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 Stat
Trang 1Endarterectomy 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,*
aDepartment of Surgery, Division of Vascular Surgery, University Medical Center Groningen, 9700 RB Groningen, The Netherlands
bDepartment of Surgery, Isala Clinics, Zwolle, The Netherlands
cDepartment of Surgery, Alysis Zorggroep, Lokatie Rijnstate, Arnhem, The Netherlands
dDepartment 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,
endo-vascular 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
compo-sition–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
publica-tion 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-event, first-year survivor are ⱕ€18,517 (USD $25,016)/ patient, and lifetime costs are ⱕ€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 $62.7 billion[2]
Extracranial cerebral atherosclerosis causes 8% to 29%
of all ischemic strokes[5] Thrombotic emboli arising from cardiac origin are another more frequent cause of ischemic strokes[6 – 8] The aim of treatment for patients with carotid stenotic disease lies in decreasing the risk of disabling
* Corresponding author Tel.: ⫹011-31-503613382; fax: ⫹1-31-503611745.
E-mail address: czeebregts@hotmail.com
0002-9610/08/$ – see front matter © 2008 Excerpta Medica Inc All rights reserved.
doi:10.1016/j.amjsurg.2007.07.022
Trang 2stroke or stroke-related death as consequences of
thrombo-embolism Different medical-treatment strategies evolved
from studies initially aimed at treating patients with
cardio-vascular 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
ca-rotid stenosis, surgical endarterectomy, rather than medical
treatment, became the treatment of choice for stroke
pro-phylaxis, with proven efficacy Symptomatic patients who
have carotid stenoses between 50% and 99% and
perioper-ative rates of stroke and/or death ⬍6% 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
Asymp-tomatic Carotid Atherosclerosis Study (ACAS) concluded
that also asymptomatic patients with a carotid artery
steno-sis ⬎60% 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
re-duction 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 ⬍3% and if the patient has a life expectancy ⬎5 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
treat-ment 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
com-paring 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
per-formed, 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
pro-cedure 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 tran-sient ischemic attack or nondisabling stroke in the internal carotid flow tract ⱕ6 months before enrollment Despite differences in carotid stenosis analysis, both trials came to the same conclusions[15] Findings in the NASCET dem-onstrated 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 ⬎70% 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 ⬎8 years[33] It was further found that the efficacy of CEA increased with increasing degree of stenosis, previous stroke presentation, and pres-ence of ulceration Furthermore, the prespres-ence 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 ⬎180 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 ⱖ70% (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 ⫽ 19), and ⫺1.7% during 5 years (P ⫽ 9) Others have debated the
benefit of CEA in patients with near occlusion For exam-ple, 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 Ath-erosclerosis 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 ⬎60%, 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 Conse-quently, a significant absolute risk reduction of 5.4% was noted, although a subgroup analysis showed clear benefits only for patients ⬍75 years old Fifty percent of people
Trang 3older in age died of unrelated causes ⬍5 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 ⬎60% The 2.3% operative
risk of stroke and/or death in this trial was low
Approxi-mately 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
Endarterec-tomy randomised controlled trial published in 2003, which
compared periop erative complications with CEA
depend-ing on different acetylsalicylic acid dosages, disclosed a
perioperative complication risk of 4.6% [37] Notable,
re-sults 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
symptom-atic patients, the risk of stroke and/or death resulting from
treatment by CEA should be ⬍6% and for asymptomatic
patients should be ⬍3%[40]
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
ste-nosis in the context of coronary artery disease, treatment of
patients with peripheral stenotic arterial vascular disease
also evolved With the advancing techniques of
percutane-ous 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]
Sev-eral arguments have been brought forward to advocate its
use The minimally invasive nature of the procedure made it
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 treat-ment 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 stud-ies 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 re-ported 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 tech-nique, especially the introduction of embolic-protection de-vices (EPDs), took place
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 continu-ously[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 rec-ommended before CAS to evaluate carotid stenosis severity, morphology, carotid tortuosity, calcification, intracranial circulation stenosis, collateral circulation, and malforma-tions 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-Table 1
Early carotid stent series data
stenosis (%)
Technical success rate (%)
Morbidity and mortality rate (30-day; %)
Stroke rate (%)
NS ⫽ not specified.
Trang 4ability of EPDs seems to decrease the risk of embolic
complications as described by the carotid artery stent
reg-istries [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,
EPD-induced vessel injury, ischemia caused by occlusion, and
incomplete embolic debris removal may all result in
em-bolic cerebral complications Microporous filters are
posi-tioned in the ICA distal to the target lesion The filter is
constrained with a delivery sheath to pass the carotid
ste-nosis 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
rela-tive 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
place-ment of the filter Occlusion balloons offer the advantage of
lower device-crossing profiles, but they still require
cross-ing 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
self-expanding, 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 ⬍30%) because aggressive balloon dilatation
ap-pears 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
pro-cedure 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
indefi-nitely thereafter
Prospective multicenter registries
Compared with the early CAS series previously
de-scribed (Table 1), prospective registries with predefined
inclusion and exclusion criteria, independent neurologic
as-sessment, and oversight committees were designed to
fur-ther assess safety and United States Food and Drug
Admin-istration 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 ⬎75 years,
severe comorbidity, planned coronary bypass, or history of
major surgery [61– 64] The most common high-risk
sur-gery 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,
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 ⬎97%
of all patients The incidence in 30-day myocardial infarc-tion, stroke, and/or death varied between 2.1% and 8.3%
[61– 63,65– 67] Unfortunately, most registries did not dif-ferentiate 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 in-farction 1.1%) and 5.0% in asymptomatic patients (mortal-ity 1.6%, stroke 3.4%, and myocardial infarction 0.7%) Importantly, other registries showed that independent pre-dictors 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 symp-tomatic patients [21] The trial enrolled symptomatic low-risk patients with carotid stenoses ⬎70% However, the study was terminated after allocation of only 17
partici-Table 2 Carotid artery stent registries Registry N (% symptomatic) Combined MI/stroke/death rate (%)
BEACH 480 (25.3) 5.8* (1.0/4.4/1.5) 9.1# (1.1/7.0/3.2) ARCHeR 581 (23.8) 8.3* (2.4/5.5/2.1) 9.6* (0/1.3/0)
CAPTURE 3,500 (13.8) 5.7* (.9/4.8/1.8) NA CREATE 543 (17.4) 6.2* (1.0/4.5/1.9) NA
SECuRITY 398 (21) 8.5# (.7/6.9/.9) NA CaRESS 143 (31) 2.1* (0/2.1/0) 10 (1.7/5.5/6.3)
PRIAMUS 416 (63.5) 4.6* (0/4.1/.5) NA ARCHeR ⫽ Acculink for Revascularization of Carotids in High-Risk Patients; CABERNET ⫽ Carotid Artery Revascularization Using Boston Sci EPI Filterwire EX/EZ and EndoTex NexStent; CAPTURE ⫽ Carotid Acculink/Accunet Postapproval Trial to Uncover Rare Events; CaRESS ⫽ Carotid Revascularization Using Endarterectomy or Stenting Systems; CREATE ⫽ Carotid Revascularization With ev3 Arterial Technology Evaluation; MI ⫽ myocardial infarction; MAVerIC ⫽ Endarteractomy Versus Angioplasty in Patients With Severe Symptomatic Carotid Steno-sis; MO.MA ⫽ Multicenter Registry to Assess the Safety and Efficacy of the MO.MA Cerebral Protection Device During Carotid Stenting; NA ⫽ not available; PRIAMUS ⫽ Proximal Flow Blockage Cerebral Protection During Carotid Stenting; SECuRITY ⫽ 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
Trang 5pants 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
Angio-plasty 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
fol-low-up, severe restenoses (70% to 90%) occurred
signifi-cantly more in the endovascular-treated group (CAS 14% vs
CEA 4%) The incidence of recurrent ipsilateral stroke
ap-peared 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
effective-ness 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
compli-cation 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 Revascular-ization Versus Stent Trial (CREST) focused on patient age and periprocedural risk for patients receiving CAS Four patient-age categories were created: ⬍60 years, 60 to 69 years, 70 to 79 years, and ⱖ80 years Risk of stroke or death increased with age, but this was seen mainly in octogenar-ians (12.1%)[24] Risk was not mediated by adjustment for symptomatic status, use of antiembolic devices, sex, or percentage of stenosis Notably, patients ⬎80 years were not excluded from actual randomization within CREST Carotid artery stenosis is relatively frequent in older pa-tients Large population-based studies indicated that the prevalence of carotid stenosis increases to 10% in persons
⬎80 years old[69] In a subgroup analysis of NASCET, the benefits of CEA in patients ⬎75 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 ⬎75 years (36.5%) The perioperative rate of stroke and/or death was not higher in patients ⬎75 years (5.2%) compared with patients ⬍65 years (7.9%) The absolute risk reduction by CEA in patients ⬎75 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] Further-more, Miller et al[72]showed, in a prospective analysis of
⬎300 CEAs performed in patients ⱖ80 years, that periop-erative risk is increased, but outcomes remain within ac-ceptable guidelines[72]
In the Stenting and Angioplasty With Protection in Pa-tients 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 par-ticipate Surgeons were required to have performed an
av-Table 3
Randomized trials of CAS versus CEA
CEA 0
CEA 4.4 SAPPHIRE 334 High-risk (a)symptomatic 30-d MI, stroke, and/or death (1-y stroke or death) CAS 12.2
CEA 20.1
CEA 1.9
CEA 0
CEA 9.9
CEA 6.3
CEA 3.9 CREST 2,500 Low-risk (a)symptomatic 30-d MI, stroke, and/or death (4-y stroke) Active enrollment
ACT ⫽ Asymptomatic Carotid Stenosis Versus Endareterectomy Trial; CAS ⫽ carotid artery stenting; CAVATAS ⫽ Carotid and Vertebral Artery Transluminal Angioplasty Study; CEA ⫽ carotid endarterectomy; ICSS ⫽ International Carotid Stenting Study; MI ⫽ myocardial infarction.
Trang 6erage of 30 CEAs/y, with low corresponding major
com-plication (eg, death, stroke, and/or myocardial infarction)
rates of ⬍1% The interventionalists were required to have
performed an average of 64 interventions/y, with low
cor-responding complication (eg, stroke, TIA) rates of ⬍2% A
total of 723 symptomatic (stenosis ⬎50%) or asymptomatic
(stenosis ⬎80%) patients–normally deemed high risk for
surgery because of concomitant morbidity, such as
cardio-pulmonary disease or previous surgery–were considered
suitable for entry to either the endovascular- or
surgical-treatment arms Consensus agreement by a
multidisciplin-ary 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
fi-nally excluded because perioperative risk with CEA was
deemed too high (n ⫽ 409) Finally, 317 patients were
randomized to CEA or CAS Among patients in the
ran-domized study, a significantly higher number of patients in
the stenting arm had undergone previous coronary artery
bypass (CAS 43% vs CEA 31%, P ⬍0.05) and also had
higher history of cardiovascular disease (CAS 85% vs CEA
74%, P ⬍.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 ⫽ 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 ⫽ 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 ⫽ 4) The majority of myocardial infarctions
were non–Q-wave events identified by routine
postproce-dural 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 noninfe-riority controlled trials, the Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE) trial and the End-arterectomy 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 ⬎70% stenosis of the ICA [25] Patients were randomly allocated to either CAS or CEA The tech-nique 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 ⬎24 hours or death between randomisa-tion and 30 days after treatment The complicarandomisa-tion rate at 30 days was 6.8% for CAS versus 6.3% for CEA The
nonin-feriority test was not significant (P ⫽ 09) In this study, the
investigators concluded that CEA remains the preferred treatment for patients with symptomatic ICA stenosis be-cause evidence is lacking for equivalent or superior endo-vascular 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 treat-ment (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 ther-apy, 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 com-pared 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 ⱖ25% 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 Inter-national 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
Trang 7se harmful in high-risk patients? It seems that when patients
meet NASCET or ACAS exclusion criteria, they are marked
as “risk.” However, complication rates in these
high-risk 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 ⬎80 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
out-comes are comparable with those reported in other
pa-tients [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
high-risk 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
fail-ure 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
mor-phology 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
an-alyze vulnerable plaques GSM is an overall measure of
plaque echogenicity in which low-GSM plaques generate
more embolic particles [85] The Imaging in Carotid
An-gioplasty and Risk of Stroke study showed that the onset of
neurologic deficits during and after intervention
signifi-cantly 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
reso-nance imaging, have also been tested as measures of plaque
composition [92–97] These imaging techniques may
be-come important in the planning of future clinical trials and
BMT modalities
Comments
The longevity of CEA predominantly has been
deter-mined by comparison among large-scale randomized trials
Randomized trials comparing CEA with BMT have
con-vincingly proven that CEA significantly decreases the risk
of subsequent stroke in patients with severe carotid stenosis Currently, surgery remains the “golden standard” of treat-ment, but CAS has progressed in recent years and chal-lenged CEA Despite many trials, only a few methodolog-ically 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 How-ever, 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 orga-nized 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 evidence-based 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 require-ments 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 partic-ipate in the study when their CAS procedures were super-vised 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 stent-ing 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
Trang 850% of patients with increased lipid levels received
lipid-lowering medication A recent meta-analysis analyzing the
relationship between statins and the risk of stroke showed a
relative stroke reduction rate ⬎21%[103] The
anti-inflam-matory effects of statins seem as important as their
lipid-lowering 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
tion for the prevention of stroke and an even greater
reduc-tion in high-risk patients [106,107] Increased levels of
homocysteine have also been associated with increased
stroke risk, and lower homocysteine levels have been
re-lated 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
Preven-tion EvaluaPreven-tion 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,
pa-tient potential to receive lesser therapy due to randomization,
and cost when advocating repetition of previous trials
Further-more, 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]
Fortu-nately, a new study–Transatlantic Asymptomatic Carotid
In-tervention 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
Delay-ing surgery in patients with symptomatic carotid stenosis
significantly decreases the aimed-for long-term stroke
re-duction [119 –121] Delaying CEA for ⬎12 weeks almost
decreased a positive effect on stroke prevention in the
long-term, still putting these patients at risk for perioperative
complications[15] Unfortunately, systematic delay in
sur-gery ⱕ12 weeks seems currently to be the common practice
[120] A recent population based study in the United
King-dom 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 ⱕ12 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
character-ized by thrombosis formation and spontaneous embolization
[122–124] Classical opinions in CEA have been that early
surgery is associated with increased perioperative risk
Nev-ertheless, delaying surgery may seem to decrease
perioper-ative 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 treat-ment Furthermore, evolving BMT, timely intervention, and analysis of plaque composition may have an important in-fluence on the future treatment of patients with carotid artery stenosis
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