents including self-expanding and drug-eluting stents specially designed for the cerebral vessels, developments in this field has come a long way. As we stand today, however, there are still mixed views on the use of these endovascular techniques vs aggressive medical management. In this article, we review the mechanisms of stroke in patients with intracranial atherosclerotic disease and review the current status of stenting in this condition. A brief discussion of the important clinical and procedural considerations is also provided along with a mention of the ongoing trials likely to provide valuable information on the future of stenting.
Keywords: Intracranial angioplasty and stenting, intracranial atherosclerotic disease, primary intracranial angioplasty
Intracranial atherosclerotic disease (ICAD) is an important cause of stroke accounting for ~56% of strokes in Asians.  Despite medical treatment, an unacceptably high proportion of patients with symptomatic intracranial stenosis have recurrent ischemic events within the first year in the territory of the stenotic vessel.  Serious efforts have been made thus far using angioplasty and stenting as a means of improving up on medical therapy alone in the treatment of symptomatic intracranial stenosis. In this article, we present an overview of the mechanisms of stroke, natural history, and factors that predispose to recurrent strokes in patients with ICAD and also review the literature regarding the status of stenting in this condition, including certain important clinical and procedural considerations vital in ensuring optimum patient outcome.
In patients with ICAD, the mechanisms for stroke include (1) artery-to-artery embolism from the thrombus at the site of ulcerated plaques in the stenotic portion of the artery; (2) in situ thrombosis from plaque rupture or local thrombus formation with complete or near-complete occlusion of the stenotic segment; (3) perfusion-related ischemia as a result of significant reduction of blood flow distal to the stenotic segment, especially in the event of relative hypotension; and (4) ostial occlusion of perforators or larger branch vessels due to atherosclerotic disease. Though each of these mechanisms is potentially important, more than one mechanism may be responsible for the stroke in a given patient. ,
In Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) study patients with severe stenosis (≥70%), patients with recent symptoms (≤17 days) and women had a greater likelihood of recurrent ischemic event in the weeks or months after the initial event.  The Groupe d'Etude des Stenoses Intra-Craniennes Atheromateuses Symptomatiques study in addition suggested higher risk of recurrent stroke in patients with hemodynamically significant stenosis.  Overall, in patients with intracranial stenosis, recurrent stroke occurs in about 11% of patients within a year of the initial event in the same territory of the stenotic artery. 
Poor clinical outcome and recurrent events despite optimal medical management spurred interest in aggressive endovascular therapeutic options which have witnessed exciting technical advancements. The American Heart Association/American Stroke Association Stroke Council has not yet issued any specific guidelines for the prevention of recurrence of strokes in patients with ICAD.  The present data supporting endovascular strategies are collated from several reported case series as well as from single prospective multicentric trial. However, there is no level I evidence at present to support angioplasty and stenting in patients with symptomatic ICAD. We categorize different endovascular options based on the techniques and briefly review the literature and current status of these methods.
Primary intracranial angioplasty
Following the first successful intracranial balloon angioplasty reported by Sundt et al. in 1980,  many case series and retrospective studies have described the feasibility, short- and long-term outcomes of this technique. The reported technical success (reduction in stenosis by <59%) was 80%, stroke or 30-day mortality rates were 4 to 40%, and restenosis rates were 24 to 40%.  The complications of this technique included vessel spasm, intimal dissection, vessel rupture, and high restenosis rates. [Table 1] summarizes the reports of various studies of primary intracranial angioplasty (PTA). ,,,, These reports suggest that PTA is a technically feasible option in the treatment of ICAD achieving high initial success rate, however, with significant periprocedural morbidity and mortality. Prospective data regarding the efficacy in PTA is not available. Given the better results of stenting in coronary vasculature and its application to intracranial circulation, it hardly seems possible that a prospective comparison evaluating PTA and stenting will ever be feasible.
Intracranial angioplasty and stenting
With advancements in stent design and delivering technologies, stents can now be delivered safely, achieving higher technical success and lower complication rates. Theoretical advantages of stenting include radial force to resist elastic recoil of the artery, prevention in acute vessel occlusion, trapping of emboli, and prevent distal embolism and improve immediate- and long-term patency rates.  Three types of stents are investigated in intracranial stenosis-bare metal balloon-expandable, drug eluting balloon-expandable, and self-expanding stents.
Initial reports include small series using coronary stents found flexible enough to navigate into the cerebral vasculature with good immediate results and clinical outcomes. ,,,,,,, Stenting of Symptomatic Atherosclerotic Lesions in the Vertebral or Intracranial Arteries was a nonrandomized multicenter prospective trial evaluating the safety and feasibility of the NEUROLINK stent system (Guidant corporation), specifically designed for cerebral vasculature.  Of the 61 patients enrolled, 43 had anterior or posterior circulation ICAD. Technical success was achieved in 95% of the patients and 30-day stroke rate was 6.6%. Forty-two patients were followed up for one year and 7.3% of them had recurrent ischemic symptoms. Restenosis was observed in 32.4% of patients and more than one-third of the patients were symptomatic. Jiang et al. prospectively evaluated technical feasibility and outcome of Apollo stent (MicroPort medical [Shanghai], Shanghai, China), a new intracranial balloon-expandable stent with technical success rate of 91.7%.  Three patients (6.8%) developed minor stroke in a period of 30 days and one patient developed minor stroke at 6 months. Restenosis rate observed was 28% in this study and only one patient was symptomatic. Vajda et al. reported the results of easily navigable coronary stent (Coroflex blue, B Braun, Germany) in 25 patients with 30 lesions.  The lesions were located in both anterior and posterior circulation. Technical success was obtained in all the patients. The degree of stenosis reduction was to 26% from 61% following stenting. Two patients suffered transient and permanent neurological deficits. All patients had angiographic follow up and one-third of the patients showed significant restenosis and underwent retreatment. Kurre et al. reported the results of intracranial stenting using a new balloon-expandable Pharos Vitesse stent system (Micrus Endovascular, San Jose, CA).  In this study, a total of 21 patients were treated including seven patients with acute stroke. Periprocedural complication rates and mid-term follow-up results were similar to the previous reports. One patient developed stroke due to restenosis, while one died in the follow-up period. In the Vitesse Intracranial Stent Study for Ischemic Therapy (VISSIT) trial, the safety and efficacy of Pharos Vitesse stent is being evaluated against the best medical practice. [Table 2] summarizes reports of bare metal balloon-expandable stents used in ICAD.
High rates of restenosis using bare metal stents led to increasing interest in the use of drug-eluting stents (DES) in the intracranial circulation with most single-center case series reporting lower rates of restenosis. These stents however are rigid with potential neurotoxicity and late restenosis limiting their use. ,,,, [Table 3] summarizes the results of DES in ICAD.
The Wingspan stent system and Gateway percutaneous transluminal angioplasty balloon catheter (Boston Scientific) was the first self-expanding intracranial stent approved by Food and Drug Administration for intracranial use under humanitarian device exemption in the year 2005. It comprises of self-expanding nitinol stent preloaded in a delivery catheter and a separate Gateway balloon catheter. Wingspan study enrolled 45 patients from multiple centers with symptomatic anterior and posterior circulation ICAD of >50% stenosis. Technical success was achieved in 98% of patients and the mean stenosis reduction was to 31.9% from 74.9% following stenting. Two patients suffered stroke and one patient died of hemorrhagic stroke. Composite 1 month stroke/death rate was 4.5%. On follow-up, two patients suffered stroke, composite ipsilateral stroke at 6 month was reported to be 7.1%, and overall stroke rate was 9.7%. Angiographic study was available in 40 patients and restenosis was observed in three patients. In none of them it was symptomatic. Procedure-related adverse events with no lasting sequelae were reported in 12 patients. There was no incidence of in stent thrombosis, perforation, or dissection.
Fiorella et al. reported their experience with Wingspan stent system in symptomatic ICAD in 78 patients with 82 atheromatous lesions.  Technical success was achieved in 98.8% and there were five major periprocedural neurological complications (6.1%), of which four proved fatal. Two major complications were related to the device-vessel rupture after angioplasty and one microwire perforation. Five patients experienced dissections of extra/intracranial vasculature, and three patients needed stenting to maintain the patency. Mean stenosis improved from 74.6 to 27.2% following stenting. Periprocedural magnetic resonance imaging (MRI) was obtained in 38 patients within 72 hours of the procedure and more than one-third of these patients had new ischemic lesions. However, a majority of the lesions were asymptomatic. Data analysis of National Institute of Health (NIH) registry on the use of Wingspan stent for symptomatic ICAD (7-90%) showed a technical success rate of 96% in 129 patients.  Mean stenosis was reduced to 20% from 82% following the procedure. Incidence of major stroke/death within 24 hours of the treatment was 6.2% and any stroke, death, or hemorrhage within 30 days or ipsilateral stroke beyond 30 days was 14% at 6 months. Restenosis rate was 25% on angiographic follow-up. These two prospective registry analyses give us an insight into the real life experience of Wingspan stent system for the treatment of ICAD. The ongoing randomized trial (Stenting vs Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis -SAMMPRIS) compares aggressive medical management with stenting (Wingspan stent), and the results of this study will help optimize various treatment strategies and offer the best therapeutic option to the patient. 
A review analysis of intracranial stenting procedures over a decade observed no significant differences in the technical results and complications between balloon-expandable and self-expanding stent groups. However, residual stenosis rate was high among the self-expandable group and this has been attributed to inherent characteristics of these stents.  A systematic analysis of published reports on intracranial angioplasty and stenting found that risk of stroke at 1 year was less with stenting compared with angioplasty.  Apart from the better technical success rate in the stenting group, none of the other parameters showed any significant change. Another multicentric study comparing angioplasty and stenting found no significant difference in the periprocedural deaths/strokes, restenosis, or survival rates.  The only difference noted was lower postoperative residual stenosis in the stenting group. Matched analysis of WASID and NIH data has provided some useful insights into one of the controversial topics of ICAD therapy--medical vs endovascular treatment. The occurrence of primary outcome at 6 months in low stenosis group (50-70%) was lower with medical management than stenting. This suggested that stenting may not be beneficial in subset of ICAD with 50 to 70% stenosis due to higher event rates. The summary of analysis of various studies is presented in [Table 4]. ,,,
The absence of randomized trials makes selection of patients for endovascular revascularization a difficult proposition. Guidelines for patient selection may be based on the following considerations:
Baseline imaging includes either brain CT or MRI scan to look for evidence of cerebral ischemia, infarction, or both. Perfusion to brain tissue may be assessed by CT xenon perfusion imaging, MR perfusion/diffusion imaging, nuclear medicine perfusion imaging, or positron emission tomography. A diagnostic cerebral arteriogram will allow accurate assessment of the site and degree of stenosis and the presence of collateral blood supply.
Prior to the procedure, antiplatelet therapy is an absolute must with a view to prevent acute in-stent thrombosis. Premedication regime may include aspirin, 325 mg, and clopidogrel (either 75 mg/d for 5 days or 600 mg; or an alternative in those allergic to clopidogrel). Intraprocedurally, intravenous heparin bolus is usually given ensuring an activated clotting time more than 250 seconds. Some centers may use additional antithrombotic agents (glycoprotein IIb/IIIa inhibitors) and antivasospastic agents. At most centers, the procedure is carried out under general anesthesia. Periprocedural fluctuations in blood pressure must be avoided as hypotension either during endotracheal intubation or in patients on angiotensin-converting enzyme inhibitors may lead to hemodynamic stroke. Following stent deployment, it is wise to ensure blood pressure below 10 to 15% of baseline to avoid hyperperfusion injury.
Following the procedure, life-long aspirin along with clopidogrel for at least 90 days will be the regime in patients where bare metal stents are used; patients in whom a DES is deployed will need dual antiplatelet cover for at least a year.
Periprocedural rates of stroke or death up to 10% are documented following intracranial stenting. Certain predictors of these cerebrovascular complications were identified by a substudy of the NIH-sponsored Wingspan Registry  and include
Contrary to expected results, neither this study nor others , found the degree of stenosis to play any significant role in procedural risk.
Patients with intracranial stenosis, especially those with severe stenosis, fare poorly despite medical therapy. Endovascular revascularization has been investigated in the past with the objective of improving outcome in such patients. Intracranial stenting is now documented as a technically feasible procedure with promising results, especially in high-risk patients. Its success however has been limited by procedural risks and restenosis in up to one-third of patients. These may be addressed to some extent by appropriate patient selection, and with newer stent designs including DES. In the absence of results from randomized clinical trials, it is difficult at this juncture to draw significant conclusions about the long-term benefits of intracranial stenting in stroke prevention. It is no surprise therefore that results of the ongoing trials including SAMPPRIS and VISSIT are highly awaited not only because they are likely to provide valuable information about the use of these stents, but also how they compare with other available medical options, enabling the clinician to offer the best possible approach in the management of patients with ICAD.
[Table 1], [Table 2], [Table 3], [Table 4]