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Journal of the American College of Cardiology

2008 by the American College of Cardiology Foundation


Published by Elsevier Inc.

Vol. 51, No. 10, 2008


ISSN 0735-1097/08/$34.00
doi:10.1016/j.jacc.2007.10.052

STATE-OF-THE-ART PAPER

Optimal Treatment of Carotid Artery Disease


Elad I. Levy, MD,* J Mocco, MD, MS,* Rodney M. Samuelson, MD,* Robert D. Ecker, MD,*
Babak S. Jahromi, MD, PHD,* L. Nelson Hopkins, MD*
Buffalo, New York
Extracranial carotid artery disease accounts for approximately 25% of ischemic strokes. Although carotid endarterectomy (CEA) is the established gold standard for carotid revascularization, carotid artery angioplasty and
stenting (CAS) is continually developing into a safer and more efficacious method of stroke prevention. Embolic
protection, improving stent designs, and ever-increasing surgeon experience are propelling CAS towards equipoise with and possible superiority to CEA. One multicenter randomized trial and several nonrandomized registries have successfully established CAS as an accepted treatment for high-risk patients. Clinicians must strive to
perform well-designed clinical trials that will continue to aid understanding and improve application of both endovascular and open techniques for extracranial carotid revascularization. We review the data published to date
regarding the indications for and recent developments in the use of CAS. (J Am Coll Cardiol 2008;51:97985)
2008 by the American College of Cardiology Foundation

Carotid artery angioplasty and stenting (CAS) has steadily


developed over the preceding decade. Current data regarding CAS and carotid endarterectomy (CEA) suggest that
CAS is quickly gaining ground on CEA as a first-line
treatment of extracranial carotid stenosis. Clinicians must
continue to refine their understanding of the appropriate
indications for both CAS and CEA. This is done through
rigorous, well-designed research. We review the data supporting the implementation of CAS for extracranial atheroocclusive carotid artery disease.
Background
Indications for and outcomes of CEA have been extensively
studied. The support for CEA utilization is generated from 4
well-designed multicenter, randomized clinical trials
NASCET (North American Symptomatic Carotid Endarterectomy Trial) (1,2), ECST (European Carotid Surgery Trial)
(3,4), ACAS (Asymptomatic Carotid Atherosclerosis Study)
(5), and ACST (Asymptomatic Carotid Surgery Trial) (6).
The NASCET (1,2) and ECST (4) trials addressed the use of
From the *Departments of Neurosurgery and Toshiba Stroke Research Center and
Department of Radiology, School of Medicine and Biomedical Sciences, University
at Buffalo, State University of New York, Buffalo, New York; and the Department
of Neurosurgery, Millard Fillmore Gates Hospital, Kaleida Health, Buffalo, New
York. Dr. Hopkins receives grant support from Boston Scientific, Cordis, and Micrus
Endovascular and honoraria from Bard, Boston Scientific, Cordis, and Medsn; owns
stock in APW Holding, Inc., Boston Scientific, and Micrus Endovascular; is a
consultant for Abbott, Bard, Boston Scientific, and Cordis; and is a board member,
trustee, or officer with Access Closure, market Rx, and Micrus Endovascular. Dr.
Levy receives grant support and honoraria from Boston Scientific and Cordis, patent
royalties from Zimmer Spine, and financial support from Abbott Vascular and ev3 for
carotid stent training. Dr. Mocco is supported by a research grant from the Brain
Aneurysm Foundation.
Manuscript received October 26, 2007; accepted October 31, 2007.

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CEA for symptomatic patients with 70% to 99% carotid


stenosis or selected patients with 50% to 69% stenosis. These
studies resulted in class IA indications for the use of CEA in
symptomatic patients meeting appropriate criteria (7). However, it is important to realize that the general population of
patients with carotid stenosis has substantially different demographics than those patients who met the strict eligibility
criteria for these studies (8). For instance, NASCET excluded
patients 80 years old and those with intracranial carotid
stenosis more severe than the surgically accessible lesion; liver,
kidney, or lung failure; cardiac valve or rhythm disorder;
previous ipsilateral CEA; uncontrolled hypertension or diabetes; recent myocardial infarction (MI); or major surgery (1).
Such patients were considered to have excessive perioperative
morbidity (i.e., high risk). Since NASCET was published,
patients considered for carotid revascularization are often
divided into low- and high-risk groups, and, in fact, recent
CAS trial investigators have used such surgical risk stratification as an integral part of their study design.
The ACAS (5) and the ACST (6) trials addressed the use
of CEA for asymptomatic patients. The degree of benefit
from CEA for asymptomatic lesions is substantially less,
and the indications for revascularization are still debated.
The ACAS and ACST trials demonstrated a 5.4% to 5.9%
absolute risk reduction over 5 years (5,6). Therefore,
periprocedural risks are particularly relevant to the decision
analysis for treatment of asymptomatic patients, with a
morbidity of 3% minimizing any benefit. Despite this,
with the publication of ACAS, nearly 75% of CEAs in the
U.S. are performed on asymptomatic patients (9).
In the aforementioned trials, carefully selected low-risk
patients were treated by highly experienced surgeons at

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high-volume medical centers.


The low complication rates seen
in NASCET and ACAS are ofACE angiotensinten not obtained in the general
converting enzyme
population. Studies have demonCAS carotid artery
strated perioperative stroke and
stenting
death to range from 0% (10) to
CEA carotid
11.1% (11) for symptomatic paendarterectomy
tients and 0% (12) to 5.5% (11)
DWI diffusion-weighted
imaging
for asymptomatic patients. In
fact, a study of Medicare mortalMI myocardial infarction
ity data from hospitals participatTIA transient ischemic
ing in NASCET and ACAS
attack
demonstrated a 1.4% perioperative mortality (8) compared with
0.6% reported in NASCET (1) and 0.1% reported in ACAS
(5). Perhaps equally concerning, CEA-related mortality
rates have been demonstrated to be higher (2.5%) for
low-volume hospitals (8), although other studies have argued that only small differences exist between mortality
rates at high- and low-volume hospitals (13).
Treatment decisions are also dependent on patientspecific factors. The presence of comorbidities has significant impact on outcome after CEA. Perioperative stroke
and death rates for common comorbidities include congestive heart failure, 8.6% (14,15); age over 75 years, 7.5%
(14,15); post-endarterectomy restenosis, 10.8% (16); ipsilateral carotid siphon stenosis, 13.9% (14); intraluminal
thrombus, 10.7% to 17.9% (14,17); contralateral carotid
occlusion, 14.3% (18); and CEA combined with coronary
artery bypass grafting, 16.4% to 26.2% (19,20). It is important to note that in the presence of such comorbidities the
natural history of carotid disease itself is more grim. The
investigators of the ACSRS natural history study followed
up 1,115 patients with asymptomatic internal carotid artery
stenosis treated with medical therapy alone (21) and identified significant differences in patient subgroups with respect to stroke and death risk. The highest risk group (82%
to 99% stenosis by NASCET criteria [1], history of contralateral transient ischemic attack [TIA], and serum creatinine level 0.085 mmol/l) had a 4.3% annual ipsilateral stroke rate compared with 0.7% in the lowest risk
group (21,22).
It should also be noted that since the aforementioned
major randomized CEA trials were begun, best medical
therapy has improved. In NASCET, the primary medical
intervention was 1,300 mg of aspirin per day (1). This dose
of aspirin is no longer used because lower doses are proven
equally efficacious with fewer side effects (2325). Other
antiplatelet drugs, such as clopidogrel and ticlopidine, are
also now available (26,27); and the aspirin-dipyridamole
combination was shown to be more efficacious than aspirin
alone (28). Methods for blood pressure control were not
specified in NASCET, whereas it is now known that blood
pressures below 120 to 130/70 mm Hg are optimum for
cardiovascular risk reduction in patients with medical coAbbreviations
and Acronyms

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morbidities (7,29,30) and that for primary stroke prevention


a 10-mm Hg reduction in systolic blood pressure produces
a 31% relative risk reduction for stroke (31). For secondary
stroke prevention, angiotensin-converting enzyme (ACE)
inhibitors (29,32) and the combination of a thiazide diuretic
with an ACE inhibitor (32) have now been proven effective.
Additionally, in the past decade, statins have assumed a
prominent role in cerebrovascular and cardiovascular risk
modification (3337). In a study of patients receiving medical
treatment for severe carotid artery disease, statin use was
associated with significantly lower rates of stroke, MI, or death
(38). It is likely that medical therapy improvement for carotid
atherosclerotic disease and related comorbidities should
prompt periodic re-evaluation and risk-benefit analysis finetuning for medical therapy versus surgical intervention.
With the great deal of complexity regarding risk assessment in this complex patient population, current standards
are limited to minimizing overall surgical risk in order to
maximize the likely benefit from surgery. Currently, the
guidelines of the American Heart Association (7) and the
Canadian Neurosurgical Society (39) establish an upper
limit of 6% for perioperative risk in symptomatic patients
(7) and a 3% upper limit in asymptomatic patients, assuming a life expectancy of 5 years (20).
Published Data Regarding CAS
The first randomized trial comparing endovascular and surgical
treatments for carotid stenosis patients, CAVATAS (CArotid
and Vertebral Artery Transluminal Angioplasty Study) (40),
which was published in 2001, included 504 patients enrolled
between 1992 and 1997 and was designed to compare
balloon angioplasty alone versus CEA. Stents, when they
became available, were incorporated as well but only accounted for 26% of cases. Twenty-four centers in Europe,
Australia, and Canada participated, and like previous CEA
trials, high-risk surgical patients were excluded from enrollmentincluding those with recent MI, poorly controlled
hypertension or diabetes mellitus, renal disease, respiratory
failure, inaccessible carotid stenosis, or severe cervical spondylosis. The CAVATAS trial demonstrated no statistically
significant difference between endovascular and surgical
treatment in the rate of disabling stroke or death within 30
days (6.4% CAS vs. 5.9% CEA) and no significant difference in the 3-year ipsilateral stroke rate. These early
encouraging results generated a great deal of interest in
CAS, and further studies were undertaken.
The Wallstent trial (41,42), the first multicenter randomized trial designed from inception to evaluate CEA and
CAS equivalence, enrolled a total of 219 symptomatic
patients with 60% to 99% stenosis. Thirty-day stroke or
death rates were 12.1% with CAS and 4.5% with CEA (p
0.049). Additionally, 12.1% of CAS patients suffered ipsilateral stroke, procedure-related death, or vascular death at
1 year versus 3.6% of CEA patients (p 0.022), and, as a
result, the trial was halted by the Data Safety and Moni-

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toring Committee after an interim analysis demonstrated


worse outcomes for the CAS group. Critical to interpreting
these results is the fact that the Wallstent trial did not
employ the use of distal protection devices. A significant
portion of major CAS neurological complications are due to
atheromatous material embolization (43 46). Devices that
capture embolic debris released during CAS have significantly improved procedural safety (43,46 50).
One of the first trials to utilize embolic protection was
CaRESS (Carotid Revascularization Using Endarterectomy
or Stenting Systems) (51,52), a multicenter, nonrandomized, prospective study comparing CAS with embolic protection (n 143) and CEA (n 254) in symptomatic
(32%) and asymptomatic (68%) patients with low- and
high-surgical risk. An important feature of CaRESS was
that the treatment procedure was chosen by the treating
physician and the patient, not randomized. Although this
study design likely introduced selection bias, the CaRESS
trial represents a generalized perspective on carotid revascularization and more closely represents its real world
application. Baseline group demographics were similar,
except patients with previous carotid intervention more
often received CAS. No statistically significant difference
between 30-day and 1-year death or stroke rates existed
between CAS and CEA (2.1% vs. 3.6% and 10.0% vs.
13.6%, respectively), nor did significant differences exist for
restenosis, residual stenosis, repeat angiography, and need
for carotid revascularization. Overall morbidity and mortality approached NASCET (1,2) and ACAS (5) standards
and represented the lowest rates among the major CAS
trials to date. The low stroke and death rates may be
attributable to the ability of the treating physician to
consider patient-specific factors and successfully assign each
patient to the safest therapy.
Carotid artery stenting was well established as a treatment option for high-risk patients by SAPPHIRE (Stenting and Angioplasty with Protection in Patients at High
Risk for Endarterectomy) (53), a randomized, multicenter
trial to determine CAS noninferiority to CEA in high-risk
patients. Eligible patients (n 344) had symptomatic
stenosis of at least 50% or asymptomatic stenosis of at least
80%. The 30-day MI, stroke, or death rate was 4.8% for
CAS and 9.8% for CEA (p 0.09). Much of this difference
was secondary to MIs in the CEA group, and although not
reported in SAPPHIRE, the 30-day rate of stroke and
death was 4.8% for CAS patients and 5.6% for CEA
patients. At 1 year, 12.2% of CAS patients had suffered
stroke, MI, or death versus 20.1% of CEA patients (noninferiority analysis: p 0.004; superiority analysis:
intention-to-treat p 0.053, as-treated p 0.048). Myocardial infarction and major ipsilateral stroke rates were
significantly better after CAS versus CEA (2.5% vs. 8.1%,
p 0.03; 0% vs. 3.5%, p 0.02; respectively).
As SAPPHIRE had shown such clear noninferiority in
high-risk patients, the SPACE (Stent-supported Percutaneous Angioplasty of the Carotid artery versus Endarterec-

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tomy) trial (54) set out to establish noninferiority for CAS


compared with CEA in patients with low risk. A multicenter trial, SPACE compared safety and efficacy of CAS
and CEA in 1,183 randomized patients with symptomatic
carotid artery stenosis (70% by duplex ultrasonography,
50% by NASCET criteria [1], or 70% by ECST criteria
[3]). The 30-day rates of ipsilateral stroke or death were
6.84% for CAS and 6.34% for CEA (p value not significant)
(54). It is important to note that embolic protection was not
required and was only used in 27% of cases, though a
subgroup analysis did not demonstrate a significant difference between patients with embolic protection versus those
without. Despite these encouraging results, SPACE failed
to prove the noninferiority of carotid-artery stenting (54)
statistically. This is because the trial was halted more than
700 patients shy of its goal enrollment of 1,900 patients as
the result of an interim analysis demonstrating that 2,500
patients would be needed to reach significance given the
results up to that point. The Steering Committee acknowledged a lack of funds (54) to expand the trial to an
enrollment of 2,500 patients and therefore halted the trial.
In essence, the study was underpowered to demonstrate
noninferiority due to incorrect estimation of the anticipated
effect sizes. Still, although its a priori goals were not
realized, the observed 0.51% difference in perioperative
stroke or death between CAS and CEA was not statistically
significant and is well within the published differences
between individuals, institutions, and variations of CEA.
The results mentioned in the preceding text, although
they were negative, were still quite encouraging to CAS
proponents. Unfortunately, a second multicenter, randomized trial to assess the noninferiority of CAS versus CEA in
patients with 60% stenosis, EVA-3S (Endarterectomy
Versus Angioplasty in Patients with Symptomatic Severe
Carotid Stenosis), was ended after interim analysis (n
527) demonstrated a 30-day rate of any stroke or death to be
significantly higher in the CAS group (9.6%) than the CEA
group (3.9%) (p 0.01) (55). Importantly, early in the trial,
the use of embolic protection was not required. Patients
treated without embolic protection experienced a 25%
30-day rate of stroke or death (5 of 20 patients), prompting
protocol changes by the EVA-3S safety committee. Additionally, EVA-3S compared groups of physicians with
unequal experience. Surgeons performing CEA had performed at least 25 endarterectomies in the year before trial
entry, yet endovascular physicians were certified after completing as few as 5 to 12 CAS procedures (5 CAS among at
least 35 stent procedures to supra-aortic vessels or 12 CAS).
Endovascular physicians were also allowed to enroll study
patients while simultaneously undergoing training and certification. Subgroup analysis based upon CAS physician
experience demonstrated a 12.3% stroke and death rate
among endovascular physicians tutored in CAS during the
trial (55), compared with 7.1% among those tutored in CAS
during their endovascular training and 10.5% among experienced CAS physicians. The resulting overall rate of stroke

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and death (9.6%) is substantially higher than in other


randomized trials. Therefore, it is hard to accept such an
elevated complication rate as representative of the practice
of CAS in general. It is more likely that EVA-3S emphasizes the importance of embolic protection as well as
rigorous training and credentialing for CAS physicians. The
implied importance in EVA-3S of embolic protection has
been further supported by numerous radiologic studies
examining the frequency of (mostly small, asymptomatic)
ischemic (DWI [diffusion-weighted imaging]) lesions on
post-operative magnetic resonance imaging. These studies
have demonstrated the following: a reduction in the frequency of DWI lesions with distal embolic protection (49%
vs. 67%) (48) and fewer DWI lesions after CEA than CAS
(11.6% vs. 42.6%, no significant clinical difference) with
current embolic protection devices (56), and a low frequency
of DWI lesions with more recent embolic protection devices, such as the NeuroProtection System (W.L. Gore &
Associates, Flagstaff, Arizona) (57), at a rate not significantly different from that incurred by diagnostic cerebral
angiography alone (18.2% vs. 11.5%) (58).
Carotid registries (CABERNET [Carotid Artery Revascularization using the Boston Scientific FilterWire EX/EZ and
the EndoTex NexStent], ARCHeR [ACCULINK for Revascularization of Carotids in High-Risk patients], CREATE
[Carotid Revascularization with ev3 Arterial Technology Evolution], CAPTURE [Carotid Acculink/Accunet Post Approval Trial to Uncover Unanticipated or Rare Events],
BEACH [Boston Scientific EPI: A Carotid Stenting Trial for
High-Risk Surgical Patients], CASES-PMS [Carotid Artery
Stenting with Emboli protection SurveillancePost Marketing Study], and ALKK [Arbeitsgemeinschaft Leitende Kardiologische Krankenhausarzte]) are nonrandomized outcome
records for symptomatic and asymptomatic high-risk CAS
patients. Although registries do not provide direct comparison
data, they do help establish true adverse event rates in high-risk
CAS patients and are a crucial component in improving our
understanding concerning the risks of CAS. The collaborators
of CABERNET (n 462 patients) found a 3.9% 30-day rate
of stroke or death (59), whereas the investigators of ARCHeR
(n 581 patients) found a 30-day stroke or death rate of 6.9%
as well as a 1-year composite outcome (30-day rate of MI,
stroke, or death plus the 1-year rate of ipsilateral stroke) of
9.6% (60). The CREATE registry (n 419 patients) demonstrated a 6.2% 30-day rate of MI, stroke, and death (61).
The CAPTURE registry (n 3,500) determined that postCAS incidence of stroke, MI, and death was 6.3% for patients
treated with the Acculink/Accunet CAS system (Abbott Vascular, Santa Clara, California), as well as a rate of major stroke
or death of 2.9% (62,63). The BEACH investigators (n 747
patients) found a 30-day MI, stroke, or death rate of 5.8% (64).
These results were similar to those in the CASES-PMS
registry (5.0%), which examined the use of distal protection by
endovascular carotid surgeons who either had previous experience with the device (Angioguard XP, Cordis Endovascular,
Miami Lakes, Florida) or who underwent formal training (n

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1,493) (65). Under these rigorous conditions, the 30-day major


adverse event rate did not vary significantly between symptomatic and asymptomatic patients and among physicians with
high- and low-volume or differing level of experience with the
specific distal protection device. The German ALKK registry
(n 1,888 patients), which included patients with standard
risk, demonstrated an in-hospital death and stroke rate of 3.8%
(66). Interestingly, when this risk was stratified by time, the
investigators saw improvement from 6.3% in 1996 to 1.9% in
2004 (p 0.021). Continued effort to maintain rigorous
registries like the above are critical to our eventual understanding of appropriate patient selection and procedural risks.
Current Trials
The 2 major ongoing, randomized trials of CAS versus
CEA are CREST (Carotid Revascularization Endarterectomy versus Stent Trial) and ICSS (International Carotid
Stenting Study). The CREST trial is an ongoing, National
Institutes of Health-funded, multicenter randomized trial
seeking to enroll 2,500 patients with 50% symptomatic
carotid stenosis or 70% asymptomatic stenosis for randomization to CEA or CAS. Primary end points include
death, stroke, or MI at 30 days, and ipsilateral stroke within
60 days. The CREST trial maintains a rigorous credentialing phase for CAS providers (67), requiring up to 20
monitored procedures. During its lead-in phase, CREST
demonstrated a 4.6% 30-day stroke and death rate, with
MI, stroke, and death rates of 5.7% for symptomatic
patients and 3.5% for asymptomatic patients. Similar stroke
and death rates were observed for both men and women
(68), as well as those treated with or without embolic
protection (69). However, patients 80 years (70,71) experienced a 30-day stroke and death rate of 12.1%, significantly higher than for patients age 60 to 69 years (1.3%) and
70 to 79 years (5.3%) (p 0.0006) (70).
The ICSS study resulted from the favorable results of
CAVATAS and is also known as CAVATAS-2 (72). It is
a multinational prospective trial randomizing symptomatic
patients equally suited for CAS or CEA. Additionally,
lessons learned from EVA-3S are being applied. Attendance at a CAS training course is required, as well as
mandatory proctoring for centers with limited experience
admitted to the trial on a probationary status. Further,
embolic protection is recommended whenever the endovascular physician believes a protection device can be safely
deployed.
An additional ongoing study is ACT I (Asymptomatic
Carotid Stenosis, Stenting versus Endarterectomy Trial), a
randomized trial of low-risk patients with asymptomatic
80% to 99% carotid stenosis at multiple centers across North
America (73,74). The primary outcomes will be 30-day MI,
stroke, and death rates and 5-year stroke-free survival. The
TACIT (Transatlantic Asymptomatic Carotid Intervention
Trial) will randomize standard- and high-risk patients with
asymptomatic carotid stenosis into 1 of 3 treatment arms:

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optimal medical therapy only (antiplatelet, antilipidemic,


antihypertensive, strict diabetes control, and smoking cessation), optimal medical therapy plus CEA, or optimal
medical therapy plus CAS with embolic protection (75,76).
Planned enrollment is 2,400 patients with a primary end
point of stroke and death occurrence at 3 years. Secondary
end points include rates of TIA and MI, economic cost,
quality-of-life analysis, neurocognitive function, and carotid
restenosis. Continued effort and the eventual completion of
these trials will improve our understanding of the relative
indications and contraindications of CAS and CEA.

Optimal Treatment Selection


Given the existence of surgical and endovascular therapies
for patients with carotid stenosis, optimal treatment selection for each given patient will be the eventual method by
which the lowest morbidity rates with the most favorable
outcomes are achieved. Fundamental to treatment selection
is an understanding of the demographics used to categorize
patients as high risk. High-risk demographics are previously
defined in large surgical studies, such as NASCET (1) and
ACAS (5). These demographic criteria include:
Anatomical: 1) restenosis after CEA; 2) contralateral
occlusion; 3) previous neck radiation or surgery; 4)
surgically inaccessible lesions (e.g., located above the
C-2 level, below the clavicle); 5) neck immobility; 6)
tracheostomy; 7) contralateral laryngeal palsy; 8) bilateral severe stenotic lesions requiring treatment; and
9) severe intracranial stenosis.
Medical comorbidities: 1) unstable angina; 2) poor
cardiac ejection fraction; 3) congestive heart failure; 4)
planned coronary artery bypass operation; 5) obstructive pulmonary disease; and 6) advanced age (75 or
80 years, depending on the trial).
Given the continually mounting evidence, it appears
appropriate to offer CAS over CEA to all patients
meeting the above high-risk categorizations, symptomatic or asymptomatic. However, whether patients do or
do not strictly meet the above criteria, other characteristics need to be taken into account. For instance, patients
with heavily calcified plaques, a complex aortic arch,
excessively tortuous vessels, or internal carotid arteries
with lumen diameters smaller than 3 mm are likely better
served with endarterectomy (77 85). This is because
heavily calcified plaques often result in insufficient endovascular revascularization secondary to their being refractory to balloon remodeling; loops and significant vessel
tortuosity make stable guide catheter placement as well as
filter and stent deployment excessively difficult, and
lumen diameters smaller than 3 mm do not safely
accommodate most distal protection devices.

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Conclusions
Carotid artery stenting is continually developing into a safer
and more efficacious therapy for extracranial carotid artery
stenosis. The greater weight of the evidence, as confirmed in
a Cochrane review (86), suggests no significant difference
between CAS and CEA. However, CAS is still a burgeoning technology with many questions still needing to be
answered. Future clinical research should address many of
these questions. As we move towards the future, the
question posed should now be what is the optimal treatment for carotid artery stenosis in this patient? not what is
the optimal treatment for carotid artery stenosis? Endovascular physicians must rigorously apply the lessons learned
from previous well-designed trials to avoid treating patients
who are at higher risk for complications with CAS. Continued enrollment in rigorously randomized trials such as
CREST will provide a great deal of insight into such
patient-specific risk factors. The use of CAS and CEA as
complementary therapies, while optimizing current medical
treatments, will provide the greatest likelihood of minimizing poor patient outcomes.
Reprint requests and correspondence: Dr. Elad I. Levy, University at Buffalo Neurosurgery, Millard Fillmore Gates Hospital, 3
Gates Circle, Buffalo New York 14209. E-mail: elevy@buffns.com.

REFERENCES

1. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic
patients with high-grade carotid stenosis. N Engl J Med 1991;325:
44553.
2. Barnett HJ, Taylor DW, Eliasziw M, et al. Benefit of carotid
endarterectomy in patients with symptomatic moderate or severe
stenosis. North American Symptomatic Carotid Endarterectomy Trial
Collaborators. N Engl J Med 1998;339:141525.
3. European Carotid Surgery Trialists Collaborative Group. MRC
European Carotid Surgery trial: interim results for symptomatic
patients with severe (70 99%) or with mild (0 29%) carotid stenosis.
Lancet 1991;337:1235 43.
4. MRC European Carotid Surgery Trialists. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of
the MRC European Carotid Surgery Trial (ECST). Lancet 1998;351:
1379 87.
5. Executive Committee for the Asymptomatic Carotid Atherosclerosis
Study. Endarterectomy for asymptomatic carotid artery stenosis.
JAMA 1995;273:1421 8.
6. Halliday A, Mansfield A, Marro J, et al. Prevention of disabling and
fatal strokes by successful carotid endarterectomy in patients without
recent neurological symptoms: randomised controlled trial. Lancet
2004;363:1491502.
7. Sacco RL, Adams R, Albers G, et al. Guidelines for prevention of
stroke in patients with ischemic stroke or transient ischemic attack: a
statement for healthcare professionals from the American Heart
Association/American Stroke Association Council on Stroke: cosponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this
guideline. Stroke 2006;37:577 617.
8. Wennberg DE, Lucas FL, Birkmeyer JD, Bredenberg CE, Fisher ES.
Variation in carotid endarterectomy mortality in the Medicare population: trial hospitals, volume, and patient characteristics. JAMA
1998;279:1278 81.
9. Halm EA, Chassin MR, Tuhrim S, et al. Revisiting the appropriateness of carotid endarterectomy. Stroke 2003;34:1464 71.

984

Levy et al.
Optimal Treatment of Carotid Artery Disease

10. Jordan WD, Jr., Voellinger DC, Fisher WS, Redden D, McDowell
HA. A comparison of carotid angioplasty with stenting versus endarterectomy with regional anesthesia. J Vasc Surg 1998;28:397 403.
11. Hartmann A, Hupp T, Koch HC, et al. Prospective study on the
complication rate of carotid surgery. Cerebrovasc Dis 1999;9:152 6.
12. Naylor AR, Hayes PD, Allroggen H, et al. Reducing the risk of carotid
surgery: a 7-year audit of the role of monitoring and quality control
assessment. J Vasc Surg 2000;32:750 9.
13. Birkmeyer JD, Siewers AE, Finlayson EV, et al. Hospital volume
and surgical mortality in the United States. N Engl J Med 2002;
346:1128 37.
14. Goldstein LB, McCrory DC, Landsman PB, et al. Multicenter review
of preoperative risk factors for carotid endarterectomy in patients with
ipsilateral symptoms. Stroke 1994;25:1116 21.
15. Goldstein LB, Samsa GP, Matchar DB, Oddone EZ. Multicenter
review of preoperative risk factors for endarterectomy for asymptomatic carotid artery stenosis. Stroke 1998;29:750 3.
16. Meyer FB, Piepgras DG, Fode NC. Surgical treatment of recurrent
carotid artery stenosis. J Neurosurg 1994;80:7817.
17. Villarreal J, Silva J, Eliasziw M, et al. North American symptomatic
carotid endarterectomy trial. Prognosis of patients with intraluminal
thrombus in the internal carotid artery (abstr). Stroke 1998;29:276.
18. Gasecki AP, Eliasziw M, Ferguson GG, Hachinski V, Barnett HJ.
Long-term prognosis and effect of endarterectomy in patients with
symptomatic severe carotid stenosis and contralateral carotid stenosis
or occlusion: results from NASCET. North American Symptomatic
Carotid Endarterectomy Trial (NASCET) group. J Neurosurg 1995;
83:778 82.
19. Kresowik TF, Bratzler D, Karp HR, et al. Multistate utilization,
processes, and outcomes of carotid endarterectomy. J Vasc Surg
2001;33:22735.
20. Moore WS, Barnett HJ, Beebe HG, et al. Guidelines for carotid
endarterectomy. A multidisciplinary consensus statement from the ad
hoc committee, American Heart Association. Stroke 1995;26:188
201.
21. Nicolaides AN, Kakkos SK, Griffin M, et al. Severity of asymptomatic
carotid stenosis and risk of ipsilateral hemispheric ischaemic events:
results from the ACSRS study. Eur J Vasc Endovasc Surg 2005;30:
275 84.
22. Nicolaides AN, Kakkos S, Griffin M, Geroulakos G, Ioannidou E.
Severity of asymptomatic carotid stenosis and risk of ipsilateral
hemispheric ischaemic events: results from the ACSRS study. Eur J
Vasc Endovasc Surg 2006;31:336.
23. Dutch TIA Trial Study Group. A comparison of two doses of aspirin
(30 mg vs. 283 mg a day) in patients after a transient ischemic attack
or minor ischemic stroke. N Engl J Med 1991;325:1261 6.
24. Antithrombotic Trialists Collaboration. Collaborative meta-analysis
of randomised trials of antiplatelet therapy for prevention of death,
myocardial infarction, and stroke in high risk patients. BMJ 2002;324:
71 86.
25. Farrell B, Godwin J, Richards S, Warlow C. The United Kingdom
transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry 1991;54:1044 54.
26. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).
Lancet 1996;348:1329 39.
27. Gent M, Blakely JA, Easton JD, et al. The Canadian American
Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989;
1:121520.
28. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A.
European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci
1996;143:113.
29. Progressive Collaborative Group. Randomised trial of a perindoprilbased blood-pressure-lowering regimen among 6,105 individuals
with previous stroke or transient ischaemic attack. Lancet 2001;358:
1033 41.
30. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the
Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure: the JNC 7 report. JAMA
2003;289:2560 72.
31. Lawes CM, Bennett DA, Feigin VL, Rodgers A. Blood pressure and
stroke: an overview of published reviews. Stroke 2004;35:776 85.

Downloaded From: http://content.onlinejacc.org/ on 11/17/2015

JACC Vol. 51, No. 10, 2008


March 11, 2008:97985
32. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G, Heart
Outcomes Prevention Evaluation Study Investigators. Effects of an
angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular
events in high-risk patients. N Engl J Med 2000;342:14553.
33. Adult Treatment Panel III. Executive summary of the third report of
the National Cholesterol Education Program (NCEP) Expert Panel
on Detection, Evaluation, and Treatment of High Blood Cholesterol
in Adults. JAMA 2001;285:2486 97.
34. Amarenco P, Bogousslavsky J, Callahan A III, et al., The Stroke
Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)
Investigators. High-dose atorvastatin after stroke or transient ischemic
attack. N Engl J Med 2006;355:549 59.
35. Amarenco P, Labreuche J, Lavallee P, Touboul PJ. Statins in stroke
prevention and carotid atherosclerosis: systematic review and up-todate meta-analysis. Stroke 2004;35:29029.
36. Collins R, Armitage J, Parish S, Sleight P, Peto R, Heart Protection
Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people
with cerebrovascular disease or other high-risk conditions. Lancet
2004;363:757 67.
37. Plehn JF, Davis BR, Sacks FM, et al., CARE Investigators. Reduction
of stroke incidence after myocardial infarction with pravastatin: the
Cholesterol and Recurrent Events (CARE) study. Circulation 1999;
99:216 23.
38. Ravipati G, Aronow WS, Ahn C, Channamsetty V, Sekhri V.
Incidence of new stroke or new myocardial infarction or death in
patients with severe carotid arterial disease treated with and without
statins. Am J Cardiol 2006;98:1170 1.
39. Findlay JM, Tucker WS, Ferguson GG, Holness RO, Wallace MC,
Wong JH. Guidelines for the use of carotid endarterectomy: current
recommendations from the Canadian Neurosurgical Society. CMAJ
1997;157:6539.
40. CAVATAS Investigators. Endovascular versus surgical treatment in
patients with carotid stenosis in the CArotid and Vertebral Artery
Transluminal Angioplasty Study (CAVATAS): a randomised trial.
Lancet 2001;357:1729 37.
41. Alberts MJ, for the Publications Committee of WALLSTENT.
Results of a multicenter prospective randomized trial of carotid artery
stenting vs. carotid endarterectomy (abstr). Stroke 2001;32:325.
42. Alberts MJ, McCann R, Smith TP, et al., for the Schneider Wallstent
Endoprosthesis Clinical Investigators. A randomized trial of carotid
stenting vs. endarterectomy in patients with symptomatic carotid
stenosis: study design. J Neurovasc Dis 1997;2:228 34.
43. Angelini A, Reimers B, Della Barbera M, et al. Cerebral protection
during carotid artery stenting: collection and histopathologic analysis
of embolized debris. Stroke 2002;33:456 61.
44. Castellan L, Causin F, Danieli D, Perini S. Carotid stenting with
filter protection. Correlation of ACT values with angiographic and
histopathologic findings. J Neuroradiol 2003;30:103 8.
45. Jaeger HJ, Mathias KD, Hauth E, et al. Cerebral ischemia detected
with diffusion-weighted MR imaging after stent implantation in the
carotid artery. AJNR Am J Neuroradiol 2002;23:200 7.
46. Kastrup A, Groschel K, Krapf H, Brehm BR, Dichgans J, Schulz JB.
Early outcome of carotid angioplasty and stenting with and without
cerebral protection devices: a systematic review of the literature. Stroke
2003;34:8139.
47. Al-Mubarak N, Roubin GS, Vitek JJ, Iyer SS. Microembolization
during carotid stenting with the distal-balloon antiemboli system. Int
Angiol 2002;21:344 8.
48. Kastrup A, Nagele T, Groschel K, et al. Incidence of new brain lesions
after carotid stenting with and without cerebral protection. Stroke
2006;37:2312 6.
49. Theron JG, Payelle GG, Coskun O, Huet HF, Guimaraens L.
Carotid artery stenosis: treatment with protected balloon angioplasty
and stent placement. Radiology 1996;201:62736.
50. Villalobos HJ, Harrigan MR, Lau T, et al. Advancements in carotid
stenting leading to reductions in perioperative morbidity among
patients 80 years and older. Neurosurgery 2006;58:233 40.
51. CaRESS Steering Committee. Carotid revascularization using endarterectomy or stenting systems (CARESS): phase I clinical trial. J
Endovasc Ther 2003;10:102130.
52. CaRESS Steering Committee. Carotid Revascularization Using Endarterectomy or Stenting Systems (CaRESS) phase I clinical trial:
1-year results. J Vasc Surg 2005;42:2139.

JACC Vol. 51, No. 10, 2008


March 11, 2008:97985
53. Yadav JS, Wholey MH, Kuntz RE, et al. Protected carotid-artery
stenting versus endarterectomy in high-risk patients. N Engl J Med
2004;351:1493501.
54. Ringleb PA, Allenberg J, Bruckmann H, et al. 30 day results from the
SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial.
Lancet 2006;368:1239 47.
55. Mas JL, Chatellier G, Beyssen B, et al. Endarterectomy versus stenting
in patients with symptomatic severe carotid stenosis. N Engl J Med
2006;355:1660 71.
56. Lacroix V, Hammer F, Astarci P, et al. Ischemic cerebral lesions after
carotid surgery and carotid stenting. Eur J Vasc Endovasc Surg
2007;33:430 5.
57. Adami CA, Scuro A, Spinamano L, et al. Use of the Parodi
anti-embolism system in carotid stenting: Italian trial results. J
Endovasc Ther 2002;9:14754.
58. Asakura F, Kawaguchi K, Sakaida H, et al. Diffusion-weighted MR
imaging in carotid angioplasty and stenting with protection by the
reversed carotid arterial flow. AJNR Am J Neuroradiol 2006;27:
753 8.
59. Hopkins LN, for the CABERNET Investigators. Results of Carotid
Artery Revascularization Using the Boston Scientific FilterWire
EX/EX and the EndoTex NexStent. Results from the CABERNET
Clinical Trial. Paper presented at: EuroPCR Conference; May 24 27,
2005; Paris, France.
60. Gray WA, Hopkins LN, Yadav S, et al. Protected carotid stenting in
high-surgical-risk patients: the ARCHeR results. J Vasc Surg 2006;
44:258 68.
61. Safian R. The 30-Day Results of the Carotid Revascularization With
ev3 Arterial Technology Evolution (CREATE) Pivotal Trial. Paper
presented at: Society of Interventional Radiology Meeting; March
31April 5, 2005; New Orleans, LA.
62. Fairman R, Gray WA, Scicli AP, et al. The CAPTURE registry:
analysis of strokes resulting from carotid artery stenting in the post
approval setting: timing, location, severity, and type. Ann Surg
2007;246:551 8.
63. Gray WA, Yadav JS, Verta P, et al. The CAPTURE registry: results
of carotid stenting with embolic protection in the post approval
setting. Catheter Cardiovasc Interv 2007;69:341 8.
64. White CJ, Iyer SS, Hopkins LN, Katzen BT, Russell ME. Carotid
stenting with distal protection in high surgical risk patients: the
BEACH trial 30 day results. Catheter Cardiovasc Interv 2006;67:
50312.
65. Katzen BT, Criado FJ, Ramee SR, et al. Carotid artery stenting with
emboli protection surveillance study: thirty-day results of the CASESPMS study. Catheter Cardiovasc Interv 2007;70:316 23.
66. Zahn R, Roth E, Ischinger T, et al. Carotid artery stenting in clinical
practice: results from the Carotid Artery Stenting (CAS)-registry of
the Arbeitsgemeinschaft Leitende Kardiologische Krankenhausarzte
(ALKK). Z Kardiol 2005;94:16372.
67. Hobson RW II, Howard VJ, Roubin GS, et al. Credentialing of
surgeons as interventionalists for carotid artery stenting: experience
from the lead-in phase of CREST. J Vasc Surg 2004;40:9527.
68. Howard VJ, Brott TG, Qureshi AI, Lutsep HL, Howard G, Hobson
RW, II, for the CREST Investigators. Gender and periprocedural
stroke and death following carotid artery stenting: results from the
CREST lead-in phase (abstr). Stroke 2004;35:253.
69. Roubin GS, Brott TG, Hopkins LN, for the CREST Investigators.
Developing embolic protection for carotid stenting in the Carotid
Revascularization Endarterectomy vs Stenting Trial (CREST) (abstr).
Circulation 2003;108 Suppl 4:IV687.

Downloaded From: http://content.onlinejacc.org/ on 11/17/2015

Levy et al.
Optimal Treatment of Carotid Artery Disease

985

70. Hobson RW II, Howard VJ, Roubin GS, et al. Carotid artery stenting
is associated with increased complications in octogenarians: 30-day
stroke and death rates in the CREST lead-in phase. J Vasc Surg
2004;40:1106 11.
71. Howard G, Hobson RW, II, Brott TG, for the CREST Investigators.
Does the stroke risk of stenting increase at older ages? Thirty-day
stroke death rates in the CREST lead-in phase (abstr). Circulation
2003;8 Suppl 4:V461.
72. Featherstone RL, Brown MM, Coward LJ, for the ICSS Investigators.
International carotid stenting study: protocol for a randomised clinical
trial comparing carotid stenting with endarterectomy in symptomatic
carotid artery stenosis. Cerebrovasc Dis 2004;18:69 74.
73. Press release (January 18, 2005): Abbott Announces Groundbreaking
New Trial in Stroke Prevention. Available at: http://www.abbott.com/
global/url/pressRelease/en_US/60.5:5/Press_Release_0227.htm. Accessed October 21, 2007.
74. Carotid Stenting vs. Surgery of Severe Carotid Artery Disease and
Stroke Prevention in Asymptomatic Patients (ACT I). Available at:
http://www.clinicaltrials.gov/ct/show/NCT00106938?order1. Accessed October 21, 2007.
75. ACST-2 and TACIT to Answer the Asymptomatic Carotid Question. Interventional News 2006;20. Available at: http://www.
cxvascular.com/InterventionalNews/InterventionalNews.cfm?ccs
296&cs1874. Accessed October 21, 2007.
76. Rundback J. Update on the TACIT trial. Endovascular Today
2006;August:93 4.
77. Akiyama T, Moussa I, Reimers B, et al. Angiographic and clinical
outcome following coronary stenting of small vessels: a comparison
with coronary stenting of large vessels. J Am Coll Cardiol 1998;32:
1610 8.
78. Bosiers M, Detoose K, Verbist J, Peeters A. Carotid artery stenting:
which stent for which lesion? Vascular 2005;13:20510.
79. Briguori C, Sarais C, Pagnotta P, et al. In-stent restenosis in small
coronary arteries: impact of strut thickness. J Am Coll Cardiol
2002;40:4039.
80. Faggioli GL, Ferri M, Freyrie A, et al. Aortic arch anomalies are
associated with increased risk of neurological events in carotid stent
procedures. Eur J Vasc Endovasc Surg 2007;33:436 41.
81. Henry M, Polydorou A, Henry I, Anagnostopoulou IS, Polydorou IA,
Hugel M. Carotid angioplasty and stenting under protection. Techniques, results and limitations. J Cardiovasc Surg (Torino) 2006;47:
519 46.
82. Henry M, Polydorou A, Klonaris C, Henry I, Polydorou AD, Hugel
M. Carotid angioplasty and stenting under protection. State of the art.
Minerva Cardioangiol 2007;55:19 56.
83. Koning R, Eltchaninoff H, Commeau P, et al. Stent placement
compared with balloon angioplasty for small coronary arteries: inhospital and 6-month clinical and angiographic results. Circulation
2001;104:1604 8.
84. Lin SC, Trocciola SM, Rhee J, et al. Analysis of anatomic factors and
age in patients undergoing carotid angioplasty and stenting. Ann Vasc
Surg 2005;19:798 804.
85. Moer R, Myreng Y, Molstad P, et al. Stenting in small coronary
arteries (SISCA) trial. A randomized comparison between balloon
angioplasty and the heparin-coated beStent. J Am Coll Cardiol
2001;38:1598 603.
86. Coward LJ, Featherstone RL, Brown MM. Safety and efficacy of
endovascular treatment of carotid artery stenosis compared with
carotid endarterectomy: a Cochrane systematic review of the randomized evidence. Stroke 2005;36:90511.