Perspectives in Medicine (2012) 1, 122128

Bartels E, Bartels S, Poppert H (Editors):

New Trends in Neurosonology and Cerebral Hemodynamics an Update.
Perspectives in Medicine (2012) 1, 122128

journal homepage: www.elsevier.com/locate/permed

Predictors of carotid artery in-stent restenosis

Katrin Wasser a, Sonja Grschel a, Janin Wohlfahrt a, Klaus Grschel b,

a
Department of Neurology, University of Gttingen, Robert-Koch-Str. 40, 37075 Gttingen, Germany
b
Department of Neurology, University of Mainz, Langenbeckstr. 1, 55131 Mainz, Germany

KEYWORDS Summary
Background: Carotid angioplasty and stenting (CAS) is increasingly being used as a treatment
Carotid artery
alternative to endarterectomy (CEA), especially in patients aged <70 years with signicant
stenosis;
carotid artery stenosis. However, an in-stent restenosis (ISR) might endangering the long-term
Stent;
efcacy of CAS. The aim of this article was to review the current literature regarding incidence
Angioplasty;
and clinical signicance as well as predictors of in-stent restenosis.
Restenosis;
Methods: We conducted a systematic review of the literature to identify all studies on the
Stroke;
abovementioned factors.
Carotid ultrasound
Results: 3 randomized-controlled trials comparing CAS and CEA and 13 single centre studies
fullled our inclusion criteria. The occurrence of ISR after CAS ranged from 2.7 to 33% and was
detected within the rst year in most of the studies. The clinical impact as well as the thera-
peutic consequence of ISR remains unclear, but many baseline characteristics (age, prior CEA or
radiation), procedural (insufcient stent deployment, stent dimensions, inammatory marker)
and follow-up factors (reduced HDL, diabetes mellitus) could be found to identify patients at
special risk for ISR. A wide heterogeneity related to the denition and their corresponding
ultrasound criteria for ISR was observed.
Conclusions: A close follow-up is suggested especially in those patients with predictors of an ISR.
The wide range of ISR ultrasound denitions urges the need for an implementation of generally
valid criteria in ISR diagnosis. Against the background of the unknown clinical signicance of
ISR and a lacking established treatment modality these ndings should be taken into account
when offering CAS as a treatment alternative to CEA.
2012 Published by Elsevier GmbH. Open access under CC BY-NC-ND license.

Introduction standard therapy for a symptomatic stenosis of the inter-

Atherosclerotic stenosis of the internal carotid artery is
known as a major risk factor for disabling stroke or
death leading to enormous socioeconomic problems. The
Corresponding author. Tel.: +49 6131 173105;
fax: +49 6131 17473105.
E-mail address: klaus.groeschel@unimedizin-mainz.de
(K. Grschel).
nal carotid artery has been a carotid endarterectomy (CEA)
in combination with best medical treatment of concomi-
tant cerebrovascular risk factors. In recent years, carotid
angioplasty and stenting (CAS) has widely been used as a
treatment of rst choice in many patients, despite the fact
that the randomized controlled trials and subsequent meta-
analyses could not prove a general superiority of CAS over
CEA [16]. However, the results of the aforementioned tri-
als have been interpreted very controversely resulting in
conicting recommendations in various current guidelines.

2211-968X 2012 Published by Elsevier GmbH. Open access under CC BY-NC-ND license.
doi:10.1016/j.permed.2012.02.051
Clinical signicance as well as predictors of carotid in-stent restenosis
In the American guidelines, for instance, the authors con-
cluded that CAS could be used as an equivalent treatment
modality to CEA in medium risk patients with a symptomatic
carotid stenosis [7], whereas elsewhere, CEA still is advo-
cated as the rst treatment of choice [8]. Despite this
ongoing current debate, there is accumulating evidence that
a subgroup of patients aged <70 years may prot from a CAS
intervention [35,9]. Because the clinical long-term out-
come is of crucial importance especially in younger patients,
the occurrence of an in-stent restenosis (ISR) could be one
factor endangering the long-term efcacy and safety of
CAS. Unfortunately, data concerning the rate and clinical
impact of ISR during long-term follow-up are still sparse
and show conicting results [3,10,11] which may in part be
attributable to different denitions of an ISR during ultra-
sound follow-up investigations [12,13].
This article briey summarizes the currently available
long-term data of randomized controlled trials comparing
CAS and CEA and of several single centre studies regarding
the incidence and clinical impact of ISR as well as clinical
predictors for ISR.
Methods
A MEDLINE search was conducted by two independent
reviewers (K.W. and J.W.) using the following keyword
searches: carotid artery, stent, and restenosis. As
a key feature before retrieving a full text article after inves-
tigating a potentially benecial abstract, the studies had to
full the following criteria: (1) studies had to be published
between January 2000 and October 2011 in a journal which
is indexed within the MEDLINE database, (2) the follow-up
of the patients had to be performed for at least six months,
(3) the occurrence of carotid in-stent restenosis had to be
mentioned within the text, (4) articles had to be written in
English and (5) at least 100 stented carotid arteries had to be
investigated. If there was more than one publication about
the same patient cohort, the most recent one or rather the
publication with the longest follow-up time was used.
After retrieving the full-text article of abstracts which
met the above mentioned criteria, the following data, if
available, were extracted in a predened data sheet: (1)
number of arteries that were treated by CAS, (2) follow-up
time, (3) baseline characteristics of patients (age, propor-
tion of male patients), (4) amount and denition of ISR, (5)
clinical complications of ISR, divided into stroke and death
and (6) clinical factors which had been identied to predict
the occurrence of an ISR during follow-up. After all relevant
data had been extracted by the two reviewers, disagree-
ments were resolved by consensus with the help of a third
independent investigator (K.G.)
Results
We could identify 3 randomized, controlled studies (CAVATAS
[14,15], SPACE [1,16] and EVA-3S [2,17]) and 13 [1830]
smaller single centre studies that fullled our inclu-
sion criteria and reported incidence, clinical signicance
and predictors of recurrent in-stent stenosis after stent-
protected angioplasty of signicant internal carotid artery
stenosis.
123
Detailed description of randomized trials of CAS
versus CEA
Carotid and Vertebral Artery Transluminal Angioplasty
Study (CAVATAS) [14,15] was the rst completed, prospec-
tive multicentre trial (24 centres in Europe, Australia and
Canada) comparing endovascular versus surgical treatment
of patients with symptomatic (96.4%) and asymptomatic
carotid artery stenosis. CEA was performed in 253 patients,
whereas 251 patients received endovascular treatment
(mainly angioplasty alone). This study excluded high-risk
patients, and stents were used selectively, when available,
and in only 26% of cases (n = 55). During a median carotid
ultrasound follow-up time of 4 years patients undergoing
endovascular treatment were found to suffer signicantly
more often from severe restenosis (70%) or occlusion than
patients after CEA [15]. When comparing balloon angioplasty
alone to angioplasty and stenting, those patients who were
treated with a stent (n = 50) had a signicantly lower risk of
developing restenosis of 70% (adjusted hazard ratio 0.43,
0.190.97; p = 0.04). Regarding the clinical complications
in patients with a restenosis, the incidence of ipsilateral
stroke or transient ischemic attack was signicantly higher
in patients with a restenosis 70% (cumulative 5-year inci-
dence 22.7% vs. 10.9%, p = 0.04) compared to those with no
ISR. Current or past smoking turned out to be independently
associated with a higher incidence of restenosis [15].
The Stent-Supported Percutaneous Angioplasty of the
Carotid Artery vs. Endarterectomy Trial (SPACE) assessed
non-inferiority of CAS to CEA and randomized 1183 patients
(CAS n = 605; CEA n = 595) with a symptomatic carotid artery
stenosis as assessed with duplex ultrasound (50% accord-
ing to NASCET criteria, or 70% according to ECST criteria)
at 35 centres in Austria, Germany and Switzerland [1]. The
type of stent and use of a protection system were chosen
at the discretion of the interventionalist. Restenosis during
follow-up were observed more frequently in those patients
treated with CAS (4.6% vs. 10.7%, p < 0.001) compared to
CEA [16]. The majority of the recurrent stenosis occurred
within the rst 6 months after the initial treatment (CAS
n = 28 (51.9%), CEA n = 12 (52.2%)). Furthermore, additional
new ISR were observed even after 24 months of follow-up
after carotid stenting whereas no new recurrent restenosis
was found after CEA beyond 2 years of follow-up. Because
a predened denition of ISR was not used during the study
period and the denition of an ISR depends on the local cri-
teria of each center, a slight overestimation of ISR might be
possible [16].
Endarterectomy versus angioplasty in patients with
symptomatic severe carotid stenosis (EVA-3S) trial [2] was
carried out to demonstrate non-inferiority of CAS compared
with CEA and enrolled 527 patients with 60% symptomatic
carotid stenosis at 30 centres in France. In 507 patients
(CAS n = 242, CEA n = 265) serial long-term carotid ultrasound
follow-up was performed during a mean follow-up time of
2.1 years [17]. Although the development of a moderate
stenosis (5069%) within 3 years was found to differ sig-
nicantly between the groups with a higher proportion after
CAS compared to CEA (12.5% vs. 5.0%, p = 0.02), the inci-
dence of a high-grade restenosis 70% showed no signicant
difference between the two groups (3.3% vs. 2.8%). A clin-
ical impact of an ISR on ipsilateral stroke or death during
124
follow-up could not be observed. Advanced age was a clini-
cal risk factor, which could be identied to be predictive for
developing carotid restenosis [17].
To date, to the best of our knowledge, no data about
rates of restenosis have yet been published by the other
commonly known large randomized controlled studies com-
paring CEA and CAS especially the International Carotid
Stenting Study (ICSS) [31], the Carotid Revascularization
Endarterectomy vs. Stenting Trial (CREST) [4], and the Stent-
ing and Angioplasty with Protection in Patients at High Risk
for Endarterectomy study (SAPPHIRE) [11,32].
Within the analysed non-randomised trials, there was a
wide range concerning the amount of treated patients. The
smallest study included 100 patients [33]; the largest num-
ber of CAS patients was enrolled in the study of Setacci et al.
(n = 814) [25]. In the vast majority, patients aged 60 years or
over with roughly two-thirds male sex were included in the
reviewed studies. The relevant data which were extracted
are delineated in Table 1. The diagnostic tool used to detect
an ISR was serial duplex ultrasound in all studies (n = 13). A
conrmatory diagnostic procedure such as CTA or conven-
tional angiography had been carried out after ultrasound
in ten studies [19,2127,29,30]. Notably, there was a wide
variation concerning the ultrasound criteria applied for the
detection of an ISR between the studies. As one of the
main key features for the detection of a restenosis, a cut-
off peak systolic velocity is mentioned [19,22,24,26,2830]
sometimes in addition to other criteria such as end-diastolic
velocity or the ICA/CCA index [18,20,21,23,25,27].
Although the minority of the studies reported concise
details about the exact time point of ISR occurrence, most
ISR were found to occur within the rst year (median: 8
months, IQR: 79) after CAS [16,18,20,21,26,29,30]. There
was a broad range concerning the clinical complications for
patients with ISR between 0% [21,22,24,26,29] and 25% [30]
for stroke and from 0% [19,2123,25,26,29] to 11.1% [18]
for death, respectively.
Common baseline characteristics like advanced age [19],
female gender [19], prior revascularization treatment,
[23,25,27,34,35] the treatment of a radiogenic stenosis [23]
or prior neck cancer [21] could be found to be predictive
for ISR development. Furthermore, some cardiovascular risk
factors such as smoking [17], lowered HDL cholesterol, [26]
diabetes mellitus [22] or elevated HbA1c [18,36] could be
identied as predictors for ISR, too. In addition to tradi-
tional cardiovascular risk factors, periprocedural elevated
inammatory markers were found to play a major role in
ISR development [20,30]. Finally, several procedure-related
factors such as stent dimensions [30], implantation of multi-
ple stents [19,28], or an insufcient dilatation effect of CAS
[19,20,28] could be identied to promote ISR.
Discussion
Recurrent stenosis after CEA was rst described by Stoney
and String in 1976 [37] and turned out to be associated with
a higher rate of periprocedural complications during a sec-
ondary operation [9]. Soon after CAS had received broader
acceptance as a potential alternative treatment option for
patients with severe carotid artery stenosis, rst reports
about ISR were published in the late 1990s [3840]. Since
K. Wasser et al.
then, the awareness for detecting an ISR has increased fur-
ther and was more frequently considered in published case
series. Within one of the most recent meta-analyses, a 180%
increase in the risk of intermediate to long-term carotid
restenosis was observed after CAS as compared to CEA. [41]
Since CAS is currently widely used as a treatment alterna-
tive to CEA, it is necessary to contribute to the ongoing
controversial discussion regarding the incidence, clinical sig-
nicance and appropriate therapeutic management of ISR in
order to ameliorate long-term efcacy.
With regard to the etiology of ISR, there may be some sim-
ilar mechanisms to recurrent stenosis after coronary artery
stenting. First of all, an endothelial injury which is caused
e.g. by balloon ination and stent placement, seems to
play a major role for the developing of ISR, both after
CAS or coronary artery stenting. This damage could initi-
ate a cascade of inammational processes, which nally
leads to a neointimal proliferation and a concentric ves-
sel lumen reduction. Like Schillinger et al. [20] we were
recently able to support the notion of an inammatory cas-
cade as a main cause for ISR by showing that elevated
periprocedural inammation markers are signicantly cor-
related with the development of an ISR [30]. The initial
injury of the endothelial layer caused by balloon ination,
guide-wire manipulation or stent placement might explain
why additional procedural factors could be identied within
our literature review to inuence the occurrence of ISR: the
use of multiple stents during CAS [19,28] or even wider and
longer stent dimensions by their own [30] could be identi-
ed to be associated with a higher incidence of ISR. Potential
endothelial injuries by either an amplied sheer force of the
stent, a more pronounced abrasion or higher ination pres-
sure during the procedure are some of the discussed issues
accountable for restenosis.
Despite the heterogeneity of the analysed studies, one
of the most common ndings was the time during which
an ISR could be detected as it seems to develop most
frequently within the rst year after a CAS intervention
[16,18,20,21,26,29,30]. This fact suggests the assumption
that rather an intimal hyperplasia than an atherosclerotic
burden is the main driven pathologic factor for an early
restenosis.
Although different diagnostic tools and criteria were cho-
sen to determine the presence of an ISR, the incidence is
surprisingly constant throughout most of the publications
under review. The rate of moderate (50%) and high-grade
ISR (70%) varies between 6.713.9% and 2.76.3%, respec-
tively (see Table 1). Notably, this rate is higher as compared
to those with a preceding CEA treatment within some of
the randomised trials [16,42], which has led to a keen
discussion on the long-term durability of a CAS procedure
[10]. Against the background that there is no established
treatment standard for patients with an ISR, this should be
considered before a CAS intervention is recommended as the
preferred treatment modality. The surgical treatment of an
ISR remains an exception since it is technically demanding
and might be associated with periprocedural complications
[43]. In most of the cases, a redo-PTA or CAS is currently
performed after ISR, which seems to be associated with an
acceptable rate of periprocedural complications [29,30,35].
As a method of rst choice to diagnose ISR, preferably a
non-invasive technique should be chosen to avoid a potential
 Clinical signicance as well as predictors of carotid in-stent restenosis
Table 1 Main characteristics of all studies included.
First author (year) Mean follow-up Number of treated Mean age Denition of ISR, Proportion of ISR Time to detection Complications of Independent
time [mo], range arteries, male (years) SD DUS criteria (cm/s) (%) during of ISR [months] ISR-patients (%) predictors of ISR
patients follow-up during follow-up
Willfort-Ehringer (2002) 12b , 624a 303, 70% 70 9 70% ICA/CCA >4 3.0 <12 Stroke 22.2 Death Elevated HbA1c at
11.1 baseline
Khan (2003) <12, n.g. 209, 71% 72% >75 50% PSV 140 6.7 n.g. Stroke 0.4 Death Age >75 y
0.0 Female gender
Multiple stent
deployment
Suboptimal CAS
result
Schillinger (2003) 6, n.g. 108, 68% ISR 62, r60-76 50% PSV 150 13.9 6 Stroke 13.3 Death Prior CAS
N-ISR 70, r65-76 +ICA/CCA >2.5 6.7 Suboptimal CAS
result
Elevated CRP after
CAS
Skelly (2006) 5b , 030 109, 55% 70 9 60% PSV 170 60% 11.0 60% 7 ISR 60% Prior neck cancer
80% 80% 4.6 80% 7, r 19 Stroke 0
60% + EDV Death 0
145
Lal (2007) 19.3, n.g. 255, n.g. ISR 71.8 40% PSV 140 33.3 n.g. Stroke 0.0 Diabetes mellitus
Death 0.0 Worsening of
suggested ISR
pattern
Younis (2007) 24, 699 399, 67% 70 3.5 80% EDV-ICA/CCA 3.8 24.5 r 590 Stroke 20.0 Prior CEA
>5.4 Death 0.0 Radiogenic
stenosis
AbuRahma (2008) 20, 178 144, 51% 70, r 4088 50% 50% 7.6 n.g. ISR 50% n.g.
PSV 224 cm/s 80% 5.6 Stroke 0.0
80% Death n.g.
PSV 325 cm/s
Setacci (2008) 45, 073 814, 64% 73 8 50% PSV 175 50% 9.0 n.g. ISR 70% Prior CEA
70% PSV 300, 70% 2.7 Stroke 9.0
EDV 140 Death 0.0
Topakian (2008) 12, n.g. 102, 66% 66 9 50% 9.8 12 Stroke 0.0 Postprocedural low
PSV 180 cm/s Death 0.0 HDL cholesterol
Zhou (2008) 32, 648 282, n.g. 69, r 5587 70% PSV 125, 6.3 n.g. Stroke 11.1 Prior CEA
EDV < 140 Death n.g.
Cosottini (2010) 26b , 099 200, 74% 72 8 50% 11.5 n.g. Stroke 13.0 Suboptimal CAS
PSV 220 cm/s Death 8.7 result
Multiple stent
deployment
Takigawa (2010) 28.6, 1267 113, 86% 70 7 50% 11.3 93 Stroke 0 Cilostazol
PSV 150 cm/s Death 0
Wasser (2011) 33.4b , 1554a 210, 72% 68b 10 70% 5.7 9b , 317a Stroke 25.0 Leukocyte count
PSV 300 cm/s Death 8.3 after CAS
Stent length
Stent width
DUS, duplex ultrasound; PSV, peak systolic velocity; EDV, end diastolic velocity; ICA/CCA, index of PSV of ICA and CCA; NISR, group of patients without ISR
r, range; n.g., not given.
a Interquartile range.
b Median.

125
126
harm for the patient during the essential long-term follow-
up. In this context, serial duplex ultrasound investigations
seem to best full the requirements for long-term follow-up
and have been used in all studies retrieved for the cur-
rent review. As a secondary validation method, high-grade
ISR could be conrmed by CT angiography in some selected
cases. Since duplex ultrasound has turned out to lead to
a reliable ISR diagnosis whereas conventional angiography
is known to be an invasive procedure possibly linked with
potentially dangerous complications such as stroke or bleed-
ings, a conventional angiography should only be considered
in those patients with a symptomatic or high-grade ISR, who
are likely to be treated afterwards or within the same angio-
graphic session.
A fact which could reduce the value of duplex ultrasound
as a rst choice method for serial follow-up investigations
is the generally lacking agreement of exact ultrasound cri-
teria to grade an ISR. Considering the peak systolic velocity
(PSV) as the most commonly used duplex criterion, a con-
siderable distribution of cut-off values could be observed.
For example, the cut-off PSV for the diagnosis of an ISR
of 50% varied from 140 cm/s in one study [19], over a
PSV 175 cm/s in the publication of Setacci et al. [25] and
a PSV 220 cm/s in the study by Cosottini et al. [28] up to
a PSV 224 cm/s by AbuRahma et al. [24]. Despite the fact
that ultrasound criteria have to be adapted to each local
high quality ultrasound laboratory, the wide range of values
between the studies urges the need for an implementation
of generally valid ultrasound criteria in ISR diagnosis [12,13].
There is currently a very controversial discussion on the
clinical impact of ISR. Amongst others, the results from the
SPACE study have encouraged those claiming that resteno-
sis might be a relatively benign pathology [16,44]. On the
other hand, especially long-term follow-up data raise con-
cern that patients with ISR could be suffering from a higher
complication rate in comparison to patients without ISR [30].
Since CAS is often recommended the treatment of choice in
younger patients (<70a) [35,9] it is of greatest interest to
evaluate the complication rates of ISR in the long run. By
now, the results regarding the incidence and clinical compli-
cations of ISR of the randomized controlled trials comparing
CAS and CEA [4,6,11] are eagerly awaited.
The unresolved clinical impact of ISR further highlights
the importance to identify independent risk factors which
are predictive for an ISR. These would be helpful to detect
those patients in which a tight follow up is necessary.
Advanced age [17,19] has been found to be predictive for an
ISR, which would further contribute to the recommendation
of choosing a CEA as a rst treatment of choice especially
in elderly patients [3,5]. CAS is frequently recommended
in patients with a restenosis after CEA because a redo-CEA
sometimes appears to be technically difcult and might bear
a higher periprocedural risk than the initial operation [7] or
in patients with a radiogenic stenosis [45]. When considering
the optimal treatment option for those patient subgroups,
one should take into account though that a CAS procedure
because of a CEA-restenosis or radiation-induced stenosis is
also associated with a higher rate of ISR [20,23,34,35]. An
insufcient result after a CAS procedure, e.g. due to insuf-
cient stent adaptation, could be shown to be associated
with a higher risk of ISR occurrence [19,20,28]. Therefore, to
ameliorate the long-term benet of a CAS, it is a worthwhile
K. Wasser et al.
aim to pursue a perfect stent adaptation to the vessel lumen.
The fact that an aggressive postdilation bears the risk of dis-
tal embolization and microvascular injury, which may itself
initiate neointimal hyperplasia complicates the procedure.
Furthermore, the characteristics of the stent deployed are
of special interest regarding the incidence of ISR. Usually,
the selection of the stent length and width are based on
angiographic ndings in order to appropriately cover the
stenosis. However, narrower and longer stents were corre-
lated with a higher ISR risk [28,30]. It is conceivable that
a stent with a larger diameter results in a reduced ow-
velocity, less turbulences and thus in less frequent ISR. A
longer stent, which is used to cover longer lesions, proba-
bly represents the presence of a high plaque burden and has
repeatedly been identied as an independent predictor for
periprocedural complications [46,47]. Although it is clear
that mainly anatomical conditions lead to the selection of a
specic stent, it is recommendable to choose the shortest
but widest stent as possible in order to minimize the risk of
ISR development and to closely follow-up those patients in
whom a longer, narrower stent has been used.
After a successful CAS, a stringent monitoring of cardio-
vascular risk factors seems to be essential. Not only with
regard to primary and secondary stroke prevention, but
also especially in the context of ISR development, several
publications show a correlation between the presence of
cardiovascular risk factors, such as tobacco use [17,42],
diabetes mellitus [18,22], e.g. represented by an elevated
HbA1c [36], low HDL cholesterol [26], and the occurrence of
an ISR.
Conclusions
ISR after CAS is frequently observed within the rst year
of follow-up and might be associated with a higher risk for
clinical complications. Against the light that a CAS interven-
tion is frequently recommended as an alternative treatment
strategy to CEA especially in patients aged <70 years, a
tight and long-lasting follow-up is warranted. Particularly
patients who are of advanced age, treated for a radio-
genic stenosis or a recurrent stenosis after CEA, or with
the presence of cardiovascular risk factors such as tobacco
use, diabetes mellitus or a dyslipoproteinemia or certain
procedure-related factors (a narrow or long stent, insuf-
cient stent adaptation after CAS or the use of multiple
stents) are prone to develop an ISR. A signicant hetero-
geneity especially regarding the exact duplex criteria to
identify an ISR has been observed between the reviewed
studies thus supporting the need to establish commonly
accepted criteria for ISR-grading. With respect to the pos-
sible clinical relevance of an ISR and a lacking commonly
accepted treatment strategy, all efforts should be made to
carefully follow-up especially those patient subgroups at risk
for ISR in order to further develop an optimized treatment
strategy.
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