Emerging Endovascular Therapies for Symptomatic Intracranial Atherosclerotic Disease
2007; Lippincott Williams & Wilkins; Volume: 38; Issue: 8 Linguagem: Inglês
10.1161/strokeaha.107.482752
ISSN1524-4628
Autores Tópico(s)Acute Ischemic Stroke Management
ResumoHomeStrokeVol. 38, No. 8Emerging Endovascular Therapies for Symptomatic Intracranial Atherosclerotic Disease Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBEmerging Endovascular Therapies for Symptomatic Intracranial Atherosclerotic Disease David Fiorella, MD, PhD and Henry H. Woo, MD David FiorellaDavid Fiorella From the Cleveland Clinic (D.F.), Cleveland, Ohio; and the Department of Endovascular and Cerebrovascular Neurosurgery (H.H.W.), State University of New York at Stony Brook, Stony Brook, NY. and Henry H. WooHenry H. Woo From the Cleveland Clinic (D.F.), Cleveland, Ohio; and the Department of Endovascular and Cerebrovascular Neurosurgery (H.H.W.), State University of New York at Stony Brook, Stony Brook, NY. Originally published21 Jun 2007https://doi.org/10.1161/STROKEAHA.107.482752Stroke. 2007;38:2391–2396Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: June 21, 2007: Previous Version 1 Over the past 2 decades there has been an exponential growth in the scope of disease processes amenable to neuroendovascular treatment. The number and sophistication of the available devices and correspondingly the number of patients undergoing treatment has expanded accordingly. The development and implementation of these new procedures has in some cases outpaced our ability to carefully assess their merits. In comparison to peripheral and coronary vascular disease, neurovascular lesions are less common and far more heterogeneous, ranging from acquired cerebrovascular ischemic disease to hemorrhagic congenital arteriovenous malformations. Each individual disease process (eg, cerebral aneurysm) is composed of a myriad of lesions with different anatomical and pathophysiological characteristics. The natural history of these lesions and their subtypes are likewise poorly defined. For these reasons, personal bias, institutional custom, and anecdotal experience rather than scientific evidence have played a dominant role in guiding therapy. We must move toward collaborative multi-center efforts, prospective data collection and well designed randomized controlled trials to mature as a field over the coming decades.In some ways, symptomatic intracranial atherosclerotic disease (SxICAD) represents an optimal disease process with which to establish this progress toward evidenced based treatment. SxICAD is considerably less heterogeneous than other cerebrovascular disease processes and is arguably best suited as a paradigm for study.In the current article we have attempted to review the available evidence describing the natural history of medically treated SxICAD to determine those patients best suited for invasive treatment strategies. We will also discuss the available treatment modalities which may represent viable options to medical therapy. These data form the basis for the design of future prospective multicenter studies to evaluate the relative merits of interventional treatment.Symptomatic ICAD: Rationale for Invasive Treatment StrategiesAny invasive treatment strategy for symptomatic intracranial atherosclerosis must satisfy two criteria to establish viability as a reasonable alternative to medical therapy. First, the treatment must be performed with a rate of periprocedural morbidity and mortality which compares favorably to the natural history of the disease process treated with medical therapy. Second, the successfully executed invasive strategy must have efficacy with respect to the reduction of stroke and neurological death in the years following treatment.Who to Treat?In the WASID study, more than one-fifth of patients with a symptomatic intracranial stenosis of greater than 50% went on to ischemic stroke, brain hemorrhage, or other vascular death during the 1.8 years of follow-up.1 Twenty-three percent (23%) of patients with high grade (>70%) intracranial stenosis presenting with stroke as their qualifying event went on to experience another ipsilateral ischemic stroke over the next year despite medical therapy.2 This high rate of ischemic stroke was experienced equally by patients regardless of whether or not they had failed medical therapy at the time of their qualifying event. Much lower rates of ipsilateral stroke were noted in patients with less than 70% stenosis ( 70%) in comparison with lower grade (50% to 69%) stenoses.31Although stenting produces better immediate angiographic results than PTA alone, it does not overcome the problem of late luminal loss or obviate the requirement for the re-treatment of some lesions. Although late luminal loss is common after PTA, occurring in 20% to 30% of patients,9,14 a similar percentage of patients undergoing PTAS also demonstrate late luminal loss as a result of in-stent restenosis (ISR). ISR produced greater than 50% luminal compromise in 32.4% of patients with intracranial stents during the SSYLVIA trial. Although ISR was relatively common, only one-third of the patients became symptomatic, and those who were symptomatic very rarely presented with stroke. Jiang et al observed a 19.2% rate (n=19) of ISR in a series of 99 patients with angiographic follow-up. Of these patients, only 6 were symptomatic and only 2 were symptomatic with stroke.These data suggest that newer generation devices (such as the Apollo stent used by Jiang et al, and previously the Neurolink stent30) and evolving techniques, such as a staged treatment strategy, may facilitate a significant reduction in the periprocedural complications associated with PTAS using balloon mounted coronary stents. More data will be required to determine whether PTAS with the newer generation balloon-mounted stents will represent a potentially viable alternative to medical therapy.Self-Expanding Intracranial StentsIn 2002 the first dedicated self-expanding intracranial stent (Neuroform) was developed to support the treatment of wide-necked intracranial aneurysms.32 Neuroform differed from its predecessor balloon mounted coronary stents in that the device was composed of Nitinol and thereby very flexible and of low profile with delivery accomplished via a standard microcatheter. These properties markedly augmented the ability to atraumatically deliver and deploy stents within almost any location throughout the tortuous cerebrovasculature. This device significantly expanded the number and complexity of cerebral aneurysms amenable to endovascular therapy.33By oversizing the Neuroform device relative to the diameter of the target vessel, the outward radial force could be significantly augmented. Because of the improved deliverability of the device, some investigators chose to use Neuroform for the treatment of selected intracranial atherostenoses which were not accessible to standard coronary stents.34 In 2005, the Wingspan stent, a modified version of Neuroform, was released in the US under a Humanitarian Device Exemption (HDE) for the treatment of symptomatic intracranial stenoses (>50%) which were refractory to medical therapy. The Wingspan stent incorporated thicker struts and additional interconnects which augmented its outward radial force to better counteract the acute recoil of atherostenoses after PTA. The Wingspan device is implemented in the context of a treatment strategy which combines aspects of the PTA alone strategy and the stenting strategy. The lesion is initially dilated with a PTA balloon sized to 80% of the "normal" vessel diameter using the slow inflation technique advocated by Connors and Wojak.13 After the initial PTA, the stent delivery system is exchanged over a 0.014" microwire and the self-expanding stent is deployed across the lesion. Postdilation of the stent after implementation is discouraged by the manufacturer. At the conclusion of the procedure, the typical residual stenosis (≈30%)35–37 is less than that observed after PTA alone (≈40%) but considerably more than what is accepted after balloon-mounted stent deployment (≈10%). Correspondingly, Wingspan represents an entirely new treatment paradigm which is essentially a hybrid between the PTA and stenting strategies that seeks to capitalize on the advantages of both techniques. For this reason, it is difficult to extrapolate the existing experiences with either of the predicate techniques to predict the results with this device.Preliminary results with Wingspan have been very favorable.37 The initial study performed in Europe and Asia demonstrated very low rates of periprocedural morbidity and mortality (4.4%) in a series of 45 patients undergoing treatment. Recent data from a multicenter US registry also reported relatively low rates of periprocedural complications (6.1%) and very high rates of successful deployment (>98%).38 Six-month follow-up data from the Eurasian study, available in 43 patients, yielded an overall rate of ipsilateral stroke or death of 9.3% from the time of treatment to last clinical follow-up. Angiographic follow-up at 6 months revealed a remarkably low rate (7.5%) of ISR. In fact, follow-up angiography overall demonstrated a slight nonstatistically significant (3%) average late luminal gain, which was attributed to the chronic outward radial force of the self-expanding Nitinol stent.39 This represents a critical point, given that late luminal loss, occurring in 32.4% of patients in the SSYLIVA trial and in at least 20% to 30% of patients after PTA alone, is a major potential downfall of the predicate technologies which might only be otherwise overcome with the implementation of drug eluting stents (see below). Unfortunately, as more data become available, it does not appear that the rates of ISR occurring after PTAS with Wingspan are any less than those observed after PTA or PTAS with other devices. In a prospective series of patients treated with Wingspan, ISR was observed at a rate of 28.8% in a group of 68 patients with 3 to 6 month imaging follow-up. Two additional patients in this series presented with complete stent occlusion at follow-up.36 Moreover, very few compelling individual examples of late luminal gain have been observed. As more data become available over the next year, the merits and limitations of the Wingspan treatment strategy will be better elucidated.Drug-Eluting StentsBalloon-mounted coronary stents coated with sirolimus (antiproliferative, antiinflammatory, and immunosuppressive agent) and paclitaxel (antiproliferative agent) have tremendously reduced coronary ISR from the greater than 30% rate observed with bare metal stents to less than 10%.40 Several groups have used these devices to treat intracranial atherosclerotic lesions in small series of patients—data have been reported for only 57 patients to date.41–43 From the small number of patients treated and the limited available follow-up, it is difficult to ascertain the safety profile or efficacy of this approach. Although the avoidance of ISR is clearly desirable, there are potential drawbacks of intracranial drug-eluting stents (DES) implantation. The concerns that intracranial drug elution could result in neurotoxicity have not been borne out in controlled animal studies44 or in any of the small human series. A more important issue is that DESs require significantly longer time to endothelialize than bare metal stents and are associated with incomplete intimal healing after implantation. In the BASKET-LATE study, this phenomenon resulted in a 2-fold increase in documented late stent thrombosis and related death/target vessel MI in patients treated with DES versus those with bare metal stents.45 In a metaanalysis of 14 randomized trials of DES, a 4- to 5-fold increase in late stent thrombosis was observed with DES, with an incidence of very late (>1 year postprocedure) thrombosis of 0.5% with DES versus 0% with bare metal stents.46 With sirolimus eluting stents, the incidence of stent thrombosis remained constant up to 4 years after implantation. These observations led the authors to conclude that the original recommended duration of dual antiplatelet therapy (3 months for sirolimus eluting and 6 months for paclitaxel eluting stents) was inadequate and that caution should be given to interrupting dual antiplatelet therapy even several years after DES implantation. Thus, the decision to place a DES within one of the relatively small target vessels within the intracranial circulation likely consigns the recipient to prolonged (>1 year), possibly lifelong, dual antiplatelet therapy because of the risk of late stent thrombosis. The precise etiology of delayed thrombosis with DES remains incompletely understood. Investigators have suggested that the defects in the drug containing polymer,47 the mechanisms of action of the various drugs,48 the ultimate distribution of the drugs within the vessel wall and the actual structure of the stent may contribute to this risk.49 It is possible that modifications in the engineering of these devices, the drugs they elute, and the elution polymers themselves may significantly reduce this risk in the future.When considering DES for intracranial use, the relative risk and implications of late stent thrombosis and the potential complications and costs of prolonged dual antiplatelet therapy must be weighed against the risk of ISR which is often asymptomatic and may be treated (if necessary) with a relatively high safety margin.ConclusionsThe current overview indicates that although our understanding of the natural history of symptomatic ICAD has progressed quite significantly with the results of the WASID trial, our understanding of those procedures available for the treatment of the disease has lagged behind. Whereas surgical revascularization is clearly not efficacious, the available endovascular strategies may have merit in the appropriate patients—particularly those with high grade (>70%) symptomatic intracranial stenosis presenting early after their qualifying event.Unfortunately very little reliable data exist about the individual treatment strategies. Each strategy has its advantages and drawbacks; however, many of these remain theoretical. PTA alone may have a relatively low rate of periprocedural complications, and existing data suggest that the long-erm efficacy may be good; however, the procedure is perceived as limited because of poor immediate angiographic results in up to half of the cases, the relatively common phenomenon of angiographically evident dissection, the relatively frequent need for retreatment, and the bias related to the dominance of stenting over PTA alone in peripheral vascular distributions. The balloon mounted stenting approach overcomes these angiographically evident and theoretical limitations, but at the cost of the increased technical difficulty involved with negotiating a more rigid, higher profile device through the cerebrovasculature, slightly higher procedural complication rates, and ultimately the potential for delayed ISR. Wingspan represents a new hybrid strategy extrapolated from these 2, relatively poorly understood, predicate techniques. As such, many important details regarding the optimal application of the Wingspan strategy and its role among the other endovascular treatment options remains unknown. Similarly, although DES provide the potential to overcome ISR—one of the major limitations of intracranial stenting—the cost with respect to late stent thrombosis and the complications associated with long-term, possibly lifelong, dual antiplatelet therapy represent important considerations.Although each treatment strategy has its enthusiasts, it is critical that neurointerventionalists move toward organized, prospective, and (when possible) independently adjudicated data collection such that the myriad of available endovascular treatments for this disease process can be better understood, optimized, and applied. This understanding can then form the basis for a randomized trial of one or more of these treatment modalities versus medical therapy.Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.DisclosuresD.F. received significant research support from Boston Scientific.FootnotesCorrespondence to David Fiorella, MD PhD, Cleveland Clinic, 9500 Euclid Avenue, S80, Cleveland, Ohio 44195. E-mail [email protected] References 1 Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ, Hertzberg VS, Frankel MR, Levine SR, Chaturvedi S, Kasner SE, Benesch CG, Sila CA, Jovin TG, Romano JG. Warfarin-Aspirin Symptomatic Intracranial Disease Trial Investigators. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med. 2005; 352: 1305–1316.CrossrefMedlineGoogle Scholar2 Kasner SE, Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ, Hertzberg VS, Frankel MR, Levine SR, Chaturvedi S, Benesch CG, Sila CA, Jovin TG, Romano JG, Cloft HJ. Warfarin Aspirin Symptomatic Intracranial Disease Trial Investigators. Predictors of ischemic stroke in the territory of a symptomatic intracranial arterial stenosis. 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