Tải bản đầy đủ (.pdf) (11 trang)

Endarterectomy or carotid artery stentin

Bạn đang xem bản rút gọn của tài liệu. Xem và tải ngay bản đầy đủ của tài liệu tại đây (113.28 KB, 11 trang )

The American Journal of Surgery 195 (2008) 259 –269

Review

Endarterectomy or carotid artery stenting: the quest continues
Michiel G. van der Vaart, M.D.a, Robbert Meerwaldt, M.D., Ph.D.b,
Michel M.P.J. Reijnen, M.D., Ph.D.c, René A. Tio, M.D., Ph.D.d,
Clark J. Zeebregts, M.D., Ph.D.a,*
a

Department of Surgery, Division of Vascular Surgery, University Medical Center Groningen, 9700 RB Groningen, The Netherlands
b
Department of Surgery, Isala Clinics, Zwolle, The Netherlands
c
Department of Surgery, Alysis Zorggroep, Lokatie Rijnstate, Arnhem, The Netherlands
d
Department of Cardiology, University Medical Center Groningen, 9700 RB Groningen, The Netherlands
Manuscript received May 24, 2007; revised manuscript July 3, 2007

Abstract
Background: Carotid endarterectomy (CEA) is still considered the “gold-standard” of the treatment of
patients with significant carotid stenosis and has proven its value during past decades. However, endovascular techniques have recently been evolving. Carotid artery stenting (CAS) is challenging CEA for the
best treatment in patients with carotid stenosis. This review presents the development of CAS according
to early reports, results of recent randomized trials, and future perspectives regarding CAS.
Methods: A literature search using the PubMed and Cochrane databases identified articles focusing on the
key issues of CEA and CAS.
Results: Early nonrandomized reports of CAS showed variable results, and the Stenting and Angioplasty
With Protection in Patients at High Risk for Endarterectomy trial led to United States Food and Drug
Administration approval of CAS for the treatment of patients with symptomatic carotid stenosis. In
contrast, recent trials, such as the Stent-Protected Angioplasty Versus Carotid Endarterectomy trial and the
Endarterectomy Versus Stenting in Patients with Symptomatic Severe Carotid Stenosis trial, (re)fuelled the


debate between CAS and CEA. In the Stent-Protected Angioplasty Versus Carotid Endarterectomy trial,
the complication rate of ipsilateral stroke or death at 30 days was 6.8% for CAS versus 6.3% for CEA and
showed that CAS failed the noninferiority test. Analysis of the Endarterectomy Versus Stenting in Patients
With Symptomatic Severe Carotid Stenosis trial showed a significant higher risk for death or any stroke
at 30 days for endovascular treatment (9.6%) compared with CEA (3.9%). Other aspects–such as evolving
best medical treatment, timely intervention, interventionalists’ experience, and analysis of plaque composition–may have important influences on the future treatment of patients with carotid artery stenosis.
Conclusions: CAS performed with or without embolic-protection devices can be an effective treatment
for patients with carotid artery stenosis. However, presently there is no evidence that CAS provides better
results in the prevention of stroke compared with CEA. © 2008 Excerpta Medica Inc. All rights reserved.
Keywords: Carotid endarterectomy; Embolic-protection device; Stenting; Stroke prevention

Stroke and stroke-related death are increasing causes of
concern in the western world. Currently, stroke is the third
most common cause of mortality [1,2]. A Swedish publication showed for the first time a stroke incidence of 213/
100,000 persons annually [3]. This generates an enormous
financial burden to the western society, as shown by a
German cost analysis [4]. Direct medical costs for a first-

* Corresponding author. Tel.: ϩ011-31-503613382; fax: ϩ1-31-503611745.
E-mail address: czeebregts@hotmail.com

event, first-year survivor are Յ€18,517 (USD $25,016)/
patient, and lifetime costs are Յ€43.129 (USD $58,257)/
patient. This in turn accounts for 3% to 4% of total health
care costs in several European countries [4]. The estimated
direct and indirect cost generated so far by stroke in 2007 in
the United States is USD $62.7 billion [2].
Extracranial cerebral atherosclerosis causes 8% to 29%
of all ischemic strokes [5]. Thrombotic emboli arising from
cardiac origin are another more frequent cause of ischemic

strokes [6 – 8]. The aim of treatment for patients with carotid
stenotic disease lies in decreasing the risk of disabling

0002-9610/08/$ – see front matter © 2008 Excerpta Medica Inc. All rights reserved.
doi:10.1016/j.amjsurg.2007.07.022


260

M.G. van der Vaart et al. / The American Journal of Surgery 195 (2008) 259 –269

stroke or stroke-related death as consequences of thromboembolism. Different medical-treatment strategies evolved
from studies initially aimed at treating patients with cardiovascular disease. For a long time, treatment consisted of 2
main modalities: medication and/or open surgery (carotid
endarterectomy [CEA]) [9 –12]. For most patients with carotid stenosis, surgical endarterectomy, rather than medical
treatment, became the treatment of choice for stroke prophylaxis, with proven efficacy. Symptomatic patients who
have carotid stenoses between 50% and 99% and perioperative rates of stroke and/or death Ͻ6% are best treated by a
combination of best medical treatment (BMT) and surgery
according to guidelines of the American Heart Association
and results of large randomized trials [12–16]. The Asymptomatic Carotid Atherosclerosis Study (ACAS) concluded
that also asymptomatic patients with a carotid artery stenosis Ͼ60% are good candidates for CEA, with a reduced
5-year ipsilateral stroke risk. Especially for this category of
patients, CEA should be performed with low morbidity and
mortality rates in order to achieve a considerable risk reduction warranting the risks of the operation [17]. The
American Heart Association therefore recommended that
(grade A) CEA be performed in asymptomatic patients with
a carotid stenosis of 60% to 99% if perioperative risk rates
are Ͻ3% and if the patient has a life expectancy Ͼ5 years
[1,12]. Results from these studies are discussed in detail
later in this review. Results, as shown by Mullenix et al

[18], show that CEA is a safe, effective, and durable treatment even when not performed in “high-volume” CEA
centers [18].
Despite the proven efficacy of CEA, great interest has
been generated in carotid angioplasty and stenting (CAS) as
an alternative to surgical therapy. The assets of CAS seem
obvious in patients with hostile necks because of previous
surgery and/or radiotherapy [19]. Moreover, CAS is less
invasive compared with CEA and has decreased risk for
cranial nerve damage as well as the ability to treat lesions
that are beyond the reach of CEA [20]. During the last
decade, several trials and series have been published comparing CAS with CEA [21–29]. The aim of this article is to
review the literature concerning the results of CAS and to
elucidate on its current status. In addition, future options are
discussed.
Methods
A literature search using the PubMed and Cochrane
databases identified articles focusing on the key issues of
CEA and CAS. Manual cross-referencing was also performed, and relevant references from selected papers were
reviewed.
History
The first successful extracranial CEA (ICEA) procedure
was performed in 1953. However, it took almost 20 years
before the results for therapy of patients with (symptomatic)
internal carotid artery (ICA) stenosis were reported [30,31].
In the 1980s, CEA was the most-performed vascular procedure. It was not until the last two decades of the 20th
century that results from large randomized controlled trials
considering BMT versus surgery were published supporting

this previously largely unfounded practice [13–15,32]. The
European Carotid Surgery Trial (ECST) and the North

American Symptomatic Carotid Endarterectomy Trial
(NASCET) are the 2 most-referred trials on the subject of
the treatment of patients with symptomatic carotid stenosis.
Inclusion criteria consisted of patients who had had a transient ischemic attack or nondisabling stroke in the internal
carotid flow tract Յ6 months before enrollment. Despite
differences in carotid stenosis analysis, both trials came to
the same conclusions [15]. Findings in the NASCET demonstrated a decreased 2-year stroke risk from 26% in the
medical group to 9% in the CEA group, yielding an absolute
risk reduction of 17% (for patients with Ͼ70% carotid
stenosis). Perioperative risk rates for stroke and/or death
were 5.8% in the surgical arm. Patients in this study who
had undergone surgical correction of high-grade stenosis
gained a durable benefit lasting Ͼ8 years [33]. It was further
found that the efficacy of CEA increased with increasing
degree of stenosis, previous stroke presentation, and presence of ulceration. Furthermore, the presence of diabetes,
coronary heart disease, or hypertension increased stroke risk
in the medically treated group but not in the CEA group.
The ECST showed a decrease in the 3-year risk of stroke
and/or death from 26.5% in the medical group to 14.9% in
the CEA group. Interestingly, the early (30-day) rates of
stroke and/or death were higher in women (10.6%), in
patients with systolic blood pressure Ͼ180 mm Hg (12.3%),
and in patients with peripheral vascular disease (12.3%).
From the results of the pooled data (6,092 patients), a
significant 16% absolute risk reduction during 5 years
(numbers needed to treat 6.3) was shown for symptomatic
patients with a stenosis Ն70% (without near occlusion). A
4.6% absolute risk benefit was shown for patients with a
50% to 69% stenosis (numbers needed to treat 22). Overall
operative risk of stroke and/or death within 30 days after

surgery was 7.1%. For patients with near occlusion, the
absolute risk reduction was 5.6% during 2 years (P ϭ .19),
and Ϫ1.7% during 5 years (P ϭ .9). Others have debated the
benefit of CEA in patients with near occlusion. For example, Fox et al [34] showed no apparent benefit of CEA in
patients with near occlusion. The absolute risk reduction in
the near-occlusion group was 4.2% compared with 17.8% in
those with severe stenoses but without near occlusion [34].
With near occlusion, there is relative protection against
emboli because arterial diameter is decreased, and this may
in part explain the relatively low long-term stroke risk in
these patients. Numerous posthoc analyses of subgroups
from the NASCET and the ECST have been published, but
they are beyond the scope of this review article.
Other studies, such as the Asymptomatic Carotid Atherosclerosis Study (ACAS) and the Asymptomatic Carotid
Surgery Trial (ACST), were designed to investigate whether
patients with asymptomatic stenotic lesions were eligible
for CEA [35,36]. In ACST, a total of 3,120 asymptomatic
patients with stenotic lesions Ͼ60%, as seen on duplex
Doppler ultrasound, were included. The 5-years risk for
stroke (minor and major) in surgical patients was 6.4%
versus 11.8% for patients who deferred surgery. Consequently, a significant absolute risk reduction of 5.4% was
noted, although a subgroup analysis showed clear benefits
only for patients Ͻ75 years old. Fifty percent of people


261

M.G. van der Vaart et al. / The American Journal of Surgery 195 (2008) 259 –269
Table 1
Early carotid stent series data

Author

Year

n

Symptomatic
stenosis (%)

Technical success
rate (%)

Morbidity and mortality rate
(30-day; %)

Stroke rate (%)

Roubin et al [50]
Theron [43]
Bergeron et al [49]
Diethrich et al [46]
Waigand [126]
Yadav et al [29,47]
Vozzi [127]
Wholey et al [44,57]
Henry et al [51]
Teitelbaum et al [52]

2001
1996

1999
1996
1998
1997
1997
1997
1998
1998

528
69
99
110
50
107
22
108
163
22

52
NS
58
38
28
64
45
56
65
68


98
100
97
99
100
100
96
95
99
100

7.4
3
7.1
7.3
2
7.9
9
5.5
5.2
27.3

5.8
NS
1
6.5
4
8.4
9

3.6
3
24

NS ϭ not specified.

older in age died of unrelated causes Ͻ5 years of follow-up.
Furthermore, the efficacy of CEA in women compared with
men was also one-third less based on higher perioperative
risks in women. Overall operative risk of stroke and/or
death within 30 days after surgery was 3.1%. The ACAS
had similar results: There was risk reduction of 5.9% in
surgical patients with a stenosis Ͼ60%. The 2.3% operative
risk of stroke and/or death in this trial was low. Approximately 50% of the strokes in the CEA arm were related to
the surgical procedure, whereas the others were related to
contrast arteriography. The ASA and Carotid Endarterectomy randomised controlled trial published in 2003, which
compared periop erative complications with CEA depending on different acetylsalicylic acid dosages, disclosed a
perioperative complication risk of 4.6% [37]. Notable, results from the ACAS trial show that 20 CEAs would be
needed to prevent 1 stroke in 5 years of follow-up. Two
analyses performed afterwards showed that despite the high
numbers needed to treat, CEA in asymptomatic patients is
cost-effective [38,39].
Guidelines for performing CEA were distilled by the
American Heart Association from these data. In symptomatic patients, the risk of stroke and/or death resulting from
treatment by CEA should be Ͻ6% and for asymptomatic
patients should be Ͻ3% [40].

suitable to treat patients with severe concomitant cardiac
and/or pulmonary disease. Other advantages include easy
access in patients with hostile necks because of previous

surgery and/or radiotherapy. In addition, patients whose
stenoses extended onto the base of the skull were accessible
for treatment.
Risk of embolic stroke limited early enthusiasm. Initial
strategies focused on neurologic rescue by fibrinolytic
agents or techniques to remove embolic debris. Later treatment shifted from rescue to protection. Most of the results
of carotid PTA proved promising, with rates of stroke
and/or death ranging between 0% and 7.9%, but most studies were rather small and nonrandomized (Table 1) [43,
44,46,47,49 –52,126,127]. Inclusion and exclusion criteria
were diverse, and PTAs were randomly carried out with or
without stenting. PTA alone had its limitations because of
its decreased (long-term) durability, but the use of a stent
certainly did not rule out possible danger. Problems reported were direct recoil of the vessel wall after dilatation,
increased embolism caused by catheter manipulation (4
times greater compared with CEA), severe bradycardia, and
hypotension after balloon dilatation and dissection [21,
53,54]. Intermingled with these reports, changes in technique, especially the introduction of embolic-protection devices (EPDs), took place.

Endovascular treatment for carotid stenosis
Early reports
As a result of the widespread use of angioplasty and
stenting in the treatment of patients who have arterial stenosis in the context of coronary artery disease, treatment of
patients with peripheral stenotic arterial vascular disease
also evolved. With the advancing techniques of percutaneous transluminal angioplasty (PTA), treatment of patients
with carotid stenosis also became feasible. The first balloon
angioplasty for carotid stenosis was performed in 1979, and
reports in the 1980s included balloon occlusion to decrease
embolic complications [41– 43]. Meanwhile, carotid artery
stenting has been presented in an increasing variety of
publications as a viable alternative to CEA in the treatment

of patients with extracranial carotid stenosis [43–50]. Several arguments have been brought forward to advocate its
use. The minimally invasive nature of the procedure made it

CAS technique and embolic protection devices
Presently, having the patient under local anesthesia is the
preferred way of performing CAS because, in this way, the
patient’s neurologic condition can be monitored continuously [55]. Access is gained by way of the common femoral
artery to perform selective catheterization of the common
carotid artery. Recognition of normal and variant anatomy
of the aortic arch and the cervicocerebral circulation is
required for successful performance of angiography and
CAS. Selective angiography of both carotid arteries is recommended before CAS to evaluate carotid stenosis severity,
morphology, carotid tortuosity, calcification, intracranial
circulation stenosis, collateral circulation, and malformations. Because there is a risk of embolization caused by
manipulation during the procedure, EPDs are increasingly
being used [56]. No randomized trials have compared CAS
with EDPS versus CAS without EPDs. However, the avail-


262

M.G. van der Vaart et al. / The American Journal of Surgery 195 (2008) 259 –269

ability of EPDs seems to decrease the risk of embolic
complications as described by the carotid artery stent registries [57,58]. Importantly, many other studies have not
been powered to show a benefit from EPD.
Three different approaches to achieve protection have
been used: (1) distal balloon occlusion, (2) distal filter
placement, and (3) proximal occlusion with flow reversal
[56,59]. Although all distal EPDs are able to capture and

remove embolic debris, this does not eradicate embolic
complications. Inability to deliver or deploy the EPD, EPDinduced vessel injury, ischemia caused by occlusion, and
incomplete embolic debris removal may all result in embolic cerebral complications. Microporous filters are positioned in the ICA distal to the target lesion. The filter is
constrained with a delivery sheath to pass the carotid stenosis. Once in position, the delivery sheath is withdrawn to
deploy the filter. Filters offer the advantage of continued
cerebral perfusion. In contrast, the delivery system is relative large, which may interfere with crossing the stenosis,
and the stiffness of the system may be a problem in tortuous
vessels, increasing the risk of embolization during placement of the filter. Occlusion balloons offer the advantage of
lower device-crossing profiles, but they still require crossing the stenosis as well as interruption of cerebral perfusion.
Once protection has been secured, the stent is put into place
under angiographic control. Stents used are mostly selfexpanding, but balloon-expandable stents can be used when
treating the ostium of the common carotid artery [55]. After
the stent is put in place, postdilatation is applied, followed
by control angiogram. A perfect anatomic end result at
angiography is not pursued (most studies accept residual
stenosis Ͻ30%) because aggressive balloon dilatation appears to increase the risk of complications, and residual
stenosis is mostly related to calcification, which often does
not resolve with repeated dilatations [60]. The entire procedure is performed with antiplatelet therapy, which in most
patients is achieved with a combination of acetyl salicylic
acid and clopidogrel. Clopidogrel is stopped 6 weeks after
the procedure, but acetyl salicylic acid is continued indefinitely thereafter.
Prospective multicenter registries
Compared with the early CAS series previously described (Table 1), prospective registries with predefined
inclusion and exclusion criteria, independent neurologic assessment, and oversight committees were designed to further assess safety and United States Food and Drug Administration approval of CAS with EPDs in high-risk patients
(Table 2). High-risk surgical patients were defined as (eg,
the Boston Sci EPI: A Carotid Stenting Trial for High-Risk
Surgical Patients [BEACH] trial) those with a surgically
inaccessible lesion, previous head and/or neck radiation,
spinal immobility, restenosis after CEA, laryngeal palsy,
tracheostoma, contralateral carotid stenosis, age Ͼ75 years,

severe comorbidity, planned coronary bypass, or history of
major surgery [61– 64]. The most common high-risk surgery categories observed were anatomic criteria or previous
CEA. Most registries were conducted to acquire United States
Food and Drug Administration or Conformité Européene (CE;
Europe) approval. The primary safety end point was
usually the combined rate of myocardial infarction,

Table 2
Carotid artery stent registries
Registry

N (% symptomatic) Combined MI/stroke/death rate (%)

BEACH
480 (25.3)
ARCHeR
581 (23.8)
CABERNET 454
CAPTURE
3,500 (13.8)
CREATE
543 (17.4)
MAVerIC
498
SECuRITY
398 (21)
CaRESS
143 (31)
CREST
749 (30.7)

MO.MA
157 (19.7)
PRIAMUS
416 (63.5)

30 d

1y

5.8* (1.0/4.4/1.5)
8.3* (2.4/5.5/2.1)
3.8#
5.7* (.9/4.8/1.8)
6.2* (1.0/4.5/1.9)
5.3#
8.5# (.7/6.9/.9)
2.1* (0/2.1/0)
4.4* (0/4.0/.8)
5.7* (0/5.1/.6)
4.6* (0/4.1/.5)

9.1# (1.1/7.0/3.2)
9.6* (0/1.3/0)
11.5#
NA
NA
NA
NA
10 (1.7/5.5/6.3)
NA

NA
NA

ARCHeR ϭ Acculink for Revascularization of Carotids in High-Risk
Patients; CABERNET ϭ Carotid Artery Revascularization Using Boston
Sci EPI Filterwire EX/EZ and EndoTex NexStent; CAPTURE ϭ Carotid
Acculink/Accunet Postapproval Trial to Uncover Rare Events; CaRESS ϭ
Carotid Revascularization Using Endarterectomy or Stenting Systems;
CREATE ϭ Carotid Revascularization With ev3 Arterial Technology
Evaluation; MI ϭ myocardial infarction; MAVerIC ϭ Endarteractomy
Versus Angioplasty in Patients With Severe Symptomatic Carotid Stenosis; MO.MA ϭ Multicenter Registry to Assess the Safety and Efficacy of
the MO.MA Cerebral Protection Device During Carotid Stenting; NA ϭ
not available; PRIAMUS ϭ Proximal Flow Blockage Cerebral Protection
During Carotid Stenting; SECuRITY ϭ Registry Study to Evaluate the
NeuroShield Bare Wire Cerebral Protection System and X-Act Stent in
Patients at High Risk for Carotid Endarterectomy.
* Data available from publications in peer-reviewed journals.
# Data from: www.strokecenter.org/trials or www.cms.hhs.gov/med.

stroke, and/or death at 30 days. The primary end point of
efficacy was the incidence of ipsilateral stroke between
30 days and 1 year. These registries did not include a
control group.
Technical success was achieved in most studies in Ͼ97%
of all patients. The incidence in 30-day myocardial infarction, stroke, and/or death varied between 2.1% and 8.3%
[61– 63,65– 67]. Unfortunately, most registries did not differentiate between symptomatic and asymptomatic patients
when analyzing results. However, the BEACH trial did and
showed a composite end point of 7.9% in symptomatic
patients (mortality 0.1%, stroke 7.4%, and myocardial infarction 1.1%) and 5.0% in asymptomatic patients (mortality 1.6%, stroke 3.4%, and myocardial infarction 0.7%).
Importantly, other registries showed that independent predictors of stroke or death at 30 days included symptomatic

carotid stenosis, duration of filter deployment, and baseline
chronic renal failure. Most registries have not yet been peer
reviewed, but they have been presented at international
meetings, so results are preliminary.
Initial randomized controlled trials comparing
CAS with CEA
The Leicester study was the first prospective randomized
singe-center trial investigating CAS versus CEA in symptomatic patients [21]. The trial enrolled symptomatic lowrisk patients with carotid stenoses Ͼ70%. However, the
study was terminated after allocation of only 17 partici-


263

M.G. van der Vaart et al. / The American Journal of Surgery 195 (2008) 259 –269
Table 3
Randomized trials of CAS versus CEA
Trial

n

Patients

Primary end point

Results (%)
CAS 70
CEA 0
CAS 10.4
CEA 4.4
CAS 12.2

CEA 20.1
CAS 1.8
CEA 1.9
CAS 0
CEA 0
CAS 10.0
CEA 9.9
CAS 6.8
CEA 6.3
CAS 9.6
CEA 3.9
Active enrollment
Active enrollment
Active enrollment
Active enrollment

Leicester

17

Low-risk symptomatic

30-d stroke and/or death

Wallstent

219

Low-risk symptomatic


1-y stroke and/or death

SAPPHIRE

334

High-risk (a)symptomatic

30-d MI, stroke, and/or death (1-y stroke or death)

Kentucky 1

104

Low-risk symptomatic

30-d stroke and/or death

Kentucky 2

84

Low-risk asymptomatic

30-d stroke and/or death

CAVATAS

504


Low-risk (a)symptomatic

30-d stroke and/or death (3-y stroke)

1,183

Low-risk symptomatic

30-d stroke and/or death

527

Low-risk symptomatic

30-d stroke and/or death (4-y stroke)

Low-risk (a)symptomatic
Low-risk symptomatic
Low-risk asymptomatic
Any risk asymptomatic

30-d
30-d
30-d
30-d

SPACE
EVA-3S
CREST
ICSS

ACT
ACST

2,500
1,500
1,540
5,000

MI,
MI,
MI,
MI,

stroke,
stroke,
stroke,
stroke,

and/or
and/or
and/or
and/or

death
death
death
death

(4-y
(3-y

(1-y
(1-y

stroke)
stroke)
stroke)
stroke)

ACT ϭ Asymptomatic Carotid Stenosis Versus Endareterectomy Trial; CAS ϭ carotid artery stenting; CAVATAS ϭ Carotid and Vertebral Artery
Transluminal Angioplasty Study; CEA ϭ carotid endarterectomy; ICSS ϭ International Carotid Stenting Study; MI ϭ myocardial infarction.

pants. Interim analysis showed that 70% of all patients in
the CAS arm had neurologic complications. In contrast,
CEA was performed uneventfully (Table 3).
The Carotid and Vertebral Artery Transluminal Angioplasty Study was an international multicenter randomized
trial with 504 patients, but it lacked strict inclusion and
exclusion criteria [27]. Major outcomes within the first 30
days of treatment, defined as any disabling stroke or death,
showed no significant difference between CAS and CEA
(10.0% vs 9.9%). Noteworthy, only 26% of patients treated
endovascularly received a stent. At 1-year ultrasound follow-up, severe restenoses (70% to 90%) occurred significantly more in the endovascular-treated group (CAS 14% vs
CEA 4%). The incidence of recurrent ipsilateral stroke appeared to be higher in the first year in cases of stenoses
occurring after CAS compared with stenoses occurring after
CEA. However, survival analysis at 3-year follow-up
showed no difference in the occurrence of ipsilateral stroke
(14.2%) between both groups [27,68]. The investigators
concluded that there was a similar major risk and effectiveness with endovascular treatment of ICA stenosis compared
with CEA, but minor complications were avoided with
endovascular treatment. Notably, the wide 95% confidence
intervals in this study for stroke rate make interpretation of

the data even harder. Results were certainly not up to the
standard advocated by the American Heart Association.
The Kentucky randomized trials comparing CAS with
CEA were published in 2001 and 2004. The first publication
focused on symptomatic patients; the latter focused on
asymptomatic patients. Both studies reported low complication rates for either treatment and challenged the “gold
standard” of CEA [22,23]. However, the small number of
patients in each group makes the extraordinarily low risk
rate difficult to interpret. Afterward, interest shifted to those
patients who might benefit most from CAS.

The run-in phase analysis from the Carotid Revascularization Versus Stent Trial (CREST) focused on patient age
and periprocedural risk for patients receiving CAS. Four
patient-age categories were created: Ͻ60 years, 60 to 69
years, 70 to 79 years, and Ն80 years. Risk of stroke or death
increased with age, but this was seen mainly in octogenarians (12.1%) [24]. Risk was not mediated by adjustment for
symptomatic status, use of antiembolic devices, sex, or
percentage of stenosis. Notably, patients Ͼ80 years were
not excluded from actual randomization within CREST.
Carotid artery stenosis is relatively frequent in older patients. Large population-based studies indicated that the
prevalence of carotid stenosis increases to 10% in persons
Ͼ80 years old [69]. In a subgroup analysis of NASCET, the
benefits of CEA in patients Ͼ75 years with symptomatic
carotid stenosis was compared with the benefit seen in
younger patients [70]. Among medically treated patients,
the highest risk of stroke at 2 years was in patients Ͼ75
years (36.5%). The perioperative rate of stroke and/or death
was not higher in patients Ͼ75 years (5.2%) compared with
patients Ͻ65 years (7.9%). The absolute risk reduction by
CEA in patients Ͼ75 years was 28.9% (number needed to

treat 3% of patients). The ECST data also indicate that
increasing age is associated with greater benefit from CEA
in patients with symptomatic carotid stenosis [71]. Furthermore, Miller et al [72] showed, in a prospective analysis of
Ͼ300 CEAs performed in patients Ն80 years, that perioperative risk is increased, but outcomes remain within acceptable guidelines [72].
In the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial,
the hypothesis was that CAS was not inferior to CEA in
high-risk patients [29]. Both surgeons and interventional
cardiologists had to meet certain procedural criteria to participate. Surgeons were required to have performed an av-


264

M.G. van der Vaart et al. / The American Journal of Surgery 195 (2008) 259 –269

erage of 30 CEAs/y, with low corresponding major complication (eg, death, stroke, and/or myocardial infarction)
rates of Ͻ1%. The interventionalists were required to have
performed an average of 64 interventions/y, with low corresponding complication (eg, stroke, TIA) rates of Ͻ2%. A
total of 723 symptomatic (stenosis Ͼ50%) or asymptomatic
(stenosis Ͼ80%) patients–normally deemed high risk for
surgery because of concomitant morbidity, such as cardiopulmonary disease or previous surgery–were considered
suitable for entry to either the endovascular- or surgicaltreatment arms. Consensus agreement by a multidisciplinary team of neurologists, surgeons, and interventionalists
was required for a patient’s enrollment into the randomized
arm of study. EPDs were used in the endovascular-treated
group. The primary end point was the cumulative incidence
of major cardiovascular events at 30 days and at 1 year after
intervention. The study was stopped prematurely because of
slow enrollment: Most patients initially included were finally excluded because perioperative risk with CEA was
deemed too high (n ϭ 409). Finally, 317 patients were
randomized to CEA or CAS. Among patients in the randomized study, a significantly higher number of patients in
the stenting arm had undergone previous coronary artery

bypass (CAS 43% vs CEA 31%, P Ͻ0.05) and also had
higher history of cardiovascular disease (CAS 85% vs CEA
74%, P Ͻ.05).
The 30-day myocardial infarction, stroke, and death rate
was 4.8% in the CAS arm versus 9.8% in the CEA arm, thus
favoring endovascular treatment (P ϭ .09) [29]. Results at
1 year (eg, myocardial infarction, ipsilateral stroke, and/or
death) were also in favor of endovascular treatment: 12.2%
versus 20.1% for patients treated by surgery (P ϭ .048).
The 3-year incidence of stroke was similar between both
arms (7%).
Importantly, differences in this trial between CAS and
CEA treatment at the composite 1-year end point were
related to a greater association of CEA with myocardial
infarction. Without the inclusion of myocardial infarction,
no statistical differences in rates of stroke and/or death
between both groups would have been noted (CAS 5.5% vs
CEA 8.4%, P ϭ .4). The majority of myocardial infarctions
were non–Q-wave events identified by routine postprocedural laboratory studies.
The majority of patients in the SAPPHIRE trial were
asymptomatic. In the CAS arm, only 30% of patients were
symptomatic; in the CEA arm, only 28% were symptomatic.
The primary end point did not differ in these symptomatic
patients. In asymptomatic patients there was a difference
after one year in favor for those treated with CAS.
A Cochrane review published in 2005 showed only 5
randomized controlled trials comparing CAS with CEA
[28]. The combined primary outcomes, defined as any
stroke or death within 30 days of intervention, did not differ
between treatment arms. The meta-analysis was limited by

the premature ending of 3 trials because of inconsistent use
of stents and EPDs and heterogeneity of groups with regard
to symptomatic status and surgical risk. Because of these
limitations, this review concluded that CEA remained the
“gold standard” of treatment.

Recent publications
Recently, results of 2 independent randomized noninferiority controlled trials, the Stent-Protected Angioplasty
versus Carotid Endarterectomy (SPACE) trial and the Endarterectomy Versus Stenting in Patients with Symptomatic
Severe Carotid Stenosis (EVA-3S) trial, were published
(Table 3). The SPACE trial included 1,183 symptomatic
patients with a Ͼ70% stenosis of the ICA [25]. Patients
were randomly allocated to either CAS or CEA. The technique used by the interventional physician (ie, type of stent,
whether or not to use a protection device) was not restricted
by protocol. Primary outcome was ipsilateral stroke, with
symptoms lasting Ͼ24 hours or death between randomisation and 30 days after treatment. The complication rate at 30
days was 6.8% for CAS versus 6.3% for CEA. The noninferiority test was not significant (P ϭ .09). In this study, the
investigators concluded that CEA remains the preferred
treatment for patients with symptomatic ICA stenosis because evidence is lacking for equivalent or superior endovascular treatment.
The EVA-3S trial included 527 symptomatic patients
with an ICA stenosis of 60% to 90% according to NASCET
guidelines [26]. The primary end point was any stroke or
death within 30 days after intervention. The systematic use
of a CPD was instituted during the trial on instigation of the
safety committee. Analysis showed a significant higher risk
for death or any stroke at 30 days for endovascular treatment (9.6%) compared with CEA (3.9%), with a relative
risk of 2.5% and an absolute risk of 5.7%. Although more
minor and systemic complications occurred after CEA, this
did not reach significance, except for patients with cranial
nerve injury. Noteworthy, the trial was ended prematurely

for safety reasons. Inclusion stopped after enrollment of 527
patients, although power analysis indicated that 872 patients
were needed to reach a statistical power of 80%. Because
the study was ended prematurely, the inferiority question
still remains. Nevertheless, the results of CAS in the
EVA-3s study differed from those in the SAPPHIRE trial.
Reasons are probably multifactorial and may have been the
inclusion of more symptomatic patients in the EVA-3s
study, the use of a protection device and antiplatelet therapy, the EVA-3s study patients not being at high risk of
developing coronary artery disease, and varying levels of
experience in performing CAS. Furthermore, a systematic
review showed that the 30-day rate of death or stroke after
CAS was 5.8% among patients treated without EPD compared with 1.8% among those treated with EPD [58]. Early
in the EVA-3S trial, EPDs were not used, and the incidence
of stroke was Ն25%. The study was even briefly stopped
and later on restarted with the incorporation of routine use
of cerebral-protection devices. Nevertheless, the incidence
of stroke remained higher compared with CEA. Further
evidence must be awaited from a meta-analysis, which has
been planned from the combined results after completion of
the SPACE and EVA-3S trials and the still-ongoing International Carotid Stenting Study [73].
The High-Risk Patient
Some conclude that CAS may be an excellent procedure
for high-risk patients who are not fit for surgery. Is CEA per


M.G. van der Vaart et al. / The American Journal of Surgery 195 (2008) 259 –269

se harmful in high-risk patients? It seems that when patients
meet NASCET or ACAS exclusion criteria, they are marked

as “high-risk.” However, complication rates in these highrisk patients are not per se increased when performing CEA.
Mozes [74] and Mozes et al [75] analyzed their CEA results
by stratifying according to SAPPHIRE criteria for high-risk
patients [74,75]. Such criteria included positive stress test,
age Ͼ80 years, contralateral carotid occlusion, and repeated
CEA. There were no statistical differences in either stroke
or death rate between low- and high-risk patients. The
investigators showed that CEA can be performed in such
high-risk patients with acceptable standard complication
rates. Ballotta et al [76] and Nguyen et al [77] showed that
high-risk patients are more common than previously
thought. Their perioperative neurologic and cardiac outcomes are comparable with those reported in other patients [76,77]. The idea that operative risk is higher in
patients excluded from NASCET or ACAS has not been
not supported. Definite accepted criteria to identify highrisk patients have not yet been developed. A study from
the Cleveland Clinic attempted by retrospective analysis
to identify a subgroup of patients who were at increased
risk for CEA. From a prospective database covering a
10-year period, 3,061 patients with histories of CEA were
examined. High-risk patients were identified on the basis
of presence of coronary artery disease, congestive heart
failure, severe chronic obstructive disease, or renal failure. The composite risk for stroke, death, and myocardial
infarction was 7.4% in high-risk patients compared with
3.8% in others. Perhaps such patients would benefit from
alternatives to CEA.
The above-mentioned risk factors, (ie, degree of stenosis,
neurologic symptoms, etc) do not sufficiently identify the
real risk presented by the patient. In contrast, plaque morphology may identify patients at risk for stroke during
intervention [78 – 82]. The risk of rupture is strongly related
to plaque composition and degree of carotid stenosis
[80,83,84]. Gray-scale measurements (GSM) of intima–

media thickness using ultrasound have been studied to analyze vulnerable plaques. GSM is an overall measure of
plaque echogenicity in which low-GSM plaques generate
more embolic particles [85]. The Imaging in Carotid Angioplasty and Risk of Stroke study showed that the onset of
neurologic deficits during and after intervention significantly increased in patients with low GSM values [86]. A
low GSM is not a contraindication to CAS but rather a
predictor of increased stroke risk. Low GSM values are
further related to future coronary events, higher rate of
restenosis, positive brain computed axial tomography for
ischemic lesions, and rapid plaque progression [87–91].
Other modalities, such as high-resolution magnetic resonance imaging, have also been tested as measures of plaque
composition [92–97]. These imaging techniques may become important in the planning of future clinical trials and
BMT modalities.
Comments
The longevity of CEA predominantly has been determined by comparison among large-scale randomized trials.
Randomized trials comparing CEA with BMT have con-

265

vincingly proven that CEA significantly decreases the risk
of subsequent stroke in patients with severe carotid stenosis.
Currently, surgery remains the “golden standard” of treatment, but CAS has progressed in recent years and challenged CEA. Despite many trials, only a few methodologically correct randomized trials compared CAS with CEA,
and they failed to establish consensus. Using predefined
margins of noninferiority, recent trials–such as the SPACE
and EVA-3S trials–indicated that CAS is not as good as
CEA. Proponents of CAS responded by focusing on the
“interventionists’ experience and CAS methods” in both
trials. Consequently, many have been left questioning the
future of CAS compared with CEA.
It is important to realize that most randomized trials
comparing CEA with CAS did not succeed in achieving

recruitment as determined before the study. The Leicester,
WALLSTENT, SPACE, and EVA-3S trials specified that
the total intended number of patients should be 3,772. However, only a total of 1,989 patients (52%) were randomized
as a result of early trial completion because of excess in risk
in the CAS arm. The expanded use of CAS outside organized randomized clinical trials further threatens studies of
alternatives to CEA.
Failure to achieve a study or meta-analysis with adequate
size will not produce convincing evidence of the value of
CAS in stroke prevention. An important reason that
NASCET, ECST, ACST, and ACAS influenced clinical
practice and proved the importance of CEA is that they
included large numbers of patients. It is therefore important
to limit the use of CAS to randomized trials to ensure
statistical power to produce a consensus in best evidencebased therapy in patients with severe carotid stenosis.
The technical expertise required from interventionists
participating in trials comparing CAS with CEA may in part
explain the excessive risk of CAS procedures. The requirements stipulated for interventionists in the EVA-3S trial
were having performed 12 previous CAS or 35 previous
supra-aortic stenting procedures, and interventionists who
had not met these requirements still were allowed to participate in the study when their CAS procedures were supervised. Furthermore, CEA has evolved during the last 30
years and has been widely used by experienced vascular
surgeons. In contrast, CAS is still in development and may
not so easily be generalized. It is important to realize that
the EVA-3S trial demonstrated what happens if CAS is
widely implemented by showing the results achieved when
CAS is performed outside of the “top” CAS units. Again,
this calls for exclusive performance of CAS procedures in
controlled clinical trials using standards of practice and
expert technical skills.
Some have concluded that CAS may be an excellent

procedure for high-risk patients who are not fit for surgery.
However, both CAS and CEA are being compared with the
BMT of more than a decade ago. Notably, the cumulative
complication risk in SAPPHIRE is striking: 17% after 3
years for both CAS and CEA. As pointed out by others,
perhaps such high-risk patients are better off without stenting or endarterectomy [77]. Medical treatment has evolved
with modern angiotensin-converting enzymes inhibitors,
other antihypertensive drugs, statin medications, and newer
antiplatelet therapies [98 –102]. In the NASCET trial, only


266

M.G. van der Vaart et al. / The American Journal of Surgery 195 (2008) 259 –269

50% of patients with increased lipid levels received lipidlowering medication. A recent meta-analysis analyzing the
relationship between statins and the risk of stroke showed a
relative stroke reduction rate Ͼ21% [103]. The anti-inflammatory effects of statins seem as important as their lipidlowering effects [104,105]. For antithrombotic therapy,
most patients in the NASCET and ACAS trials were taking
aspirin only. In a large study, clopidogrel was compared
with aspirin, and clopidogrel conferred an 8.7% risk reduction for the prevention of stroke and an even greater reduction in high-risk patients [106,107]. Increased levels of
homocysteine have also been associated with increased
stroke risk, and lower homocysteine levels have been related to a lower risk of cardiovascular restenosis [108 –110].
However, high levels of homocysteine seem not to increase
the risk of restenosis after CEA [111,112]. Finally, the use
of angiotensin-converting enzyme inhibitors also decreases
stroke risk, as demonstrated by the Heart Outcome Prevention Evaluation Study [113]. In this study, patients not
known to have low ventricular ejection fraction or heart
failure derived benefit from using ramipril, not only for
coronary events but also for ischemic strokes.

In contrast, one should consider patient commitment, patient potential to receive lesser therapy due to randomization,
and cost when advocating repetition of previous trials. Furthermore, despite the proven efficacy of BMT, it is important to
realize that only a small number of patients actually take their
drugs; it takes sometimes several years of treatment before
benefit in risk reduction is reached; and the mentioned risk
reductions are sometimes “misleading” [114 –117]. Fortunately, a new study–Transatlantic Asymptomatic Carotid Intervention Trial, a randomized trial–is currently comparing
CEA, CAS, and current BMT [118].
Time to surgery after the first event in carotid stenosis is
another important aspect to consider when comparing the
results and effectiveness of different interventions. Delaying surgery in patients with symptomatic carotid stenosis
significantly decreases the aimed-for long-term stroke reduction [119 –121]. Delaying CEA for Ͼ12 weeks almost
decreased a positive effect on stroke prevention in the longterm, still putting these patients at risk for perioperative
complications [15]. Unfortunately, systematic delay in surgery Յ12 weeks seems currently to be the common practice
[120]. A recent population based study in the United Kingdom showed that only 43% of symptomatic patients with
severe carotid stenosis and who had a stroke risk before
CEA of 32% at week 12 underwent surgery at Յ12 weeks
[120]. The highest risk of stroke in the first weeks after the
primary event may be related to plaque vulnerability and/or
morphology. Plaque in the early period has been characterized by thrombosis formation and spontaneous embolization
[122–124]. Classical opinions in CEA have been that early
surgery is associated with increased perioperative risk. Nevertheless, delaying surgery may seem to decrease perioperative risk but at the expense of long-term benefits: Delaying
CEA can be accompanied by stroke risks up to 20% at 4
weeks [120,125]. Overall, many patients may benefit from
fast-track CEA regarding prevention of stroke.
In conclusion, CAS performed with embolic EPDs can
be an effective treatment for patients with carotid artery
stenosis. However, presently there is no evidence that CAS

provides better stroke prevention compared with CEA.
Therefore, CEA still remains the “gold standard” of treatment. Furthermore, evolving BMT, timely intervention, and

analysis of plaque composition may have an important influence on the future treatment of patients with carotid
artery stenosis.
References
[1] Moore WS, Barnett HJ, Beebe HG, et al. Guidelines for carotid
endarterectomy. A multidisciplinary consensus statement from the
Ad Hoc Committee, American Heart Association. Circulation 1995;
91:566 –79.
[2] Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke
statistics–2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007;115:e69 – e71.
[3] Ghatnekar O, Persson U, Glader EL, et al. Cost of stroke in
Sweden: an incidence estimate. Int J Technol Assess Health Care
2004;375– 80.
[4] Kolominsky-Rabas PL, Heuschmann PU, Marschall D, et al. Lifetime cost of ischemic stroke in Germany: results and national projections from a population-based stroke registry: the Erlangen
Stroke Project. Stroke 2006;37:1179 – 83.
[5] Meyers PM, Schumacher HC, Higashida RT, et al. Use of stents to
treat extracranial cerebrovascular disease. Annu Rev Med 2006;57:
437–54.
[6] Sauerbeck LR. Primary stroke prevention. Am J Nurs 2006;106:
40 – 8.
[7] Weinberger J. Prevention of ischemic stroke. Curr Treat Options
Cardiovasc Med 2002;4:393– 403.
[8] Weinberger J. Stroke and TIA. Prevention and management of
cerebrovascular events in primary care. Geriatrics 2002;57:38 – 43.
[9] Hemphill JC III. Ischemic stroke. Clinical strategies based on mechanisms and risk factors. Geriatrics 2000;55:42–52.
[10] Ad Hoc Committee on Guidelines for the Management of Transient
Ischemic Attacks, Stroke Council of the American Heart Association. Guidelines for the management of transient ischemic attacks.
Stroke 1994;25:1320 –35.
[11] Moore WS. The American Heart Association Consensus Statement
on guidelines for carotid endarterectomy. Semin Vasc Surg 1995;8:
77– 81.

[12] Goldstein LB, Adams R, Alberts MJ, et al. Primary prevention of
ischemic stroke: a guideline from the American Heart Association/
American Stroke Association Stroke Council: cosponsored by the
Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology
Council; Nutrition, Physical Activity, and Metabolism Council; and
the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2006;113:e873– e923.
[13] Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery
Trial (ECST). Lancet 1998;351:1379 – 87.
[14] 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;
325:445–53.
[15] Rothwell PM, Eliasziw M, Gutnikov SA, et al. Analysis of pooled
data from the randomised controlled trials of endarterectomy for
symptomatic carotid stenosis. Lancet 2003;361:107–16.
[16] Ederle J, Brown MM. The evidence for medicine versus surgery for
carotid stenosis. Eur J Radiol 2006;60:3–7.
[17] Moore WS. Resolved: NASCET and ACAS need not be repeated:
the affirmative position. Arch Neurol 2003;60:775– 8.
[18] Mullenix PS, Tollefson DF, Olsen SB, et al. Intraoperative duplex
ultrasonography as an adjunct to technical excellence in 100 consecutive carotid endarterectomies. Am J Surg 2003;185:445–9.
[19] Bettendorf MJ, Mansour MA, Davis AT, et al. Carotid angioplasty
and stenting versus redo endarterectomy for recurrent stenosis. Am J
Surg 2007;193:356 –9.
[20] Satler LF, Hoffmann R, Lansky A, et al. Carotid stent-assisted
angioplasty: preliminary technique, angiography, and intravascular
ultrasound observations. J Invasive Cardiol 1996;8:23–30.


M.G. van der Vaart et al. / The American Journal of Surgery 195 (2008) 259 –269
[21] Naylor AR, Bolia A, Abbott RJ, et al. Randomized study of carotid
angioplasty and stenting versus carotid endarterectomy: a stopped

trial. J Vasc Surg 1998;28:326 –34.
[22] Brooks WH, McClure RR, Jones MR, et al. Carotid angioplasty and
stenting versus carotid endarterectomy: randomized trial in a community hospital. J Am Coll Cardiol 2001;38:1589 –95.
[23] Brooks WH, McClure RR, Jones MR, et al. Carotid angioplasty and
stenting versus carotid endarterectomy for treatment of asymptomatic carotid stenosis: a randomized trial in a community hospital.
Neurosurgery 2004;54:318 –24.
[24] Hobson RW, 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.
[25] 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.
[26] 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.
[27] 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.
[28] 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;36:905–11.
[29] Yadav JS, Wholey MH, Kuntz RE, et al. Protected carotid-artery
stenting versus endarterectomy in high-risk patients. N Engl J Med
2004;351:1493–501.
[30] Debakey ME. Carotid endarterectomy revisited. J Endovasc Surg
1996;3:4.
[31] Debakey ME. Successful carotid endarterectomy for cerebrovascular
insufficiency. Nineteen-year follow-up. JAMA 1975;233:1083–5.
[32] Mayberg MR, Wilson SE, Yatsu F, et al. Carotid endarterectomy
and prevention of cerebral ischemia in symptomatic carotid stenosis.

Veterans Affairs Cooperative Studies Program 309 Trialist Group.
JAMA 1991;266:3289 –94.
[33] 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;339:1415–25.
[34] Fox AJ, Eliasziw M, Rothwell PM, et al. Identification, prognosis,
and management of patients with carotid artery near occlusion.
AJNR Am J Neuroradiol 2005;26:2086 –94.
[35] Endarterectomy for asymptomatic carotid artery stenosis. Executive
Committee for the Asymptomatic Carotid Atherosclerosis Study.
JAMA 1995;273:1421– 8.
[36] 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;363:1491–502.
[37] Taylor DW, Barnett HJ, Haynes RB, et al. Low-dose and high-dose
acetylsalicylic acid for patients undergoing carotid endarterectomy:
a randomised controlled trial. ASA and Carotid Endarterectomy
(ACE) Trial Collaborators. Lancet 1999;353:2179 – 84.
[38] Cronenwett JL, Birkmeyer JD, Nackman GB, et al. Cost-effectiveness of carotid endarterectomy in asymptomatic patients. J Vasc
Surg 1997;25:298 –309.
[39] Kuntz KM, Kent KC. Is carotid endarterectomy cost-effective? An
analysis of symptomatic and asymptomatic patients. Circulation
1996;94:II194 –II198.
[40] 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.
[41] Bockenheimer SA, Mathias K. Percutaneous transluminal angioplasty in arteriosclerotic internal carotid artery stenosis. AJNR Am J
Neuroradiol 1983;4:791–2.
[42] Courtheoux P, Theron J, Tournade A, et al. Percutaneous endoluminal angioplasty of post endarterectomy carotid stenoses. Neuroradiology 1987;29:186 –9.

267


[43] Theron J. Protected carotid angioplasty and carotid stents. J Mal
Vasc 1996;21(suppl A):113–22.
[44] Wholey MH, Wholey MH, Jarmolowski CR, et al. Endovascular
stents for carotid artery occlusive disease. J Endovasc Surg 1997;4:
326 –38.
[45] Kachel R. Results of balloon angioplasty in the carotid arteries. J
Endovasc Surg 1996;3:22–30.
[46] Diethrich EB, Ndiaye M, Reid DB. Stenting in the carotid artery:
initial experience in 110 patients. J Endovasc Surg 1996;3:42– 62.
[47] Yadav JS, Roubin GS, Iyer S, et al. Elective stenting of the extracranial carotid arteries. Circulation 1997;95:376 – 81.
[48] Criado FJ, Wellons E, Clark NS. Evolving indications for and early
results of carotid artery stenting. Am J Surg 1997;174:111– 4.
[49] Bergeron P, Roux M, Khanoyan P, et al. Long-term results of
carotid stenting are competitive with surgery. J Vasc Surg 2005;41:
213–21.
[50] Roubin GS, New G, Iyer SS, et al. Immediate and late clinical
outcomes of carotid artery stenting in patients with symptomatic and
asymptomatic carotid artery stenosis: a 5-year prospective analysis.
Circulation 2001;103:532–7.
[51] Henry M, Amor M, Masson I, et al. Angioplasty and stenting of the
extracranial carotid arteries. J Endovasc Surg 1998;5:293–304.
[52] Teitelbaum GP, Lefkowitz MA, Giannotta SL. Carotid angioplasty
and stenting in high-risk patients. Surg Neurol 1998;50:300 –11.
[53] Jordan Jr WD, Voellinger DC, Doblar DD, et al. Microemboli
detected by transcranial Doppler monitoring in patients during carotid angioplasty versus carotid endarterectomy. Cardiovasc Surg
1999;7:33– 8.
[54] Crawley F, Clifton A, Buckenham T, et al. Comparison of hemodynamic cerebral ischemia and microembolic signals detected during carotid endarterectomy and carotid angioplasty. Stroke 1997;28:
2460 – 4.
[55] Stockx L. Techniques in carotid artery stenting. Eur J Radiol 2006;

60:11–3.
[56] Macdonald S. The evidence for cerebral protection: an analysis and
summary of the literature. Eur J Radiol 2006;60:20 –5.
[57] Wholey MH, Al Mubarek N, Wholey MH. Updated review of the
global carotid artery stent registry. Catheter Cardiovasc Interv 2003;
60:259 – 66.
[58] Kastrup A, Groschel K, Krapf H, et al. Early outcome of carotid
angioplasty and stenting with and without cerebral protection devices: a systematic review of the literature. Stroke 2003;34:813–9.
[59] Fanelli F, Bezzi M, Boatta E, et al. Techniques in cerebral protection. Eur J Radiol 2006;60:26 –36.
[60] Vitek JJ, Roubin GS, Al Mubarek N, et al. Carotid artery stenting:
technical considerations. AJNR Am J Neuroradiol 2000;21:1736 – 43.
[61] White CJ, Iyer SS, Hopkins LN, et al. Carotid stenting with distal
protection in high surgical risk patients: the BEACH trial 30 day
results. Catheter Cardiovasc Interv 2006;67:503–12.
[62] Safian RD, Bacharach JM, Ansel GM, et al. Carotid stenting with a
new system for distal embolic protection and stenting in high-risk
patients: the carotid revascularization with ev3 arterial technology
evolution (CREATE) feasibility trial. Catheter Cardiovasc Interv
2004;63:1– 6.
[63] 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.
[64] Gonzalez A, Gonzalez-Marcos JR, Martinez E, et al. Safety and
security of carotid artery stenting for severe stenosis with contralateral occlusion. Cerebrovasc Dis 2005;20(suppl 2):123– 8.
[65] 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 2006;69:341– 8.
[66] CaRESS Steering Committee. Carotid Revascularization Using
Endarterectomy or Stenting Systems (CaRESS) phase I clinical trial:
1-year results. J Vasc Surg 2005;42:213–9.

[67] Dudek D, Bartus S, Rakowski T, et al. MO.MA–a new cerebral
stroke protection system during carotid artery stenting. Kardiol Pol
2005;62:559 –70.
[68] McCabe DJ, Pereira AC, Clifton A, et al. Restenosis after carotid
angioplasty, stenting, or endarterectomy in the Carotid and Vertebral
Artery Transluminal Angioplasty Study (CAVATAS). Stroke 2005;
36:281– 6.


268

M.G. van der Vaart et al. / The American Journal of Surgery 195 (2008) 259 –269

[69] Prati P, Vanuzzo D, Casaroli M, et al. Determinants of carotid
plaque occurrence. A long-term prospective population study: the
San Daniele Project. Cerebrovasc Dis 2006;22:416 –22.
[70] Alamowitch S, Eliasziw M, Algra A, et al. Risk, causes, and prevention of ischaemic stroke in elderly patients with symptomatic
internal-carotid-artery stenosis. Lancet 2001;357:1154 – 60.
[71] Rothwell PM, Warlow CP. Prediction of benefit from carotid endarterectomy in individual patients: a risk-modelling study. European
Carotid Surgery Trialists’ Collaborative Group. Lancet 1999;353:
2105–10.
[72] Miller MT, Comerota AJ, Tzilinis A, et al. Carotid endarterectomy
in octogenarians: does increased age indicate “high risk”? J Vasc
Surg 2005;41:231–7.
[73] Featherstone RL, Brown MM, Coward LJ. 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.
[74] Mozes G, Sullivan TM, Torres-Russotto DR, et al. Carotid endarterectomy in SAPPHIRE-eligible high-risk patients: implications for
selecting patients for carotid angioplasty and stenting. J Vasc Surg

2004;39:958 – 65.
[75] Mozes G. High-risk carotid endarterectomy. Semin Vasc Surg 2005;
18:61– 8.
[76] Ballotta E, Da Giau G, Baracchini C, et al. Carotid endarterectomy
in high-risk patients: a challenge for endovascular procedure protocols. Surgery 2004;135:74 – 80.
[77] Nguyen LL, Conte MS, Reed AB, et al. Carotid endarterectomy:
who is the high-risk patient? Semin Vasc Surg 2004;17:219 –23.
[78] Verhoeven B, Hellings WE, Moll FL, et al. Carotid atherosclerotic
plaques in patients with transient ischemic attacks and stroke have
unstable characteristics compared with plaques in asymptomatic and
amaurosis fugax patients. J Vasc Surg 2005;42:1075– 81.
[79] Trivedi RA, King-Im JM, Graves MJ, et al. Non-stenotic ruptured
atherosclerotic plaque causing thrombo-embolic stroke. Cerebrovasc Dis 2005;20:53–5.
[80] McCarthy MJ, Loftus IM, Thompson MM, et al. Angiogenesis and
the atherosclerotic carotid plaque: an association between symptomatology and plaque morphology. J Vasc Surg 1999;30:261– 8.
[81] Carr SC, Farb A, Pearce WH, et al. Activated inflammatory cells are
associated with plaque rupture in carotid artery stenosis. Surgery
1997;122:757– 63.
[82] Balzer K, Boesger U, Muller KM. Plaque morphology of the carotid
bifurcation and incidence of embolisms in relation clinical stage of
cerebrovascular insufficiency. Kongressbd Dtsch Ges Chir Kongr
2002;119:631– 4.
[83] Fisher M, Paganini-Hill A, Martin A, et al. Carotid plaque pathology: thrombosis, ulceration, and stroke pathogenesis. Stroke 2005;
36:253–7.
[84] Rothwell PM, Gibson R, Warlow CP, on behalf of the European
Carotid Surgery Trialists’ Collaborative Group. Interrelation between plaque surface morphology and degree of stenosis on carotid
angiograms and the risk of ischemic stroke in patients with symptomatic carotid stenosis. Stroke 2000;31:615–21.
[85] Ackerstaff RG, Jansen C, Moll FL, et al. The significance of microemboli detection by means of transcranial Doppler ultrasonography monitoring in carotid endarterectomy. J Vasc Surg 1995;21:
963–9.
[86] Biasi GM, Froio A, Diethrich EB, et al. Carotid plaque echolucency

increases the risk of stroke in carotid stenting: the Imaging in
Carotid Angioplasty and Risk of Stroke (ICAROS) study. Circulation 2004;110:756 – 62.
[87] Flach HZ, Ouhlous M, Hendriks JM, et al. Cerebral ischemia after
carotid intervention. J Endovasc Ther 2004;11:251–7.
[88] Wolf O, Heider P, Heinz M, et al. Microembolic signals detected by
transcranial Doppler sonography during carotid endarterectomy and
correlation with serial diffusion-weighted imaging. Stroke 2004;35:
e373– e375.
[89] Johnsen SH, Mathiesen EB, Fosse E, et al. Elevated high-density
lipoprotein cholesterol levels are protective against plaque progression: a follow-up study of 1952 persons with carotid atherosclerosis:
the Tromso study. Circulation 2005;112:498 –504.
[90] Honda O, Sugiyama S, Kugiyama K, et al. Echolucent carotid
plaques predict future coronary events in patients with coronary
artery disease. J Am Coll Cardiol 2004;43:1177– 84.

[91] Setacci C, de Donato G, Setacci F, et al. In-stent restenosis after
carotid angioplasty and stenting: a challenge for the vascular surgeon. Eur J Vasc Endovasc Surg 2005;29:601–7.
[92] Touze E, Toussaint JF, Coste J, et al. Reproducibility of highresolution MRI for the identification and the quantification of carotid
atherosclerotic plaque components. Consequences for prognosis
studies and therapeutic trials. Stroke 2007;38:1812–9.
[93] Liu F, Xu D, Ferguson MS, Chu B, et al. Automated in vivo
segmentation of carotid plaque MRI with morphology-enhanced
probability maps. Magn Reson Med 2006;55:659 – 68.
[94] Wolf RL, Wehrli SL, Popescu AM, et al. Mineral volume and
morphology in carotid plaque specimens using high-resolution MRI
and CT. Arterioscler Thromb Vasc Biol 2005;25:1729 –35.
[95] Luo Y, Polissar N, Han C, et al. Accuracy and uniqueness of three
in vivo measurements of atherosclerotic carotid plaque morphology
with black blood MRI. Magn Reson Med 2003;50:75– 82.
[96] Estes JM, Quist WC, Lo Gerfo FW, et al. Noninvasive characterization of plaque morphology using helical computed tomography.

J Cardiovasc Surg (Torino) 1998;39:527–34.
[97] Gronholdt ML, Wagner A, Wiebe BM, et al. Spiral computed
tomographic imaging related to computerized ultrasonographic images of carotid plaque morphology and histology. J Ultrasound Med
2001;20:451– 8.
[98] Adams Jr HP, del Zoppo G, Alberts MJ, et al. Guidelines for the
early management of adults with ischemic stroke: a guideline from
the American Heart Association/American Stroke Association
Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral
Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology
affirms the value of this guideline as an educational tool for neurologists. Stroke 2007;38:1655–711.
[99] Touze E, Mas JL, Rother J, et al. Impact of carotid endarterectomy
on medical secondary prevention after a stroke or a transient ischemic attack: results from the Reduction of Atherothrombosis for
Continued Health (REACH) registry. Stroke 2006;37:2880 –5.
[100] Frawley JE, Hicks RG, Woodforth IJ. Risk factors for peri-operative
stroke complicating carotid endarterectomy: selective analysis of a
prospective audit of 1000 consecutive operations. Aust N Z J Surg
2000;70:52– 6.
[101] Somerfield J, Barber PA, Anderson NE, et al. Changing attitudes to
the management of ischaemic stroke between 1997 and 2004: a
survey of New Zealand physicians. Intern Med J 2006;36:276 – 80.
[102] Idris I, Thomson GA, Sharma JC. Diabetes mellitus and stroke. Int
J Clin Pract 2006;60:48 –56.
[103] Amarenco P, Labreuche J, Lavallee P, et al. Statins in stroke prevention and carotid atherosclerosis: systematic review and up-todate meta-analysis. Stroke 2004;35:2902–9.
[104] Davignon J. Beneficial cardiovascular pleiotropic effects of statins.
Circulation 2004;109:III39 –III43.
[105] Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity
statin therapy on regression of coronary atherosclerosis: the
ASTEROID trial. JAMA 2006;295:1556 – 65.
[106] CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events
(CAPRIE). Lancet 1996;348:1329 –39.

[107] Bhatt DL, Chew DP, Hirsch AT, et al. Superiority of clopidogrel
versus aspirin in patients with prior cardiac surgery. Circulation
2001;103:363– 8.
[108] Hankey GJ. Secondary prevention of recurrent stroke. Stroke 2005;
36:218 –21.
[109] Smith TP, Cruz CP, Brown AT, et al. Folate supplementation inhibits intimal hyperplasia induced by a high-homocysteine diet in a
rat carotid endarterectomy model. J Vasc Surg 2001;34:474 – 81.
[110] Southern F, Eidt J, Drouilhet J, et al. Increasing levels of dietary
homocystine with carotid endarterectomy produced proportionate
increases in plasma homocysteine and intimal hyperplasia. Atherosclerosis 2001;158:129 –38.
[111] Assadian A, Rotter R, Assadian O, et al. Homocysteine and early
re-stenosis after carotid eversion endarterectomy. Eur J Vasc Endovasc Surg 2006;33:144 – 8.
[112] Samson RH, Yungst Z, Showalter DP. Homocysteine, a risk factor
for carotid atherosclerosis, is not a risk factor for early recurrent


M.G. van der Vaart et al. / The American Journal of Surgery 195 (2008) 259 –269

[113]

[114]
[115]

[116]

[117]

[118]

[119]


carotid stenosis following carotid endarterectomy. Vasc Endovasc
Surg 2004;38:345– 8.
Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events in
high-risk patients. The Heart Outcomes Prevention Evaluation
Study Investigators. N Engl J Med 2000;342:145–53.
Hansson L. ‘Why don’t you do as I tell you?’ Compliance and
antihypertensive regimens. Int J Clin Pract 2002;56:191– 6.
Jones JK, Gorkin L, Lian JF, et al. Discontinuation of and changes
in treatment after start of new courses of antihypertensive drugs: a
study of a United Kingdom population. Br Med J 1995;311:293–5.
Hamilton-Craig I. The Heart Protection Study: implications for
clinical practice. The benefits of statin therapy do not come without
financial cost. Med J Aust 2002;177:407– 8.
Naylor AR. Does the modern concept of ‘best medical therapy’
render carotid surgery obsolete? Eur J Vasc Endovasc Surg 2004;
28:457– 61.
Gaines PA, Randall MS. Carotid artery stenting for patients with
asymptomatic carotid disease (and news on TACIT). Eur J Vasc
Endovasc Surg 2005;30:461–3.
Rothwell PM. Symptomatic and asymptomatic carotid stenosis:
how, when, and who to treat? Curr Atheroscler Rep 2006;8:
290 –7.

269

[120] Fairhead JF, Mehta Z, Rothwell PM. Population-based study of
delays in carotid imaging and surgery and the risk of recurrent
stroke. Neurology 2005;65:371–5.
[121] Johnston SC, Nguyen-Huynh MN, Schwarz ME, et al. National

Stroke Association guidelines for the management of transient ischemic attacks. Ann Neurol 2006;60:301–13.
[122] Molloy KJ, Thompson MM, Jones JL, et al. Unstable carotid
plaques exhibit raised matrix metalloproteinase-8 activity. Circulation 2004;110:337– 43.
[123] Loftus IM, Naylor AR, Goodall S, et al. Increased matrix metalloproteinase-9 activity in unstable carotid plaques. A potential role in
acute plaque disruption. Stroke 2000;31:40 –7.
[124] Molloy KJ, Thompson MM, Schwalbe EC, et al. Elevation in
plasma MMP-9 following carotid endarterectomy is associated with
particulate cerebral embolisation. Eur J Vasc Endovasc Surg 2004;
27:409 –13.
[125] Baron EM, Baty DE, Loftus CM. The timing of carotid endarterectomy post stroke. Neurol Clin 2006;24:669 – 80.
[126] Waigand J, Gross CM, Uhlich F, et al. Elective stenting of carotid
artery stenosis in patients with severe coronary artery disease. Eur
Heart J 1998;19:1365–70.
[127] Vozzi CR, Rodriguez AO, Paolantonio D, et al. Extracranial carotid
angioplasty and stenting. Initial results and short-term follow-up.
Tex Heart Inst J 1997;24:167–72.



×