© 2005 American Academy of Neurology

© 2005 American Academy of Neurology February 25, 2004

Assessment: Carotid Endarterectomy―

An Evidence-Based ReviewReport of the Therapeutics and Technology

Subcommittee of the American Academy of Neurology

S Chaturvedi MD, A Bruno MD, T Feasby MD, R Holloway MD, O Benavente MD, SN Cohen MD, R Cote MD, D Hess MD, J Saver MD, JD Spence MD, B Stern

MD, J Wilterdink MD

Published in Neurology 2005;65:794-801


Objective

• The objective of this report is to provide an updated statement on the efficacy of carotid endarterectomy (CE) for stroke prevention in asymptomatic and symptomatic patients with internal carotid artery stenosis. (Updates previous guideline Neurology 1990;40:682)

• Additional clinical scenarios, such as use of CE combined with cardiac surgery (CABG), are also reviewed.


Introduction

• Depending on the population, extracranial internal carotid artery (ICA) stenosis accounts for 15-20% of ischemic strokes.

• CE is the most frequently performed operation to prevent stroke.

• Since 1990 guideline, several multi-center trials have been completed. This statement reflects an update on major developments.


Methods• Vascular neurologists were appointed by the

Therapeutics and Technology Assessment Subcommittee (TTA) of the AAN.

• Nine clinical questions were identified and selected due to clinical importance.

• A systematic search was performed for articles from 1990-2001.

• Additional articles from 2002-2004 were included using pre-specified criteria.


Methods

• Case reports, review articles, technical studies, and single surgeon case series were excluded.

• After exclusions, total of 186 articles were reviewed independently by 2 committee members.

• Number needed to treat (NNT) and number needed to harm (NNH) were evaluated in studies.

• Recommendations generated based on application of levels of evidence to the abstracted articles using AAN schemes.


AAN Strength of EvidenceClass I Class II

Evidence provided by a prospective study in a broad spectrum of persons with the suspected condition, using a “gold standard” for case definition, where test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy. In addition, there must be adequate accounting for drop-outs with numbers sufficiently low to have minimal potential for bias

Evidence provided by a prospective study of a narrow spectrum of persons with the suspected condition, or a well designed retrospective study of a broad spectrum of persons with an established condition (by “gold standard”) compared to a broad spectrum of controls, where test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy


AAN Strength of Evidence

Class III Class IV

Evidence provided by a retrospective study where either persons with the established condition or controls are of a narrow spectrum, and where test is applied in a blinded evaluation.

Any design where test is not applied in blinded evaluation OR evidence provided by expert opinion alone or in descriptive case series (without controls).


Translation of Evidence to Recommendation Level

Level A Level B

Level A = Established as useful/predictive or not useful/predictive for the given condition in the specified populationLevel A rating requires at least one convincing class I study or at least two consistent, convincing class II studies

Level B = Probably useful/predictive or not useful/predictive for the given condition in the specified populationLevel B rating requires at least one convincing class II study or at least three consistent class III studies


Translation of Evidence to Recommendation Level

Level C Level U

Level C = Possibly useful/predictive or not useful/predictive for the given condition in the specified populationLevel C rating requires at least two convincing and consistent class III studies

Level U = Data inadequate or conflicting. Given current knowledge, test/predictor is unproven


Clinical Question

Does CE benefit symptomatic and asymptomatic patients?


Analysis of the EvidenceSymptomatic patients

Author/ Year Ipsilateral Stroke risk plus periop stroke & death

Periop stroke & death

Periop disabling stroke & death

Any stroke

Major stroke or death

NASCET Collab. 1991 Stenosis= 70-99%

CE + BMT=9%BMT=26%

5.8%3.3%

2.7%0.9%

12.627.6

8.0%18.1%

ECST Collab. Group 1991 Stenosis= 70-99%

CE+BMT=9.5% BMT = 13.6%

7.5%NA

3.7%NA

NANA

4.8%8.4%

BMT = best medical therapy





Any stroke


Mayberg 1991 Stenosis=50-99%

CE + BMT=4.4%BMT=7.1%

6.5%2.2%

4.4%0%

NANA

NANA

ECST Collab. Group 1996 Stenosis=50-69%

CE + BMT=NABMT=NA

NANA

7.9% 16.8%14.2%

NANA

NASCET collab.1998 Stenosis=50-69%

CE + BMT=1.9% BMT=7.0%

22.2% 15.7%

NANA

19.8%26.4%

14.9%20.1%






Any stroke


ECST Collab. Group 1996 Stenosis=30-49%

CE + BMT=NABMT=NA

NANA

8.0% NA

16.2% 10.4%

NANA

ECST Collab. Group 1991, 1998Stenosis=0-29%

CE+BMT=11.3% BMT=5.6%

3.3% 0

1.7%0 %

17.1%12.8%

36.7%30.7%

Rothwell 2003 Stenosis=<50%

CE+BMT=NA BMT=NA

6.7% NA

NANA

NANA

NANA



Clinical Question

Does CE benefit asymptomatic patients?


Analysis of the Evidence Asymptomatic patients

• 3 Class I studies are available– Asymptomatic Carotid Atherosclerosis

Study (ACAS), Veterans Affairs Study, Asymptomatic Carotid Surgery Trial (ACST)

• 2 other studies were completed or planned but were stopped prematurely or had a suboptimal study design

– Mayo Clinic trial stopped due to a high rate of MI (22%) in the surgical group, CASANOVA


Analysis of the Evidence Asymptomatic patients

• The Veterans Affairs study – 444 men with angiographically-proven 50-99%

asymptomatic stenosis

– Nonsignficant trend favoring CE for prevention of ipsilateral stroke (9.4% vs. 4.7% at 4 years)

– Primary endpoint = transient ischemic attack (TIA)

– The 30 day perioperative stroke and death rate was 4.7%, NNH = 21


Analysis of the EvidenceAsymptomatic patients

• Asymptomatic Carotid Atherosclerosis Study (ACAS) – 1662 patients, 60-99% stenosis angiographically-

proven for the surgical group primarily-proven with ultrasound for the medical group

– Enrollment 1993-2003 with planned10 year follow-up

– Eligibility = carotid artery diameter reduction of at least 60%,no symptoms within the past six months

– Patients were randomized to best medical TX (BMT) or BMT + CE



• Asymptomatic Carotid Atherosclerosis Study (ACAS) – Study stopped after 2.7 years median follow-up

5.9% ARR at 5 years favoring CE (NNT =17)

– 5 year projected rate of ipsilateral stroke • medically treated patients 11.0% • surgically treated patients 5.1% • relative risk reduction 53%

– 5 year projected rate for major ipsilateral stroke any perioperative major ipsilateral stroke• medically treated patients 6.0% • surgical patients 3.4%



• Asymptomatic Carotid Atherosclerosis Study (ACAS) – The perioperative stroke rate = 2.3%, NNH=43

– Such a low perioperative stroke/death rate has not been achieved in most recent observational studies or in the Aspirin and Carotid Endarterectomy (ACE) trial (n=1512, stroke and death = 4.6%)



• Asymptomatic Carotid Surgery Trial (ACST)

– Randomized study of immediate vs. indefinite deferral of CE

– 5 five year follow-up at 126 centers in 30 countries

– % diameter reduction stenosis by carotid ultrasound

– Eligibility = carotid artery diameter reduction of at least 60% on ultrasound and no symptoms within the past six months

– Enrollment 1993 – 2003 planned 10 year follow-up

– 3120 randomized patients - 2 groups of 1560 each




– Perioperative events (stroke and death within 30 days) and the non-perioperative strokes combined

• Net 5 year risks were 6.4% (immediate CE) versus 11.8% (deferred CE) for all strokes; 3.5% vs. 6.1% for fatal or disabling strokes

– Gain mostly in non-perioperative carotid territory ischemic strokes

– The benefit was seen in both contralateral and ipsilateral carotid-territory strokes




– Subgroup analyses showed • benefits were significant for those < 65 years, those

between 65 and 74 years, but uncertain for those > 75 years

• Men and women both benefited but there were only a total of 40 non-perioperative strokes in women so the results were not as definite (p=0.02)

• 5 year benefit of CE appeared to be as great for those with <80% diameter reduction (mean 69% stenosis) as for those with 80-99% (mean 87%) reduction

• No significant difference in results in those patients who were never symptomatic compared to those with symptoms > six months previously (7.1% and 4.6% absolute five year gain, respectively)


Clinical Question

Is emergent CE beneficial in patients with progressing stroke of <24 hours?


Analysis of the EvidenceEmergent CE

• Four Class IV studies met the criteria

• In 3 studies, neurological improvement was noted in 81-93% of patients who underwent emergent CE

• Studies were fairly small in size, lacked objective evaluation of the reported neurological outcomes, and one study was clouded by coexisting treatments including emergent thrombolysis


Clinical Question

What are the most important clinical variables that impact the risk/benefit ratio?


Analysis of the EvidenceClinical Variables

• None of the trials had clinical variables that impact risk/benefit as predetermined endpoints

• In post-hoc analyses 2 variables stand out: gender and nature of the presenting symptoms

– In NASCET 50-69% stenosis group & ACAS no benefit shown for CE in women

– NASCET showed lower subsequent stroke risk in patients w/ retinal ischemia compared to patients with hemispheric events

– A pooled analysis of the 3 symptomatic studies identified modifiers of CE benefit. Greatest benefit in men, patients above age 75 years, and those randomized within 2 weeks of their last symptomatic event


Clinical Question

What are the most important radiologic factors that impact the risk/benefit ratio?


Analysis of the EvidenceRadiologic Factors

• Several studies addressed issues (status of the contralateral carotid artery, angiographic appearance of the ICA, and other factors).

• NASCET and ACAS studies had highest level data on contralateral occlusion.

– For symptomatic patients: • Contralateral occlusion present: surgical complication

rate is higher than if the contralateral ICA is patent• Better outcome compared to medical management for

patients with 70-99% stenosis – For asymptomatic patients:

• Contralateral occlusion present: randomized evidence suggests that patients do slightly better with medical management (2.0% absolute increase in risk with CE at 5 years)


Analysis of the EvidenceRadiologic Factors

• For patients with angiographic near-occlusion– Pooled analysis of the symptomatic studies

suggests: • CE is associated with trend toward benefit at 2 years

but no clear benefit at 5 years• BMT severe stenosis patients in NASCET-including

those with near-occlusion-were offered CE after the 2 year results made available

• Only Class IV evidence or below available for other factors such as influence of carotid siphon stenosis or posterior circulation stenosis.


Clinical Question

What is the ideal dose of aspirin preoperatively in patients undergoing CE?


Analysis of the EvidenceAspirin therapy

• Aspirin and Carotid Endarterectomy trial (ACE)– 2,849 subjects, double-blind randomized clinical

trial

– Compared aspirin before carotid endarterectomy & continued for 3 months at doses 81 mg, 325 mg, 650 mg and 1300 mg

– Primary outcome = combined rate of stroke, myocardial infarction, and death was the

– Outcome lower in the low-dose groups (81 mg and 325 mg) than in the high-dose groups (650 mg and 1300 mg) at 30 days and 3 months


Analysis of the EvidenceAspirin therapy

• Another trial enrolled 232 subjects to 75mg aspirin or placebo before CE and continued for 6 months.

– Aspirin compared with placebo: Trial demonstrated fewer strokes without recovery in those subjects randomized aspirin at 1 month and 6 months


Clinical Question

What are the data regarding CE concurrent with or prior to CABG?


Analysis of the EvidenceCABG

• 48 studies for review, nine met criteria for inclusion (≥50 subjects).

• No randomized clinical trials addressing this question; the best available evidence comes from retrospective case control (class III) and case series (class IV) reports.

• Some studies compared findings between groups with different surgical strategies, but because prospective criteria were not applied, a selection bias is likely.



Author/ Year Group Periop stroke %

Periop MI %

Periop death %

Long-term survival

Ennix, 1979 Class III

Simultaneous CE-CABG

0 3.9 5.9 NR

Ennix, 1979Class III

Staged CABG then CE

0 2.4 1.2 NR

Carrel, 1992Class III


1.9 0 3.8 91 at 6 yrs

Carrel, 1992Class III

Staged CE then CABG

0 8.8 4.4 87 at 6 yrs

Takach, 1997 Class III


3.9 4.7 3.5 NR

Takach, 1997 Class III

Staged CE then CABG

1.9 4.7 1.6 NR



Author/ Year Group Periop stroke %

Periop MI %

Periop death %

Long-term survival

Hertzer, 1997 Class IV


4.3 0 5.3 NR

Kaul, 2000 Class IV


1.4 within 3 Months

NA 3.4 NR

Minami, 2000 Class IV


3.2 0.6 2.6 79 at 5 yrs

Evageloupoulos, 2000 Class IV


2.2 3.2 8.9 NR


Clinical Question

How long should one wait after a stroke to perform CE?


Analysis of the EvidenceTime to CE surgery

• 6 retrospective cohort studies comparing timing of CE in patients after a stroke. Significant limitations in the designs of these studies.

• 4 of the studies defined early surgery as < 6 weeks from the stroke.

• 2 studies defined early surgery as < four weeks from the stroke.

• None of the studies found differences in the outcomes in terms of operative morbidity and longer-term follow-up.


RecommendationsUse of Carotid Endarterectomy in Symptomatic Patients

Stenosis (%) Recommendation

70-99% CE is established as effective for recently symptomatic (within previous 6 months) patients with 70-99% ICA angiographic stenosis (Level A).

50-69%

•CE may be considered for patients with 50-69% symptomatic stenosis (Level B) but the clinician should consider additional clinical and angiographic variables (Level C). See tables below.

•It is recommended that the patient have at least a five year life expectancy and that the peri-operative stroke/death rate should be <6% for symptomatic patients (Level A).

<50% •CE should not be considered for symptomatic patients with <50% stenosis (Level A).•Medical management is preferred to CE for symptomatic patients with <50% stenosis (Level A).


Recommendations

Use of Carotid Endarterectomy in Asymptomatic Patients

Stenosis (%)

Recommendation

60-99%

It is reasonable to consider CE for patients between the ages of 40-75 years and with asymptomatic stenosis of 60-99% if the patient has an expected five year life expectancy and if the surgical stroke or death frequency can be reliably documented to be <3% (Level A). The five year life expectancy is important since peri-operative strokes pose an up front risk to the patient and the benefit from CE emerges only after a number of years.


Recommendations

Patient Variables to Consider in Carotid Endarterectomy Decision-making

Patientvariables

Recommendation

Symptomatic women

Women with 50-69% symptomatic stenosis did not show clear benefit in previous trials (Level C).

Patients w/ hemispheric TIA or stroke

•Patients with hemispheric TIA or stroke had greater benefit from CE than patients with retinal ischemic events (Level C). •Patients operated on within two weeks of their last TIA or mild stroke derive greater benefit from CE (Level C).

Progressing neurological deficit

•No recommendation can be provided regarding the value of emergent CE in patients with a progressing neurological deficit (Level U).


Recommendations

Radiologic Factors to Consider in Carotid Endarterectomy Decision-making

Radiologic Factors Recommendation

Contralateral occlusion in symptomatic patients

Contralateral occlusion is associated with increased operative risk but persistent benefit (Level C).

Contralateral occlusion in asymptomatic patients

Contralateral occlusion erases the small benefit of CE in asymptomatic patients (Level C).

Near-occlusion in symptomatic patients

CE for patients with angiographic near-occlusion in symptomatic patients is associated with a trend toward benefit at two years but not associated with a clear long-term benefit (Level C).


Recommendations

Reviewed Clinical Scenarios

Peri-operative aspirin

• Symptomatic and asymptomatic patients undergoing CE should be given aspirin (81 or 325 mg/day) prior to surgery and for at least 3-months following surgery to reduce the combined endpoint of stroke, myocardial infarction, and death (Level A). Although data are not available, it is recommended that aspirin (81 or 325 mg/day) be continued indefinitely provided that contraindications are absent. Aspirin at 650 or 1300 mg/day is less effective in the peri-operative period.

• The data are insufficient to recommend the use of other anti-platelet agents in the peri-operative setting.


Recommendations

Reviewed Clinical Scenarios

Recent TIA or non-disabling stroke

• For patients with severe stenosis and a recent TIA or nondisabling stroke, CE should be performed without delay, preferably within two weeks of the patient’s last symptomatic event (Level C).

• There is insufficient evidence to support or refute the performance of CE within four to six weeks of a recent moderate to severe stroke (Level U).

CE prior to or concurrent with CABG

At this time the available data are insufficient to declare either CE before or simultaneous with CABG as superior in patients with concomitant carotid and coronary artery occlusive disease (Level U).


Recommendations for Future Research

• Improve quality of data is needed: – The setting of urgent CE in patients with progressing stroke– The appropriateness of CE in community settings– The management of coexisting carotid and coronary artery

disease– The timing of CE in patients with recent stroke.

• Data are needed on newer antiplatelet agents in the perioperative setting

• Data are needed on how CE compares to less invasive, endovascular treatment with stenting in patients with symptomatic and asymptomatic carotid stenosis.


Recommendations for Future Research

• Data are needed on the role of cerebral hemodynamics in risk stratification for patients with carotid stenosis.

• Data are needed to examine indices of vasoreactivity and cerebral perfusion in future studies of patients with both symptomatic and asymptomatic carotid stenosis.

• There is a paucity of data on stroke rates in patients with carotid stenosis who receive an aggressive treatment regimen with statins, newer antiplatelet agents, and targeted blood pressure lowering.


Disclaimer

This statement is provided as an educational service of the American Academy of Neurology. It is based on an assessment of current scientific and clinical information. It is not intended to include all possible proper methods of care for a particular neurological problem or all legitimate criteria for choosing to use a specific procedure. Neither is it intended to exclude any reasonable alternative methodologies. The AAN recognizes that specific patient care decisions are the prerogative of the patient and the physician caring for the patient, based on all of the circumstances involved.


Acknowledgments

The committee thanks Drs. Chung Hsu and David Lefkowitz as liaisons from the TTA Subcommittee, Alison Nakashima, Paul Hetland, Nancy King, and Wendy Edlund from the American Academy of Neurology for their superb assistance in coordinating the review, and Vicki Glasgow for assistance with the literature search.


TTA Subcommittee Members

Therapeutics and Technology Assessment Subcommittee Members:

Douglas S. Goodin, MD (Chair); Yuen T. So, MD, PhD (Vice-Chair); Carmel Armon, MD; Richard M. Dubinsky, MD: Mark Hallett, MD; David Hammond, MD; Cynthia Harden, MD; Chung Hsu, MD, PhD (ex-officio); Andres M. Kanner, MD (ex-officio); David S. Lefkowitz, MD ;Janis Miyasaki, MD; Michael A. Sloan, MD; James C. Stevens, MD


To view the entire guideline and additional AAN guidelines visit:

www.aan.com/professionals/practice/index/cfm

Published in Neurology 2005;65:794-801

© 2005 American Academy of Neurology

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