Intracranial Stent Debuts to Rave Reviews, but Even Advocates Advise Caution

April 4, 2006

stroke, stenting, stent deployment, Wingspan Stent System

Even as interventional neurologists and neuroradiologists across the country welcomed the availability of a self-expandable stent for treating intracranial atherosclerotic disease in stroke patients, researchers emphasized the need for further study to identify the specific patient populations who stand to benefit most from the new tool-lest its users become the neurovascular equivalent of the proverbial man with a hammer, to whom everything appears to be a nail.The tool in question is Boston Scientific's Wingspan Stent System, which is designed specifically for intracranial stenosis: thin and flexible enough to navigate tiny and tortuous intracranial arteries and self-expanding to avoid the vascular injury that can be associated with balloon-assisted stent expansion. The Wingspan stent received a humanitarian device exemption (HDE) from the FDA last August for use in stroke patients who have more than 50% stenosis and who are inadequately responsive to medical therapy. In December, a flurry of press releases touted the stent's initial deployment at a handful of select institutions.Testimonials thus far have been positive, lauding the device's ease of use, high rates of technical success, and low rates of periprocedural adverse events. Twelve-month follow-up data for the trial on which the HDE was based, presented in February during a sponsored educational symposium at the annual International Stroke Conference in Kissimmee, FL, compare favorably with 12-month outcomes seen in patients treated with medical therapy alone, particularly in patients with severe stenosis.However, without a randomized controlled study directly comparing intracranial stenting with medical therapy, researchers are advising caution. "Technology often moves ahead faster than science," said Scott E. Kasner, MD, associate professor of neurology and director of the Comprehensive Stroke Center at the University of Pennsylvania in Philadelphia. "We have to prove that stenting is better than medical therapy. Realistically we're not even quite there yet because stents are still being developed and have only been studied in a small number of patients."EVIDENCE AND EXPERIENCETo be sure, the results in that small number of patients are encouraging. In the Wingspan HDE study,1 ischemic stroke and vascular death occurred within 30 days in 2 (4.4%) of 45 patients, within 6 months in 3 (7%) of 43 patients, and within 12 months in 4 (9.3%) of 43 patients. By comparison, in the retrospective Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial,2 the same end point at 1 year occurred in 125 (22%) of 569 patients randomly assigned to receive either aspirin or warfarin; this rate did not differ significantly between treatment groups. Overall rates of stroke in the region of the stenotic artery were 11% at 1 year for both treatment groups.The Wingspan HDE findings also compare favorably with an earlier trial of a balloon-expandable intracranial stent, the Neurolink stent from Guidant that also received an HDE in 2002 but was never distributed. In the Stenting of Symptomatic Atherosclerotic Lesions in the Vertebral or Intracranial Arteries (SSYLVIA) trial,3 stroke occurred in the intracranial arteries within 30 days of stent deployment in 4 (7.2%) of 61 patients and within a year in 7 (10.9%).All 3 of the aforementioned studies involved patients with a history of stroke or transient ischemic attack and at least 50% stenosis; the mean baseline intracranial stenosis was 74.9% in the Wingspan study, 63.5% in the WASID study, and 71.1% in the SSYLVIA study. But Kasner and other WASID investigators, after analyzing the WASID data to identify predictors of stroke in patients with symptomatic intracranial stenosis, have reason to believe that patients with more than 70% stenosis face a significantly higher risk of ipsilateral ischemic stroke and therefore may benefit more from stenting than patients with more than 50% but less than 70% stenosis. That analysis, published in the January 31 issue of Circulation,4 showed that the risk of ipsilateral ischemic stroke or death after 1 year was 19% in patients with stenosis between 70% and 99%, compared with just 6% in patients with 50% to 69% stenosis. By comparison, the Wingspan HDE trial found a 10.3% incidence of ipsilateral stroke or death at 1 year in patients with baseline stenosis greater than 70%. (The WASID analysis also found that women appeared to be at increased risk, although this finding was of borderline statistical significance.)Kasner urged that the data be interpreted cautiously. "These results don't imply that stenting should be the first-line therapy for these patients," he said. "But it does mean that we should identify these patients and try to aggressively treat their risk factors and at least think about the potential for other interventions."Early clinical experience with the device suggests that its users are adopting a similarly conservative approach. At Oregon Health Sciences University (OHSU) in Portland, where Wingspan stents were deployed successfully in 10 patients in a 3-month period, patients must have at least 70% stenosis and be refractory to medical therapy to qualify for intracranial stenting, according to Stanley Barnwell, MD, PhD, associate professor of neurological surgery at OHSU."It's relatively new technology," said Barnwell, who works closely with 2 interventional radiologists on intracranial stenting cases. "Unless we think it's severe disease, we tend to not use the stent."David Fiorella, MD, PhD, an interventional neuroradiologist at the Cleveland Clinic, presented preliminary results of 30 patients at a symposium at the International Stroke Conference.5 Mean baseline stenosis in the patients was 81.1%, which decreased to 30% after stent placement.A team that includes neurosurgeon David B. Niemann, MD, an assistant professor of neurosurgery at the University of Wisconsin in Madison, uses the 50% stenosis threshold rather than the 70% threshold for intracranial stenting, but only in patients who have failed medical therapy. Only about 10% of patients qualify, Niemann said. In the first 12 patients, the Wisconsin team achieved 0% to 30% stenosis after stenting, he said. No technical failures with the device were reported by Niemann, Barnwell, or Fiorella.FROM THE HEARTAlthough the Wingspan stent has yet to withstand the rigors of a randomized clinical trial, the vote of confidence from the FDA was welcome news for a growing population of patients with few options once medical therapy has failed. Percutaneous transluminal angioplasty alone is associated with elastic recoil, which can lead to restenosis, and with dissection, which can be particularly problematic in small vessels. Intracranial stenting using balloon-expandable devices designed for larger, less tortuous coronary arteries also has been associated with high rates of periprocedural adverse events, often resulting from the difficulties of accurately matching stent size to vessel size."The intracranial arteries often vary in size at the area of narrowing, which is different from coronary arteries that are more gradually tapering," Niemann said. "Coronary stents need to be sized accurately to prevent rupture, because the vessel may not accommodate the amount of balloon inflation needed to deploy the stent. It is also important that the stent closely approximate the size of the vessel to reduce the risk of restenosis."In a review of 56 articles published in the medical literature between 1993 and 2004, a team represented by Salvador Cruz-Flores, MD, director of the Souers Stroke Institute at Saint Louis University, found that the perioperative risk of stroke or death after angioplasty with or without stent deployment ranged from 0% to 50%.6 Twenty-four of the 56 articles discussed stenting."Given the wide range in the risk of periprocedural complications seen in this review, it seems that the risk of the procedure can be as high or higher than that of the disease itself," said Cruz-Flores, who presented his group's findings at the International Stroke Conference.Neurointerventionalists from Beijing Tiantan Hospital in China have experienced similar frustration, reporting periprocedural cerebrovascular complications in 10.6% of 189 targeted patients with intracranial stenoses in a 5-year period, during which they experimented with 8 different types of balloon-expandable stents in search of one that met their needs.7 Thirteen of 15 stent-deployment failures occurred because excessive vessel tortuosity impeded stent, guidewire, or guide catheter access to the stenotic area; 2 of those stent-deployment failures involved the only 2 patients in the series who experienced recurrent stroke after 30 days postprocedure (mean follow-up of 422 days).The Apollo stent from Shanghai-based MicroPort Medical and the BiodivYsio stent from Abbott Vascular Devices in Galway, Ireland, have come closest to meeting the requirements of being low-profile, flexible, and exerting low nominate pressure, according to Wei Jian Jiang, MD, chairman of interventional neuroradiology, who presented his group's findings at the International Stroke Conference. The Apollo stent received approval from the State Food and Drug Administration in China in 2004; the Wingspan stent is not available in China.WELCOME DEVELOPMENTSWith experience, neurointerventionalists have been able to achieve some success with coronary stents and with angioplasty alone, but nonetheless welcomed the development of the Neurolink stent, which was smaller in diameter than coronary stents and, notably, was more flexible."Coronary stents are stiff as a ten-penny nail and don't go around bends very well," said Barnwell, who participated in the SSYLVIA trial on which the Neurolink HDE was based. "Once the Neurolink stent became available, it was clearly better than anything on the market for intracranial stenoses."But Guidant-which, in an interesting twist, was acquired by Boston Scientific in January-decided not to market the Neurolink stent after receiving the HDE. (Guidant spokeswoman Kim Boetsch declined to comment on the reasons underlying that decision.) In the meantime, Boston Scientific had introduced a self-expanding stent for brain aneurysms called the Neuroform stent, which is made of a flexible nitinol material and was designed to be delivered via a microcatheter-2 technological features that ultimately were also incorporated into the Wingspan stent.The similarities between the 2 devices have made the learning curve for the Wingspan stent much less steep than it otherwise might have been. "Most of the practitioners who will be using the Wingspan stent use the Neuroform stent on a weekly basis to treat aneurysms, so it's something we're familiar with," Fiorella said.In addition to being flexible longitudinally-handy for navigating the tortuous intracranial vasculature-the nitinol stent is also flexible radially, which allows it to conform to tapered vessels and to expand without the assistance of a balloon. A balloon catheter is still used to pre-dilate the stenotic lesion before stent deployment, but because the stent continues to expand outward once deployed, a lesser degree of balloon dilation-and therefore less potentially injurious pressure on the vessel wall-is required for this technique than when using a balloon-expandable device."Instead of having the balloon do all the work up front and using the stent there to avoid the recoil, you can have the stent do some of the work," Fiorella said.RESTENOSISResearchers are also hopeful that the outward force exerted by the stent on the vessel will help prevent delayed restenosis. In the 5-year Beijing series, more than 50% restenosis after at least 6 months was found in 23% of 61 patients with treated stenoses for whom angiographic follow-up was available. In the SSYLVIA study, 12 of 37 patients with intracranial stents demonstrated more than 50% restenosis at 6 months, despite mean poststent stenosis of 19.7%. In the Wingspan HDE trial, by comparison, just 3 of 40 patients with stents exhibited more than 50% restenosis at 6 months, and the mean 6-month stenosis for all patients was actually less than the mean poststent stenosis (28% vs 31.9%). Although the stent's early adopters lacked 6-month outcomes at press time, a similar trend seemed to be developing. "Residual stenosis in the patients we've treated with the Wingspan stent is often improved on the follow-up scan, due to the positive remodeling effects of the stent," Niemann said.In the coronary arteries, interventionalists have had success in combating restenosis using drug-eluting stents, including the Cypher stent from Cordis and the Taxus stent from Boston Scientific, but there is little published evidence to support their use for intracranial applications. At the 2005 meeting of the American Academy of Neurology, researchers from the University of Medicine & Dentistry of New Jersey in Newark reported on the successful deployment of drug-eluting stents in 10 of 11 patients with intracranial artery stenosis; 1 of 5 patients who completed 6-month follow-up suffered a transient ischemic attack.8 Restenosis rates were not reported in that study, but Barnwell said he and colleagues achieved very low rates of restenosis using drug-eluting stents intracranially, before the Wingspan became available. Now, he said, they still use the drug-eluting stents for treating extracranial stenosis at the vertebral artery origin, but not for other neurovascular applications.However, interventional cardiology research suggests that drug-eluting stents may only delay restenosis rather than prevent it,9 and researchers from the Armed Forces Institute of Pathology in Washington, DC, have reported autopsy evidence of delayed stent thrombosis, aneurysm, and arterial wall inflammation specific to the stented area, suggesting that a hypersensitivity to the drug-eluting stent materials leads to incomplete healing and increases the risk of delayed complications.10 Plus, without a drug-eluting stent designed specifically for intracranial use, all of the aforementioned challenges associated with using coronary stents in the brain still apply. Daniel Tuden, PhD, director of marketing for ischemic stroke at Boston Scientific, said his company currently has no plans to develop a drug-eluting intracranial stent.PERSUASIONAll told, it seems the Wingspan stent could not have debuted at a more opportune time. But as promising as the early experience with the Wingspan device has been, even its most ardent advocates stress the need for more definitive evidence that its potential benefits outweigh its risks. In particular, such evidence must be convincing to neurologists, on whose referrals the success of the device will largely depend."Most of the patients in this population are under the care of neurologists who don't have a lot of options in terms of treatment," Tuden said. "Neurologists tend to be very data-driven. So we need to provide evidence that will persuade neurologists about the effectiveness of stenting."JORDANA BIEZE FOSTER is a freelance writer in Massachusetts and former editorial director of Applied Neurology.REFERENCES1. Hartmann M. One year stroke risks in high grade, symptomatic, medically refractory intracranial atherosclerosis after angioplasty and stenting: The Wingspan trial. Presented at: "Intracranial Atherosclerotic Disease (ICAD): Latest research findings and newest interventional devices" educational symposium, International Stroke Conference; February 17, 2006; Kissimmee, FL.2. Chimowitz MI, Kokkinos J, Strong J, et al. The Warfarin-Aspirin Symptomatic Intracranial Disease Study. Neurology. 1995;45:1488-1493.3. SSYLVIA Study Investigators. Stenting of Symptomatic Atherosclerotic Lesions in the Vertebral or Intracranial Arteries (SSYLVIA): study results. Stroke. 2004;35:1388-1392.4. Kasner SE, Chimowitz MI, Lynn MJ, et al. Predictors of ischemic stroke in the territory of a symptomatic intracranial stenosis. Circulation. 2006;113:555-563.5. Fiorella D. Early U.S. Wingspan with Gateway case experience from three centers. Presented at: "Intracranial Atherosclerotic Disease (ICAD): Latest research findings and newest interventional devices" educational symposium, International Stroke Conference; February 17, 2006; Kissimmee, FL.6. Cruz-Flores S, Diamond AL. Abstracts from the International Stroke Conference. Angioplasty for intracranial artery stenosis: A systematic review. Stroke. 2006;37:664.7. Jiang W-J, Leung TW, Xu X-T, et al. Intracranial stent-assisted angioplasty in symptomatic intracranial stenosis. Presented at: International Stroke Conference; February 16, 2006; Kissimmee, FL.8. Kirmani JF, Harris-Lane P, Divani AA, et al. Initial experience with drug eluting stents for symptomatic intracranial stenosis. Neurology. 2005;64(suppl 1):A179.9. Liistro F, Stankovic G, Di Mario C, et al. First clinical experience with a paclitaxel derivate-eluting polymer stent system implantation for in-stent restenosis: immediate and long-term clinical and angiographic outcome. Circulation. 2002;105:1883-1886.10. Virmani R, Kolodgie FD, Farb A. Drug-eluting stents: are they really safe? Am Heart Hosp J. 2004;2:85-88.