1. New Therapies for Unruptured
Intracranial Aneurysms
Philipp Taussky, MD
a,b
, Rabih G. Tawk, MD
c
,
David A. Miller, MD
c,d
, William D. Freeman, MD
e
,
Ricardo A. Hanel, MD, PhD
c,
*
INTRODUCTION
The use of flow diverters introduced an exciting new concept in the current treatment
of 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 North
Medical Drive East Salt Lake City, UT 84132, USA; b
Department of Radiology, University of
Utah, 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 San
Pablo 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
KEYWORDS
Aneurysm Treatment Endovascular Flow diverter
KEY POINTS
The concept of flow diversion is based on placing a stent across the neck of an intracranial
aneurysm, which then results in flow away from the aneurysm, inducing thrombosis and
occlusion of the aneurysm over time.
The stent itself experiences neointimal coverage, thus resulting in a remodeling of the
parent vessel.
As the use and application of flow diverters becomes more widespread, some important
questions remain relating to the effective treatment of dual antiplatelet therapy, the occur-
rence of delayed aneurysm ruptures and intraparenchymal hemorrhages, and long-term
patency rates.
Novel flow diverters are currently being investigated for approval of the Food and Drug
Administration in a large prospective multicentric trial, which may offer different treatment
options 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.
Neurol Clin 31 (2013) 737–747
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2. 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, cover
the neck of the aneurysm and function by 2 distinct modes: The flow-diversion aspect
diverts blood flow away from the aneurysm sac, thus promoting intra-aneurysmal sta-
sis and subsequent thrombosis. In addition, the flow diverter induces neointimal
growth along its mesh, resulting in neoendothelialization and remodeling of the parent
artery, with occlusion of the neck of the aneurysm as the neointima covers the ostium
of the aneurysm. The only flow diverter currently approved in the United States is the
Pipeline 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 petrous
segment to the superior hypophyseal segment. Aneurysms may be saccular or fusi-
form (Box 1). Patients need to be pretreated with dual antiplatelet therapy (aspirin
and clopidogrel). Different loading algorithms exist; the authors’ includes pretreatment
for 7 days, after which the response to aspirin (325 mg) and clopidogrel (75 mg) is
tested (aspirin function testing, P2Y12 testing [Accumetrics, San Diego, CA])
(Box 2). Aspirin and clopidogrel therapy is continued postprocedure for a duration
of 3 to 6 months, again with different algorithms in place. Most centers will discontinue
clopidogrel 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 at
least 3 to 6 months. As the use of flow diverters becomes more widespread, current
treatment indications may expand, most notably with respect to aneurysm size and
location, with the possibility of including smaller aneurysms, aneurysms to the carotid
terminus, and posterior circulation aneurysms. Although many such as aneurysms are
currently treated using Pipeline flow diverters, use of the device for such aneurysms is
considered 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 to
approval by the Food and Drug Administration (FDA) in April 2011. The trial was a
multicenter, prospective, interventional, single-arm trial of the PED for the treatment
of uncoilable or failed aneurysms of the internal carotid artery, enrolling patients
from November 2008 to July 2009. A total of 108 patients were enrolled.5
The primary
effectiveness 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
Taussky et al738

3. aneurysm occlusion and absence of major stenosis at 180 days. The primary safety
end point was occurrence of major ipsilateral stroke or neurologic death at
180 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). Of
the 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 the
107 patients in the safety cohort experienced a major ipsilateral stroke or neurologic
death (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 Pipeline
device conducted at 3 medical centers in Europe and 1 center in Argentina.6
Subjects
were included if they had wide-necked intracranial aneurysms (neck of 4 mm or
dome/neck ratio of 1.5) or intracranial aneurysms that had failed previous attempts
at endovascular treatment. Patients were excluded if they had subarachnoid hemor-
rhage within 60 days, an unstable neurologic deficit, or greater than 50% stenosis
of the parent artery. Thirty-one patients with 31 intracranial aneurysms with an average
age of 54.6 years were treated during the study period. Twenty-eight aneurysms arose
from 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 aneurysm
size was 11.5 mm and mean neck size was 5.8 mm. Twelve (38.7%) aneurysms
had failed (or recurred after) a previous endovascular treatment. PED placement
was technically successful in 30 of 31 patients (96.8%). Most aneurysms were treated
with either 1 (n 5 18) or 2 (n 5 11) PEDs. Fifteen aneurysms (48.4%) were treated with
a PED alone while 16 were treated with both PED and embolization coils. Two patients
experienced 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 at
follow-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 reported
series, Saatci and colleagues4
reported their experience with 251 aneurysms in 191
patients. 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 a
branch 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 or
giant (10 mm). In 34 of 251 (13.5%), the Pipeline device was used for retreatment.
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 aspirin
reaction units
Followed by P2Y12 testing with a goal of 100 to 150 P2Y12 reaction units.
Unruptured Intracranial Aneurysms 739

4. Adjunctive coiling was performed in 11 aneurysms (2.1%). The mean number of
devices 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 aneurysm
occlusion rate was 91.2% in 6 months, increasing to 94.6%.4
CONTROVERSIES IN THE USE OF FLOW DIVERTERS: LIMITATIONS AND AREAS OF
INVESTIGATION
Although flow diversion offers to be a promising endovascular tool to treat challenging
intracranial aneurysms, real-life experience with the device and its properties is only
beginning. One of the most concerning aspects in the use of flow diverters is the
occurrence of delayed aneurysm rupture after flow diversion, which seems to occur
after all types of flow diversion.4,7–9
Although there was no delayed aneurysm rupture
in the PUFS trial, there was one cavernous carotid artery aneurysm that on follow-up
showed features of a carotid-cavernous fistula, which may imply a delayed rupture of
the treated cavernous aneurysm.5
Numerous retrospective and prospective studies
have 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 put
forward. The first hypothesis stresses the association with aggressive and rapid
thrombus formation in the aneurysm sac, possibly triggering increased autolysis,
which may overload the biological defense mechanisms of the vessel wall and result
in aneurysm rupture.8–10
Similar biological processes have been noted in abdominal
aortic aneurysms, where mural thrombi within aortic aneurysms are characterized
by an absence of organization and cell colonization and are associated with a thinner
arterial wall and more extensive elastolysis. The mural thrombus acts as a source of
secreted proteases within the aneurysm, leading to further chemical degradation
and weakening of the aneurysm wall.11–13
Alternatively, delayed aneurysm rupture
may be caused by the flow-diversion device causing an inflow jet into the aneurysm
wall with minimal outflow from the aneurysmal sac, thus causing a rupture of the
vessel 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 the
aneurysm, especially giant aneurysms that may have very weak walls.14
Although the exact pathologic mechanisms leading to delayed aneurysm rupture
after flow diversion remain unclear at this point, some common characteristics that
may predispose an aneurysm to rupture after flow diversion have been identified.
These characteristics, elucidated by Kulcsar and colleagues,9
include: large and giant
aneurysms; 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 platelet
inhibition testing; the length of antiplatelet therapy; the occurrence of intraparenchy-
mal hemorrhages or subarachnoid hemorrhages not associated with aneurysm
rupture; and technical aspects, including optimal sizing and placement of the device.
Taussky et al740

5. 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 flow
diverter (Box 3). The ASPIRE study (Aneurysm Study of Pipeline in an Observational
Registry) is an observational, case-only prospective registry analyzing the incidence
of 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 end
point 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 asymptomatic
parent artery stenosis; permanent cranial neuropathy; and change in baseline neurologic
signs/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
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
Fig. 1. Giant right cavernous carotid aneurysm as seen on noncontrast computed tomogra-
phy of the head.
Unruptured Intracranial Aneurysms 741

6. next-generation flow diverter currently being tested in the United States as part of the
ongoing surpass intracranial aneurysm embolization system pivotal (SCENT) trial. This
trial is a multicenter, prospective, interventional, single-arm trial of the Surpass Neuro-
Endograft device aimed at obtaining FDA approval. The Surpass device consists of a
chromium cobalt mesh with 12 platinum markers for visibility and is preloaded onto its
own microcatheter delivered using an over-the-wire technique.
Fig. 2. Three-dimensional conventional angiogram showing partially thrombosed right
cavernous segment aneurysm.
Fig. 3. Native angiogram showing placement of Pipeline flow diverter across the neck of the
aneurysm with the device extending into the petrous portion.
Taussky et al742

7. 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 diverters
being developed, questions arise as to whether the current indication for flow diverters
will be expanded and may possibly include smaller aneurysms and aneurysms of the
posterior 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. 4. Computed tomographic angiogram at 3 months, showing near complete occlusion of
the aneurysm with minimal neck residual.
Fig. 5. Magnetic resonance image showing a giant partially thrombosed supraclinoidal
aneurysm.
Unruptured Intracranial Aneurysms 743

8. when compared with other treatment options. Critics of flow diverters have noted the
absence of any randomized controlled trials comparing flow diverters with other
conventional endovascular aneurysm treatments, such as balloon-assisted or
stent-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. 6. Three-dimensional conventional angiogram showing 16-mm residual filling of this
supraclinoidal aneurysm.
Fig. 7. Native view of the deployed Pipeline device from the supraclinoidal portion across
the neck of the aneurysm into the cavernous segment.
Taussky et al744

9. of a randomized controlled trial. In the study protocol, best standard treatment is left to
the physician’s discretion and may include conservative management, coiling with or
without 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 not
indicated in the acute phase of ruptured aneurysm. New devices, so-called intrasacc-
ular occlusion devices, consist of different shapes of self-expanding mesh deployed
into the aneurysm, thus attaining immediate aneurysm occlusion by intraluminal
flow diversion.16,17
Such devices as the Woven Endobridge (WEB) device (Sequent
Medical, 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 are
intrasaccular (ie, placed inside the sac of the aneurysm covering the neck) there
seems to be no need for dual antiplatelet therapy, which is clinically significant in
the context of a subarachnoid hemorrhage. Although these devices are not currently
Fig. 8. Follow-up at 6 months, showing complete aneurysm occlusion and remodeling of the
dysplastic supraclinoidal segment.
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 treated
with placement of a Pipeline flow diverter across the neck of the aneurysm. A CT angiogram at
3 months showed near complete occlusion of the aneurysm with a minimal 4-mm neck residual
and clinical improvement of her ophthalmoplegia (Figs. 1–4).
Unruptured Intracranial Aneurysms 745

10. available in the United States, it is anticipated that they will undergo testing and seek
FDA approval in the near future, adding further tools to the treatment armamentarium
for intracranial aneurysms.16,17
REFERENCES
1. Piano M, Valvassori L, Quilici L, et al. Midterm and long-term follow-up of cerebral
aneurysms treated with flow diverter devices: a single-center experience. J Neu-
rosurg 2013;118:408–16.
2. Consoli A, Renieri L, Nappini S, et al. Endovascular treatment with ‘kissing’ flow
diverter stents of two unruptured aneurysms at a fenestrated vertebrobasilar
junction. J Neurointerv Surg 2013;5:e9.
3. Burrows AM, Zipfel G, Lanzino G. Treatment of a pediatric recurrent fusiform
middle cerebral artery (MCA) aneurysm with a flow diverter. J Neurointerv Surg
2012. [Epub ahead of print].
4. Saatci I, Yavuz K, Ozer C, et al. Treatment of intracranial aneurysms using the
pipeline flow-diverter embolization device: a single-center experience with
long-term followup results. AJNR Am. J Neuroradiol 2012;33:1436–46.
5. Becske T, Kallmes OF, Saatci I, et al. Pipeline for Uncoilable or Failed Aneurysms:
Results from a Multicenter Clinical Trial. Radiology 2013. [Epub ahead of print].
6. Nelson PK, Lylyk P, Szikora I, et al. The pipeline embolization device for the
intracranial treatment of aneurysms trial. AJNR Am. J Neuroradiol 2011;32:
34–40.
7. Yu SC, Kwok CK, Cheng PW, et al. Intracranial aneurysms: midterm outcome of
pipeline embolization device–a prospective study in 143 patients with 178 aneu-
rysms. Radiology 2012;265:893–901.
8. Turowski B, Macht S, Kulcsar Z, et al. Early fatal hemorrhage after endovascular
cerebral aneurysm treatment with a flow diverter (SILK-Stent): do we need to
rethink our concepts? Neuroradiology 2011;53:37–41.
9. Kulcsar Z, Houdart E, Bonafe A, et al. Intra-aneurysmal thrombosis as a possible
cause of delayed aneurysm rupture after flow-diversion treatment. AJNR Am J
Neuroradiol 2011;32:20–5.
10. Kulcsa´r Z, Szikora I. The ESMINTRetrospective Analysis of Delayed Aneurysm
Ruptures after flow diversion (RADAR)study. EJ Minim Invas Neurol Ther 2012;
2012:1244000088.
11. Touat Z, Ollivier V, Dai I, et al. Renewal of mural thrombus releases plasma
markers and is involved in aortic abdominal aneurysm evolution. Am J Pathol
2006;168:1022–30.
12. Fontaine V, Jacob MP, Houard X, et al. Involvement of the mural thrombus as a
site of protease release and activation in human aortic aneurysms. Am J Pathol
2002;161:1701–10.
13. Coutard M, Touat Z, Houard X, et al. Thrombus versus wall biological activities in
experimental aortic aneurysms. J Vasc Res 2010;47:355–66.
Case study 2
A 76-year-old woman presented with progressive visual loss. A magnetic resonance image
showed a giant supraclinoidal aneurysm with partial thrombosis. The aneurysm was treated
using a Pipeline flow diverter deployed across the neck of the aneurysm. A follow-up at
6 months showed complete occlusion of the aneurysm and remodeling of this dysplastic
segment (Figs. 5–8).
Taussky et al746

11. 14. Cebral JR, Mut F, Raschi M, et al. Aneurysm rupture following treatment with flow-
diverting stents: computational hemodynamics analysis of treatment. AJNR Am J
Neuroradiol 2011;32:27–33.
15. Fiorella O, Sadasivan C, Woo HH, et al. Regarding “Aneurysm rupture following
treatment with flow-diverting stents: computational hemodynamics analysis of
treatment”. AJNR Am J Neuroradiol 2011;32:E95–97. [author reply E98–100].
16. Kwon SC, Ding YH, Dai O, et al. Preliminary results of the luna aneurysm embo-
lization system in a rabbit model: a new intrasaccular aneurysm occlusion device.
AINR Am J Neuroradiol 2011;32:602–6.
17. Klisch J, Sychra V, Strasilla C, et al. The Woven EndoBridge cerebral aneurysm
embolization device (WEB II): initial clinical experience. Neuroradiology 2011;
53:599–607.
Unruptured Intracranial Aneurysms 747