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Recent advances in neuroendovascular therapy
Clinical Neurology and Neurosurgery 115 (2013) 853–858
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Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Review
Recent advances in neuroendovascular therapy E. Jesús Duffis a,b,∗ , Vivek Tank a , Chirag D. Gandhi a,c , Charles J. Prestigiacomo a,b,c a
Deparment of Neurological Surgery, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103, United States Deparment of Neurology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103, United States c Deparment of Radiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103, United States b
a r t i c l e
i n f o
Article history: Received 5 December 2012 Received in revised form 11 January 2013 Accepted 20 January 2013 Available online 26 February 2013 Keywords: Endovascular Stroke Aneurysm Treatment
a b s t r a c t The field of neurointerventional surgery has grown in recent years. Endovascular therapies for both ischemic stroke and intracranial aneurysms have become important components in the multimodal treatment of these conditions. Familiarity with these treatment options by general neurologists is important for patient care. This article reviews recent trials and devices representing important advances in the field. © 2013 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4.
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Carotid atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intracranial atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanical thrombectomy for acute ischemic stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Solitaire FR stent retriever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. The TREVO stent-like retriever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment of wide neck and large cerebral aneurysms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Flow diverting stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Onyx HD 500 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Stroke is the fourth leading cause of death in the United States and is the leading cause of disability [1]. Approximately 87% of strokes are ischemic, 10% are intracerebral hemorrhages, and 3% represent subarchnoid hemorrhage. Endovascular therapy for ischemic stroke and intracranial aneurysms has become an important component of multimodal treatment for these diseases. Recent advances in endovascular therapy are likely to expand its role in treatment. This article will review recent trials and devices
∗ Corresponding author at: Department of Neurological Surgery, UMDNJ-New Jersey Medical School, DOC Suite 8100, Newark, NJ 07103, United States. Tel.: +1 973 972 9626; fax: +1 973 972 2333. E-mail address: duffi[email protected] (E.J. Duffis). 0303-8467/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2013.01.015
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pertinent to the endovascular management of ischemic stroke patients and the treatment of intracranial aneurysms. 2. Carotid atherosclerosis Carotid artery disease due to atherosclerosis is an important cause of ischemic stroke in the United States. The prevalence of carotid artery disease in the general population is estimated to be between 2% and 18% [2]. In fact, it has been estimated that about two million people in North America and Europe have asymptomatic carotid artery stenosis [3]. The major risk factors for carotid atherosclerosis include hypertension, hyperlipidemia, diabetes, smoking, age, and male sex. Currently, there are two surgical treatment options for carotid atherosclerotic disease: carotid endarterectomy (CEA) and carotid artery stenting (CAS).
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The benefit of CEA in stroke prevention for both symptomatic and asymptomatic carotid disease was established in landmark randomized trials conducted in North America and Europe in the 1980s–1990s [4–7]. CAS is a relatively new treatment modality which has undergone several advances in technique and devices in recent years. In particular, the advent of distal protection devices has improved the overall safety of these procedures. The premise of distal protection is to prevent emboli that are formed during stenting or endarterectomy from migrating up into the intracranial circulation where they are likely to cause stroke. There are three general categories of distal protection devices: filter-type devices that are deployed distally and catch any emboli that is created at the procedure site, occlusive devices that are deployed and temporarily block blood flow distal to the procedure site with subsequent aspiration of embolic material prior to reestablishment of flow, and flow reversal in which there is temporary occlusion proximal to the procedure site resulting in retrograde blood flow from intracranial to extracranial circulation. The importance of distal protection devices was highlighted in the Endarterectomy versus Stenting in patients with Symptomatic Severe carotid stenosis (EVA-3S) trial which demonstrated a 30 day stroke risk of 25% and 8% in those treated without and with distal protection respectively [8]. Overall, the EVA-3S trial was halted prematurely due to safety concerns given a more than 2-fold excess of strokes and death seen in the CAS group. A higher stroke and death rate was also noted in the International Carotid Stenting Study (ICSS) [9] while the Stent Protected Angioplasty versus Carotid Endarterectomy in symptomatic patients (SPACE) trial failed to prove non-inferiority of CAS compared to CEA [10]. It is important to note several limitations of these studies which make conclusions drawn from them questionable. First, the stroke rates seen in these trials were significantly higher than those seen in most modern registries and studies of CAS. Several factors likely contributed to the excess of strokes and deaths seen in these trials the most important of which is operator experience. As an example the requirements for participation in EVA-3S were the performance of only 5 stenting procedures or supervision of a qualified physician. Similar relaxed qualification criteria were seen in ICSS and SPACE which required only a minimum of 10 carotid stenting procedures for participation. Furthermore, inexperienced operators could still qualify for participation with the assistance of a tutor. Thus, the high complication rates seen in these trials are most likely a reflection of inexperience rather than shortcomings of the procedure itself. Other factors which may have contributed to the high complication rates seen with CAS in these trials include the variable use of distal protection devices and dual antiplatelet agents. More recently, the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST) sought to again compare CAS and CEA for stroke prevention in both symptomatic and asymptomatic patients [11]. Patients were included if they were symptomatic and had 50% or more stenosis on angiography, 70% or more stenosis on ultrasound, or 70% or more stenosis on CTA or MRA if the ultrasound showed 50–69% stenosis. Asymptomatic patients who had 60% or more stenosis on angiography, 70% or more stenosis on ultrasound, or 80% or more stenosis on CTA or MRA if the ultrasound showed 50–69% stenosis also qualified for inclusion. The trial was conducted at 117 centers in the United States and Canada. Over 2500 patients underwent randomization. With respect to the primary composite endpoint of stroke, any cause death, or myocardial infaction (MI) within 30 days or ipsilateral stroke within 4 years there was no difference in the rates seen for CEA and CAS. There was no differential treatment effect for symptomatic versus asymptomatic patients. With respect to the individual components of the endpoint, CAS demonstrated a significantly higher risk of 30 day stroke (4.1%) compared to CEA (2.3%) while patients undergoing CEA had higher rates of MI versus those treated with CAS (2.3% and
1.1% respectively, p = 0.03). Of note, 71% of the strokes in the CAS group were minor ipsilateral strokes. Another important finding was that age had an effect on benefit. It was noted that younger patients had better results with CAS while older patients fared better with CEA. This age-outcome correlation was also seen in other studies including the SPACE and ICSS trials [9,10]. The critical age was approximately 69 years old. The increased risk of stroke with CAS in elderly patients is likely due to increased vessel tortuosity and severe atherosclerotic calcification associated with increasing age. The CREST findings provide high quality evidence for the equivalence of CAS and CEA in stroke prevention and therefore the decision to choose CAS versus CEA should be individualized. This includes risk stratification into high vs. low risk surgical or CAS candidates. The SAPPHIRE trial, which recruited 334 patients who were considered high risk surgical patients (defined as having one of the following features: age greater than 80 years, the presence of clinically significant cardiac disease, severe pulmonary disease, previous endarterectomy with restenosis, previous radiation therapy or radical neck surgery, contralateral carotid occlusion, or contralateral laryngeal nerve palsy) found an absolute reduction of 8% in the composite end point of stroke, death, or MI within 30 days or stroke within 1 year with CAS compared to CEA. Conversely as mentioned earlier, older patients in CREST did not appear to benefit as much from CAS compared to CEA. A recent post market analysis of the Acculink stent system used in CREST has further identified lesion length and embolic protection device dwell time as additional risk factors in CAS in older patients [12]. At our institution we review risk factors and appropriateness of either procedure in a multi-disciplinary group comprised of vascular surgeons, neurointerventionalists, and stroke neurologists when considering CEA versus CAS. 3. Intracranial atherosclerosis Intracranial atherosclerotic disease (ICAD) is a major cause of ischemic stroke, accounting for almost 10% of strokes [13]. The prevalence of ICAD varies by race and the condition is more common in Asian, Black and Hispanic individuals compared to whites [13,14]. Despite medical management patients with severe 70–99% stenosis and recent stroke or transient ischemic attack are at a relatively high risk of stroke, 23% at 1 year [15]. Given the high risk of subsequent stroke in patients with severe stenosis these patients likely represent a target population for trials of aggressive therapy for secondary prevention. The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) study sought to compare stenting to aggressive medical management for stroke prevention [16]. The trial was conducted at 50 sites in the United States. Patients were randomized if they had a recent stroke or TIA attributable to a stenotic major intracranial artery and 70–99% stenosis of that vessel. Patients were randomized to receive either aggressive medical management (AMM) or AMM with percutaneous transluminal angioplasty and stenting (PTAS) using the Wingspan stent and Gateway balloon system (Boston Scientific, Natick MA). Aggressive medical management consisted of aspirin 326 mg daily, clopidogrel 75 mg daily for 90 days after enrollment, treatment of primary risk factors (hypertension and hyperlipidemia), and a lifestyle modification program to address secondary risk factors such as smoking, diabetes, obesity, and lack of exercise. The primary endpoint was any stroke or death within 30 days after enrollment or stroke after 30 days in the territory of the symptomatic vessel. The enrollment was halted after 451 patients were randomized due to safety concerns and futility analysis showing little chance of benefit in the stenting arm. The 30 day rate of stroke or death was reported to be 14.7% in the PTAS group versus 5.8% in the AMM group. After 30 days
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the probability of the primary endpoint at 1 year was significantly higher with PTAS compared to aggressive medical management (20.0% and 12.2% respectively). It is important to note that the 30 day stroke rates reported in SAMMPRIS were more than double the rates seen in registries of the Wingspan system [17]. The SAMMPRIS trial has been criticized for including patients who otherwise would have been ineligible for treatment using the Wingspan stent system under its then approved indications. Specifically, a little over 1/3 of patients enrolled in SAMMPRIS were not receiving antithrombotic treatment at the time of enrollment and thus did not qualify as medical treatment failures, a requisite of the HDE indications for use. In addition 1/3 of the immediate stroke complications seen in the PTAS arm were hemorrhagic strokes, either parenchymal or subarachnoid hemorrhage, which suggests that suboptimal technique and reperfusion hemorrhages in patients with very recent stroke may have played a role in the unexpectedly high rates of stroke observed in this arm. In August of 2012, based on analysis of SAMMPRIS, the FDA revised the indications for use of the Wingspan stent system to limit its use to patients with severe 70–99% stenosis who have experienced 2 or more strokes on aggressive medical treatment and who have been free of recurrent stroke for 7 days. 4. Mechanical thrombectomy for acute ischemic stroke Timely recanalization of occluded cerebral vessels has consistently been shown to correlate with functional independence and decreased mortality after ischemic stroke [18–20]. However, studies of intravenous tissue plasminogen activator (IV tpa) which have reported recanalization rates demonstrate an essentially inverse relationship between recanalization rates and the size of the occluded vessel [21–23]. Furthermore, given the multiple exclusion criteria and stringent 3–4.5 h time window from symptom onset, as few as 2–5% of patients are treated with IV tpa nationwide [24,25]. Compared to IV tpa alone, adjunct mechanical thrombectomy offers the promise to increase the time window for treatment up to 8 h as well as improve recanalization rates for large vessel occlusions [26–28]. Until recently only two devices (MERCI retriever and Penumbra system) were approved for mechanical thrombectomy within 8 h of stroke onset in the United States. The MERCI retriever consists of a corkscrew like device which is used to snare thrombus within the intracranial vessels while the Penumbra system consists of an aspiration catheter and suction system. The reported recanalization rates using these devices varied considerably from 57 to 87% with reported good clinical outcomes (modified Rankin score, mRS, of 2 or less) ranging from 25 to 41% [29–31]. In an effort to improve these rates newer generation stent retriever devices have been developed. The Solitaire stent retriever was recently approved by the FDA for mechanical thrombectomy in stroke patients with large vessel occlusions presenting within 8 h of stroke onset. A similar device, the TREVO stent retriever, has shown great promise in a prospective clinical trial as well as case series in Europe. Both are discussed in detail below. 4.1. Solitaire FR stent retriever The Solitaire FR stent retriever (Fig. 1) is a retrieval stent device which is deployed into the occlusive thrombus and withdrawn after allowing integration of the clot into the stent cells. The device was tested against the established MERCI thrombectomy device in the SWIFT (Solitaire FR With the Intention for Thrombectomy) Trial [32]. This study was a multicenter, randomized, non-inferiority trial comparing the two clot removal devices. The primary endpoints were successful recanalization (TIMI 2 or 3), no symptomatic
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Fig. 1. Solitaire FR stent retriever device. Solitaire is a registered trade mark of Covidien. Printed with permission from Covidien.
intracranial hemorrhage (SICH), and no need for rescue therapy. Secondary endpoints were good clinical outcome at 90 days (modified Rankin score (MRS) of 2 or less, or equal to the prestrike MRS if it was higher than 2, or an improvement in the NIHSS of at least 10 points), mortality, and serious adverse events. During the course of the study, 144 patients were enrolled at 18 sites. The study was prematurely halted by the DSMB due to overwhelmingly positive clinical outcomes with the Solitaire FR device compared to the Merci device. Successful recanalization without SICH was seen in 60.7% of cases with the Solitaire FR device versus 24.1% with the Merci device (non-inferiority p ≤ 0.0001; superiority p = 0.0001). Also, good clinical outcome was higher (58.2% vs. 33.6%) and mortality was lower (17.2% vs. 38.2%) in patients treated with Solitaire FR as compared to the Merci device (both non-inferiority p = 0.0001). 4.2. The TREVO stent-like retriever Similar to the Solitaire FR stent, the TREVO stent-like retriever (Stryker, Fremont, CA) consists of a flexible stent device and is also designed for deployment within the clot by unsheathing from the microcatheter and then allowing clot to integrate within the stent cells. The stent is then retrieved with the clot embedded into it. The TREVO device was compared to the Merci device in the Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischemic stroke (TREVO 2): a randomized trialan open-label, randomized controlled, non-inferiority trial, incorporating 26 sites in the USA and one in Spain [33]. 88 consecutive patients were enrolled with an NIHSS of 8–29 and presenting within 8 h of symptom onset. Recanalization, defined as a thrombolysis in cerebral ischemia (TICI) score of 2 or greater, was achieved in 86% of patients treated with the TREVO device versus 60% of patients treated with the Merci device (odds ratio 4.22, 95% CI 1.92–9.69; superiority p < 0.0001). There was no statistically significant difference in the primary safety endpoints between the two devices [33]. A recent European case series of 60 consecutive patients treated with the Trevo stent showed a 73% recanalization rate (TICI 2b-3) for patients treated exclusively with the Trevo stent retriever [34]. This number increased to 93% (TICI 2a-3) with the use of adjunct devices. More significantly, 45% of patients achieved a modified Rankin score of 2 or less at 90 days which compared favorably to the clinical outcomes seen with devices currently on the market. The authors observed an 11.7% rate of symptomatic intracerebral hemorrhage and a mortality rate of 28% comparable to previous endovascular reperfusion studies. The median base line NIHSS was 18 which may have contributed to the relatively high mortality.
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Fig. 2. Pipeline embolization device for the treatment of large wide neck aneurysm. Pipeline is a registered trade mark of Covidien. Printed with permission from Covidien.
5. Treatment of wide neck and large cerebral aneurysms Spontaneous subarachnoid hemorrhage is associated with high mortality. The International Subarachnoid Aneurysm Trial (ISAT) demonstrated a lower morbidity and mortality with coiling compared to surgical treatment for selected ruptured aneurysms amenable to both therapies [35]. Endovascular coiling of aneurysms has since become a widespread mainstay of treatment for aneurysms with narrow necks at most institutions. Complex and wide neck aneurysms have historically been treated surgically, however, new advances in endovascular techniques including flow diverting stents and high viscosity liquid embolic agents are making endovascular treatment of these challenging aneurysm feasible. Wide neck cerebral aneurysms are typically defined as having a neck ≥ 4 mm or a neck to dome ratio of < 2. The challenge in treating these aneurysms endovascularly with parent vessel preservation is achieving a good packing density (at least 25%) of the aneurysm with coils while avoiding prolapse into the parent vessel. The packing density achieved with coils alone in large aneurysms (measuring > 10 mm) is often insufficient given the large volume of these aneurysms which often leads to coil compaction and need for retreatment even after adequate initial angiographic results. With the introduction of stent assisted coiling and the balloon remodeling technique a larger number of these challenging aneurysms can be safely and effectively treated endovascularly with parent artery preservation. The recent introduction of flow diverting stents and high viscosity Onyx HD 500 liquid embolic agent will likely expand this number. 5.1. Flow diverting stents A new technique referred to as flow diversion consists of placing a low porosity stent across the neck of an aneurysm and thus “diverting” flow away from the aneurysmal sac downstream into the parent vessel. This leads to stagnation of blood flow within the aneurysmal sac and progressive thrombosis. Over time the stent acts as a scaffold for neointimal proliferation thus reconstructing the parent vessel lumen while preserving normal branches [36,37]. The Pipeline embolization device (PED, EV3, Irvine, CA) is a flow diverting stent which was recently approved for the treatment of large or giant intracranial aneurysms in the internal carotid artery from the petrous segment to the superior hypophyseal segment in adult patients 22 years of age or older (Fig. 2). Clinical data on its safety and efficacy comes from a prospective trial as well as postmarket experience in Europe and South America [36,38,39]. The Pipeline embolization device for the Intracranial Treatment of Aneurysms trial (PITA) was a single arm prospective multicenter
Fig. 3. Technique for Onyx HD 500 embolization of large wide neck aneurysm. Onyx HD 500 is a registered trade mark of Covidien. Figure printed with permission from Covidien (EV3).
study which evaluated the technical success rate of stent delivery and safety of pipeline in the treatment of unruptured wide neck aneurysms and aneurysms with failed conventional treatment [36]. Of 31 patients treated 2 (6.5%) experienced a major periprocedural stroke. The device was delivered successfully in 30/31 patients. Aneurysm occlusion at 6 months, a secondary outcome, was seen in 93% of aneurysms treated. Although not yet published the results of the Pipeline for Untreatable and Failed aneurysms (PUFs) trial have been presented and confirm the efficacy of the device. 104 patients with 106 intracranial aneurysms were treated using the device with a resulting 82% occlusion rate at 6 months and 85% rate at 1 year [40]. The rate of major stroke or death was 5.6%. Additional data regarding the safety and efficacy of the PED comes from two single center case series [38,39]. No strokes or deaths were observed in 63 aneurysms treated in Buenos Aires with the PED [38]. The reported occlusion rate at 6 months and 1 year were 93% and 95% respectively. A similar 94% 6 month occlusion rate was seen in a case series from Budapest [39]. That study reported a 5.3% rate of stroke or death per aneurysm treated. Although flow diverting stents have been received with much enthusiasm little information is known about the long term outcomes of patients treated with these devices. Furthermore, the need for dual antiplatelet therapy as well as the delay in aneurysm thrombosis limits their utility to patients with unruptured aneurysms. In addition, the risks of pipeline in distal aneurysms are unknown however a recent report suggests that it may be safe in aneurysms of the circle of willis and beyond [41]. Finally, recurrent aneurysms previously treated with stenting may also represent an area of limitation for flow diverters [38,42]. 5.2. Onyx HD 500 Ethylene vinyl alcohol co-polymer (Onyx, EV3, Irvine California) is a liquid embolic agent which polymerizes upon contact with blood. It is dissolved in dimethyl sulfoxide (DMSO) with small amount of tantalum powder to provide radiopacity. HD 500 represents a highly viscous form of the compound designed specifically for aneurysm embolization. The technique for aneurysm
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Fig. 4. Illustrative clinical case of Onyx HD 500 embolization of a right internal carotid aneurysm. (A) AP angiograms before embolization shows coil compaction and filling of a previously embolized large ICA aneurysm. (B) Unsubstracted AP angiograms obtained during embolization. Note the balloon inflated over the neck of the aneurysm (white arrow). (C) AP angiograms after completion of the procedure show no residual filling of the aneurysm.
embolization involves catheterizing the aneurysm with a DMSO compatible microcatheter and temporarily inflating a balloon across the neck of the aneurysm while injecting the Onyx solution into the aneurysm (Figs. 3 and 4). HD 500 offers the advantage of being able to fill the entire volume of the aneurysm with the liquid embolic agent in contrast to the variable packing densities achieved with coils thus decreasing recanalization rates. The Cerebral Aneurysm Multicenter European Onyx trial (CAMEO) was a prospective observational study which evaluated the safety of an earlier Onyx formulation in the treatment of cerebral aneurysms [43]. A total of 100 aneurysms were treated across 20 centers in Europe. The authors reported an 8% device or procedure related rate of permanent morbidity and a 2% mortality rate. At 1 year the occlusion rate in small (<10 mm) aneurysms was 93% while that of large (10–24 mm) and giant (>25 mm) aneurysms were 77 and 57% respectively. The trial also demonstrated a 10% retreatment rate as well as a 9% rate of parent vessel occlusion. The authors noted that parent vessel occlusion tended to occur with “spills” of Onyx into the parent artery beyond the balloon [44]. A later higher viscosity preparation was developed to address these concerns. Subsequent publications reporting on efficacy of HD 500 have noted aneurysm occlusion rates of 90% at 1 year with morbidity rates 4.5–8% and mortality rates of 0–2.9% [44–46]. The major technical limitation of Onyx HD 500 is the tedious nature of the repeated cycles of inflation and deflation of the balloon and slow controlled injection of the liquid embolic agent which leads to prolonged fluoroscopy times. In the era of flow diversion some authors have advocated a role for HD 500 in aneurysms previously treated with stents or those with only a small amount of recurrent filling which can be easily sealed with Onyx [47].
6. Summary Recent advances in the endovascular technique and data from recent trials have the potential to expand the role of minimally invasive treatments in the management of stroke patients. Further randomized controlled trials and long term safety data are needed before these techniques become the standard of care. However, carotid artery stenting, mechanical thrombectomy for acute ischemic stroke, as well as new novel devices for the treatment of large aneurysms offer great promise in the management of these patients. Familiarity by general neurologists and neurosurgeons with these devices and trials will help to improve patient care.
References [1] Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, et al. Heart disease and stroke statistics – 2012 update: a report from the American Heart Association. Circulation 2012;125(1):e2–220. [2] First ed: Cambridge University Press. [3] Barnett HJ, Eliasziw M, Meldrum HE, Taylor DW. Do the facts and figures warrant a 10-fold increase in the performance of carotid endarterectomy on asymptomatic patients? Neurology 1996;46(3):603–8. [4] Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. New England Journal of Medicine 1991;325(7): 445–53. [5] Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA 1995;273(18):1421–8. [6] Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet 1998;351(9113):1379–87. [7] Halliday A, Mansfield A, Marro J, Peto C, Peto R, Potter J, et al. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial. Lancet 2004;363(9420):1491–502. [8] Mas JL, Chatellier G, Beyssen B, Branchereau A, Moulin T, Becquemin JP, et al. Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. New England Journal of Medicine 2006;355(16):1660–71. [9] Ederle J, Dobson J, Featherstone RL, Bonati LH, van der Worp HB, de Borst GJ, et al. Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial. Lancet 2010;375(9719):985–97. [10] SPACE Collaborative GroupRingleb PA, Allenberg J, Brückmann H, Eckstein HH, Fraedrich G, et al. 30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial. Lancet 2006;368(9543):1239–47. [11] Brott TG, Hobson 2nd RW, Howard G, Roubin GS, Clark WM, Brooks W, et al. Stenting versus endarterectomy for treatment of carotid-artery stenosis. New England Journal of Medicine 2010;363(1):11–23. [12] Chaturvedi S, Matsumura JS, Gray W, Xu C, Verta P, CAPTURE 2 Investigators and Executive Committee, et al. Carotid artery stenting in octogenarians: periprocedural stroke risk predictor analysis from the multicenter Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover Rare Events (CAPTURE 2) clinical trial. Stroke 2010;41(4):757–64. [13] Wityk RJ, Lehman D, Klag M, Coresh J, Ahn H, Litt B. Race and sex differences in the distribution of cerebral atherosclerosis. Stroke 1996;27(11):1974–80. [14] Inzitari D, Hachinski VC, Taylor DW, Barnett HJ. Racial differences in the anterior circulation in cerebrovascular disease. How much can be explained by risk factors? Archives of Neurology 1990;47(10):1080–4. [15] Kasner SE, Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ, Hertzberg VS, et al. Predictors of ischemic stroke in the territory of a symptomatic intracranial arterial stenosis. Circulation 2006;113(4):555–63. [16] Chimowitz MI, Lynn MJ, Derdeyn CP, Turan TN, Fiorella D, Lane BF, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. New England Journal of Medicine 2011;365(11):993–1003. [17] Zaidat OO, Klucznik R, Alexander MJ, Chaloupka J, Lutsep H, Barnwell S, et al. The NIH registry on use of the Wingspan stent for symptomatic 70–99% intracranial arterial stenosis. Neurology 2008;70(17):1518–24.
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[18] Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke 2007;38(3):967–73. [19] Fields JD, Lutsep HL, Smith WS, MERCI Multi MERCI Investigators. Higher degrees of recanalization after mechanical thrombectomy for acute stroke are associated with improved outcome and decreased mortality: pooled analysis of the MERCI and Multi MERCI trials. American Journal of Neuroradiology 2011;32(11):2170–4. [20] Flint AC, Duckwiler GR, Budzik RF, Liebeskind DS, Smith WS, MERCI and Multi MERCI Writing Committee. Mechanical thrombectomy of intracranial internal carotid occlusion: pooled results of the MERCI and Multi MERCI Part I trials. Stroke 2007;38(4):1274–80. [21] Saqqur M, Uchino K, Demchuk AM, Molina CA, Garami Z, Calleja S, et al. Site of arterial occlusion identified by transcranial Doppler predicts the response to intravenous thrombolysis for stroke. Stroke 2007;38(3):948–54. [22] Linfante I, Llinas RH, Selim M, Chaves C, Kumar S, Parker RA, et al. Clinical and vascular outcome in internal carotid artery versus middle cerebral artery occlusions after intravenous tissue plasminogen activator. Stroke 2002;33(8):2066–71. [23] Wunderlich MT, Goertler M, Postert T, Schmitt E, Seidel G, Gahn G, et al. Recanalization after intravenous thrombolysis: does a recanalization time window exist? Neurology 2007;68(17):1364–8. [24] Adeoye O, Hornung R, Khatri P, Kleindorfer D. Recombinant tissue-type plasminogen activator use for ischemic stroke in the United States: a doubling of treatment rates over the course of 5 years. Stroke 2011;42(7):1952–5. [25] Kleindorfer D, Lindsell CJ, Brass L, Koroshetz W, Broderick JP. National US estimates of recombinant tissue plasminogen activator use: ICD-9 codes substantially underestimate. Stroke 2008;39(3):924–8. [26] Noser EA, Shaltoni HM, Hall CE, Alexandrov AV, Garami Z, Cacayorin ED, et al. Aggressive mechanical clot disruption: a safe adjunct to thrombolytic therapy in acute stroke? Stroke 2005;36(2):292–6. [27] Pfefferkorn T, Mayer TE, Opherk C, Peters N, Straube A, Pfister HW, et al. Staged escalation therapy in acute basilar artery occlusion: intravenous thrombolysis and on-demand consecutive endovascular mechanical thrombectomy: preliminary experience in 16 patients. Stroke 2008;39(5):1496–500. [28] Shi ZS, Loh Y, Walker G, Duckwiler GR. Endovascular thrombectomy for acute ischemic stroke in failed intravenous tissue plasminogen activator versus non-intravenous tissue plasminogen activator patients: revascularization and outcomes stratified by the site of arterial occlusions. Stroke 2010;41(6):1185–92. [29] Penumbra Pivotal Stroke Trial Investigators. The penumbra pivotal stroke trial: safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke 2009;40(8):2761–8. [30] Tarr R, Hsu D, Kulcsar Z, Bonvin C, Rufenacht D, Alfke K, et al. The POST trial: initial post-market experience of the Penumbra system: revascularization of large vessel occlusion in acute ischemic stroke in the United States and Europe. Journal of NeuroInterventional Surgery 2010;2(4):341–4. [31] Smith WS, Sung G, Saver J, Budzik R, Duckwiler G, Liebeskind DS, et al. Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke 2008;39(4):1205–12. [32] Saver JL, Jahan R, Levy EI, Jovin TG, Baxter B, Nogueira RG, et al. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial. The Lancet 2012;380(9849):1241–9.
[33] Nogueira RG, Lutsep HL, Gupta R, Jovin TG, Albers GW, Walker GA, et al. Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial. The Lancet 2012;380:1231–40. [34] San Román L, Obach V, Blasco J, Macho J, Lopez A, Urra X, et al. Single-center experience of cerebral artery thrombectomy using the TREVO device in 60 patients with acute ischemic stroke. Stroke 2012;43(6): 1657–9. [35] Molyneux AJ, Kerr RS, Yu LM, Clarke M, Sneade M, Yarnold JA, et al. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet 2005;366(9488): 809–17. [36] Nelson PK, Lylyk P, Szikora I, Wetzel SG, Wanke I, Fiorella D, et al. The pipeline embolization device for the intracranial treatment of aneurysms trial. American Journal of Neuroradiology 2011;32(1):34–40. [37] Kallmes DF, Ding YH, Dai D, Kadirvel R, Lewis DA, Cloft HJ. A new endoluminal, flow-disrupting device for treatment of saccular aneurysms. Stroke 2007;38(8):2346–52. [38] Lylyk P, Miranda C, Ceratto R, Ferrario A, Scrivano E, Luna HR, et al. Curative endovascular reconstruction of cerebral aneurysms with the pipeline embolization device: the Buenos Aires experience. Neurosurgery 2009;64(4):632–42 [discussion 642–3; quiz N6]. [39] Szikora I, Berentei Z, Kulcsar Z, Marosfoi M, Vajda ZS, Lee W, et al. Treatment of intracranial aneurysms by functional reconstruction of the parent artery: the Budapest experience with the pipeline embolization device. American Journal of Neuroradiology 2010;31(6):1139–47. [40] Available from: http://www.ev3.net/neuro/intl/flow-diversion/embolizationdevice-product.htm [41] Pistocchi S, Blanc R, Bartolini B, Piotin M. Flow diverters at and beyond the level of the circle of willis for the treatment of intracranial aneurysms. Stroke 2012;43(4):1032–8. [42] McAuliffe W, Wycoco V, Rice H, Phatouros C, Singh TJ, Wenderoth J. Immediate and midterm results following treatment of unruptured intracranial aneurysms with the pipeline embolization device. American Journal of Neuroradiology 2012;33(1):164–70. [43] Molyneux AJ, Cekirge S, Saatci I, Gál G. Cerebral Aneurysm Multicenter European Onyx (CAMEO) trial: results of a prospective observational study in 20 European centers. American Journal of Neuroradiology 2004;25(1): 39–51. [44] Piske RL, Kanashiro LH, Paschoal E, Agner C, Lima SS, Aguiar PH. Evaluation of Onyx HD-500 embolic system in the treatment of 84 wide-neck intracranial aneurysms. Neurosurgery 2009;64(5):E865–75 [discussion E875]. [45] Simon SD, Eskioglu E, Reig A, Mericle RA. Endovascular treatment of side wall aneurysms using a liquid embolic agent: a US single-center prospective trial. Neurosurgery 2010;67(3):855–60 [discussion 860]. [46] Weber W, Siekmann R, Kis B, Kuehne D. Treatment and follow-up of 22 unruptured wide-necked intracranial aneurysms of the internal carotid artery with Onyx HD 500. American Journal of Neuroradiology 2005;26(8): 1909–15. [47] Dalyai RT, Randazzo C, Ghobrial G, Gonzalez LF, Tjoumakaris SI, Dumont AS, et al. Redefining Onyx HD 500 in the flow diversion era. International Journal of Vascular Medicine 2012;2012, 435490.
Contents lists available at SciVerse ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Review
Recent advances in neuroendovascular therapy E. Jesús Duffis a,b,∗ , Vivek Tank a , Chirag D. Gandhi a,c , Charles J. Prestigiacomo a,b,c a
Deparment of Neurological Surgery, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103, United States Deparment of Neurology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103, United States c Deparment of Radiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103, United States b
a r t i c l e
i n f o
Article history: Received 5 December 2012 Received in revised form 11 January 2013 Accepted 20 January 2013 Available online 26 February 2013 Keywords: Endovascular Stroke Aneurysm Treatment
a b s t r a c t The field of neurointerventional surgery has grown in recent years. Endovascular therapies for both ischemic stroke and intracranial aneurysms have become important components in the multimodal treatment of these conditions. Familiarity with these treatment options by general neurologists is important for patient care. This article reviews recent trials and devices representing important advances in the field. © 2013 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4.
5.
6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Carotid atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intracranial atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanical thrombectomy for acute ischemic stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Solitaire FR stent retriever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. The TREVO stent-like retriever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment of wide neck and large cerebral aneurysms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Flow diverting stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Onyx HD 500 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Stroke is the fourth leading cause of death in the United States and is the leading cause of disability [1]. Approximately 87% of strokes are ischemic, 10% are intracerebral hemorrhages, and 3% represent subarchnoid hemorrhage. Endovascular therapy for ischemic stroke and intracranial aneurysms has become an important component of multimodal treatment for these diseases. Recent advances in endovascular therapy are likely to expand its role in treatment. This article will review recent trials and devices
∗ Corresponding author at: Department of Neurological Surgery, UMDNJ-New Jersey Medical School, DOC Suite 8100, Newark, NJ 07103, United States. Tel.: +1 973 972 9626; fax: +1 973 972 2333. E-mail address: duffi[email protected] (E.J. Duffis). 0303-8467/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2013.01.015
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pertinent to the endovascular management of ischemic stroke patients and the treatment of intracranial aneurysms. 2. Carotid atherosclerosis Carotid artery disease due to atherosclerosis is an important cause of ischemic stroke in the United States. The prevalence of carotid artery disease in the general population is estimated to be between 2% and 18% [2]. In fact, it has been estimated that about two million people in North America and Europe have asymptomatic carotid artery stenosis [3]. The major risk factors for carotid atherosclerosis include hypertension, hyperlipidemia, diabetes, smoking, age, and male sex. Currently, there are two surgical treatment options for carotid atherosclerotic disease: carotid endarterectomy (CEA) and carotid artery stenting (CAS).
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The benefit of CEA in stroke prevention for both symptomatic and asymptomatic carotid disease was established in landmark randomized trials conducted in North America and Europe in the 1980s–1990s [4–7]. CAS is a relatively new treatment modality which has undergone several advances in technique and devices in recent years. In particular, the advent of distal protection devices has improved the overall safety of these procedures. The premise of distal protection is to prevent emboli that are formed during stenting or endarterectomy from migrating up into the intracranial circulation where they are likely to cause stroke. There are three general categories of distal protection devices: filter-type devices that are deployed distally and catch any emboli that is created at the procedure site, occlusive devices that are deployed and temporarily block blood flow distal to the procedure site with subsequent aspiration of embolic material prior to reestablishment of flow, and flow reversal in which there is temporary occlusion proximal to the procedure site resulting in retrograde blood flow from intracranial to extracranial circulation. The importance of distal protection devices was highlighted in the Endarterectomy versus Stenting in patients with Symptomatic Severe carotid stenosis (EVA-3S) trial which demonstrated a 30 day stroke risk of 25% and 8% in those treated without and with distal protection respectively [8]. Overall, the EVA-3S trial was halted prematurely due to safety concerns given a more than 2-fold excess of strokes and death seen in the CAS group. A higher stroke and death rate was also noted in the International Carotid Stenting Study (ICSS) [9] while the Stent Protected Angioplasty versus Carotid Endarterectomy in symptomatic patients (SPACE) trial failed to prove non-inferiority of CAS compared to CEA [10]. It is important to note several limitations of these studies which make conclusions drawn from them questionable. First, the stroke rates seen in these trials were significantly higher than those seen in most modern registries and studies of CAS. Several factors likely contributed to the excess of strokes and deaths seen in these trials the most important of which is operator experience. As an example the requirements for participation in EVA-3S were the performance of only 5 stenting procedures or supervision of a qualified physician. Similar relaxed qualification criteria were seen in ICSS and SPACE which required only a minimum of 10 carotid stenting procedures for participation. Furthermore, inexperienced operators could still qualify for participation with the assistance of a tutor. Thus, the high complication rates seen in these trials are most likely a reflection of inexperience rather than shortcomings of the procedure itself. Other factors which may have contributed to the high complication rates seen with CAS in these trials include the variable use of distal protection devices and dual antiplatelet agents. More recently, the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST) sought to again compare CAS and CEA for stroke prevention in both symptomatic and asymptomatic patients [11]. Patients were included if they were symptomatic and had 50% or more stenosis on angiography, 70% or more stenosis on ultrasound, or 70% or more stenosis on CTA or MRA if the ultrasound showed 50–69% stenosis. Asymptomatic patients who had 60% or more stenosis on angiography, 70% or more stenosis on ultrasound, or 80% or more stenosis on CTA or MRA if the ultrasound showed 50–69% stenosis also qualified for inclusion. The trial was conducted at 117 centers in the United States and Canada. Over 2500 patients underwent randomization. With respect to the primary composite endpoint of stroke, any cause death, or myocardial infaction (MI) within 30 days or ipsilateral stroke within 4 years there was no difference in the rates seen for CEA and CAS. There was no differential treatment effect for symptomatic versus asymptomatic patients. With respect to the individual components of the endpoint, CAS demonstrated a significantly higher risk of 30 day stroke (4.1%) compared to CEA (2.3%) while patients undergoing CEA had higher rates of MI versus those treated with CAS (2.3% and
1.1% respectively, p = 0.03). Of note, 71% of the strokes in the CAS group were minor ipsilateral strokes. Another important finding was that age had an effect on benefit. It was noted that younger patients had better results with CAS while older patients fared better with CEA. This age-outcome correlation was also seen in other studies including the SPACE and ICSS trials [9,10]. The critical age was approximately 69 years old. The increased risk of stroke with CAS in elderly patients is likely due to increased vessel tortuosity and severe atherosclerotic calcification associated with increasing age. The CREST findings provide high quality evidence for the equivalence of CAS and CEA in stroke prevention and therefore the decision to choose CAS versus CEA should be individualized. This includes risk stratification into high vs. low risk surgical or CAS candidates. The SAPPHIRE trial, which recruited 334 patients who were considered high risk surgical patients (defined as having one of the following features: age greater than 80 years, the presence of clinically significant cardiac disease, severe pulmonary disease, previous endarterectomy with restenosis, previous radiation therapy or radical neck surgery, contralateral carotid occlusion, or contralateral laryngeal nerve palsy) found an absolute reduction of 8% in the composite end point of stroke, death, or MI within 30 days or stroke within 1 year with CAS compared to CEA. Conversely as mentioned earlier, older patients in CREST did not appear to benefit as much from CAS compared to CEA. A recent post market analysis of the Acculink stent system used in CREST has further identified lesion length and embolic protection device dwell time as additional risk factors in CAS in older patients [12]. At our institution we review risk factors and appropriateness of either procedure in a multi-disciplinary group comprised of vascular surgeons, neurointerventionalists, and stroke neurologists when considering CEA versus CAS. 3. Intracranial atherosclerosis Intracranial atherosclerotic disease (ICAD) is a major cause of ischemic stroke, accounting for almost 10% of strokes [13]. The prevalence of ICAD varies by race and the condition is more common in Asian, Black and Hispanic individuals compared to whites [13,14]. Despite medical management patients with severe 70–99% stenosis and recent stroke or transient ischemic attack are at a relatively high risk of stroke, 23% at 1 year [15]. Given the high risk of subsequent stroke in patients with severe stenosis these patients likely represent a target population for trials of aggressive therapy for secondary prevention. The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) study sought to compare stenting to aggressive medical management for stroke prevention [16]. The trial was conducted at 50 sites in the United States. Patients were randomized if they had a recent stroke or TIA attributable to a stenotic major intracranial artery and 70–99% stenosis of that vessel. Patients were randomized to receive either aggressive medical management (AMM) or AMM with percutaneous transluminal angioplasty and stenting (PTAS) using the Wingspan stent and Gateway balloon system (Boston Scientific, Natick MA). Aggressive medical management consisted of aspirin 326 mg daily, clopidogrel 75 mg daily for 90 days after enrollment, treatment of primary risk factors (hypertension and hyperlipidemia), and a lifestyle modification program to address secondary risk factors such as smoking, diabetes, obesity, and lack of exercise. The primary endpoint was any stroke or death within 30 days after enrollment or stroke after 30 days in the territory of the symptomatic vessel. The enrollment was halted after 451 patients were randomized due to safety concerns and futility analysis showing little chance of benefit in the stenting arm. The 30 day rate of stroke or death was reported to be 14.7% in the PTAS group versus 5.8% in the AMM group. After 30 days
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the probability of the primary endpoint at 1 year was significantly higher with PTAS compared to aggressive medical management (20.0% and 12.2% respectively). It is important to note that the 30 day stroke rates reported in SAMMPRIS were more than double the rates seen in registries of the Wingspan system [17]. The SAMMPRIS trial has been criticized for including patients who otherwise would have been ineligible for treatment using the Wingspan stent system under its then approved indications. Specifically, a little over 1/3 of patients enrolled in SAMMPRIS were not receiving antithrombotic treatment at the time of enrollment and thus did not qualify as medical treatment failures, a requisite of the HDE indications for use. In addition 1/3 of the immediate stroke complications seen in the PTAS arm were hemorrhagic strokes, either parenchymal or subarachnoid hemorrhage, which suggests that suboptimal technique and reperfusion hemorrhages in patients with very recent stroke may have played a role in the unexpectedly high rates of stroke observed in this arm. In August of 2012, based on analysis of SAMMPRIS, the FDA revised the indications for use of the Wingspan stent system to limit its use to patients with severe 70–99% stenosis who have experienced 2 or more strokes on aggressive medical treatment and who have been free of recurrent stroke for 7 days. 4. Mechanical thrombectomy for acute ischemic stroke Timely recanalization of occluded cerebral vessels has consistently been shown to correlate with functional independence and decreased mortality after ischemic stroke [18–20]. However, studies of intravenous tissue plasminogen activator (IV tpa) which have reported recanalization rates demonstrate an essentially inverse relationship between recanalization rates and the size of the occluded vessel [21–23]. Furthermore, given the multiple exclusion criteria and stringent 3–4.5 h time window from symptom onset, as few as 2–5% of patients are treated with IV tpa nationwide [24,25]. Compared to IV tpa alone, adjunct mechanical thrombectomy offers the promise to increase the time window for treatment up to 8 h as well as improve recanalization rates for large vessel occlusions [26–28]. Until recently only two devices (MERCI retriever and Penumbra system) were approved for mechanical thrombectomy within 8 h of stroke onset in the United States. The MERCI retriever consists of a corkscrew like device which is used to snare thrombus within the intracranial vessels while the Penumbra system consists of an aspiration catheter and suction system. The reported recanalization rates using these devices varied considerably from 57 to 87% with reported good clinical outcomes (modified Rankin score, mRS, of 2 or less) ranging from 25 to 41% [29–31]. In an effort to improve these rates newer generation stent retriever devices have been developed. The Solitaire stent retriever was recently approved by the FDA for mechanical thrombectomy in stroke patients with large vessel occlusions presenting within 8 h of stroke onset. A similar device, the TREVO stent retriever, has shown great promise in a prospective clinical trial as well as case series in Europe. Both are discussed in detail below. 4.1. Solitaire FR stent retriever The Solitaire FR stent retriever (Fig. 1) is a retrieval stent device which is deployed into the occlusive thrombus and withdrawn after allowing integration of the clot into the stent cells. The device was tested against the established MERCI thrombectomy device in the SWIFT (Solitaire FR With the Intention for Thrombectomy) Trial [32]. This study was a multicenter, randomized, non-inferiority trial comparing the two clot removal devices. The primary endpoints were successful recanalization (TIMI 2 or 3), no symptomatic
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Fig. 1. Solitaire FR stent retriever device. Solitaire is a registered trade mark of Covidien. Printed with permission from Covidien.
intracranial hemorrhage (SICH), and no need for rescue therapy. Secondary endpoints were good clinical outcome at 90 days (modified Rankin score (MRS) of 2 or less, or equal to the prestrike MRS if it was higher than 2, or an improvement in the NIHSS of at least 10 points), mortality, and serious adverse events. During the course of the study, 144 patients were enrolled at 18 sites. The study was prematurely halted by the DSMB due to overwhelmingly positive clinical outcomes with the Solitaire FR device compared to the Merci device. Successful recanalization without SICH was seen in 60.7% of cases with the Solitaire FR device versus 24.1% with the Merci device (non-inferiority p ≤ 0.0001; superiority p = 0.0001). Also, good clinical outcome was higher (58.2% vs. 33.6%) and mortality was lower (17.2% vs. 38.2%) in patients treated with Solitaire FR as compared to the Merci device (both non-inferiority p = 0.0001). 4.2. The TREVO stent-like retriever Similar to the Solitaire FR stent, the TREVO stent-like retriever (Stryker, Fremont, CA) consists of a flexible stent device and is also designed for deployment within the clot by unsheathing from the microcatheter and then allowing clot to integrate within the stent cells. The stent is then retrieved with the clot embedded into it. The TREVO device was compared to the Merci device in the Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischemic stroke (TREVO 2): a randomized trialan open-label, randomized controlled, non-inferiority trial, incorporating 26 sites in the USA and one in Spain [33]. 88 consecutive patients were enrolled with an NIHSS of 8–29 and presenting within 8 h of symptom onset. Recanalization, defined as a thrombolysis in cerebral ischemia (TICI) score of 2 or greater, was achieved in 86% of patients treated with the TREVO device versus 60% of patients treated with the Merci device (odds ratio 4.22, 95% CI 1.92–9.69; superiority p < 0.0001). There was no statistically significant difference in the primary safety endpoints between the two devices [33]. A recent European case series of 60 consecutive patients treated with the Trevo stent showed a 73% recanalization rate (TICI 2b-3) for patients treated exclusively with the Trevo stent retriever [34]. This number increased to 93% (TICI 2a-3) with the use of adjunct devices. More significantly, 45% of patients achieved a modified Rankin score of 2 or less at 90 days which compared favorably to the clinical outcomes seen with devices currently on the market. The authors observed an 11.7% rate of symptomatic intracerebral hemorrhage and a mortality rate of 28% comparable to previous endovascular reperfusion studies. The median base line NIHSS was 18 which may have contributed to the relatively high mortality.
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Fig. 2. Pipeline embolization device for the treatment of large wide neck aneurysm. Pipeline is a registered trade mark of Covidien. Printed with permission from Covidien.
5. Treatment of wide neck and large cerebral aneurysms Spontaneous subarachnoid hemorrhage is associated with high mortality. The International Subarachnoid Aneurysm Trial (ISAT) demonstrated a lower morbidity and mortality with coiling compared to surgical treatment for selected ruptured aneurysms amenable to both therapies [35]. Endovascular coiling of aneurysms has since become a widespread mainstay of treatment for aneurysms with narrow necks at most institutions. Complex and wide neck aneurysms have historically been treated surgically, however, new advances in endovascular techniques including flow diverting stents and high viscosity liquid embolic agents are making endovascular treatment of these challenging aneurysm feasible. Wide neck cerebral aneurysms are typically defined as having a neck ≥ 4 mm or a neck to dome ratio of < 2. The challenge in treating these aneurysms endovascularly with parent vessel preservation is achieving a good packing density (at least 25%) of the aneurysm with coils while avoiding prolapse into the parent vessel. The packing density achieved with coils alone in large aneurysms (measuring > 10 mm) is often insufficient given the large volume of these aneurysms which often leads to coil compaction and need for retreatment even after adequate initial angiographic results. With the introduction of stent assisted coiling and the balloon remodeling technique a larger number of these challenging aneurysms can be safely and effectively treated endovascularly with parent artery preservation. The recent introduction of flow diverting stents and high viscosity Onyx HD 500 liquid embolic agent will likely expand this number. 5.1. Flow diverting stents A new technique referred to as flow diversion consists of placing a low porosity stent across the neck of an aneurysm and thus “diverting” flow away from the aneurysmal sac downstream into the parent vessel. This leads to stagnation of blood flow within the aneurysmal sac and progressive thrombosis. Over time the stent acts as a scaffold for neointimal proliferation thus reconstructing the parent vessel lumen while preserving normal branches [36,37]. The Pipeline embolization device (PED, EV3, Irvine, CA) is a flow diverting stent which was recently approved for the treatment of large or giant intracranial aneurysms in the internal carotid artery from the petrous segment to the superior hypophyseal segment in adult patients 22 years of age or older (Fig. 2). Clinical data on its safety and efficacy comes from a prospective trial as well as postmarket experience in Europe and South America [36,38,39]. The Pipeline embolization device for the Intracranial Treatment of Aneurysms trial (PITA) was a single arm prospective multicenter
Fig. 3. Technique for Onyx HD 500 embolization of large wide neck aneurysm. Onyx HD 500 is a registered trade mark of Covidien. Figure printed with permission from Covidien (EV3).
study which evaluated the technical success rate of stent delivery and safety of pipeline in the treatment of unruptured wide neck aneurysms and aneurysms with failed conventional treatment [36]. Of 31 patients treated 2 (6.5%) experienced a major periprocedural stroke. The device was delivered successfully in 30/31 patients. Aneurysm occlusion at 6 months, a secondary outcome, was seen in 93% of aneurysms treated. Although not yet published the results of the Pipeline for Untreatable and Failed aneurysms (PUFs) trial have been presented and confirm the efficacy of the device. 104 patients with 106 intracranial aneurysms were treated using the device with a resulting 82% occlusion rate at 6 months and 85% rate at 1 year [40]. The rate of major stroke or death was 5.6%. Additional data regarding the safety and efficacy of the PED comes from two single center case series [38,39]. No strokes or deaths were observed in 63 aneurysms treated in Buenos Aires with the PED [38]. The reported occlusion rate at 6 months and 1 year were 93% and 95% respectively. A similar 94% 6 month occlusion rate was seen in a case series from Budapest [39]. That study reported a 5.3% rate of stroke or death per aneurysm treated. Although flow diverting stents have been received with much enthusiasm little information is known about the long term outcomes of patients treated with these devices. Furthermore, the need for dual antiplatelet therapy as well as the delay in aneurysm thrombosis limits their utility to patients with unruptured aneurysms. In addition, the risks of pipeline in distal aneurysms are unknown however a recent report suggests that it may be safe in aneurysms of the circle of willis and beyond [41]. Finally, recurrent aneurysms previously treated with stenting may also represent an area of limitation for flow diverters [38,42]. 5.2. Onyx HD 500 Ethylene vinyl alcohol co-polymer (Onyx, EV3, Irvine California) is a liquid embolic agent which polymerizes upon contact with blood. It is dissolved in dimethyl sulfoxide (DMSO) with small amount of tantalum powder to provide radiopacity. HD 500 represents a highly viscous form of the compound designed specifically for aneurysm embolization. The technique for aneurysm
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Fig. 4. Illustrative clinical case of Onyx HD 500 embolization of a right internal carotid aneurysm. (A) AP angiograms before embolization shows coil compaction and filling of a previously embolized large ICA aneurysm. (B) Unsubstracted AP angiograms obtained during embolization. Note the balloon inflated over the neck of the aneurysm (white arrow). (C) AP angiograms after completion of the procedure show no residual filling of the aneurysm.
embolization involves catheterizing the aneurysm with a DMSO compatible microcatheter and temporarily inflating a balloon across the neck of the aneurysm while injecting the Onyx solution into the aneurysm (Figs. 3 and 4). HD 500 offers the advantage of being able to fill the entire volume of the aneurysm with the liquid embolic agent in contrast to the variable packing densities achieved with coils thus decreasing recanalization rates. The Cerebral Aneurysm Multicenter European Onyx trial (CAMEO) was a prospective observational study which evaluated the safety of an earlier Onyx formulation in the treatment of cerebral aneurysms [43]. A total of 100 aneurysms were treated across 20 centers in Europe. The authors reported an 8% device or procedure related rate of permanent morbidity and a 2% mortality rate. At 1 year the occlusion rate in small (<10 mm) aneurysms was 93% while that of large (10–24 mm) and giant (>25 mm) aneurysms were 77 and 57% respectively. The trial also demonstrated a 10% retreatment rate as well as a 9% rate of parent vessel occlusion. The authors noted that parent vessel occlusion tended to occur with “spills” of Onyx into the parent artery beyond the balloon [44]. A later higher viscosity preparation was developed to address these concerns. Subsequent publications reporting on efficacy of HD 500 have noted aneurysm occlusion rates of 90% at 1 year with morbidity rates 4.5–8% and mortality rates of 0–2.9% [44–46]. The major technical limitation of Onyx HD 500 is the tedious nature of the repeated cycles of inflation and deflation of the balloon and slow controlled injection of the liquid embolic agent which leads to prolonged fluoroscopy times. In the era of flow diversion some authors have advocated a role for HD 500 in aneurysms previously treated with stents or those with only a small amount of recurrent filling which can be easily sealed with Onyx [47].
6. Summary Recent advances in the endovascular technique and data from recent trials have the potential to expand the role of minimally invasive treatments in the management of stroke patients. Further randomized controlled trials and long term safety data are needed before these techniques become the standard of care. However, carotid artery stenting, mechanical thrombectomy for acute ischemic stroke, as well as new novel devices for the treatment of large aneurysms offer great promise in the management of these patients. Familiarity by general neurologists and neurosurgeons with these devices and trials will help to improve patient care.
References [1] Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, et al. Heart disease and stroke statistics – 2012 update: a report from the American Heart Association. Circulation 2012;125(1):e2–220. [2] First ed: Cambridge University Press. [3] Barnett HJ, Eliasziw M, Meldrum HE, Taylor DW. Do the facts and figures warrant a 10-fold increase in the performance of carotid endarterectomy on asymptomatic patients? Neurology 1996;46(3):603–8. [4] Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. New England Journal of Medicine 1991;325(7): 445–53. [5] Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA 1995;273(18):1421–8. [6] Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet 1998;351(9113):1379–87. [7] Halliday A, Mansfield A, Marro J, Peto C, Peto R, Potter J, et al. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial. Lancet 2004;363(9420):1491–502. [8] Mas JL, Chatellier G, Beyssen B, Branchereau A, Moulin T, Becquemin JP, et al. Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. New England Journal of Medicine 2006;355(16):1660–71. [9] Ederle J, Dobson J, Featherstone RL, Bonati LH, van der Worp HB, de Borst GJ, et al. Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial. Lancet 2010;375(9719):985–97. [10] SPACE Collaborative GroupRingleb PA, Allenberg J, Brückmann H, Eckstein HH, Fraedrich G, et al. 30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial. Lancet 2006;368(9543):1239–47. [11] Brott TG, Hobson 2nd RW, Howard G, Roubin GS, Clark WM, Brooks W, et al. Stenting versus endarterectomy for treatment of carotid-artery stenosis. New England Journal of Medicine 2010;363(1):11–23. [12] Chaturvedi S, Matsumura JS, Gray W, Xu C, Verta P, CAPTURE 2 Investigators and Executive Committee, et al. Carotid artery stenting in octogenarians: periprocedural stroke risk predictor analysis from the multicenter Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover Rare Events (CAPTURE 2) clinical trial. Stroke 2010;41(4):757–64. [13] Wityk RJ, Lehman D, Klag M, Coresh J, Ahn H, Litt B. Race and sex differences in the distribution of cerebral atherosclerosis. Stroke 1996;27(11):1974–80. [14] Inzitari D, Hachinski VC, Taylor DW, Barnett HJ. Racial differences in the anterior circulation in cerebrovascular disease. How much can be explained by risk factors? Archives of Neurology 1990;47(10):1080–4. [15] Kasner SE, Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ, Hertzberg VS, et al. Predictors of ischemic stroke in the territory of a symptomatic intracranial arterial stenosis. Circulation 2006;113(4):555–63. [16] Chimowitz MI, Lynn MJ, Derdeyn CP, Turan TN, Fiorella D, Lane BF, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. New England Journal of Medicine 2011;365(11):993–1003. [17] Zaidat OO, Klucznik R, Alexander MJ, Chaloupka J, Lutsep H, Barnwell S, et al. The NIH registry on use of the Wingspan stent for symptomatic 70–99% intracranial arterial stenosis. Neurology 2008;70(17):1518–24.
858
E.J. Duffis et al. / Clinical Neurology and Neurosurgery 115 (2013) 853–858
[18] Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke 2007;38(3):967–73. [19] Fields JD, Lutsep HL, Smith WS, MERCI Multi MERCI Investigators. Higher degrees of recanalization after mechanical thrombectomy for acute stroke are associated with improved outcome and decreased mortality: pooled analysis of the MERCI and Multi MERCI trials. American Journal of Neuroradiology 2011;32(11):2170–4. [20] Flint AC, Duckwiler GR, Budzik RF, Liebeskind DS, Smith WS, MERCI and Multi MERCI Writing Committee. Mechanical thrombectomy of intracranial internal carotid occlusion: pooled results of the MERCI and Multi MERCI Part I trials. Stroke 2007;38(4):1274–80. [21] Saqqur M, Uchino K, Demchuk AM, Molina CA, Garami Z, Calleja S, et al. Site of arterial occlusion identified by transcranial Doppler predicts the response to intravenous thrombolysis for stroke. Stroke 2007;38(3):948–54. [22] Linfante I, Llinas RH, Selim M, Chaves C, Kumar S, Parker RA, et al. Clinical and vascular outcome in internal carotid artery versus middle cerebral artery occlusions after intravenous tissue plasminogen activator. Stroke 2002;33(8):2066–71. [23] Wunderlich MT, Goertler M, Postert T, Schmitt E, Seidel G, Gahn G, et al. Recanalization after intravenous thrombolysis: does a recanalization time window exist? Neurology 2007;68(17):1364–8. [24] Adeoye O, Hornung R, Khatri P, Kleindorfer D. Recombinant tissue-type plasminogen activator use for ischemic stroke in the United States: a doubling of treatment rates over the course of 5 years. Stroke 2011;42(7):1952–5. [25] Kleindorfer D, Lindsell CJ, Brass L, Koroshetz W, Broderick JP. National US estimates of recombinant tissue plasminogen activator use: ICD-9 codes substantially underestimate. Stroke 2008;39(3):924–8. [26] Noser EA, Shaltoni HM, Hall CE, Alexandrov AV, Garami Z, Cacayorin ED, et al. Aggressive mechanical clot disruption: a safe adjunct to thrombolytic therapy in acute stroke? Stroke 2005;36(2):292–6. [27] Pfefferkorn T, Mayer TE, Opherk C, Peters N, Straube A, Pfister HW, et al. Staged escalation therapy in acute basilar artery occlusion: intravenous thrombolysis and on-demand consecutive endovascular mechanical thrombectomy: preliminary experience in 16 patients. Stroke 2008;39(5):1496–500. [28] Shi ZS, Loh Y, Walker G, Duckwiler GR. Endovascular thrombectomy for acute ischemic stroke in failed intravenous tissue plasminogen activator versus non-intravenous tissue plasminogen activator patients: revascularization and outcomes stratified by the site of arterial occlusions. Stroke 2010;41(6):1185–92. [29] Penumbra Pivotal Stroke Trial Investigators. The penumbra pivotal stroke trial: safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke 2009;40(8):2761–8. [30] Tarr R, Hsu D, Kulcsar Z, Bonvin C, Rufenacht D, Alfke K, et al. The POST trial: initial post-market experience of the Penumbra system: revascularization of large vessel occlusion in acute ischemic stroke in the United States and Europe. Journal of NeuroInterventional Surgery 2010;2(4):341–4. [31] Smith WS, Sung G, Saver J, Budzik R, Duckwiler G, Liebeskind DS, et al. Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke 2008;39(4):1205–12. [32] Saver JL, Jahan R, Levy EI, Jovin TG, Baxter B, Nogueira RG, et al. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial. The Lancet 2012;380(9849):1241–9.
[33] Nogueira RG, Lutsep HL, Gupta R, Jovin TG, Albers GW, Walker GA, et al. Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial. The Lancet 2012;380:1231–40. [34] San Román L, Obach V, Blasco J, Macho J, Lopez A, Urra X, et al. Single-center experience of cerebral artery thrombectomy using the TREVO device in 60 patients with acute ischemic stroke. Stroke 2012;43(6): 1657–9. [35] Molyneux AJ, Kerr RS, Yu LM, Clarke M, Sneade M, Yarnold JA, et al. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet 2005;366(9488): 809–17. [36] Nelson PK, Lylyk P, Szikora I, Wetzel SG, Wanke I, Fiorella D, et al. The pipeline embolization device for the intracranial treatment of aneurysms trial. American Journal of Neuroradiology 2011;32(1):34–40. [37] Kallmes DF, Ding YH, Dai D, Kadirvel R, Lewis DA, Cloft HJ. A new endoluminal, flow-disrupting device for treatment of saccular aneurysms. Stroke 2007;38(8):2346–52. [38] Lylyk P, Miranda C, Ceratto R, Ferrario A, Scrivano E, Luna HR, et al. Curative endovascular reconstruction of cerebral aneurysms with the pipeline embolization device: the Buenos Aires experience. Neurosurgery 2009;64(4):632–42 [discussion 642–3; quiz N6]. [39] Szikora I, Berentei Z, Kulcsar Z, Marosfoi M, Vajda ZS, Lee W, et al. Treatment of intracranial aneurysms by functional reconstruction of the parent artery: the Budapest experience with the pipeline embolization device. American Journal of Neuroradiology 2010;31(6):1139–47. [40] Available from: http://www.ev3.net/neuro/intl/flow-diversion/embolizationdevice-product.htm [41] Pistocchi S, Blanc R, Bartolini B, Piotin M. Flow diverters at and beyond the level of the circle of willis for the treatment of intracranial aneurysms. Stroke 2012;43(4):1032–8. [42] McAuliffe W, Wycoco V, Rice H, Phatouros C, Singh TJ, Wenderoth J. Immediate and midterm results following treatment of unruptured intracranial aneurysms with the pipeline embolization device. American Journal of Neuroradiology 2012;33(1):164–70. [43] Molyneux AJ, Cekirge S, Saatci I, Gál G. Cerebral Aneurysm Multicenter European Onyx (CAMEO) trial: results of a prospective observational study in 20 European centers. American Journal of Neuroradiology 2004;25(1): 39–51. [44] Piske RL, Kanashiro LH, Paschoal E, Agner C, Lima SS, Aguiar PH. Evaluation of Onyx HD-500 embolic system in the treatment of 84 wide-neck intracranial aneurysms. Neurosurgery 2009;64(5):E865–75 [discussion E875]. [45] Simon SD, Eskioglu E, Reig A, Mericle RA. Endovascular treatment of side wall aneurysms using a liquid embolic agent: a US single-center prospective trial. Neurosurgery 2010;67(3):855–60 [discussion 860]. [46] Weber W, Siekmann R, Kis B, Kuehne D. Treatment and follow-up of 22 unruptured wide-necked intracranial aneurysms of the internal carotid artery with Onyx HD 500. American Journal of Neuroradiology 2005;26(8): 1909–15. [47] Dalyai RT, Randazzo C, Ghobrial G, Gonzalez LF, Tjoumakaris SI, Dumont AS, et al. Redefining Onyx HD 500 in the flow diversion era. International Journal of Vascular Medicine 2012;2012, 435490.