carotid artery stenting in patients with carotid artery stenosis

8/8/2019 Carotid Artery Stenting In Patients With Carotid Artery Stenosis

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TITLE: Carotid Artery Stenting In Patients With Carotid Artery

Stenosis

AUTHOR: Jeffrey A. Tice M.D.

Assistant Professor of Medicine

Division of General Internal Medicine

Department of Medicine

University of California San Francisco

PUBLISHER: California Technology Assessment Forum

DATE OF PUBLICATION: October 13, 2010

PLACE OF PUBLICATION: San Francisco, CA


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CAROTID ARTERY STENTING IN PATIENTS WITH CAROTID ARTERY STENOSIS

A Technology Assessment

INTRODUCTION

The California Technology Assessment Forum was asked to update its review of the scientific evidence for

the use of carotid artery stenting for patients with carotid artery stenosis. The topic was last reviewed on

June 17, 2009. At that time, the data raised concerns about an increased risk of early strokes with

angioplasty and stenting. Many of the published trials at that time did not use distal embolization protection.

Since the prior review, there has been increasing emphasis on the use of distal embolization protection

devices during the angioplasty and stenting procedure in order to prevent early strokes and in 2010

investigators published the results of the two largest randomized trials directly comparing carotid artery

stenting to carotid endarterectomy. Thus, it is an opportune time to update the CTAF review on the efficacy

of carotid artery stenting compared to carotid endarterectomy.

BACKGROUND

In the U.S., cerebrovascular disease is currently the third leading cause of death with more than 137,000

stroke-related fatalities in 2006.1 Annually, there are almost 800,000 strokes and currently there are more

than 6.4 million stroke survivors with varying degrees of disability.1 In patients with acute stroke,

angiography studies done within six hours of symptom onset have demonstrated that 75-80% of patients

with an acute ischemic stroke have an angiographically visible occlusion of an extracranial and/or

intracranial artery as its cause.2

Carotid Arterial Disease

Atherosclerotic stenosis of the carotid artery close to the carotid bifurcation in the neck causes about 20% of

all ischemic strokes and transient ischemic attacks (TIAs).3, 4 Antiplatelet therapy (e.g., with aspirin and / or

clopidogrel) and warfarin have been employed for stroke prevention in patients with carotid stenosis. 5, 6

However, patients with new neurological symptoms associated with severe carotid stenosis have greater

than a 20% risk of stroke in the following two years. Symptomatic patients are usually defined as individuals

with TIAs, unilateral transient monocular blindness (amaurosis fugax), or non-disabling stroke on the same

side as the carotid artery stenosis. Currently, carotid endarterectomy is considered standard treatment for


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severe carotid artery stenosis.7 In patients with symptomatic, severe (>70%) internal carotid artery stenosis,

two large randomized clinical trials, the North American Symptomatic Carotid Endarterectomy Trial

(NASCET) and the European Carotid Surgery Trial (ECST) demonstrated that carotid endarterectomy is

more beneficial than medical therapy in reducing the risk of stroke.8, 9 In addition, the Asymptomatic Carotid

Atherosclerosis Study (ACAS) and the Asymptomatic Carotid Surgery Trial (ACST) demonstrated that

carotid endarterectomy is beneficial in reducing the stroke risk for asymptomatic patients with significant

carotid artery stenosis.10, 11 Carotid endarterectomy has been shown to normalize impaired cerebral

hemodynamics.12

However, carotid endarterectomy surgery usually requires general anesthesia and involves incision of the

neck, which can lead to cranial or superficial nerve injury and to wound complications. Carotid

endarterectomy also carries a risk of stroke, sometimes disabling or fatal, and of myocardial infarction sincemany patients with carotid artery stenosis also have coronary artery disease.3 Coexisting medical

morbidities greatly influence outcomes of, and therefore decisions to undertake, carotid endarterectomy.5

The American Heart Association and the American Stroke Association jointly recommend that it is

reasonable to perform revascularization of the carotid artery if the 30-day stroke and death rate is expected

to be less than six percent for symptomatic patients and less than three percent for asymptomatic

patients.13, 14 European specialty societies have the same recommendations.15 Advances in medical therapy

since the ACAS and ACST trials, including statins, better blood pressure control, better control of diabetes,

and new antiplatelet agents may make medical therapy more effective today than it was in the early 1990s,narrowing the window of benefit for surgical intervention, particularly in asymptomatic patients.16-18 Among

asymptomatic patients, the annual rate of strokes on the same side as the carotid stenosis has declined

from approximately 2.2% in 1995 to 0.7% in 2009.19 Thus, the 30-day event rate may need to be much

lower than 3% in order for the long-term benefits of carotid artery procedures to outweigh their short term

risks.

Carotid Artery Angioplasty and Stenting

Angioplasty of both coronary and non-coronary arteries was introduced in the 1970s. Initially, many

surgeons had avoided carotid and cerebral artery angioplasty because of the potential for procedure-related

stroke. Recently, however, angioplasty has been suggested as a safer and more cost-effective alternative to

carotid endarterectomy in the management of significant carotid artery stenosis. 20, 21 Theoretical benefits

include reduced morbidity rates, improved long-term patency rates and less anesthetic risks. 22

Percutaneous transluminal angioplasty, also known as endovascular treatment, is an interventional

procedure involving balloon dilatation of the atheromatous plaque or vasospasm narrowing the artery.


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Angioplasty is usually undertaken under local anesthesia, though general anesthesia standby may be

needed for patient monitoring or management of complications. For example, angioplasty of the carotid

bulb may precipitate symptomatic bradycardia, tachycardia or a profound vagal response. A temporary

pacemaker may be needed if temporary complete heart block occurs. Systemic anticoagulation is usually

started prior to the procedure and baseline angiography is performed to evaluate the diameter of the

affected vessel. An angioplasty catheter is then introduced into the femoral artery in the groin and

advanced to the site of arterial stenosis and the balloon inflated across the lesion. After balloon deflation, a

second angiogram is then performed to assess residual stenosis. Additional balloon inflations may be

needed. Anticoagulation is continued after the procedure.23

Recently, angioplasty has been combined with primary stenting of the artery to prevent plaque rupture,

arterial dissection and acute occlusion of the blood vessel. In this procedure, a catheter carrying the stent, atiny wire mesh tube, is inserted with the catheter into the femoral artery. From there, it is carefully threaded

to the site of arterial narrowing in the neck or elsewhere. Once in proper position, the stent is mechanically

expanded so that it can serve as a scaffold to prop open the artery.

With carotid angioplasty, transcranial Doppler recordings from the ipsilateral middle cerebral artery found

that that blood flow velocity falls transiently during passage of the balloon catheter through the stenosis in

the artery or during balloon inflation. However, after the procedure there was a significant improvement in

blood flow, resulting in normalization of impaired hemodynamics similar to that seen after carotid

endarterectomy.12

One of the primary benefits of carotid artery stenting is that it avoids neck dissection and requires only local

anesthetic for insertion of the catheter in the groin. Thus, the risks associated with general anesthesia are

minimized, there is no scarring of the neck, and there is minimal risk for injury to the recurrent laryngeal

nerve.

Placement of a carotid stent compresses a large proportion of the plaque against the arterial wall, but

multiple pieces of the plaque may escape through the stent and cause cerebral emboli. Recognition of the

significance of this problem has led to the development of devices to provide distal embolization protection

at the time of carotid artery angioplasty and stent deployment, although the value of distal embolization

protection remains controversial.24-31 The major harm associated with carotid stenting remains the short and

long term consequences of embolization of plaque debris to the brain during the procedure.32-35


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In addition, if restenosis occurs after stenting, the standard surgical approach of endarterectomy may be

either impossible or substantially more difficult to perform because of the stent.36 Finally, stent technology is

rapidly evolving and the best currently available stent may soon be supplanted.21, 36-41 Thus, carotid

angioplasty/stenting has remained controversial42-51 and many large, randomized trials have been launched

to evaluate the procedure.52-58

TA Criterion 1: The technology must have the appropriate regulatory approval.

The procedure of Carotid Artery Stenting and Angioplasty does not require FDA clearance. However, the

devices used in the procedure do. As of this date there are several manufacturers of carotid artery stents

and embolic protection devices that have received FDA pre-market approval (PMA) for their devices. The

specific FDA indication for the approved devices is for combined use of a stent with a device for distal

embolization protection in symptomatic patients with 50% or greater stenosis and in asymptomatic patients

with 80% or greater stenosis. Any use of a device for other than the FDA approved indication would be

considered off label use.

TA Criterion 1 is met.

TA Criterion 2: The scientific evidence must permit conclusions concerning the

effectiveness of the technology regarding health outcomes.

The Medline database, Cochrane clinical trials database, Cochrane reviews database and the Database of

Abstracts of Reviews of Effects (DARE) were searched using the key words Carotid Stenosis or

Endarterectomy, Carotid. These were cross-referenced with the keyword stents. The prior search (see

Appendix) was updated to include the period from January 2009 through September 2010. The

bibliographies of systematic reviews and key articles were manually searched for additional references.

References were also solicited from the manufacturers and local experts. The abstracts of citations were

reviewed for relevance and all potentially relevant articles were reviewed in full.

Full details of the search terms are included in the Appendix. The Figure describes the search results from

the updated search. In brief, a total of 304 new references were reviewed (138 from Embase, 132 from

PubMed, and 34 from the combined Cochrane databases). Many case-series and non-randomized trials


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were evaluated in prior CTAF reviews.59 The results from the large, prospective stent registries60-78 were

also reviewed recently.35, 79 Because of the strong evidence base for carotid endarterectomy in the treatment

of carotid artery stenosis, the improvements in medical and surgical management over the past 20 years,

and the sensitivity of procedural outcomes to patient characteristics, cohort studies cannot provide reliably

unbiased results. For instance among the stent registries following 7919 patients treated with stents, the 30-

day combined stroke, myocardial infarction (MI), and death rate varied from a low of 2.1% in one registry to

a high of 8.5% in another.79 It is impossible to make valid comparisons between cohorts with such varied

results to cohorts describing carotid endarterectomy. Thus, we included only randomized trials directly

comparing carotid artery stenting to carotid endarterectomy in this review.

Figure: Selection of Studies for Inclusion in Review

The prior search identified multiple publications from eleven clinical trials that randomized 3,283 patients.3,

20, 52, 53, 55, 80-97 The updated search identified two new trials32, 98-101 that randomized an additional 4235

patients and additional reports from three of the trials102-105 described in the prior review. All thirteen of these

trials are summarized in Tables 1 through 4 below. The majority of the patients randomized to the stent arm

in the new trials had the procedure performed with some form of distal embolization protection. There are at

least six additional randomized trials54, 56-58, 106 (Table 2A) comparing stents with distal embolization

304 potentially relevantreferences screened

73 abstracts for assessment

5 studies included in assessment( 9 publications):

2 new RCTs, updates on 3

34 studies for full text review

120 duplicate citations excluded111 excluded: not extracranial, not

randomized, no endarterectomy

39 studies excluded(Editorials, reviews, abstracts, no

clinical outcomes)

3 studies excluded

(No clinical outcomes)


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protection to carotid endarterectomy (http://www.strokecenter.org/trials/, http://www.ClinicalTrials.gov).

These seven trials plan to randomize more than 14,000 patients and follow from 12 to 60 months.

The major clinical outcomes assessed in the various trials include the occurrence of neurological deficits, inparticular, amaurosis fugax (transient visual loss), TIA, defined as a neurological deficit persisting 24 hours. Minor strokes have been defined as those causing

minimal neurological deficit yet no loss of the patients functional independence.107 Major strokes have been

defined as deficits that persisted beyond 30 days and that caused a change in the patients lifestyle. Other

outcomes include degree of residual stenosis on immediate post-angioplasty angiography, recurrence of

carotid stenosis on follow-up Doppler ultrasonography or angiography and occurrence of procedure-related

complications such as myocardial infarction, cranial nerve palsies, arrhythmias and bleeding complications.

Complications have been defined as events or conditions that led to additional procedures or prolongedhospitalization.

Levels of Evidence: 1, 2

TA Criterion 2 is met.

TA Criterion 3: The technology must improve the net health outcomes.

Key health outcomes

The primary organizations in the United States and Europe agree that in order for the net health outcomes

to be positive for patients undergoing a procedure to treat carotid artery stenosis, the combined 30 day

death or stroke rate must be less than 3% for patients who are asymptomatic and less than 6% for those

who are symptomatic. Furthermore, because there is an immediate risk of stroke and death with the

procedure, it takes up to five years for the benefits of stroke prevention to outweigh the early harms. The

landmark studies demonstrating benefit to carotid endarterectomy focused on either symptomatic (ECST,

NASCET) or asymptomatic patients (ACAS, ACST) and followed more than 3000 symptomatic patients and

4000 asymptomatic patients for three to five years: the benefits of endarterectomy were not evident until at

least two to five years of follow-up. Thus, the most important clinical outcomes are the rates of stroke and

death at 30 days and the combination of those events with stroke and death through five years of follow-up.

Extended follow-up is particularly important for studies of carotid artery stents given the concerns about late
http://www.strokecenter.org/trials/http://www.strokecenter.org/trials/http://www.strokecenter.org/trials/http://www.strokecenter.org/trials/


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in-stent thrombosis observed with coronary artery stents. Other important outcomes include the 30-day rate

of myocardial infarctions (MI), cranial nerve palsies, long-term cognitive function and quality of life.

Randomized Trials

High quality, randomized controlled trials provide the most reliable data for evaluating the effectiveness of

carotid artery stenting. There are only two small randomized trials comparing stent placement with medical

management.108, 109 Although underpowered, both reported no trend towards a reduction in strokes among

patients treated with carotid stenting compared with those treated with medical management alone.

Descriptions of the thirteen randomized trials comparing stent placement with carotid endarterectomy are

summarized in Tables 1 through 4. Table 1 summarizes the quality of the trials. Table 2 describes details

about the patients enrolled in the trials and includes descriptions of the six ongoing clinical trials (Table 2A).

Table 3 summarizes the primary outcomes and Table 4 describes procedural complications. The prior CTAF

reviews59, 110 described the first eleven trials in detail. Since that review, long-term follow-up of the Carotid

and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) trial was published 103 as were two new,

large trials, the International Carotid Stenting Study (ICSS) and the Carotid Revascularization

Endarterectomy versus Stenting Trial (CREST), which more than doubles the number of patients

randomized to treatment with carotid artery stents or carotid endarterectomy.99, 100


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Table 1: Quality of the Randomized Clinical Trials Comparing Carotid Artery Stent Placement to Carotid Endarterectomy for Carotid Artery Stenosis

Study Randomization Allocationconcealment

Comparable groups atrandomization

Loss to follow-upcomparable?

Blinded outcomeassessment

Patientblinding

Co-interventionsequivalent

ITT (lost to follow-up included?)

Overall quality

Naylor 1998

Leicester

Yes Yes NR Yes No No Yes Yes Fair

CAVATAS 2001

CAVATAS-CEA

Yes Yes Yes Yes Yes No Yes Yes Fair

Alberts 2001

WALLSTENT

Yes Yes Yes

CEA 4 years older

NR NR No NR NR Poor

Brooks 2001

Kentucky 1 (Symp)

Yes NR YesCEA 3 years older, less

CAD (31% vs. 39%)

Yes NR No NR NR Fair-poor

Brooks 2004

Kentucky 2 (Asymp)

Yes NR No: More CAD in stentgroup (35% vs. 20%)

NR No No Yes NR Fair-poor

Yadav 2004, 2008

SAPPHIRE

Yes

Non-inferiority

Yes No: More CAD and priorPTCA in stent groupp10% absolute

difference in prior PTCA,CABG, CAD

Yes for 1 yearoutcomes, not for 3

year outcomes

Partial (eventidentification not

blinded)

No No

Clopidogrel only instent group

Yes Fair

Study terminatedearly due to slowed

recruitment

Ling 2006

TESCAS-C

Yes NR NR NR NR No NR NR Poor due to limitedreporting

Mas 2006, 2008

EVA-3S

Yes

Non-inferiority

NR No: CEA had more strokes(20% vs. 13%, P=0.02);

more subjects older than 75(20% vs. 13%), but fewercontralateral occlusions

(1.2% vs. 5%)

Yes Yes No No: Moreanticoagulation and

dual antiplatelettherapy in the stent

group

Yes in 2008publication

Fair

Terminated early dueto excess strokes in

stent group

2006; Eckstein 2008

SPACE

Yes

Non-inferiority

Yes Yes Yes Partial (event

identification notblinded)

No No: ASA in both,

clopidogrel in stentgroup only

Yes in 2008

publication

Fair

Hoffmann 2008

BACASS

Yes Yes No: large differences in %with prior stroke and % with

amaurosis fugax

Yes NR No No: clopidogrel only instent group

Yes Fair-poor

Steinbauer 2008 Yes NR Yes Yes NR No Yes Yes Fair

ICSS Investigators2010ICSS

Yes Yes Yes Yes Partial (eventidentification not

blinded)

No NR, likely more ASA+ clopidogrel in the

stent group

Yes Fair

Brott 2010

CREST

Yes Yes Yes Yes Partial (eventidentification not

blinded)

No No. Clopidogrel orticlopine for 4 weeksin stent group only.

Yes Fair

CEA Carotid endarterectomy PTCA Percutaneous transluminal coronary angioplasty EVA-3S Endarterectomy vs. Angioplasty in Patients with Symptomatic Severe Carotid Stenosis TrialCAD Coronary artery disease CABG Coronary artery bypass graft surgery SPACE Stent-protected Percutaneous Angioplasty of the Carotid vs. EndarterectomySAPPHIRE Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy ASA Aspirin


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Table 2: Description of the Procedures and Participants in the Randomized Clinical Trials Comparing Carotid Artery Stent Placement to CarotidEndarterectomy for Carotid Artery Stenosis

Study Indication

% symptomatic

Device

DEP (%)

Co-intervention N Follow-upfor primaryoutcome

Age, yrs

Sex, %F

Primaryoutcome

Inclusion criteria Exclusion criteria Comment

Naylor 1998

Leicester

Symptomatic Wallstent

No (0%)

ASA not stopped 23

Earlytermination

30 days 67

47%

Stroke +death

70-90% ICAstenosis by U/S

Stroke in evolutionCrescendo TIAsNon-hemisphericsymptoms

Single center.Mean stenosis82%. Stoppedearly due to harm.

CAVATAS 2001

CAVATAS-CEA

Symptomatic CAS

90%

Angioplasty + 55stents

No (0%)

ASA 150 mg +heparin

504 36 months 67

30%

Ipsilateraldisablingstroke +death

Stenosis requiringinterventionamenable to surgeryor endovascular

Disabling stroke.Thrombus.Severe intracranialarterial stenosis.

Multicenter.

Alberts 2001

WALLSTENT

Symptomatic CAS

100%

Wallstent

No (0%)

ASA 325 bidTiclopidine 250 bid

For 4 weeks

219

Earlytermination

12 months 68

36%

Ipsilateralstroke +death

60-99% stenosis byangiogram.

NR Stopped early forharm. Planned n =700

Brooks 2001

Kentucky 1 (Symp)

Symptomatic CAS

100%

Wallstent

No (0%)

ASA 325 +Clopidogrel 75

Heparin in stent arm

104 NR 68

NR

NR >70% stenosis byNASCET criteriaLife expectancy > 5years

Disabling strokeRecent intracranialhemorrhage

Single center.

Brooks 2004

Kentucky 2 (Asymp)

AsymptomaticCAS0%

Wallstent orDynalink

No (0%)

ASA 325 +Clopidogrel 75

Heparin in stent arm

85

Earlytermination

48 months 68

NR

NR >80% stenosis byNASCET criteriaLife expectancy > 5years

ArrhythmiaAllergy to ASA,Clopidogrel, heparin

Single center.

Yadav 2004, 2008

SAPPHIRE

Asymptomatic(238/334 = 71%)

Symptomatic(96/334 = 29%)

High risk forsurgical

complication and

Cordis Precise orSmart stent with

Angioguard orAngioguard XP

Yes (96%)

Clopidogrel 75 for 2-4weeks in stent group.

ASA 81 or 325starting 72 hours priorto procedure in bothgroups continued

indefinitely.

334

Earlytermination

12 months 73

33%

Stoke + MI +death

At least one highrisk factor>18 years old50% stenosissymptomatic or80% stenosisasymptomatic byU/S

CVA in past 48hoursThrombus present100% occlusionUnable to usecatheter2 stents neededSurgery planned w/I

30 daysLife expectancy < 1yearOsteal lesion

Multicenter

High RiskSignificant heartor lung diseaseContralateralcarotid occlusionPrior radical neck

surgery, radiation,or endarterectomyon this artery

Age 80

Ling 2006

TESCAS-C

Symptomatic +asymptomatic

Unknown %

NR NR 166 6 months NR 30 day Stoke+ MI + death+ strokes 6

months

Severe stenosis NR Multicenter, China

Paper is inChinese.

Mas 2006, 2008

EVA-3S

Symptomatic CAS

100%

Multiple

Yes (86%)

100 to 300 mg ASAplus 500 mg

ticlopidine or 75 mgclopidogrel 3 daysprior to procedure

and 1 month after instent arm only

527

Earlytermination

48 months 70

25%


>60%TIA or Ischemicstroke within 4months

Disabling strokeNon-atheroscleroticcarotid diseaseSevere intracranialcarotid stenosisContraindication toheparin, ticlopidine,or clopidogrelLife expectancy < 2years

Multicenter,France.

Stopped early forharm. Planned n =900


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Study Indication

% symptomatic

Device

DEP (%)


Age, yrs

Sex, %F

Primaryoutcome

Inclusion criteria Exclusion criteria Comment

2006; Eckstein 2008

SPACE

Symptomatic CAS

100%

Multiple

Yes (27%)No (73%)

100 mg ASA for all

75 mg/d clopidogrel x33 days for stent arm

1214

Earlytermination

24 months 68

28%


>50% by angiogramor 70% by U/S

Age > 50 years

PregnantIntracranial bleedingwithin 90 days ofrandomization

Arteriovenousmalformation oraneurysmLife expectancy < 2yearsContraindication forheparin, ASA,

clopidogrel, orcontrast media

Multicenter,Europe.

Stopped early forharm \ futility.Planned n = 1900

Hoffmann 2008

BACASS

Symptomatic CAS

100%

Wallstent

Yes (100%)

ASA + clopidogrel forstents

Antiplatelet therapyfor CEA

20 48 months 70

15%

30 day Stoke+ MI + death

+ strokesthrough 48

months

> 70% stenosis Unable to FU for 2yearsICA occlusion

Arteriovenousmalformation oraneurysmLife expectancy < 2yearsContraindication forheparin, ASA,clopidogrel, orcontrast media

Single center

Low power

Steinbauer 2008 Symptomatic CAS

100%

Wallstent

No (0%)

All subjects: 100 mgASA + 75 mgclopidogrel x 1

month, then 300 mgASA indefinitely

87 12 months

Median 65months

68

NR

30 day Stoke+ MI + death

+ strokesthrough 12

months

> 70% stenosis NR Single center

Low power

ICSS Investigators2010

ICSS

Symptomatic CAS

100%

Multiple

Yes (72%)

ASA + clopidogrelrecommended for all

receiving stents

1713 4 months forthis analysis,

36 monthsplanned.

70

30%

30 daysStoke + MI +

death andstroke

through 3years

70%Suitable for stenting

or endarterectomy,No contraindicationto either treatment

Major strokeThrombus at site

Life expectancy < 2years

Multicenter,international.

Large.

Brott 2010

CREST

Symptomatic(1326) andasymptomatic(1196)

53%

ACCULINK

Yes (96%)

ASA + clopidogrel orticlopidine for allreceiving stents

2522 30 monthsfor thisanalysis, 48monthsplanned.

69

35%

30 daysStoke + MI +

death andipsilateral

strokethrough 4

years

>50% by angiogramor 70% by U/S

Comorbiditiesinterfering withevaluation endpointsCEA or CAScontraindicatedLife expectancy < 4years

Multicenter, U.S. -NIH funded trial.Large. Mix ofsymptomatic andasymptomatic.

CAVATAS Carotid and Vertebral Artery Transluminal Angioplasty Study CAS Carotid artery stenosisNR Not reported NASCET North American Symptomatic Endarterec tomy TrialCVA Cerebral vascular accident CHD Coronary heart diseaseTESCAS-C Trial of endarterectomy versus stenting for the treatment of carotid atherosclerotic stenosis in China


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Table 2A: Description of the Procedures and Participants in the Ongoing Randomized Clinical Trials Comparing Carotid Artery Stent Placement to CaroEndarterectomy for Carotid Artery Stenosis

Study

Year started

Indication Device

DEP?


Primary outcome Inclusioncriteria

Exclusion criteria Comment

Ongoing trials

Link

1999

Symptomatic Stents 200 ? 30 days Stoke + MI+ death

> 70%stenosis

Ages 40-79years

> 70% stenosis incontralateral carotidartery

ACT-1

2005

Asymptomatic EXACT Stent

Yes

1858 12 months 30 days stroke +MI + death andipsilateral strokes

through 1 year

Severe carotidartery disease Symptoms in the last180 daysHigh risk for surgery

Multicenter.

ACST-2

2006

Asymptomatic Stents

Yes

5000 12 months 30 days Stoke + MI+ death and stroke

through 1 year

UK

Comparing CarotidStenting WithEndarterectomy inSevere

AsymptomaticCarotid Stenosis

2009

Asymptomatic Stent

Yes

500 24 months 30 days Stoke + MI+ death and stroke

through 2 years

> 70%stenosis

Age 18-79

US

Agostini

?

Symptomatic Stents 400 24 months 30 days Stoke + MI+ death and stroke

through 2 years

Italy

TACIT

?

Asymptomatic Stents

Yes

Best medical care 3500 60 months 30 days Stoke + MI+ death and stroke

through 5 years

>60% by U/S

Age 18-79

Atrial fibrillationEF < 30%

3 arms: medicalcare, CEA, stent +DEP. Multicenter,international

SPACE-2 Asymptomatic Stents

Yes

Best medical care 3640 60 months 30 days Stoke + MI+ death and

ipsilateral strokethrough 5 years

>70% by U/S

Age 50-85

3 arms: medicalcare, CEA, stent +DEP. Multicenter,German.


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Table 3: Outcomes and Adverse Events in the Randomized Clinical Trials Comparing Carotid Artery Stent Placement to Carotid Endarterectomy for Carotid ArteryStenosis

Study Procedure N stent

N CEA

30 day 1 year Restenosis(70%)

30 daystroke or

death

30 daystroke,

death, orMI

30d plus 1year

ipsilateralstroke

Stroke MI Dea th Stroke MI Death

Naylor 1998

Leicester

Stent

Endarterectomy

7

10

5 (45%)

0 (0%)

NR

NR

0 (0%)

0 (0%)

NR NR NR NR 45%

0%

NR NR

CAVATAS 2001

CAVATAS-CEA

Angioplasty orStent

Endarterectomy

251

253

18 (7.1%)

21 (8.3%)

0 (0%)

3 (1.2%)

7 (2.8%)

4 (1.6%)

NR NR NR 14%

4%

10%

10%

NR 12%

12%

Alberts 2001

WALLSTENT

Stent

Endarterectomy

107

112

NR NR NR 4%

1%

NR NR NR 12%

4.5%

NR 12%

4%

Brooks 2001

Kentucky 1 (Symp)

Stent

Endarterectomy

53

51

0 (0%)

0 (0%)

NR 0 (0%)

1 (2%)

NR NR NR NR 0%

2%

NR NR

Brooks 2004

Kentucky 2 (Asymp)

Stent

Endarterectomy

43

42

0 (0%)

0 (0%)

NR 0 (0%)

0 (0%)

NR NR NR NR 0%

0%

NR NR

Yadav 2004, 2008

SAPPHIRE

Stent

Endarterectomy

167

167

6 (3.6%)

5 (3.1%)

4 (2.4%)

10 (6.1%)

2 (1.2%)

4 (2.5%)

10 (6.2%)

12 (79%)

5 (3.0%)

10 (6.2%)

12 (7.4%)

21 (13.5%)

0.6%

4.3%

5%

5%

8 (4.8)

16 (9.8)

12%

20%**

Ling 2006

TESCAS-C

Stent

Endarterectomy

82

84

NR NR NR NR NR NR NR NR NR 10%

12%

Mas 2006, 2008

EVA-3S

Stent

Endarterectomy

261

259

23 (8.8%)

7 (2.7%)

1 (0.4%)

2 (0.8%)

2 (0.8%)

3 (1.2%)

NR NR NR NR 9.6%

3.9%

NR 10%

4.2%

2006; Eckstein 2008

SPACE

Stent

Endarterectomy

607

589

44 (7.2%)

37 (6.3%)

NR 6 (1.0%)

5 (1.0%)

NR NR NR 11%

4.6%

6.9%

6.5%

NR 8.1%

6.8%Hoffmann 2008

BACASS

Stent

Endarterectomy

10

10

0 (0%)

1 (10%)

0 (0%)

0 (0%)

0 (0%)

0 (0%)

0 (0%)

0 (0%)

NR 0 (0%)

1 (10%)

0%

0%

0%

10%

NR 0%

20%

Steinbauer 2008 Stent

Endarterectomy

43

44

0 (0%)

0 (0%)

NR NR 1 (2.3%)

0 (0%)

0 (0%)

1 (2.3%)

0 (0%)

0 (0%)

19%

0%

NR NR 1 (2.3%)

0 (0%)


Stent

Endarterectomy

828

821

58 (7.0)

27 (3.5)

3 (0.4)

5 (0.6)

11 (1.3)

4(0.5)

NR NR NR NR 61 (7.4)

28 (3.4)

61 (7.4)

33 (4.0)

NR

Brott 2010

CREST

Stent

Endarterectomy

1262

1240

52 (4.1)

29 (2.3)

14 (1.1)

28 (2.3)

9 (0.7)

4 (0.3)

NR NR NR NR 55 (4.4)

29 (2.3)

66 (5.2)

56 (4.5)

NR

* Follow-up for primary endpoint ** Includes 30 day MI rate

CREST Carotid Endarterectomy vs. Stent Trial ICSS International Carotid Stenting Study ACT-1 Asymptomatic Carotid Stenosis, Stenting versus Endarterectomy Trial TACIT Transatlantic Asymptomatic Carotid Intervention Trial. ACST Asymptomatic Carotid Surgery Trial


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Table 4: Early Complications in the Randomized Clinical Trials Comparing Carotid Artery Stent Placement to Carotid Endarterectomy for Carotid Artery Stenosis

Study Procedure N stent

N CEA

Woundinfection

Cranialnerve injury

Hematoma orvascular

complication

Bradycardia Hemodynamicinstability

Naylor 1998

Leicester

Stent

Endarterectomy

11

12

NR

NR

0 (0%)

0 (0%)

NR

NR

NR

NR

NR

NR

CAVATAS 2001

CAVATAS-CEA

Stent

Endarterectomy

251

253

NR

NR

0 (0%)

22 (8.7%)

3 (1)

17 (7)

NR

NR

NR

NR

Alberts 2001

WALLSTENT

Stent

Endarterectomy

107

112

NR

NR

NR

NR

4%

NR

7%

NR

NR

NRBrooks 2001

Kentucky 1 (Symp)

Stent

Endarterectomy

53

51

NR

NR

0 (0%)

4 (7.8)

3 (6)

1 (2)

7 (14)

0 (0)

12 (24)

3 (6)Brooks 2004

Kentucky 2 (Asymp)

Stent

Endarterectomy

43

42

NR

NR

0 (0%)

0 (0%)

0 (0)

0 (0)

5 (12)

0 (0)

NR

NR

Yadav 2004, 2008

SAPPHIRE

Stent

Endarterectomy

167

167

NR

NR

0 (0%)

8 (4.8%)

2 (1.2)

1 (0.6)

NR

NR

NR

NR

Ling 2006

TESCAS-C

Stent

Endarterectomy

82

84

NR

NR

NR

NR

NR

NR

NR

NR

NR

NRMas 2006, 2008

EVA-3S

Stent

Endarterectomy

261

259

1 (0.4%)

1 (0.4%)

3 (1.1%)

20 (7.7%)

9 (3.4%)

2 (0.8%)

0 (0%)

11 (4.2%)

NR

NR

2006; Eckstein 2008

SPACE

Stent

Endarterectomy

607

589

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

Hoffmann 2008

BACASS

Stent

Endarterectomy

10

10

NR

NR

0 (0%)

0 (0%)

NR

NR

NR

NR

NR

NRSteinbauer 2008 Stent

Endarterectomy

43

44

0 (0%)

1 (2.3%)

0 (0%)

1 (2.3%)

1 (2.3%)

6 (14%)

NR

NR

NR

NR


Stent

Endarterectomy

828

821

NR

NR

1 (0.1%)

45 (5.5%)

30 (3.6%)

50 (6.1%)

NR

NR

NR

NR

Brott 2010

CREST

Stent

Endarterectomy

1262

1240

NR

NR

1 (0.3%)

58 (4.7%)

NR

NR

NR

NR

NR

NR


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The International Carotid Stenting Study (ICSS)

ICSS is the largest randomized trial of patients who are symptomatic from carotid artery stenosis. 99 The

study randomized 1713 study subjects at 50 centers in Europe, Australia, New Zealand, and Canada toeither carotid artery stenting (n=855) or carotid endarterectomy (n=858). Patients over 40 years of age were

eligible for randomization if they were symptomatic with at least 50% stenosis of the carotid artery and a

multidisciplinary team certified them as eligible for both surgery and stenting. Patients were excluded if they

had experienced a major stroke without recovery of function or had undergone prior endarterectomy or

stenting or if coronary artery bypass surgery was planned. Experienced centers were required to have a

surgeon who had performed at least 50 carotid operations and a physician who had performed at least 50

stenting procedures. The centers could use their preferred stent, but they were encouraged to use a distal

embolization protection device when possible and to use a combination of aspirin and clopidogrel for thestenting procedure. Investigators and the endpoint adjudication committee were blinded to treatment

assignment, but neither the patients nor the treating physicians were blinded. The primary outcome for the

trial is the rate of fatal or disabling stroke in any territory after three years of follow-up. This publication

presented an interim analysis with follow-up through 120 days.

The two study groups were similar at baseline. The average age of both groups was 70 years and 30% of

the subjects were women. Vascular risk factors equally distributed in the two groups as was the most recent

neurologic event on the side of the carotid artery stenosis. The degree of stenosis was greater than 70% in

all but 10% of the study subjects. Among the 855 patients randomized to carotid artery stenting, nine

crossed over to endarterectomy and 18 did not have either procedure performed. Among the 858 patient

randomized to carotid endarterectomy, 15 crossed over to stenting and 22 did not have either procedure

performed.

The 30-day risk of stroke, death or MI was higher in the stenting group (7.4% versus 4.0%, RR 1.83, 95% CI

1.2 to 2.8, p=0.003). Similarly the risk of stroke or death was higher in the stenting group (7.4% versus

3.40%, RR 2.16, 95% CI 1.4 to 3.3, p=0.0004). There was also a trend towards higher procedural mortality

in the stenting group (1.3% versus 0.5%, RR 2.73, 95% CI 0.9-8.5, p=0.072). On the other hand, the rate ofcranial nerve palsies (0.1% versus 5.5%, RR 0.02, 95% CI 0.0-0.16, p


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death was higher in the stenting group (8.5% versus 4.7%, RR 1.86, 95% CI 1.3 to 2.7, p=0.001). All-cause

mortality was higher in the stenting group (2.3% versus 0.8%, RR 2.76, 95% CI 1.2-6.6, p=0.017).

A subset of the subjects enrolled in the ICSS also had an MRI performed using diffusion-weighted imaging(DWI) within a week prior to treatment, one to three days after treatment, and 27 to 33 days after

treatment.32 The primary endpoint of the study was the presence of at least one new ischemic lesion on the

MRI performed within three days of treatment. Two hundred and thirty-one subjects had an MRI before and

after treatment (124 in the stenting group, 107 in the endarterectomy group). Clinically, there were more

procedural strokes or TIAs in the stenting group (10% versus 3%, RR 4.06, 95% CI 1.2-13.6, p=0.035).

Similarly, there were more new DWI lesions in the stenting group (62/124 = 50% versus 18/107 = 17%, RR

5.21, 95% CI 2.8-9.8, p


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The most recently published randomized trial was the NIH-sponsored CREST.54, 100, 101 The trial compares

the efficacy of carotid stenting using a single extending system (ACCULINK, Guidant, Temecula, CA) versus

endarterectomy in symptomatic patients with carotid stenosis.112-114 The RX Accunet embolic protection

device was used whenever possible (96% of cases in the stenting group). Primary outcome measures are

stroke, myocardial infarction, or death during a 30-day peri-procedural period, or ipsilateral stroke over a

follow-up period extending up to four years. The primary eligibility criterion included symptomatic patients

with carotid artery stenosis >70% by ultrasound or >50% by angiography and asymptomatic patients with

carotid artery stenosis >70% by ultrasound or >60% by angiography. Patients with medical conditions likely

to limit their participation during the follow-up or to interfere with outcome evaluation were excluded.

Patients randomized to the stenting group received aspirin 325 mg twice daily and clopidogrel 75 mg twice

daily for at least 48 hours prior to stenting and continued aspirin 325 mg daily and either clopidogrel 75 mgdaily or ticlopidine 250 mg twice daily for at least four weeks after the procedure. Patients in the

endarterectomy group received aspirin 325 mg daily at least 48 hours prior to endarterectomy and daily for a

year after the procedure. An electrocardiogram was performed prior to both procedures and approximately

one day and one month after the procedures. Cardiac enzymes were also measured before and after the

procedure.

Of the 2522 patients randomized, 53% were symptomatic and 47% asymptomatic. Their average age was

69 years and 35% were female. The baseline characteristics were similar in the group randomized to

stenting and the group randomized to endarterectomy. Among the 1271 randomized to stenting, 73

underwent endarterectomy and 54 had neither procedure. Among the 1251 subjects randomized to

endarterectomy, 13 received stenting and 44 had neither procedure. All patients from one center (n=20)

were excluded after randomization because of scientific misconduct at the center.

The 30-day risk of stroke, death or MI was non-significantly higher in the stenting group (5.2% versus 4.5%,

RR 1.18, 95% CI 0.8 to 1.7, p=0.38). However, the risk of stroke or death was significantly higher in the

stenting group (4.4% versus 2.3%, RR 1.90, 95% CI 1.2 to 3.0, p=0.005). There was also a trend towards

higher procedural mortality in the stenting group (0.7% versus 0.3%, RR 2.25, 95% CI 0.7-7.3, p=0.18). Onthe other hand, the rate of cranial nerve palsies (0.3% versus 4.7%, RR 0.07, 95% CI 0.02-0.18, p NR) and

of MI were lower in the stenting group.

CREST also reported their results through four years of follow-up. The four-year risk of stroke, death or MI

was non-significantly higher in the stenting group (7.2% versus 6.8%, RR 1.11, 95% CI 0.8 to 1.5, p=0.51).


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The risk of stroke or death remained significantly higher in the stenting group (6.4% versus 4.7%, RR 1.50,

95% CI 1.05 to 2.1, p=0.03). All-cause mortality was non-significantly higher in the stenting group

(uncorrected error in the table for %, RR 1.12, 95% CI 0.8 to 1.5, p=0.45).

There was no interaction with symptomatic status (p=0.84) or sex (p=0.34) for the primary outcome and the

point estimates were similar for the main outcomes. For example, the relative risks during the periprocedural

period were similar for any stroke or death (RR 1.88 for asymptomatic patients; RR 1.89 for symptomatic

patients). Among asymptomatic patients, the 30-day rate of stroke or death was 2.5% for the stenting group

and 1.4% for the endarterectomy group p=0.15). Among symptomatic patients, the 30-day rate of stroke or

death was 6.0% for the stenting group and 3.2% for the endarterectomy group (p=0.02). There was an

interaction with age (p=0.02). Patients older than age 70 tended to do better with carotid endarterectomy

while patients under the age of 70 tended to do better with carotid stenting. This is similar to the finding inthe subgroup analyses of the EVA-3S and SPACE trials described in the prior CTAF review.110

The CREST investigators also explored the impact of the various adverse events on quality of life using the

short-form 36 (SF-36) at one year. Compared with patients not experiencing an adverse event, patients who

suffered a major stroke experienced a statistically significant decrease in the physical component score (-

15.8 points, 95% CI -25.1 to -6.4), but not the mental component score (approximately -8.5 points, 95% CI

crosses 0.). Patients who suffered a minor stroke experienced statistically significant decreases in both the

physical component score (-4.5 points, 95% CI -7.9 to -1.2) and the mental component score (-3.4 points,

95% CI-6.3 to -0.5), though the absolute decrement was less on both scales than that reported by patients

suffering a major stroke. The decrement in the mental component score for major stroke was not statistically

significant because there were few events, thus the confidence intervals were wide. Patients suffering MIs

reported non-significant decreases in both the physical and mental component scores that were smaller in

magnitude than those reported by patients suffering minor strokes. Patients experiencing cranial nerve

palsies had non-significant increases on all eight subscales of the SF-36. Thus, the investigators found that

strokes, both major and minor, had a larger impact on patients long-term quality of life than did MIs or

cranial nerve palsies.

CREST is the largest randomized trial comparing carotid artery stenting to carotid endarterectomy. In

general it was a high quality trial, but patients could not be blinded due to the nature of the two interventions

and case identification was not blinded, although the final adjudication process was blinded. Interpretation is

also complicated by the mix of asymptomatic and symptomatic patients in the trial. The difference in their

primary endpoint, stroke, myocardial infarction or death during the periprocedural period or any ipsilateral


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stroke through four years was not statistically significant. The estimated four-year rate of the primary

endpoint was 7.2% in the stenting group and 6.8% in the endarterectomy group (absolute difference 0.4%,

95% CI -1.7 to 2.6%). The rate of stroke or death within 30 days of the stenting procedure was 2.5% for

asymptomatic patients and 6% for symptomatic patients. The trial also added to the literature on quality of

life by demonstrating significant decrements in quality of life for patients experiencing both minor and major

strokes, while no significant decreases were reported by patients experiencing myocardial infarctions or

cranial nerve injuries. Finally, subgroup analyses suggest that stenting performs significantly worse in older

patients, but may have improved outcomes when limited to patients younger than 70 years of age.

Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) updates

CAVATAS was the first large randomized trial comparing endovascular treatment to endarterectomy in a

population of patients with primarily (90%) symptomatic carotid artery stenosis. The study began

randomization in 1992, prior to the approval of carotid artery stents. Stenting was added to the trial in 1994.

Two recent publications presented data on the long-term outcomes of the CAVATAS study.98, 102 One

presented the clinical outcomes for up to eleven years of follow-up (median follow-up five years). 98 The

second publication compared the restenosis rates of subjects in the angioplasty or stenting group to that of

the endarterectomy group. 102 The CAVATAS investigators randomized 504 patients to endovascular

treatment (angioplasty n = 196, stenting in 55) or carotid endarterectomy (n = 253). For the clinical

outcomes, there were no significant differences between the two groups after long-term follow-up. This

included disabling stroke or death (RH 1.02, 95% CI 0.79 to 1.32), any stroke or perioperative death (RH

1.32, 95% CI 0.94 to 1.93), non-perioperative stroke (RH 1.66, 95% CI 0.99 to 2.80), and all cause mortality

(RH 1.07, 95% CI 0.82 to 1.40). Four hundred and thirteen of the patients had a carotid duplex ultrasound at

a median of four years follow-up (200 in endovascular group; 213 in endarterectomy group). The five-year

cumulative incidence of severe carotid artery restenosis (70% restenosis) was 30.7% in the endovascular

treatment group and 10.5% in the endarterectomy group (p


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Summary

As noted above, there is consensus in the literature and among experts that in order for carotid artery

revascularization to improve net health outcomes, the rate of stroke or death within 30 days of theprocedure must be less than 3% for asymptomatic patients and less than 6% for symptomatic patients.

Studies using administrative databases in the United States consistently report higher rates of stroke and

death following carotid artery stenting than following carotid endarterectomy.115-118 A large meta-analysis

that combined the published literature on carotid artery stenting, including the major registries, found that

the summary estimate for the 30-day rate of strokes and death was 3.3% for asymptomatic patients and

7.6% for symptomatic patients,35 although there was a significant trend towards lower rates over time. In the

ICSS, the largest randomized trial of symptomatic patients, the rate of stroke or death within 30 days was

7.4%.99

However, in the most recent randomized trial (CREST), with careful credentialing of the physicians,the rate of stroke or death within 30 days was 2.5% among asymptomatic patients and 6.0% among

symptomatic patients.100 Thus, in all but the most recent study, experienced clinicians using carotid stents

with distal embolization protection devices have not been able to meet the standards set for periprocedural

events rates. Furthermore, in the randomized trials outcomes with carotid artery stenting are consistently

inferior to those achieved with carotid endarterectomy.34, 99, 119 Subgroup analyses suggest that stents

perform better in younger patients, but these were post-hoc findings in studies that performed many

subgroup analyses and may represent the play of chance. Finally, there remains uncertainty about the

long-term patency of carotid stents, with several studies suggesting higher restenosis rates with stentingthan with endarterectomy. 53, 86, 96, 102

TA Criterion 3 is not met.

TA Criterion 4: The technology must be as beneficial as any established alternatives.

Carotid endarterectomy is the established alternative to carotid angioplasty/stenting for treatment of high-

grade stenosis of extracranial carotid arteries. The strongest evidence for benefit for the treatment of

symptomatic patients; carotid endarterectomy also has been shown to reduce the risk of stroke in

asymptomatic patients with significant carotid artery stenoses, but the net benefit is smaller and is

dependant upon low perioperative complication rates.


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In comparative trials, Crawley et al.,120, 121 found that there were significantly more microembolic signals

during carotid angioplasty than during endarterectomy, though there was no correlation with peri-procedural

stroke121 or neuropsychological outcomes.120 The current standard is to use distal embolization protection

when performing angioplasty/stenting. However, there is still controversy about the best way to minimize

embolization and evidence of greater microembolization with stenting and embolization protection compared

to carotid endarterectomy.24, 26, 122-124 Using such devices makes the procedure more technically demanding

and there is conflicting clinical trial literature on the clinical benefits. For instance, in the EVA-3S trial, which

started requiring use of the distal embolization protection partway through the trial, the 30-day incidence of

stroke or death was higher in procedures not using the device compared to procedures with the device

(25% vs. 7.9%, p=0.03). However, the relative risk for 30-day stroke or death compared with

endarterectomy was higher after distal embolization protection was recommended (3.4, 99% CI 1.1 - 10)

compared to the prior period (relative risk (RR) 2.0, 95% CI 0.8 5.0).92 As demonstrated in the ICSS, the

rate of emboli resulting in strokes seen on diffusion weighted imaging with MRI is significantly higher with

stenting combined with embolization protection than with carotid endarterectomy (73% versus 17%).32

The most recent Cochrane meta-analysis125 summarized the results of ten randomized trials comparing

carotid stenting to endarterectomy. They found that the rate of cranial neuropathy was significantly lower

with stenting (OR 0.16, 95% CI 0.09-0.28) and that there was a potentially important trend towards fewer

myocardial infarctions (OR 0.24, 95% CI 0.05-1.04). However, the stroke and mortality outcomes all favored

carotid endarterectomy. The rate of ipsilateral strokes at six months plus 30-day stroke and mortality ratewas significantly higher for patients treated with stenting (OR 1.53, 95% CI 1.14-2.05). The 30-day

perioperative rates for death (OR 1.14, 95% CI 0.54-2.40), stroke or death (OR 1.53, 95% CI 0.89-2.62),

disabling stroke or death (OR 1.30, 95% CI 0.87-1.96), and stroke, MI or death (OR 1.37, 95% CI 0.91-2.08)

all favored carotid endarterectomy, although none achieved statistical significance. The authors concluded

that the evidence does not support changing clinical practice from carotid endarterectomy as the treatment

of choice for carotid artery stenosis. Updated meta-analyses, included one performed as part of the ICSS

primary results publication come to similar conclusions.34, 2010 #235

Most recently, the investigators of the EVA-3S, SPACE, and ICSS trials submitted their data for a meta-

analysis of individual patient focusing on short-term outcomes.119 The results were published online in

September 2010. They presented the results from intention-to-treat analyses done through 120 days of

follow-up and per protocol analyses through 30 days of follow-up. The goal of the per protocol analysis was

to accurately assess the rates of major outcomes in patients who actually received the treatment. The per

protocol was performed on 97% of the patients included in the intention-to-treat meta-analysis (3324/3433).


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In the 120-day intention to treat analysis, stenting had worse outcomes than endarterectomy for any stroke

or death (8.9% versus 5.8%, RR 1.53, 95% CI 1.20 to 1.95), disabling stroke or death (4.8% versus 3.7%,

RR 1.27, 95% CI 0.92 to 1.74), all cause death (1.9% versus 1.3%, RR 1.44, 95% CI 0.84 to 2.47), and any

stroke (8.2% versus 4.9%, RR 1.66, 95% CI 1.28 to 2.15). The estimates from the 30-day per protocol

analysis more strongly favored carotid endarterectomy: any stroke or death (7.7% versus 4.4%, RR 1.74,

95% CI 1.32 to 2.30), disabling stroke or death (3.9% versus 2.6%, RR 1.48, 95% CI 1.0 to 2.15), all cause

death (1.1% versus 0.6%, RR 1.86, 95% CI 0.87 to 4.00), and any stroke (7.4% versus 4.3%, RR 1.74, 95%

CI 1.31 to 2.32). They also reported 14 subgroup analyses for the 120-day intention-to-treat analyses of any

stroke or death and found one significant interaction: stenting appeared comparable to endarterectomy for

patients younger than 70 years (RR 1.00, 95% CI 0.68 to 1.47), while patients 70 years and older faired

poorly (RR 2.04, 95% CI1.48 to 2.82, p for interaction = 0.0053).

In order to assess the impact of embolization protection devices on short term outcomes, we performed our

own meta-analysis of the 30-day rate of death or stroke in symptomatic patients with subgroups for the

studies that predominantly used or did not use DEP devices and included results for the symptomatic

patients in the CREST study (Figure 1). The summary estimate for the recent studies using DEP was 1.8

(95% CI 1.3 to 2.5) and was essentially identical to that reported by the CREST investigators. The summary

estimate for the older studies that did not use DEP was 1.5 (95% CI 0.6 to 3.5), suggesting that the use of

DEP devices has not substantially reduced the excess early strokes and death observed with stenting

compared to endarterectomy.


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Figure 1: 30-day rates of stroke and death for randomized trials comparing carotid artery stenting to

endarterectomy in symptomatic patients.

The majority of randomized patients included in these meta-analyses were symptomatic, so the resultsapply primarily to that patient group. Only one small randomized trial (n=85) studied exclusively

asymptomatic patients and there were no events in that trial.85 In addition, the SAPPHIRE trial randomized

predominantly asymptomatic patients (238/334, 71%), but there was insufficient power to determine if

differences in outcomes between symptomatic and asymptomatic patients was real (p for interaction = 0.55).

Similarly, in the CREST trial, about half of the patients were asymptomatic (47%), but there was no

evidence for better outcomes with stenting in the asymptomatic group (p for interaction = 0.84).

In summary, for symptomatic patients, the comparative trials convincingly show that carotid artery stenting

increases the risk for death or stroke. When perioperative myocardial infarctions are included, the trends still

suggest worse outcomes in the stenting groups. Subgroup analyses clearly demonstrate that patients ages

70 years and older do much worse with stenting. In younger patients, stenting may be non-inferior to

endarterectomy, but no randomized trials have focused on this subgroup. Randomized trial data have

demonstrated higher rates of severe restenosis in the stenting groups at two and five years, even though


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ipsilateral stroke rates do not appear to differ significantly between the two procedures after the

perioperative period. The higher rates of restenosis following stenting raises concerns about using the

devices in younger patients who are likely to have a longer life expectancy than five years. There are too

few data to draw any firm conclusions about asymptomatic patients. One trial 52, 97 found carotid artery

stenting to be equivalent to endarterectomy in high risk patients, but the definition of high risk needs further

refinement. In particular, older patients (>80 years was one of the high risk criteria) fared better with

endarterectomy than stenting in all of the major randomized trials. It is likely that stents are not inferior to

endarterectomy (and may be superior) for symptomatic patients in some of the high risk categories, but the

complex mix of patients and low power in the SAPPHIRE trial do not permit definitive conclusions. Based on

these findings, it is impossible to conclude that carotid angioplasty/stenting results in net health outcomes

that are equivalent to or better than the established alternatives of carotid endarterectomy, either for

symptomatic or asymptomatic patients.


TA Criterion 5: The improvement must be attainable outside the investigational setting.

Carotid angioplasty/stenting have been performed in multiple centers in the U.S., Europe, Australia, Canada

and Japan. Centers performing the technique must have available one or more physicians who have

received significant specific training in and who have experience with neuroradiology and

angioplasty/stenting techniques. Complication rates must be kept low if carotid artery stenting is to achieve

net clinical outcomes that are not inferior to carotid endarterectomy. These procedures are technically

demanding and patients must be carefully selected. The high 30-day rates of stroke and death for the

relatively inexperienced clinicians in the EVA-3S trial highlight the importance of training and volume in the

minimizing the harms associated with stent deployment. The credentialing program for the CREST trial may

serve as a model in the future, if stents prove useful in a subset of patients with carotid artery stenosis.126, 127

However, given that no improvement has clearly been demonstrated in the investigational setting for the use

of carotid angioplasty/stenting for either symptomatic or asymptomatic carotid artery stenosis, no

conclusions can be drawn regarding its effectiveness in the community setting.



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CONCLUSION

The published literature regarding carotid angioplasty/stenting for atherosclerotic primary and recurrent

stenosis includes many case series, nonrandomized comparative trials and thirteen randomizedcomparative trials. However, much of the early literature evaluates angioplasty/stenting without distal

embolization protection, a procedure that has fallen out of favor. Both the non-randomized, comparative

trials and the randomized trials report conflicting results regarding complications associated with carotid

angioplasty/stenting compared with carotid endarterectomy. In particular, four of the thirteen randomized

trials were suspended prematurely because of a higher incidence of stroke in the angioplasty/stenting group

than in the endarterectomy group. A fifth trial (SPACE) was terminated early because it was determined that

it would have insufficient power to demonstrate the non-inferiority of carotid stenting to endarterectomy.

Results from the two largest trials were published in 2010, although the ICSS trial has only published shortterm results. Summary estimates from the meta-analyses of the completed trials demonstrated that stenting

had an increased risk of stroke and death compared to endarterectomy, although stenting has a lower risk

for cranial nerve palsy and peri-operative MIs compared to endarterectomy. It is important to note that data

from the CREST trial showed that stokes, even if relatively minor, decrease quality of life significantly, while

there were no significant changes in quality of life following MI or cranial nerve palsy. Seven large, ongoing

multicenter trials will randomize over 14,000 patients and follow them for up to five years. These trials

should continue to clarify the relative risks and benefits of stenting and endarterectomy, particularly in

asymptomatic patients.

There is little randomized trial data comparing carotid artery stenting to carotid endarterectomy in

asymptomatic, low risk patients. Data from the subgroup of asymptomatic patients enrolled in the

SAPPHIRE trial should not be generalized to lower risk patients. In particular, it is worth noting that the 5.4%

30-day rate of strokes and death in asymptomatic patients enrolled in the SAPPHIRE trial is higher than the

three percent threshold recommended by the American Heart Association and the American Stroke

Association for treatment of asymptomatic patients with carotid stenosis. The CREST trial did report a 2.5%

30-day rate of strokes and death in their subset of asymptomatic patients, but the much larger database

from observational studies consistently reports event rates greater than 3%. Additionally, the improvements

in medical treatment for over the fifteen years since the pivotal trials of endarterectomy for asymptomatic

carotid artery stenosis suggest that the three percent threshold may be too high. There are two large,

ongoing randomized trials comparing current stenting and endarterectomy approaches to the current best

medical therapy (TACIT, SPACE-2). The results of those trials should clarify the role of procedural

interventions for patients with asymptomatic carotid artery stenosis.


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Data from the SAPPHIRE trial support the non-inferiority of stent placement with distal embolization

protection compared to carotid endarterectomy for up to three years in patients at high risk for complications

from endarterectomy. Many people are advocating the use of stenting in symptomatic, high-risk patients

based on this trial. However, the SAPPHIRE trial only randomized 95 symptomatic patients. One-year

results for the primary outcome were similar in the two groups (16.5% stent vs. 16.8% endarterectomy) and

there were more events in the stent arm from 30 days to one year (14% stent vs. 7% endarterectomy, p not

reported). Furthermore, the early benefit in the stent arm (primarily a reduction in myocardial infarctions)

may be due to the use of clopidogrel in the peri-operative period in the stent arm but not in the

endarterectomy arm of the trial. Finally, in two of the larger randomized trials, patients in at least one of the

high risk categories, older patients, had better outcomes with carotid endarterectomy. Hence, it appears

premature to recommend the use of stents over carotid endarterectomy in symptomatic high-risk patients.

Based on currently available publications, it is impossible to conclude that carotid angioplasty with stenting

improves the net health outcomes as much as or more than the established alternative of carotid

endarterectomy for atherosclerotic carotid stenosis. In most of the randomized trial data, carotid

endarterectomy outperformed carotid stenting. Carotid endarterectomy should remain the procedure of

choice until randomized trials clearly define a role for carotid artery stenting. Until that time, the use of

carotid artery stenting to treat carotid artery stenosis should remain a technology used in clinical trials.

RECOMMENDATION

It is recommended that carotid artery angioplasty with stenting does not meet California Technology

Assessment Forum TA Criterion 3 through 5 for improvement in health outcomes.

October 13, 2010

This topic was last reviewed by the California Technology Assessment Forum in June 2009 and previouslyin 2005.

The CTAF panel voted to accept the recommendation as presented.


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RECOMMENDATIONS OF OTHERS

Blue Cross Blue Shield Association (BCBSA)

In an August 2010 assessment of Angioplasty and Stenting of the Cervical Carotid Artery with Embolic

Protection of the Cerebral Circulation, the Technology Evaluation Center Medical Advisory Panel

determined that the use of carotid artery angioplasty and stenting with embolic protection of the cerebral

circulation for patients with carotid artery stenosis does not meet the TEC criteria.

Centers for Medicare and Medicaid Services (CMS)

On December 9, 2009, CMS posted a revised National Coverage Decision for Percutaneous Transluminal

Angioplasty. The NCD notes the following:

Medicare covers PTA of the carotid artery concurrent with the placement of an FDA-approved carotid stent

and an FDA-approved or cleared embolic protection device for an FDA-approved indication when furnished

in accordance with FDA-approved protocols governing post-approval studies..

We have decided to make no changes in coverage of patient groups for percutaneous transluminal

angioplasty (PTA) of the carotid artery concurrent with stenting (Medicare NCD Manual 20.7B3 and B). We

have decided to retain our existing coverage policy with a slight revision to the language regarding embolic

protection devices.

The NCD is available on the CMS web site:

:http://www.cms.gov/mcd/viewdecisionmemo.asp?id=230

American College of Cardiology, California Chapter (ACCCA)

The CAACC was invited to provide written opinion and to have a representative attend the meeting to

provide testimony.

Society for Cardiovascular and Angiography Interventions (SCAI)

The SCAI provided a position statement supporting the use of this technology.

American Society of Neuroradiology (ASN)

The ASM was invited to provide a position statement and testimony at the meeting.
http://www.cms.gov/mcd/viewdecisionmemo.asp?id=230http://www.cms.gov/mcd/viewdecisionmemo.asp?id=230http://www.cms.gov/mcd/viewdecisionmemo.asp?id=230http://www.cms.gov/mcd/viewdecisionmemo.asp?id=230


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Society of Neurointerventional Surgery (SNIS)

The SNIS was invited to provide a position statement and testimony at the meeting.

Society for Vascular Surgery (SVS)

A representative of the SVS attended the meeting to provide testimony and an opinion.

Association of California Neurologists (ACN)

The ACN was invited to provide a position statement and testimony at the meeting

California Association of Neurological Surgeons (CANS)

CANS was invited to provide a position statement and testimony at the meeting.


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ABBREVIATIONS USED IN THIS ASSESSMENT:

OR Odds ratio IDE Investigational Device Exemption

CI Confidence interval DWI diffusion-weighted imaging

TIA Transient Ischemic Attack SF-36 Short-Form 36 ACAS Asymptomatic Carotid Atherosclerosis Study

FDA Food and Drug Administration

PMA Pre-market Approval

DARE Database of Abstracts of Reviews of Effects

MI Myocardial infarction

CEA Carotid Endarterectomy

CAD Coronary artery disease

SAPPHIRE Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy

PTCA Percutaneous transluminal coronary angioplasty

CABG Coronary artery bypass graft surgery

EVA-3S Endarterectomy vs. Angioplasty in Patients with Symptomatic Severe Carotid StenosisTrial

SPACE Stent-protected Percutaneous Angioplasty of the Carotid vs. Endarterectomy

ASA Aspirin

CAVATAS Carotid and Vertebral Artery Transluminal Angioplasty Study

CAS Carotid Artery Stenosis

NR Not reported

NASCET North American Symptomatic Carotid Endarterectomy Trial

CVA Cerebral vascular accident

CHD Coronary heart disease

TESCAS Trial of endarterectomy versus stenting for the treatment of carotid atheroscleroticstenosis in China

CREST Carotid Endarterectomy vs. Stent Trial

ICSS International Carotid Stenting Study

ACT Asymptomatic Carotid Stenosis, Stenting versus Endarterectomy Trial

TACIT Transatlantic Asymptomatic Carotid Intervention Trial

EF Ejection fraction

DEP Distal embolization protection

ECST European Carotid Surgery Trial

ACST Asymptomatic Carotid Surgery Trial

RR Relative risk


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APPENDIX: Search strategy

PubMed:

Search Most Recent Queries Time Result

#19Search #17 NOT #18 14:27:45 461

#18Search #17 AND Animals, English 14:18:04 20

#17Search #9 OR #14 Limits: Publication Date from 2004 to 2009, English 14:17:42 481

#16Search #9 OR #14 Limits: English 14:17:25 702

#15Search #9 OR #14 14:17:14 770

#14Search #11 OR #12 OR #13 14:16:57 146

#13Search #10 AND (RANDOM* OR CONTROLLED) AND (IN

PROCESS[SB] OR PUBLISHER[SB] OR

PUBMEDNOTMEDLINE[SB])

14:16:38 32

#12Search #10 AND SYSTEMATIC REVIEW* 14:16:12 23

#11Search #10 Limits: Meta-Analysis, Randomized Controlled Trial,

Controlled Clinical Trial

14:16:00 99

#10Search CAROTID AND STENT* 14:15:35 3514

#9Search #4 OR #5 OR #6 OR #7 OR #8 14:15:24 716

#8Search #3 AND TREATMENT OUTCOME[MH] AND (CLINICAL

TRIAL[PT] OR MULTICENTER STUDY[PT] OR VALIDATION

STUDIES[PT] OR EVALUATION STUDIES[PT] OR

LONGITUDINAL STUDIES[MH] OR FOLLOW-UP STUDIES[MH]

OR COMPARATIVE STUDY[PT])

14:15:11 392

#7Search #3 AND SYSTEMATIC REVIEW* 14:14:40 16

#6Search #3 AND OBSERVATIONAL[TIAB] 14:14:30 14

#5Search #3 AND (RANDOMIZED CONTROLLED TRIALS AS

TOPIC[MH] OR CONTROLLED CLINICAL TRIALS AS

TOPIC[MH] OR RANDOM ALLOCATION[MH])

14:14:19 187

#4Search #3 Limits: Meta-Analysis, Randomized Controlled Trial,

Controlled Clinical Trial, Research Support, N I H, Extramural,

Research Support, N I H, Intramural, Research Support, Non U S

Gov't, Research Support, U S Gov't, Non P H S, Research Support, U S

Gov't, P H S

14:13:49 255

#3Search #1 AND #2 14:13:15 2194

#2Search STENT* 14:13:10 46825

#1Search CAROTID STENOSIS/SURGERY OR CAROTID

STENOSIS/THERAPY[MH:NOEXP] OR CAROTID

STENOSIS[MAJR] OR CAROTID

ARTERIES/SURGERY[MAJR:NOEXP] OR CEREBROVASCULAR

DISORDERS/SURGERY [MAJR:NOEXP] ORCEREBROVASCULAR DISORDERS/THERAPY[MAJR:NOEXP]

OR CAROTID ARTERY DISEASES/SURGERY[MAJR:NOEXP] OR

CAROTID ARTERY DISEASES/THERAPY[MAJR:NOEXP]

14:13:00 14204
http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=19&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=19&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=19&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=19&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=18&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=18&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=18&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=18&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=17&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=17&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=17&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=17&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=16&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=16&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=16&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=16&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=15&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=15&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=15&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=15&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=14&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=14&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=14&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=14&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=13&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=13&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=13&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=13&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=12&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=12&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=12&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=12&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=11&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=11&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=11&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=11&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=10&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=10&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=10&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=10&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=9&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=9&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=9&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=9&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=8&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=8&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=8&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=8&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=7&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=7&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=7&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=7&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=6&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=6&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=6&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=6&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=5&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=5&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=5&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=5&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=4&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=4&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=4&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=4&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=3&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=3&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=3&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=3&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=2&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=2&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=2&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=2&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=1&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=1&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=1&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=1&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=1&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=1&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=2&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=2&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=3&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=3&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=4&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=4&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=5&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=5&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=6&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=6&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=7&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=7&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=8&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=8&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=9&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=9&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=10&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=10&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=11&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=11&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=12&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=12&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=13&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=13&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=14&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=14&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=15&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=15&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=16&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=16&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=17&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=17&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=18&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=18&dbase=pubmed&tab=History&querytype=eSearch&http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=HistorySearch&querykey=19&tab=&http://www.ncbi.nlm.nih.gov/sites/entrez?querykey=19&dbase=pubmed&tab=History&querytype=eSearch&


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EMBASE.com

Search Queries

Access the EMBASE.comInfo siteif you have questions about this message or other features ofthis service. Please do not reply to this email.

No. Query Results Date

#1 'carotid artery obstruction'/exp 17,307 06 May 2009

#2 'stent'/de OR 'coronary stent'/de OR 'drug elutingstent'/de OR 'bare metal stent'/de OR stent*:ti

49,455 06 May 2009

#3 'carotid artery obstruction'/exp/mj 8,924 06 May 2009

#4 'stent'/mj OR 'coronary stent'/mj OR 'drug elutingstent'/mj OR 'bare metal stent'/mj OR stent*:ti 29,653 06 May 2009

#5 #1 AND #4 1,595 06 May 2009

#6 #2 AND #3 1,415 06 May 2009

#7 #5 OR #6 1,946 06 May

carotid artery stenting in patients with carotid artery stenosis

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