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BarnardZR, AlexanderMJ. Stroke & Vascular Neurology 2019;0. doi:10.1136/svn-2019-000279
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Update in the treatment of intracranial
atherosclerotic disease
Zachary R Barnard, Michael J Alexander
Neurosurgery, Cedars-Sinai
Medical Center, Los Angeles,
California, USA
Correspondence to
Dr Michael J Alexander;
michael. alexander@ cshs. org
To cite: BarnardZR,
AlexanderMJ. Update in
the treatment of intracranial
atherosclerotic disease. Stroke
& Vascular Neurology 2019;0.
doi:10.1136/svn-2019-000279
Received 7 September 2019
Accepted 24 September 2019
Review
© Author(s) (or their
employer(s)) 2019. Re-use
permitted under CC BY-NC. No
commercial re-use. See rights
and permissions. Published by
BMJ.
ABSTRACT
This review highlights the recent evolution of the imaging,
medical management, surgical options and endovascular
therapies for symptomatic intracranial atherosclerotic
disease (ICAD). Recent imaging developments including
optical coherence tomography and other modalities to
assess the intracranial arteries for symptomatic ICAD are
reviewed, not only to diagnose ICAD but to determine if
ICAD plaques have any high-risk features for treatment.
Potential future developments in the treatment of ICAD are
discussed, including the development of trackable drug-
coated balloons for the cerebral circulation to treat primary
or restenotic arteries, new iterations of self-expanding
intracranial stents with easier delivery systems, and the
re-examination of indirect surgical bypass techniques
for revascularisation. In addition to these important
technological developments, however, is the evolving
evidence regarding the best treatment window for these
techniques and additional factors in medical management
which can improve patient outcomes in this devastating
pathology.
INTRODUCTION
The management of symptomatic intrac-
ranial atherosclerotic disease (ICAD) has
some similarities with the management of
atherosclerotic coronary artery and periph-
eral artery disease, and some key differences.
The standard management of ICAD is still
in evolution, but we are beginning to obtain
more refined data through recent studies to
determine the best medical, endovascular and
possibly surgical management of this disease.
Atherosclerotic disease within the arteries is
thought to begin with retention of low-den-
sity lipoprotein (LDL) particles within the
inner arterial wall and inflammation causing
endothelial cell dysfunction. Subsequent
migration of smooth muscle cells and other
cellular inflammatory processes lead to the
development of an atherosclerotic plaque.
The composition of the atherosclerotic
plaque may be relatively soft, or firm with
additional deposition of fibrous tissue and
calcium. The build-up of plaque within the
cerebral arteries is known as ICAD or intra-
cranial atherosclerotic stenosis. As in other
anatomical locations, cerebral atheroscle-
rotic disease leads to a loss of compliance and
elasticity of the arteries, can lead to arterial
lumen narrowing, progressing to ischaemia
or embolic events, or exhibiting ruptured
plaque, which may lead to embolic events
or in-situ arterial thrombosis. These factors
and plaque characteristics are key in under-
standing the safe future endovascular treat-
ment of ICAD.
INCIDENCE
ICAD demonstrates variable incidence among
different races. Most studies indicate Asians
have the highest incidence of ICAD, followed
by African–Americans, Hispanics, then Cauca-
sians. In the USA, stroke is the fifth most
common cause of death, and ICAD is esti-
mated to represent 8%–10% of the aetiology
in patients with stroke.1 This is approximately
50 000–80 000 patients per year. In China,
however, where stroke is the most common
cause of death, ICAD has been reported as a
contributory cause of stroke in 20%–46% of
patients.2 The CICAS (Chinese Intracranial
Atherosclerosis) study showed ICAD in 46%
of patients with acute stroke.3 As expected,
there does appear to be an increased inci-
dence in patients who are cigarette smokers,
and patients with hyperlipidaemia, diabetes,
hypertension and obesity.
DIAGNOSIS
Cerebral intra-arterial narrowing is not always
secondary to ICAD, so other aetiologies much
be considered in the differential diagnosis for
treatment. Vasculitis many involve multiple
intracranial arteries; however, usually an
inflammatory or infectious cause is found.
Cerebral artery dissection, either sponta-
neous or traumatic, typically has a more char-
acteristic angiographic appearance and may
be associated with other predisposing factors
such as fibromuscular dysplasia or collagen
vascular disease. Moyamoya disease is char-
acterised by progressive supraclinoid carotid
artery stenosis. These diseases may appear
like ICAD in certain stages, and efforts should
be made to identify the correct diagnosis
prior to managing the patient like a patient
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Open access
with ICAD, since the optimal treatment paradigms are
different.
Endovascular intravascular ultrasound (IVUS) and
optical coherence tomography (OCT) have recently been
used in cerebral artery evaluation to determine plaque
characteristics and composition, as well as perforator
artery identification.4 More recently, OCT has shown
to have better imaging characteristics than IVUS. OCT
involves coherent light from an intra-arterial catheter to
perform three-dimensional imaging of the vessel wall.
This technique, pioneered in the coronary arteries, can
be used to characterise atherosclerotic plaque, diagnose
arterial dissection, demonstrate stent apposition to the
arterial wall and show tissue prolapse through the stent
struts in cerebral arteries.5 Likewise, the use of high-res-
olution MRI (HR-MRI) has helped better characterise
cerebral artery plaques and active inflammatory activity,
as well as anatomical relationship of atherosclerotic
lesions to adjacent perforator arteries non-invasively.6
MEDICAL THERAPY
The early treatment of ICAD with medical therapy
consisted of warfarin anticoagulant therapy. The WASID
trial (Warfarin vs Aspirin for Symptomatic Intracranial
Disease) compared high-dose aspirin with warfarin and
demonstrated a 14% stroke and death rate at 1 year in
patients presenting with transient ischaemic attack (TIA)
and intracranial arterial stenosis 70% or greater, and 23%
stroke and death rate in patients presenting with stroke
and 70% or greater stenosis.7
The greater adoption of statins and at least 3 months
of dual antiplatelet therapy in medical management of
symptomatic ICAD led to the SAMMPRIS trial (Stenting
vs Aggressive Medical Therapy for Intracranial Artery
Stenosis). This trial used aggressive medical therapy
including dual antiplatelet therapy for 3 months, then
aspirin only, and use of a statin with goal LDL of 70 mg/
dL or less, blood pressure control, blood glucose and
haemoglobin A1C control, smoking cessation, and weight
loss, and compared it with intracranial stenting with the
same medical regimen. The aggressive medical therapy
arm demonstrated a 30-day stroke, bleed and death
rate of 5.8%, and a 1-year stroke, bleed and death rate
of 12.2%.8 Since this was a combination of patients who
presented with TIA (36.6%) and those who presented
with stroke (63.4%), we would expect by extrapolation
that if only patients presenting with stroke were included
in the trial, the 1-year event rate would be higher than
12.2%, since the WASID trial demonstrated a differential
outcome with higher subsequent stroke rates in patients
presenting with stroke compared with those presenting
with TIA and the same degree of stenosis.
The medical therapy arm of the prospective randomised
COSS trial (Carotid Occlusion Surgery Study) comparing
surgical bypass with medical therapy alone had a mean
time from stroke or TIA to enrolment of 75 days. Then
postrandomisation showed a 30-day stroke and death rate
of 2% in the medical therapy arm of the trial, a 1-year
stroke and death rate of 16%, and a 2-year total stroke and
death rate of 22.3%.9 These high recurrent stroke rates
with ICAD indicate that the patients remain at significant
risk for recurrent stroke in the first 2 years after stroke
from symptomatic severe ICAD, and other non-medical
therapies should be considered, particularly in medically
refractory patients.
SURGICAL THERAPY
The early surgical therapy for ICAD was pioneered by
Sundt et al,10 who performed open surgical endarterec-
tomy of cerebral arteries. The cerebral arteries amenable
to endarterectomy ranged from 2 to 4 mm, so technically
this was a challenging procedure. Later, extracranial-in-
tracranial (EC-IC) bypass with either the use of a donor
artery from the scalp, such as the superficial temporal
artery (STA),11 a radial artery graft or a saphenous vein
graft,12 was used. The prospective randomised EC-IC
bypass trial, comparing direct bypass with the STA versus
medical therapy for patients with symptomatic cerebral
atherosclerotic disease with either total occlusion or high-
grade stenosis, failed to show a benefit with surgery.13
Subsequently, another EC-IC bypass trial, COSS,9 used
oxygen extraction positron emission tomography scan-
ning to determine candidates for the trial based on
oxygen extraction fracture, demonstrating severely
impaired collateral blood flow with hypoperfusion of the
target territory. This trial also failed to show a benefit with
surgical bypass.
While direct bypass had failed to show a clinical benefit
in patients with symptomatic ICAD, the use of an indirect
bypass with encephaloduroarteriosynangiosis (EDAS),
transposing the STA adjacent to the cortical middle cere-
bral artery branches, has shown some initial encouraging
results in a pilot National Institutes of Health (NIH)-
funded trial, ERSIAS (Surgical Indirect Revascularization
for Symptomatic Intracranial Arterial Stenosis).14 Similar
to the process of revascularisation with EDAS indirect
bypass in Moyamoya disease, the indirect bypass in symp-
tomatic ICAD has demonstrated gradual neovascularisa-
tion of the ischaemic territory through angiogenesis from
the donor artery. Further studies will be needed to deter-
mine which patients may best benefit from this treatment
option and whether it may be competitive with or supe-
rior to long-term medical therapy alone.
ENDOVASCULAR THERAPY: BALLOON ANGIOPLASTY
Historically there were early reports on balloon angi-
oplasty of intracranial arteries performed via surgical
exposure for arterial access.15 While these early attempts
demonstrated some angiographic successes, this treat-
ment paradigm did not gain popular acceptance and has
for the most part been abandoned. The development of
less compliant balloons which were suitable for the revas-
cularisation of atherosclerotic arteries was pioneered
by Dotter16 in the peripheral circulation. However,
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angioplasty alone in cerebral arteries has often resulted
in arterial recoil and restenosis, requiring subsequent
repetitive treatments. Early reports on the use of angio-
plasty balloons for ICAD involved balloons designed for
coronary arteries. However, the cerebral arteries histolog-
ically do not have the same structural integrity. Cerebral
arteries have a much thinner muscularis layer compared
with coronary or other peripheral arteries. Cerebral
arteries also lack an external elastic layer that coronary
or peripheral arteries exhibit. Therefore, aggressive dila-
tion of a cerebral artery with an intraluminal non-com-
pliant angioplasty balloon may result in vascular rupture
or dissection. Nevertheless, balloon angioplasty alone has
been recommended by several investigators as a less inva-
sive endovascular treatment for ICAD.17 18 Such studies
have demonstrated a low periprocedural complication
rate but significant residual stenosis, often requiring
repeat treatments, and high recoil and dissection rates
resulting in unclear long-term results.
The more recent use of drug-coated balloons for treat-
ment of ICAD remains controversial. While the idea
of inhibiting restenosis with a drug-coated balloon is
appealing, there are questions on long-term effects of this
type of treatment, particularly since the cerebral artery
walls are much thinner than similar diameter coronary
arteries. Preliminary reports have been mixed, with one
study using a paclitaxel-coated balloon leading to a 31.8%
periprocedural complication rate.19 Another small recent
study demonstrated a good periprocedural safety, but
poor efficacy in stenotic artery revascularisation, with a
mean postangioplasty residual stenosis of 50%.20 However,
other studies have shown more reasonable periproce-
dural complication rates with lower restenosis incidence,
including a series of 30 patients treated by Han et al21 with
a periprocedural complication rate of 6.7% and a short-
term restenosis rate at a mean of 7 months of 3.2%.
ENDOVASCULAR THERAPY: INTRACRANIAL STENTING
The early treatment of ICAD with angioplasty and
stenting involved the use of balloon-expandable coronary
stents.22 The first stent specifically designed for intrac-
ranial stenting was a balloon-expandable stent that was
fairly successful in the SSYLVIA clinical trial (Stenting of
Symptomatic Atherosclerotic Lesions in the Vertebral or
Intracranial Arteries), but was never manufactured and
marketed subsequently.23
The Wingspan stent was the first self-expanding stent,
specifically designed for treatment of symptomatic ICAD.
Currently, it is the only Food and Drug Administration
(FDA)-approved stent for the treatment of symptom-
atic intracranial ICAD. The initial Humanitarian Device
Exemption (HDE) approval trial treated 44 patients with
the stent and demonstrated excellent periprocedural
safety results, with a 4.5% complication rate, and this was
subsequently marketed under the HDE application.24
There were two subsequent registries, each enrolling
over 150 patients with the delivery of Wingspan stents, the
US Wingspan stent registry and the NIH Wingspan stent
registry.25–28 These both demonstrated approximately
6% periprocedural complication rate and represented
the initial clinical experience with the stent in the USA.
Subsequent large clinical series were reported by multiple
centres in both single-centre registries and multicentre
trials.29–36
The SAMMPRIS trial was a prospective randomised
trial comparing the Wingspan stent with aggressive
medical management alone; however, the use of the
stent was in an Investigational Device Exemption FDA
application with expanded indications including early
treatment and treatment of patients with TIAs alone, as
opposed to stroke presentation solely.8 With this indica-
tion, approximately 8% of patients were stented on-label
and the remainder would not have met the original
HDE application indications. This study demonstrated
a markedly higher periprocedural complication rate of
14.7%, and these results hindered the use of the stent
following the trial. The FDA subsequently mandated a
postmarket surveillance study of the Wingspan stent,
following the poor SAMMPRIS results. The WEAVE trial
(Wingspan Stent System Post Market Surveillance) was
designed to determine the safety of the stent when used
strictly on-label by experienced interventionalists.37 The
trial enrolled 152 on-label patients, which was the largest
on-label trial performed in the USA to date, and excel-
lent results were seen. The periprocedural complica-
tion rate of 2.6% was also the lowest complication rate
obtained in prior trials. The trial inclusion protocol
and patient management protocol were very strict, and
these clinical outcomes were adjudicated by core stroke
neurologists.
In retrospect, one of the primary differences between
the various registries and trials is that there were much
lower periprocedural complication rates when patients
were stented 2 or 3 weeks following their last stroke as
opposed to 7 days or less, as they were in the SAMMPRIS
trial. The poor results in the SAMMPRIS trial, however,
were not due to the long-term effects of the stenting. The
initial high periprocedural complication rate of 14.7% was
insurmountable compared with long-term complications
of medical treatment only. In a separate analysis by Yu and
Jiang38 of the SAMMPRIS data, looking only at patients
beyond 30 days following stenting or the initiation of
medical therapy alone, there was a threefold higher rate
of disabling or fatal strokes in a medical therapy group
compared with the stenting group, with a 6.2% event rate
in the medical group and 2.2% in the stenting group. This
implies that if angioplasty and stenting can be performed
with a low periprocedural complication rate, then the
long-term benefit of the stent provides some protection
from disabling stroke and death compared with medical
therapy alone.
There have been various other publications demon-
strating the poor clinical design of SAMMPRIS. Subse-
quent analyses included criticisms of the inexperience
of the investigators, the early treatment with stenting of
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Table 1 Major Wingspan stent trials with mean time to treatment and complication rates
Publication
Patients
stented (n)
Percentage stented
on label for stroke
Periprocedural
complications %)
Time to stent
from stroke or
TIA (days)
HDE trial Stroke, 200724 44 93 4.5 22
US registry Stroke, 200727
Stroke, 201128
158 57 6.9 Not reported
NIH registry Neurology, 200825 160 61 6.2 10
SAMMPRIS New England Journal
of Medicine, 20118
208 8.2 14.7 7
Jiang Stroke, 201130 100 71 5.0 34
Miao Stroke, 201529 141 56 4.3 19 for TIA/32 for
stroke
Zhao Journal of Stroke
and Cerebrovascular
Diseases, 201633
278 Not reported 4.3 21
Gao American Journal
of Neuroradiology,
201635
100 50 2.0 21
Ma Stroke and Vascular
Neurology, 201834
141 56 4.0 22
WEAVE Stroke, 201937 152 100 2.6 22
HDE, Humanitarian Device Exemption; NIH, National Institutes of Health; SAMMPRIS, Stenting vs Aggressive Medical Therapy for Intracranial
Artery Stenosis; TIA, transient ischaemic attack; WEAVE, Wingspan Stent System Post Market Surveillance.
patients with stroke, the potential inadequate antiplatelet
therapy and the inclusion of other off-label patients.39 40
Following SAMMPRIS, there have been several single-
centre and multicentre trials and registries that have
demonstrated much safer periprocedural results with the
Wingspan stent, provided that the time to treatment was
delayed 2–3 weeks following the last stroke.29–36 In a multi-
centre trial comparing a balloon-expandable stent with
the Wingspan self-expanding stent in over 300 patients,
Ma et al.34 demonstrated a 4% periprocedural complica-
tion rate, and a total 1-year follow-up stroke, TIA, bleed
and death rate of 7.9% in the Wingspan-treated group.
The WEAVE trial was different from the SAMMPRIS
trial in that 100% of the patients in the WEAVE trial were
treated on-label with the Wingspan stent. WEAVE did not
enrol patients with stroke 7 days or earlier following their
index event. It did not allow lesions greater than 14 mm
in length or target vessels less than 2 mm. It did not allow
patients presenting only with TIA or vertebrobasilar insuf-
ficiency without stroke. Also, there was formal training of
the interventionalists regarding the best practices that
have been learnt from previous trials. Patient selection was
key and the premedication regimen with the antiplatelet
therapy at least started 5 days prior to the stenting was
very strict. Interventionalists were also instructed in the
best practice techniques of control of the exchange wire,
use of support catheters, intra-arterial vasolytic use and
underdilating the angioplasty balloon in perforator-rich
areas. Also, the recommendation to decrease the systolic
blood pressure to less than 140 postoperatively was strictly
enforced. Finally, the experience of the operators in the
WEAVE trial was superior to SAMMPRIS. The goal expe-
rience for the interventionalist in the WEAVE trial was
greater than 25 Wingspan stents placed, and the mean
was 37 Wingspan stents prior to enrolling a patient in the
trial. In contrast, the SAMMPRIS trial interventionalists
had a mean experience of 10 Wingspan stents, and some
treated as few as three patients in their career. The impact
of the experience of the interventionist was also demon-
strated in the WEAVE trial, as those interventionists who
had a case experience of 50 Wingspan stents or greater
had no index events in the periprocedural period, and
those with less than 50 had a 4.8% periprocedural compli-
cation rate.37
There is a clear trend from multiple recent trials and
registries that performing angioplasty and stenting in the
early time period, particularly 7 days or less from the qual-
ifying stroke, results in a higher periprocedural compli-
cation rate. We have yet to define the reason for this.
However, there has been speculation that with a recent
stroke, there is a ruptured plaque or hot plaque which is
highly inflammatory and thrombogenic and more likely
to cause embolic events with the additional placement of
a foreign body such as a stent.39 There is also speculation
that many patients may be subtherapeutic on their anti-
platelet therapy in the SAMMPRIS trial because many were
loaded with antiplatelet therapy 6–24 hours prior to their
stenting procedure. Finally, there is a trend of thought
that revascularisation of a recently stroked territory has
a higher risk for reperfusion haemorrhage, particularly
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Table 2 Comparisonsvn-2019 of 1-year stroke and death
rates with medical therapy and stenting 21 days or longer
after qualifying event
Medical
therapy Publication
Patients
(n)
One-year
stroke and
death rate
(%)
WASID New England Journal
of Medicine, 20057
569 18
SAMMPRIS New England Journal
of Medicine, 20118
227 12.2
COSS The Journal of the
American Medical
Association, 20119
98 16
Total/mean
event rate
894 15.4
Stenting
Jiang Stroke, 201130 100 7.3
Li PloS One, 201531 429 9.5
Wang Neuroradiology, 201632 196 9.6
Zhao Journal of Stroke
and Cerebrovascular
Diseases, 201633
278 5.8
Ma Stroke and Vascular
Neurology, 201834
141 7.9
Total/mean
event rate
1134 8.0
COSS, Carotid Occlusion Surgery Study; SAMMPRIS, Stenting
vs Aggressive Medical Therapy for Intracranial Artery Stenosis;
WASID, Warfarin vs Aspirin for Symptomatic Intracranial Disease.
in areas that have poor collateral and are essentially an
isolated circulation. This high periprocedural complica-
tion rate in patients treated early after stroke or TIA was
seen in the SAMMPRIS trial, which had a mean time to
treatment of 7 days, and in the subgroup analysis of the
NIH Wingspan registry, which showed a higher compli-
cation rate periprocedurally in patients treated less than
10 days from their stroke compared with those stented
greater than 10 days after their stroke,26 whereas the HDE
trial, WEAVE trial and multiple large studies from China,
with a mean time to treatment of 21 days or longer post-
stroke, have demonstrated significantly lower periproce-
dural complication rates (table 1).
Finally, if we analyse studies that demonstrate the
longer-term 1-year stroke and death rate with medical
therapy compared with the 1-year stroke and death rates
of those trials that have stented patients in the 21-day
or longer range, we see that there are significantly less
strokes and death in the stented patients (table 2).
This comparative study analysis showed a mean 1-year
stroke and death rate of 15.4% in the medical therapy
groups and a mean 1-year stroke and death rate of 8.0%
in the Wingspan stent groups. Studies were not included
in the analysis if the published paper either did not state
what the mean time to stenting was in the cohort or if the
mean time to treatment was less than 21 days following
stroke or TIA. These data suggest that, if the periproce-
dural complication rate can be kept low with experienced
interventionalists, best practices are used regarding
periprocedural patient management, and if patients
undergo delayed stenting, a mean of 21 days or longer
postevent, stenting may be competitive with, or poten-
tially superior to, medical therapy for patients presenting
with 70%–99% intracranial artery stenosis, presenting
with a stroke.
Currently the study results of two additional Wing-
span trials are pending, the CASSISS trial (China Angio-
plasty and Stenting for Symptomatic Intracranial Severe
Stenosis) from China41 and the WICAD study (Wingspan
for IntraCranial Atherosclerotic Disease) from Japan.
Both trials have demonstrated in early reports similar
safety results with the on-label use of the stent and likely
will give additional supporting data for the safe use of
self-expanding stents.
SUMMARY
The recent imaging developments of OCT and HR-MRI
to assess intracranial arteries for symptomatic ICAD has
helped us to diagnose ICAD and to determine if ICAD
plaques have any high-risk features for treatment. Future
developments in the treatment of ICAD may include
further development of trackable drug-coated balloons
for the cerebral circulation to treat primary or resten-
otic arteries, new iterations of self-expanding intracranial
stents with easier delivery systems, and the re-examina-
tion of indirect surgical bypass techniques for revascular-
isation. Nearly as important as these technological devel-
opments, however, is to determine the best treatment
window for these techniques and additional medical
management factors which can improve patient outcomes
in this devastating pathology.
Contributors I am the sole author.
Funding The authors have not declared a specic grant for this research from any
funding agency in the public, commercial or not-for-prot sectors.
Competing interests MJA is a consultant for Stryker Neurovascular, manufacturer
of the Wingspan Stent, which is discussed in the manuscript.
Patient consent for publication Not required.
Provenance and peer review Commissioned; internally peer reviewed.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-commercially,
and license their derivative works on different terms, provided the original work is
properly cited, appropriate credit is given, any changes made indicated, and the use
is non-commercial. See:http:// creativecommons. org/ licenses/ by- nc/ 4. 0/.
ORCID iD
Michael JAlexander http:// orcid. org/ 0000- 0003- 0280- 809X
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