New Therapies for UnrupturedIntracranial Aneurysms

Philipp Taussky, MDa,b, Rabih G. Tawk, MDc,David A. Miller, MDc,d, William D. Freeman, MDe,Ricardo A. Hanel, MD, PhDc,*

KEYWORDS

� Aneurysm � Treatment � Endovascular � Flow diverter

KEY POINTS

� The concept of flow diversion is based on placing a stent across the neck of an intracranialaneurysm, which then results in flow away from the aneurysm, inducing thrombosis andocclusion of the aneurysm over time.

� The stent itself experiences neointimal coverage, thus resulting in a remodeling of theparent vessel.

� As the use and application of flow diverters becomes more widespread, some importantquestions remain relating to the effective treatment of dual antiplatelet therapy, the occur-rence of delayed aneurysm ruptures and intraparenchymal hemorrhages, and long-termpatency rates.

� Novel flow diverters are currently being investigated for approval of the Food and DrugAdministration in a large prospective multicentric trial, which may offer different treatmentoptions and benefits, but whose safety and efficacy are currently under investigation.

� Intrasaccular devices lead to immediate aneurysm occlusion by deployment of a self-expanding ovoid-shaped metal mesh into the aneurysm sac, thus providing an intralumi-nal flow diversion, also indicated in acutely ruptured aneurysms.

INTRODUCTION

The use of flow diverters introduced an exciting new concept in the current treatmentof intracranial aneurysm. Standard endovascular treatment of aneurysms included

Disclosures: Covidien Proctor (R.A. Hanel).a Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, 175 NorthMedical Drive East Salt Lake City, UT 84132, USA; b Department of Radiology, University ofUtah, 100 North Medical Drive Salt Lake City, UT 84132, USA; c Department of Neurosurgery,Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA;d Department of Radiology, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jackson-ville, FL 32224, USA; e Department of Neurology, Mayo Clinic College of Medicine, 4500 SanPablo Road, Jacksonville, FL 32224, USA* Corresponding author. Department of Neurosurgery, Mayo Clinic, 4500 San Pablo Road,Jacksonville, FL 32224.E-mail address: hanel.ricardo@mayo.edu

Neurol Clin 31 (2013) 737–747http://dx.doi.org/10.1016/j.ncl.2013.03.011 neurologic.theclinics.com0733-8619/13/$ – see front matter � 2013 Elsevier Inc. All rights reserved.

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packing the aneurysm with platinum coils, thus preventing inflow into the aneurysm,occlusion of the aneurysmal sac by the coil mass, and subsequent thrombosis.Flow diverters, which are essentially self-expanding, cylindrical meshed stents, coverthe neck of the aneurysm and function by 2 distinct modes: The flow-diversion aspectdiverts blood flow away from the aneurysm sac, thus promoting intra-aneurysmal sta-sis and subsequent thrombosis. In addition, the flow diverter induces neointimalgrowth along its mesh, resulting in neoendothelialization and remodeling of the parentartery, with occlusion of the neck of the aneurysm as the neointima covers the ostiumof the aneurysm. The only flow diverter currently approved in the United States is thePipeline embolization device (PED) (Covidien, Irvine, CA), which consists of 48 inter-woven strands of 25% platinum tungsten and 75% cobalt chromium. It features diam-eters from 2.5 to 5 mm, with 0.025-mm increments, and lengths from 10 to 35 mm.

CURRENT FLOW-DIVERSION INDICATIONS AND CONTRAINDICATIONS

Current indications for the use of Pipeline flow diverters include large and giant unrup-tured intracranial aneurysms (�10 mm) of the anterior circulation from the petroussegment to the superior hypophyseal segment. Aneurysms may be saccular or fusi-form (Box 1). Patients need to be pretreated with dual antiplatelet therapy (aspirinand clopidogrel). Different loading algorithms exist; the authors’ includes pretreatmentfor 7 days, after which the response to aspirin (325 mg) and clopidogrel (75 mg) istested (aspirin function testing, P2Y12 testing [Accumetrics, San Diego, CA])(Box 2). Aspirin and clopidogrel therapy is continued postprocedure for a durationof 3 to 6 months, again with different algorithms in place. Most centers will discontinueclopidogrel after 3 to 6 months and keep the patient on life-long daily aspirin therapy(81–325 mg).Strict contraindications are ruptured aneurysms, prior stented aneurysms, patients

with acute infection, and patients unable to remain on dual antiplatelet therapy for atleast 3 to 6 months. As the use of flow diverters becomes more widespread, currenttreatment indications may expand, most notably with respect to aneurysm size andlocation, with the possibility of including smaller aneurysms, aneurysms to the carotidterminus, and posterior circulation aneurysms. Although many such as aneurysms arecurrently treated using Pipeline flow diverters, use of the device for such aneurysms isconsidered to be off-label.1–4

INITIAL EXPERIENCE WITH FLOW DIVERTERS

In the United States, the PUFS trial (Pipeline for Uncoilable or Failed Aneurysms) led toapproval by the Food and Drug Administration (FDA) in April 2011. The trial was amulticenter, prospective, interventional, single-arm trial of the PED for the treatmentof uncoilable or failed aneurysms of the internal carotid artery, enrolling patientsfrom November 2008 to July 2009. A total of 108 patients were enrolled.5 The primaryeffectiveness end point was angiographic evaluation that demonstrated complete

Box 1

Current indications for Pipeline flow diverter

� Unruptured intracranial aneurysms

� Large or giant intracranial aneurysms with a diameter of 10 mm or greater

� Internal carotid artery from the petrous to the superior hypophyseal artery segments

Box 2

Recommended loading and treatment schemes for dual antiplatelet therapy for Pipeline flow

diverters

� Aspirin 325 mg for 7 days

� Clopidogrel 75 mg for 7 days

Followed by aspirin function testing (aspirin reaction unit) with a goal of less than 550 aspirinreaction units

Followed by P2Y12 testing with a goal of 100 to 150 P2Y12 reaction units.

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aneurysm occlusion and absence of major stenosis at 180 days. The primary safetyend point was occurrence of major ipsilateral stroke or neurologic death at180 days.5 Placement was technically successful in 107 of 108 patients (99.1%).Mean aneurysm size was 18.2 mm; 22 aneurysms (20.4%) were giant (>25 mm). Ofthe 106 aneurysms in the effectiveness cohort, 78 met the study’s primary effective-ness end point (73.6%; 95% posterior probability interval: 64.4%–81.0%). Six of the107 patients in the safety cohort experienced a major ipsilateral stroke or neurologicdeath (5.6%; 95% posterior probability interval: 2.6%–11.7%).An earlier study in 2007, the PITA trial (Pipeline Embolization Device for the Intracra-

nial Treatment of Aneurysms), was a multicenter, single-arm clinical trial of the Pipelinedevice conducted at 3 medical centers in Europe and 1 center in Argentina.6 Subjectswere included if they had wide-necked intracranial aneurysms (neck of >4 mm ordome/neck ratio of <1.5) or intracranial aneurysms that had failed previous attemptsat endovascular treatment. Patients were excluded if they had subarachnoid hemor-rhage within 60 days, an unstable neurologic deficit, or greater than 50% stenosisof the parent artery. Thirty-one patients with 31 intracranial aneurysms with an averageage of 54.6 years were treated during the study period. Twenty-eight aneurysms arosefrom the intracerebral artery (5 cavernous, 15 paraophthalmic, 4 superior hypo-physeal, and 4 posterior communicating segments), 1 from the middle cerebral artery,1 from the vertebral artery, and 1 from the vertebrobasilar junction. Mean aneurysmsize was 11.5 mm and mean neck size was 5.8 mm. Twelve (38.7%) aneurysmshad failed (or recurred after) a previous endovascular treatment. PED placementwas technically successful in 30 of 31 patients (96.8%). Most aneurysms were treatedwith either 1 (n5 18) or 2 (n5 11) PEDs. Fifteen aneurysms (48.4%) were treated witha PED alone while 16 were treated with both PED and embolization coils. Two patientsexperienced major periprocedural stroke. Follow-up angiography demonstrated com-plete aneurysm occlusion in 28 (93.3%) of the 30 patients who underwent an-giographic follow-up. No significant in-construct stenosis (�50%) was identified atfollow-up angiography.Since then several real-life clinical experiences have been published, of both a retro-

spective and prospective nature. Yu and colleagues7 reported their results in a pro-spective study of 143 patients with 178 aneurysms. In one of the largest reportedseries, Saatci and colleagues4 reported their experience with 251 aneurysms in 191patients. Indications were side-wall aneurysms with a wide neck (�4 mm) or unfavor-able dome-neck ratio (�1.5); large/giant, fusiform, dissecting, blister-like, and recur-rent side-wall aneurysms; aneurysms at difficult angles; and aneurysms in which abranch was originating directly from the sac. Clinical and angiographic follow-up infor-mation for up to 2 years were included. Ninety-six aneurysms (38.3%) were large orgiant (�10 mm). In 34 of 251 (13.5%), the Pipeline device was used for retreatment.

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Adjunctive coiling was performed in 11 aneurysms (2.1%). The mean number ofdevices per aneurysm was 1.3. One aneurysm ruptured in the fourth month after treat-ment (0.5%), and symptomatic in-construct stenosis was detected in 1 patient (0.5%)treated with percutaneous transarterial angioplasty. Any-event rate was 27 of 191(14.1%), with a permanent morbidity of 1% and mortality of 0.5%. Control angiog-raphy was available in 182 (95.3%) patients with 239 (95.2%) aneurysms. In 121 aneu-rysms (48.2%), 1- to 2-year control angiography was available. The aneurysmocclusion rate was 91.2% in 6 months, increasing to 94.6%.4

CONTROVERSIES IN THE USE OF FLOW DIVERTERS: LIMITATIONS AND AREAS OFINVESTIGATION

Although flow diversion offers to be a promising endovascular tool to treat challengingintracranial aneurysms, real-life experience with the device and its properties is onlybeginning. One of the most concerning aspects in the use of flow diverters is theoccurrence of delayed aneurysm rupture after flow diversion, which seems to occurafter all types of flow diversion.4,7–9 Although there was no delayed aneurysm rupturein the PUFS trial, there was one cavernous carotid artery aneurysm that on follow-upshowed features of a carotid-cavernous fistula, which may imply a delayed rupture ofthe treated cavernous aneurysm.5 Numerous retrospective and prospective studieshave reported about the occurrence of delayed aneurysm rupture after flow diversion,with the RADAR study (rupture after flow diversion), a multicentric retrospective study,finding a 1% delayed rupture risk after flow diversion in 1421 studied aneurysms.10

The cause of delayed rupture is poorly understood, and 2 main hypotheses are putforward. The first hypothesis stresses the association with aggressive and rapidthrombus formation in the aneurysm sac, possibly triggering increased autolysis,which may overload the biological defense mechanisms of the vessel wall and resultin aneurysm rupture.8–10 Similar biological processes have been noted in abdominalaortic aneurysms, where mural thrombi within aortic aneurysms are characterizedby an absence of organization and cell colonization and are associated with a thinnerarterial wall and more extensive elastolysis. The mural thrombus acts as a source ofsecreted proteases within the aneurysm, leading to further chemical degradationand weakening of the aneurysm wall.11–13 Alternatively, delayed aneurysm rupturemay be caused by the flow-diversion device causing an inflow jet into the aneurysmwall with minimal outflow from the aneurysmal sac, thus causing a rupture of thevessel wall by force of the inflow jet.14,15 This theory stresses the importance of an in-crease in the intra-aneurysmal pressure, which can potentially cause the rupture of theaneurysm, especially giant aneurysms that may have very weak walls.14

Although the exact pathologic mechanisms leading to delayed aneurysm ruptureafter flow diversion remain unclear at this point, some common characteristics thatmay predispose an aneurysm to rupture after flow diversion have been identified.These characteristics, elucidated by Kulcsar and colleagues,9 include: large and giantaneurysms; symptomatic aneurysms suggesting recent growth and wall instability;saccular aneurysms with an aspect ratio of greater than 1.6; and morphologic charac-teristics predisposing to an inertia-driven inflow at baseline.The occurrence of delayed aneurysm rupture may be the most concerning aspect of

flow diversion, and unanswered questions remain with respect to the use of flow diver-sion. Such aspects include the optimal use of antiplatelet therapy, including plateletinhibition testing; the length of antiplatelet therapy; the occurrence of intraparenchy-mal hemorrhages or subarachnoid hemorrhages not associated with aneurysmrupture; and technical aspects, including optimal sizing and placement of the device.

Box 3

Current areas of investigation after treatment with Pipeline flow diverters

� Occurrence and pathologic mechanism of delayed aneurysm rupture

� Occurrence and pathologic mechanism of nonaneurysmal intracranial hemorrhage

� Consensus of use and testing for dual antiplatelet therapy

� Expansion of indication to smaller aneurysms and posterior circulation aneurysms

� Long-term device patency and in-stent stenosis

� Thromboembolic complications and perforator occlusion

� Long-term follow-up and efficacy of long-term aneurysm occlusion

Unruptured Intracranial Aneurysms 741

Finally, although early long-term results appear to be very promising, reported out-comes beyond a few years are missing at this point.

ONGOING STUDIES AND OUTLOOK FOR THE FUTURE

Several studies are currently investigating real-life experiences with the Pipeline flowdiverter (Box 3). The ASPIRE study (Aneurysm Study of Pipeline in an ObservationalRegistry) is an observational, case-only prospective registry analyzing the incidenceof neurologic adverse events following the use of the Pipeline device until last follow-up, for an average of 3 years of follow-up for each subject enrolled. The primary endpoint will consist of a composite of any/all of the events including: incidence of sponta-neous rupture of Pipeline-treated aneurysm; other (nonaneurysmal) intracranial hemor-rhage, ipsilateral and contralateral; ischemic stroke; symptomatic and asymptomaticparent artery stenosis; permanent cranial neuropathy; and change inbaseline neurologicsigns/symptoms related to Pipeline-treated internal carotid arteries at last assessment.At present, the Pipeline device is the only FDA-approved flow diverter in the United

States. The Surpass NeuroEndograft (Stryker Neurovascular, Fremont, CA) is a

Fig. 1. Giant right cavernous carotid aneurysm as seen on noncontrast computed tomogra-phy of the head.

Fig. 2. Three-dimensional conventional angiogram showing partially thrombosed rightcavernous segment aneurysm.

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next-generation flow diverter currently being tested in the United States as part of theongoing surpass intracranial aneurysm embolization system pivotal (SCENT) trial. Thistrial is a multicenter, prospective, interventional, single-arm trial of the Surpass Neuro-Endograft device aimed at obtaining FDA approval. The Surpass device consists of achromium cobalt mesh with 12 platinum markers for visibility and is preloaded onto itsown microcatheter delivered using an over-the-wire technique.

Fig. 3. Native angiogram showing placement of Pipeline flow diverter across the neck of theaneurysm with the device extending into the petrous portion.

Fig. 4. Computed tomographic angiogram at 3 months, showing near complete occlusion ofthe aneurysm with minimal neck residual.

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Other companies are currently in the process of developing flow diverters for intracra-nial aneurysms, which will be tested over the coming years. With new flow divertersbeing developed, questions arise as to whether the current indication for flow diverterswill be expanded and may possibly include smaller aneurysms and aneurysms of theposterior circulation. Finally, questions remain as regards whether flow diversion man-ifests a true paradigm shift and performs more favorably in terms of safety and efficacy

Fig. 5. Magnetic resonance image showing a giant partially thrombosed supraclinoidalaneurysm.

Fig. 6. Three-dimensional conventional angiogram showing 16-mm residual filling of thissupraclinoidal aneurysm.

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when compared with other treatment options. Critics of flow diverters have noted theabsence of any randomized controlled trials comparing flow diverters with otherconventional endovascular aneurysm treatments, such as balloon-assisted orstent-assisted coiling. In Canada, the FIAT trial (Flow Diversion of Intracranial Aneu-rysms) aims at comparing flow diversion with best standard treatment in the context

Fig. 7. Native view of the deployed Pipeline device from the supraclinoidal portion acrossthe neck of the aneurysm into the cavernous segment.

Fig. 8. Follow-up at 6 months, showing complete aneurysm occlusion and remodeling of thedysplastic supraclinoidal segment.

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of a randomized controlled trial. In the study protocol, best standard treatment is left tothe physician’s discretion and may include conservative management, coiling with orwithout high-porosity stenting, parent vessel occlusion with or without bypass, or sur-gical clipping.

INTRASACCULAR FLOW DIVERSION

One of the main limitations of flow diversion is its application only for unruptured aneu-rysm and the strict adherence to dual antiplatelet therapy. Because the treated aneu-rysm will only thrombose and occlude over weeks and months, flow diversion is notindicated in the acute phase of ruptured aneurysm. New devices, so-called intrasacc-ular occlusion devices, consist of different shapes of self-expanding mesh deployedinto the aneurysm, thus attaining immediate aneurysm occlusion by intraluminalflow diversion.16,17 Such devices as the Woven Endobridge (WEB) device (SequentMedical, Inc, Aliso Viejo, CA) and the Luna device (NFocus Neuromedical, Palo Alto,CA) have currently achieved a CE Mark in Europe and are being used for ruptured an-eurysms as well as bifurcation and trifurcation aneurysms. Because these devices areintrasaccular (ie, placed inside the sac of the aneurysm covering the neck) thereseems to be no need for dual antiplatelet therapy, which is clinically significant inthe context of a subarachnoid hemorrhage. Although these devices are not currently

Case study 1

A 78-year-old woman presented acutely with new-onset headaches and complete ophthalmo-plegia. A computed tomography (CT) scan of her head showed a giant, partially thrombosed,cavernous carotid aneurysm. The patient was loaded on dual antiplatelet therapy and treatedwith placement of a Pipeline flow diverter across the neck of the aneurysm. A CTangiogram at3 months showed near complete occlusion of the aneurysm with a minimal 4-mm neck residualand clinical improvement of her ophthalmoplegia (Figs. 1–4).

Case study 2

A 76-year-old woman presented with progressive visual loss. A magnetic resonance imageshowed a giant supraclinoidal aneurysm with partial thrombosis. The aneurysm was treatedusing a Pipeline flow diverter deployed across the neck of the aneurysm. A follow-up at6 months showed complete occlusion of the aneurysm and remodeling of this dysplasticsegment (Figs. 5–8).

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available in the United States, it is anticipated that they will undergo testing and seekFDA approval in the near future, adding further tools to the treatment armamentariumfor intracranial aneurysms.16,17

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