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Starpath.co.nzCarotid endarterectomy—An evidence-based review: Report of the Therapeutics
and Technology Assessment Subcommittee of the American Academy of Neurology
S. Chaturvedi, A. Bruno, T. Feasby, R. Holloway, O. Benavente, S. N. Cohen, R. Cote, D. Hess, J. Saver, J. D. Spence, B. Stern and J. Wilterdink Neurology 2005;65;794-801 DOI: 10.1212/01.wnl.0000176036.07558.82 This information is current as of October 7, 2007
The online version of this article, along with updated information and services, is located on the World Wide Web at: ® is the official journal of the American Academy of Neurology. Published continuously Neurologysince 1951, it is now a weekly with 48 issues per year. Copyright 2005 by AAN Enterprises, Inc. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
An evidence-based review
Report of the Therapeutics and Technology Assessment
Subcommittee of the American Academy of Neurology
S. Chaturvedi, MD; A. Bruno, MD; T. Feasby, MD; R. Holloway, MD, MPH; O. Benavente, MD; S.N. Cohen, MD; R. Cote, MD; D. Hess, MD; J. Saver, MD; J.D. Spence, MD; B. Stern, MD; and J. Wilterdink, MD Abstract—Objective: To assess the efficacy of carotid endarterectomy for stroke prevention in asymptomatic and symp-
tomatic patients with internal carotid artery stenosis. Additional clinical scenarios, such as use of endarterectomy
combined with cardiac surgery, are also reviewed. Methods: The authors selected nine important clinical questions. A
systematic search was performed for articles from 1990 (the year of the last statement) until 2001. Additional articles from
2002 through 2004 were included using prespecified criteria. Two reviewers also screened for other relevant articles from
2002 to 2004. Case reports, review articles, technical studies, and single surgeon case series were excluded. Results: For
several questions, high quality randomized clinical trials had been completed. Carotid endarterectomy reduces the stroke
risk compared to medical therapy alone for patients with 70 to 99% symptomatic stenosis (16% absolute risk reduction at
5 years). There is a smaller benefit for patients with 50 to 69% symptomatic stenosis (absolute risk reduction 4.6% at 5
years). There is a small benefit for asymptomatic patients with 60 to 99% stenosis if the perioperative complication rate is
low. Aspirin in a dose of 81 to 325 mg per day is preferred vs higher doses (650 to 1,300 mg per day) in patients undergoing
endarterectomy. Conclusions: Evidence supports carotid endarterectomy for severe (70 to 99%) symptomatic stenosis
(Level A). Endarterectomy is moderately useful for symptomatic patients with 50 to 69% stenosis (Level B) and not
indicated for symptomatic patients with ⬍50% stenosis (Level A). For asymptomatic patients with 60 to 99% stenosis, the
benefit/risk ratio is smaller compared to symptomatic patients and individual decisions must be made. Endarterectomy
can reduce the future stroke rate if the perioperative stroke/death rate is kept low (⬍3%) (Level A). Low dose aspirin (81
to 325 mg) is preferred for patients before and after carotid endarterectomy to reduce the rate of stroke, myocardial
infarction, and death (Level A).
Extracranial internal carotid artery stenosis ac- Neurology regarding CE was published in 1990.1 counts for 15 to 20% of ischemic strokes, depending Since then, several multicenter trials have been com- on the population studied. Carotid endarterectomy pleted and this statement reflects an update on ma- (CE) is the most frequently performed operation to jor developments since 1990.
The last statement from the American Academy of Vascular neurologists were appointed by the Thera- peutics and Technology Assessment Subcommittee of the Ameri-can Academy of Neurology. A literature search was performed Additional material related to this article can be found on the Neurology using Ovid Medline for relevant articles published from 1990 to Web site. Go to www.neurology.org and scroll down the Table of Con- 2001 using the following key words: carotid endarterectomy, ca- tents for the September 27 issue to find the title link for this article.
rotid stenosis, carotid artery diseases, clinical trials. Further de- From the Stroke Program and Department of Neurology (Dr. Chaturvedi), Wayne State University; Department of Neurology (Dr. Bruno), IndianaUniversity; University of Alberta (Dr. Feasby); Department of Neurology (Dr. Holloway), University of Rochester, NY; Department of Neurology (Dr.
Benavente), University of Texas-San Antonio; Stroke Prevention Program (Dr. Cohen), Sunrise Hospital, Las Vegas, NV; Department of Neurology (Dr.
Cote), McGill University; Department of Neurology (Dr. Hess), Medical College of Georgia; UCLA Stroke Center (Dr. Saver); Robarts Research Institute(Dr. Spence); Department of Neurology (Dr. Stern), University of Maryland; and Department of Neurology (Dr. Wilterdink), Brown University.
This guideline was approved by the Therapeutics and Technology Assessment Subcommittee on November 19, 2004; by the Practice Committee on April 13,2005; and by the Board of Directors on June 26, 2005.
Disclosure: The authors report no conflicts of interest.
Received February 18, 2005. Accepted in final form June 15, 2005.
Address correspondence and reprint requests to American Academy of Neurology, 1080 Montreal Ave., St. Paul, MN 55116.
Copyright 2005 by AAN Enterprises, Inc.
Table 1 Relevant formulas
mated diameter of the normal carotid bulb. Thismeans for a given level of stenosis, the percentage narrowing would be lower using the NASCET No. needed to treat (NNT) 100/absolute risk reduction method compared to the ECST method. For example, No. needed to harm (NNH) 100/absolute risk increase a NASCET 70% stenosis corresponds to an 82%ECST stenosis.
The principal result of NASCET was a significant benefit of CE in patients with 70 to 99% symptom- tails of the search process can be found in appendix E-1 (go to theNeurology Web site at www.neurology.org). Standard search pro- atic stenosis. The 2-year ipsilateral stroke risk was cedures were used and subheadings were applied as appropriate.
26% in the medically treated patients and 9% in the Two committee members also reviewed the Cochrane Library BMT ⫹ CE group (p ⬍ 0.001). The absolute risk statements on CE for symptomatic and asymptomatic stenosis in reduction (ARR) was 17.0% and the number needed August 2004 to confirm that relevant citations from 2002 to 2004were identified.
to treat (NNT) was six at 2 years. In patients with 50 The initial search was done in July 2001 and identified 1,462 to 69% symptomatic stenosis, the 5-year rate of ipsi- citations. This list was refined further by reviewing these citation lateral stroke was 15.7% in patients treated with abstracts with exclusion of the following types of articles: casereports, letters to the editor, review articles without primary data, BMT ⫹ CE and 22.2% in patients who received BMT studies addressing CE technical issues, case series from a single alone (ARR 6.5%, NNT 15.4, p ⫽ 0.045). There was a surgeon, and non-English articles. Case series from a single insti- nonsignificant difference in patients with ⬍50% tution were not excluded. This reduced the articles to 186 and symptomatic stenosis, with a 5-year rate of ipsilat- each of these articles was reviewed independently by two commit-tee members. The committee also stipulated that if a pooled anal- eral stroke of 14.9% in the CE group and 18.7% in ysis of the major symptomatic CE studies or if the results of the the medical therapy group (p ⫽ 0.16). Results of Asymptomatic Carotid Surgery Trial were published prior to the ECST were slightly different if the comparison was completion of the committee's manuscript, these would subse-quently be reviewed. For some of the clinical questions, additional undertaken using the ECST method of stenosis mea- screening criteria were used before the study was selected for full surement but when the ECST angiograms were re- abstraction (see below). The number needed to treat and harm analyzed using the NASCET method, the two trials were evaluated in studies as described in table 1. Recommenda- produced remarkably consistent results.6,7 tions were generated based on the application of levels of evidenceto the abstracted articles (Appendices 1 and 2).
In the NASCET 50 to 69% group, post hoc analy- ses found that the benefit was heterogeneous. In the Analysis of the evidence.
Nine clinical questions 50 to 69% group, there was a greater benefit from CE were identified and they are as follows.
in men compared to women. For prevention of an 1. Does CE benefit symptomatic patients? ipsilateral stroke of any severity or for prevention of Class I studies have been completed: the North a disabling stroke, the NNT was 12 and 16 for men American Symptomatic Carotid Endarterectomy and 67 and 125 for women. In addition, there was no Trial (NASCET) and the European Carotid Surgery demonstrable benefit in patients with retinal stroke Trial (ECST) (these trials and other articles reported or retinal TIA.
in results can be found in supplementary appendix A combined analysis of the symptomatic trials, E-1).2-4 A third well-designed study, the Veterans Af- done by Rothwell et al., included 6,092 patients with fairs Cooperative Studies Program 309 Trial, was 35,000 patient-years of follow-up.8 The combined stopped prematurely after the initial NASCET re- analysis included individual patient data, reassessed sults were announced.5 In the symptomatic studies, the angiograms, and standardized the outcomes. Due patients were classified as symptomatic if they had a to differences in the three trials in terms of defini- carotid distribution TIA or nondisabling stroke in tion of stroke outcome events and disabling stroke, the preceding 6 months (originally 4 months in NASCET), and these patients were assigned to best NASCET definitions: 1) stroke was defined as any medical therapy (BMT) or BMT ⫹ CE. Aspirin was cerebral or retinal event with symptoms lasting longer than 24 hours; 2) disabling stroke was defined NASCET, patients were required to have a 5-year as a stroke that resulted in a Rankin score of 3 or life expectancy to ensure adequate follow-up in both more, or an equivalent rating, at a defined follow-up interval. For all these studies, the outcome was ipsi- Table 2 provides a summary of the main features lateral stroke or perioperative (30 days) stroke or of the two completed symptomatic studies, NASCET death. Also, in the three studies represented in the and ECST. Although the overall design of the two combined analysis, the degree of stenosis was proven studies was comparable, one major difference be- by contrast angiography. The major conclusions were tween the two trials was in the method of angio- graphic measurement. NASCET calculated the Benefit for CE was shown for: degree of stenosis using the site of maximal narrow- sis, ARR of 4.6% (over 5 years), NNT ⫽ 22.
ing as the numerator, divided by the distal ICA di- ⱖ70% stenosis (not near occlusion), ARR of 16% ameter where the vessel walls became parallel and (over 5 years), NNT ⫽ 6.3.
beyond any area of post-stenotic dilatation. ECST Near occlusion, ARR of 5.6% over 2 years (p ⫽ calculated the degree of stenosis using the diameter 0.19) but only –1.7% (p ⫽ 0.9) over 5 years. Near at the site of maximal narrowing divided by the esti- occlusion is defined as the angiographic appearance September (2 of 2) 2005
Table 2 Overview of symptomatic trials
NASCET collaborators/ ECST Collab. Group/ ECST Collab. Group/ NASCET collaborators/ ECST Collab. Group/ ECST Collab. Group/ 1991, 1998 (398, 155) CE Trialists/2003 * Estimated using Kaplan–Meyer survival curves.
† Measured using narrowest diameter compared to normal upstream internal carotid diameter.
‡ Measured using narrowest diameter compared to estimated original carotid diameter.
¶ Stroke lasting ⬎7 days.
CEA ⫽ carotid endarterectomy; BMT ⫽ Best medical therapy.
of a collapsed internal carotid artery (ICA) distal to Surgery Trial (ACST).9-11 Two other studies were ei- the stenosis, faster filling in the external carotid ar- ther completed or planned but these were either tery compared to the ICA, and preferential filling of stopped prematurely (Mayo Clinic trial) or poorly de- the intracranial circulation via collaterals.
signed (Carotid Artery Stenosis with Asymptomatic CE was not beneficial for symptomatic patients Narrowing: Operation Vs Aspirin [CASANOVA] with 30 to 49% angiographic stenosis and surgery was harmful for symptomatic patients with ⬍30% The Mayo Asymptomatic Carotid Endarterectomy stenosis (2.2% absolute increase in stroke risk). In (MACE) study was prematurely stopped after only the combined analysis, the overall rate of periopera- 71 patients due to a high rate of myocardial infarc- tive stroke or death for all surgical patients within tion (22%) in the surgical group.12 This was likely 30 days of trial surgery was 7.1%, giving a number due to the trial policy of withholding aspirin from the needed to harm (NNH) of 14. As mentioned above, surgical group.
the robust benefits of future reduction in stroke risk The CASANOVA study had a suboptimal study for patients with severe stenosis and to a lesser ex- design and conduct.13 A total of 410 patients with 50 tent for patients with 50 to 69% stenosis justified the to 90% stenosis were enrolled. There was a high rate surgical risks.
of crossovers. A total of 17% of the surgical patients 2. Does CE benefit asymptomatic patients? never received a CE and 20% of the medical patients Three Class I studies are available: the Asymptom- were given a unilateral or bilateral CE. In addition, atic Carotid Atherosclerosis Study (ACAS), the Vet- there were many criteria for which medical patients erans Affairs Study, and the Asymptomatic Carotid could receive a CE, including progression of stenosis September (2 of 2) 2005
to ⬎90%. This deprived the study of the high risk benefited but there were only a total of 40 (12 vs 28 patients who were of greatest interest and confused strokes in the surgical and medical groups) non- the overall interpretation of the data.
perioperative strokes in women so the results were The Veterans Affairs study enrolled 444 men with not as definite (p ⫽ 0.02). The 5-year benefit of CE angiographically proven 50 to 99% asymptomatic appeared to be as great for those with ⬍80% diame- stenosis.10 There was a nonsignificant trend favoring ter reduction (mean 69% stenosis) as for those with CE for prevention of ipsilateral stroke (9.4% vs 4.7% 80 to 99% (mean 87%) reduction. There was no sig- at 4 years). However, this was a secondary endpoint.
nificant difference in results in those patients who The primary endpoint included TIA, which most cli- were never symptomatic (7.1% absolute 5-year gain) nicians consider as an inappropriate endpoint since, compared to those with symptoms greater than 6 by definition, TIA does not leave the patient with months previously (4.6% absolute 5-year gain).
any lasting clinical deficit. The 30-day perioperative A significant difference between ACAS and ACST stroke and death rate was 4.7%, equating to a NNH was the primary endpoint. ACAS and the previous symptomatic trials utilized ipsilateral stroke as the ACAS enrolled 1,662 patients with 60 to 99% ste- primary endpoint whereas ACST included all nosis with the stenosis defined angiographically for strokes, including contralateral events and vertebro- the surgical group and primarily with ultrasound for basilar strokes. If the ACST analysis was limited to the medical group.9 Patients were randomized to ipsilateral stroke only, the absolute benefit would be BMT or BMT ⫹ CE. The study was halted by the Data Safety and Monitoring Board after 2.7 years 3. Is emergent CE beneficial in patients with pro- median follow-up because of a projected 5.9% ARR at gressing stroke of ⬍24 hours? Four Class IV studies 5 years favoring CE (NNT ⫽ 17). The 5-year pro- were identified that met the criteria. In three of the jected rate of ipsilateral stroke was 11.0% for the studies, neurologic improvement was noted in 81 to medically treated patients and 5.1% for the surgi- 93% of patients who underwent emergent CE. At one cally treated patients (53% relative risk reduction, p institution, however, a postoperative stroke and ⫽ 0.004). For major ipsilateral stroke (defined as a death rate of 20% was reported for urgent CE. Over- Glasgow scale of 2 or higher) or any perioperative all, these studies were fairly small, lacked objective major ipsilateral stroke, the 5-year projected rates evaluation of the reported neurologic outcomes, and were 6.0% for the medically treated patients and one study was clouded by coexisting treatments in- 3.4% for the surgical patients (p ⫽ 0.12). The periop- cluding emergent thrombolysis.
erative stroke rate was 2.3%, providing a NNH of 43.
4. What are the most important clinical variables The very low perioperative stroke/death rate of 2.3% that impact the risk/benefit ratio? None of the iden- has not been achieved in most recent observational tified trials had clinical variables that impact risk/ studies or in the Aspirin and Carotid Endarterectomy benefit as predetermined endpoints. Two variables (ACE) trial (n ⫽ 1,512, stroke and death ⫽ 4.6%).14 that stand out in post hoc analyses are sex and na- The ACST was a randomized study of immediate ture of the presenting symptoms. In both the CE vs indefinite deferral of CE with a 5-year NASCET 50 to 69% group and in ACAS, there was follow-up at 126 centers in 30 countries. Determina- no benefit shown for CE in women. A subgroup anal- tion of stenosis was made by carotid ultrasound and ysis from NASCET also demonstrated that patients expressed as percent diameter reduction. Eligibility presenting with retinal ischemia (amaurosis fugax or included carotid artery diameter reduction of at least retinal infarction) have a lower subsequent stroke 60% on ultrasound and no symptoms within the past risk compared to patients with hemispheric events.15 6 months. Enrollment began in 1993 and continued In a pooled analysis of the three symptomatic stud- until 2003 and there is planned 10-year follow-up. A ies, the authors identified male sex (p ⫽ 0.003), age total of 3,120 patients were randomized, 1,560 into (p ⫽ 0.03), and study entry within 2 weeks of the last each group. Combining the perioperative events symptomatic event (p ⫽ 0.009) as modifiers of CE (stroke and death within 30 days) and the non- benefit,16 with the greatest benefit found in men, perioperative strokes, the net 5-year risks were 6.4% patients above age 75 years, and those randomized (immediate CE) vs 11.8% (deferred CE) for all within 2 weeks of their last symptomatic event.
strokes [net gain 5.4% (95% CI, 3.0 to 7.8) p ⬍ 5. What are the most important radiologic factors 0.0001] and 3.5% vs 6.1% for fatal or disabling that impact the risk/benefit ratio? strokes (Rankin ⬎ 2) [net gain 2.5% (0.8 to 4.3), p ⫽ studies addressed issues such as status of the con- 0.004]. The gain mostly involved non-perioperative tralateral carotid artery, angiographic appearance of carotid territory ischemic strokes [2.7% vs 9.5%; gain the ICA, and other factors. The highest level data of 6.8% (4.8 to 8.8), p ⬍ 0.0001)]. The benefit was regarding contralateral occlusion came from the seen in both contralateral and ipsilateral carotid- NASCET and ACAS studies. These analyses found territory strokes. Subgroup analyses showed that the that for symptomatic patients, if there is a contralat- benefits were significant for those younger than 65 eral occlusion, the surgical complication rate is years, those between 65 and 74 years, but uncertain higher than if the contralateral ICA is patent but for those older than 75 years. The study included there is still a better outcome compared to medical 2,044 men and 1,076 women. Men and women both management for patients with 70 to 99% stenosis.17 September (2 of 2) 2005
Table 3 Carotid endarterectomy (CE)– coronary artery bypass graft (CABG) studies
Simultaneous CE-CABG (n ⫽ 51) Staged CABG then CE (n ⫽ 84) Simultaneous CE-CABG (n ⫽ 52) Staged CE then CABG (n ⫽ 45) Simultaneous CE-CABG (n ⫽ 100) Simultaneous CE-CABG (n ⫽ 100) Simultaneous CE-CABG (n ⫽ 255 with Staged CE then CABG (n ⫽ 257 without Simultaneous CE-CABG (n ⫽ 304) Simultaneous CE-CABG (n ⫽ 408) Simultaneous CE-CABG (n ⫽ 340) Simultaneous CE-CABG (n ⫽ 313) Qualified studies on CE before or simultaneous with CABG.
* Statistical comparison between the two surgical groups of interest not reported.
MI ⫽ myocardial infarction; NR ⫽ not reported.
Conversely, for patients with asymptomatic stenosis, 7. What is the evidence/practice gap? Can trial if there is a contralateral occlusion, the only random- results be achieved in practice? Only studies with at ized evidence suggests that patients do slightly bet- least 100 patients were included in the final analysis.
ter with medical management (2.0% absolute Some previous publications have raised concerns increase in risk with CE at 5 years).18 that the CE results achieved in the clinical trials For patients with angiographic near-occlusion, the may not be reproducible in routine clinical practice.
pooled analysis of the symptomatic studies suggests This is referred to as the evidence/practice gap. To that CE is associated with a trend toward benefit at address this issue, 33 total articles within this cate- 2 years but no clear benefit at 5 years (1.7% trend gory were identified and 17 were excluded for the favoring medical treatment at 5 years).8 It should be reason mentioned above. Several methodologic short- recognized that BMT patients in NASCET with se- comings in these articles were identified, including vere stenosis, including those with near-occlusion, the following: inconsistency in the time horizon (in- were offered CE after the 2-year results were made patient vs 30 day results), inconsistency in the available. Only Class IV evidence or below was avail- method of reporting (self-report from one's own able for other factors such as influence of carotid records vs "vascular database" vs medical record au- siphon stenosis or posterior circulation stenosis.
dit), difficulty in drawing conclusions about symp- 6. What is the ideal dose of aspirin preoperatively tomatic status of the patients and degree of stenosis.
in patients undergoing CE? The ACE trial enrolled "Appropriateness" studies and studies on volume/ 2,849 subjects into a double-blind randomized clini- outcome relationships were also not well repre- cal trial comparing 81 mg, 325 mg, 650 mg, and sented. Due to the methodologic shortcomings in this 1,300 mg of aspirin, starting before carotid endarter- area, we recommend further high quality studies to ectomy, and continued for 3 months (Class I).14 The evaluate these issues in the future (see Future re- combined rate of stroke, myocardial infarction, and death was the primary outcome. This endpoint was 8. What are the data regarding CE concurrent with lower in the low-dose groups (81 mg and 325 mg) or prior to coronary artery bypass graft (CABG)? than in the high-dose groups (650 mg and 1,300 mg) The initial search identified 48 studies for review and 9 at 30 days (5.4 vs 7.0%, p ⫽ 0.07) and at 3 months of these met criteria for inclusion (50 or more subjects).
(6.2 vs 8.4%, p ⫽ 0.03). Another trial enrolled 232 There are no randomized clinical trials addressing this subjects to 75 mg aspirin or placebo started before question and the best available evidence comes from CE and continued for 6 months (Class I).19 Although retrospective case control (Class III) and case series likely underpowered, this trial demonstrated fewer (Class IV) reports (table 3). Some studies compared strokes without recovery in those subjects random- findings between groups with different surgical strate- ized to aspirin compared with placebo at 1 month gies, but because prospective criteria were not applied, (zero strokes vs 7 strokes, p ⫽ 0.003) and 6 months a selection bias is likely that precludes making defini- (2 strokes vs 11 strokes, p ⫽ 0.01).
September (2 of 2) 2005
Table 4 Timing of carotid endarterectomy
groups at baseline Retrospective, IV Comparable except Retrospective, IV Two institutions, Retrospective, II Retrospective, IV Retrospective, IV Greater vascular risk Retrospective, IV * ⬍4 wk, ⬎4 wk.
There were nine studies with 50 or more subjects None of the studies found any differences in the out- having simultaneous CE-CABG totaling 1,923 sub- comes in terms of operative morbidity and longer- jects. These studies included subjects with a combi- term follow-up. There were significant limitations in nation of stable and unstable coronary artery disease the designs of these studies. Only the NASCET sub- and symptomatic as well as asymptomatic carotid group analysis had randomized patient assignment.
artery disease. The carotid artery disease was usu- Three of the studies (references 117, 112, and 80 ally greater than 70% stenosis or there was an ulcer- from table 3) had differences in baseline characteris- ated plaque. The overall average perioperative tics between the group and adjustments were made complication rate is 3.0% stroke (range 0 to 9%), in terms of the outcome assessment. Finally, sample 2.2% myocardial infarction (range 0 to 6%), and 4.7% sizes were small across all studies.
death (range 2.6 to 8.9%). Three studies reported In the pooled analysis of the three symptomatic long-term survival and the 5- to 6-year survival CE studies, the Carotid Endarterectomy Trialists among 492 subjects ranged between 73 and 91%. In Collaboration found that patients who were random- the only study with more than 50 subjects where CE ized in the trials within 2 weeks of the last symptom- preceded the CABG, 257 patients with stable coro- atic event had greater benefit from CE.16 This nary artery disease were studied and the periopera- finding held up in both the severe (70 to 99%) steno- tive stroke rate was 1.9%, for myocardial infarction sis group and the 50 to 69% stenosis group. It should 4.7%, and for death 1.6%. Thus, the perioperative be reiterated, however, that only patients with TIA complication rates appear similar in CE before or or nondisabling stroke were enrolled in these trials.
simultaneous with CABG based on reports with ret- Perioperative morbidity and mortality. rospective data, although the death rates with com- I studies discussed above for patients with symptom- bined CE-CABG are higher than with CE alone.
atic and asymptomatic stenosis serve as a bench- 9. How long should one wait after a stroke to per- mark for desirable surgical results. In the severe It should be recognized that NASCET group with 70 to 99% stenosis in NASCET, the peri- and ECST excluded patients with no useful function operative stroke and death rate was 5.8%. In ACAS, in the ipsilateral carotid territory and randomization the stroke and death figure was 2.3%. In the pooled was delayed in patients who were drowsy or had analysis of the symptomatic studies, the stroke and significant edema on neuroimaging studies. There death rate was 7.1% and in the ACST, it was 3.1%.
have been six retrospective cohort studies comparing Based on these results and statements from other the timing of CE in patients after a stroke (table 4).
professional groups,20 recommendations are given be- Of these six studies, four studies were retrospective low for maximal acceptable levels of perioperative reviews from a single institution, one study included morbidity and mortality for CE in symptomatic and two institutions, and another study was a subgroup asymptomatic patients. Due to the importance of the analysis of the NASCET trial. The total sample sizes surgical complication rate in the risk/benefit equa- ranged from 45 to 201 subjects. The total number of tion, it is recommended that hospitals or government subjects included in the comparative analyses was regulatory bodies should provide risk adjusted CE 641, 307 in the early group and 334 in the late group.
morbidity and mortality data to referring physicians.
Four of the studies defined early surgery as less than6 weeks from the stroke and two studies defined 1. CE is established as effec- early surgery as less than 4 weeks from the stroke.
tive for recently symptomatic (within previous 6 September (2 of 2) 2005
months) patients with 70 to 99% ICA angiographic tient's last symptomatic event (Level C). There is stenosis (Level A). CE should not be considered for insufficient evidence to support or refute the perfor- symptomatic patients with less than 50% stenosis mance of CE within 4 to 6 weeks of a recent moder- (Level A). CE may be considered for patients with ate to severe stroke (Level U).
50 to 69% symptomatic stenosis (Level B) but theclinician should consider additional clinical and an- Recommendations for future research.
giographic variables (Level C, see below). It is recom- though the quality of data for CE decision making mended that the patient have at least a 5-year life has improved since the last statement from the expectancy and that the perioperative stroke/death American Academy of Neurology in 1990, our review rate should be ⬍6% for symptomatic patients (Level highlighted persisting areas of deficiency pertaining A). Medical management is preferred to CE for symp- to CE. Future research should address these areas, tomatic patients with ⬍50% stenosis (Level A).
including the setting of urgent CE in patients with 2. It is reasonable to consider CE for patients be- progressing stroke, the appropriateness of CE in tween the ages of 40 and 75 years and with asymp- community settings, the management of coexisting tomatic stenosis of 60 to 99% if the patient has an carotid and coronary artery disease, and the timing expected 5-year life expectancy and if the surgical of CE in patients with recent stroke. In addition, stroke or death frequency can be reliably docu- data are needed on newer antiplatelet agents in the mented to be ⬍3% (Level A). The 5-year life expect- ancy is important since perioperative strokes pose an There are several other important areas for fur- up front risk to the patient and the benefit from CE ther investigation pertaining to CE. One area of cur- emerges only after a number of years.
rent investigation is how CE compares to less 3. No recommendation can be provided regarding invasive, endovascular treatment with stenting in the value of emergent CE in patients with a pro- patients with symptomatic and asymptomatic ca- gressing neurologic deficit (Level U).
rotid stenosis.21 The Stenting and Angioplasty with 4. Clinicians should consider patient variables in Protection in Patients at High Risk for Endarterec- CE decision making. Women with 50 to 69% symp- tomy (SAPPHIRE) study reported improved out- tomatic stenosis did not show clear benefit in previ- comes in patients at high risk for surgery who were ous trials. In addition, patients with hemispheric treated with carotid stenting.22 In low to medium TIA/stroke had greater benefit from CE than pa- risk patients, the Carotid Revascularization Endar- tients with retinal ischemic events (Level C). Clini- terectomy vs Stent Trial (CREST) is comparing CE cians should also consider several radiologic factors vs carotid stenting in patients with symptomatic, 50 in decision making about CE. For example, con- to 99% angiographic stenosis.23 An amendment to tralateral occlusion erases the small benefit of CE in include patients with severe asymptomatic stenosis asymptomatic patients whereas in symptomatic pa- in CREST has recently been approved. Several other tients, it is associated with increased operative risk trials are in progress as well.
but persistent benefit (Level C). CE for patients with Also, the role of cerebral hemodynamics in risk angiographic near-occlusion in symptomatic patients stratification for patients with carotid stenosis was is associated with a trend toward benefit at 2 years not emphasized in the recent multicenter trials. It but not associated with a clear long-term benefit would be of great interest to examine indices of vaso- (Level C). Patients operated on within 2 weeks of reactivity and cerebral perfusion in future studies of their last TIA or mild stroke derive greater benefit patients with both symptomatic and asymptomatic from CE (Level C).
carotid stenosis.24 5. Symptomatic and asymptomatic patients un- Medical treatment for atherosclerosis has evolved dergoing CE should be given aspirin (81 or 325 mg/ considerably since the original CE trials. In studies day) prior to surgery and for at least 3 months such as NASCET and ECST, statins were not in following surgery to reduce the combined endpoint of widespread use and only a minority of patients was stroke, myocardial infarction, and death (Level A).
aggressively treated with lipid lowering agents. A Although data are not available, it is recommended panel of experts has recommended statins for pa- that aspirin (81 or 325 mg/day) be continued indefi- tients with a LDL of ⬎100 mg/dL and symptomatic nitely provided that contraindications are absent.
carotid stenosis or carotid stenosis of ⬎50%.25,26 Aspirin at 650 or 1,300 mg/day is less effective in the Other agents have also been approved for stroke pre- perioperative period. The data are insufficient to rec- vention such as newer antiplatelet agents and angio- ommend the use of other antiplatelet agents in the tensin receptor blockers. There is a paucity of data on stroke rates in patients with carotid stenosis who 6. At this time the available data are insufficient receive an aggressive treatment regimen with stat- to declare either CE before or simultaneous with ins, newer antiplatelet agents, and targeted blood CABG as superior in patients with concomitant ca- pressure lowering. Intensive medical therapy of this rotid and coronary artery occlusive disease (Level U).
type may erase the small benefit of CE in patients 7. For patients with severe stenosis and a recent with asymptomatic stenosis or 50 to 69% symptom- TIA or nondisabling stroke, CE should be performed atic stenosis.27 Studies to address this issue are without delay, preferably within 2 weeks of the pa- September (2 of 2) 2005
This statement is provided as an edu- 3. North American Symptomatic Carotid Endarterectomy Trial Collabora- cational service of the American Academy of Neurol- tors. Beneficial effect of carotid endarterectomy in symptomatic pa-tients with high-grade carotid stenosis. N Engl J Med 1991;325:445– ogy. It is based on an assessment of current scientific and clinical information. It is not intended to include 4. European Carotid Surgery Trialists' Collaborative Group. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final all possible proper methods of care for a particular results of the MRC European Carotid Surgery Trial (ECST). Lancet neurologic problem or all legitimate criteria for choosing to use a specific procedure. Neither is it 5. Mayberg MR, Wilson SE, Yatsu F, et al. Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis. Veter- intended to exclude any reasonable alternative ans Affairs Cooperative Studies Program 309 Trialist Group. JAMA methodologies. The AAN recognizes that specific pa- 6. Barnett HJ, Warlow CP. Carotid endarterectomy and the measurement tient care decisions are the prerogative of the patient of stenosis. Stroke 1993;24:1281–1284.
and the physician caring for the patient, based on all 7. Rothwell PM, Gutnikov SA, Warlow CP. Reanalysis of the final results of the circumstances involved.
of the European Carotid Surgery Trial. Stroke 2003;34:514–523.
8. Rothwell PM, Eliasziw M, Fox AJ, et al. , for the Carotid Endarterec- tomy Trialists' Collaboration. Analysis of pooled data from the random- ised controlled trials of endarterectomy for symptomatic carotidstenosis. Lancet 2003;361:107–116.
The committee thanks Drs. Chung Hsu and David Lefkowitz as 9. Executive Committee for the Asymptomatic Carotid Atherosclerosis liaisons from the TTA Subcommittee, Alison Nakashima, Paul Study. Endarterectomy for asymptomatic carotid stenosis. JAMA 1995; Hetland, Nancy King, and Wendy Edlund from the American Academy of Neurology for their assistance in coordinating the 10. Hobson RW, Weiss DG, Fields WS, et al. Efficacy of carotid endarterec- review, and Vicki Glasgow for assistance with the literature tomy for asymptomatic carotid stenosis. N Engl J Med 1993;328:221– 11. MRC Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group.
Prevention of disabling and fatal strokes by successful carotid endarter- Appendix 1
ectomy in patients without recent neurological symptoms: randomised Classification of evidence controlled trial. Lancet 2004;363:1491–1502.
12. Mayo Asymptomatic Carotid Endarterectomy Study Group. Effective- Class I: Prospective, randomized, controlled clinical trial with masked out-come assessment, in a representative population. The following are re- ness of carotid endarterectomy for asymptomatic carotid stenosis: de- sign of a clinical trial. Mayo Clin Proc 1992;64:897–904.
a) primary outcome(s) clearly defined 13. Carotid surgery versus medical therapy in asymptomatic carotid steno- b) exclusion/inclusion criteria clearly defined sis. The CASANOVA Study Group. Stroke 1991;22:1229–1235.
c) adequate accounting for drop-outs and cross-overs with numbers suf- 14. Taylor DW, Barnett HJM, Haynes RB, et al. Low-dose and high-dose ficiently low to have minimal potential for bias acetylsalicylic acid for patients undergoing carotid endarterectomy: a d) relevant baseline characteristics are presented and substantially randomised controlled trial. Lancet 1999;353:2179–2184.
equivalent among treatment groups or there is appropriate statisti- 15. Benavente O, Eliasziw M, Streifler JY, et al. Prognosis after transient cal adjustment for differences monocular blindness associated with carotid-artery stenosis. N EnglJ Med 2001;345:1084–1090.
Class II: Prospective matched group cohort study in a representative popu- 16. Rothwell PM, Eliasziw M, Gutnikov SA, Warlow CP, Barnett HJM, for lation with masked outcome assessment that meets a-d above OR a RCT in the Carotid Endarterectomy Trialists Collaboration.Endarterectomy for a representative population that lacks one criterion a-d.
symptomatic carotid stenosis in relation to clinical subgroups and tim- Class III: All other controlled trials (including well-defined natural history ing of surgery. Lancet 2004;363:915–924.
controls or patients serving as own controls) in a representative population, 17. Gasecki AP, Eliasziw M, Ferguson GG, et al. Long-term prognosis and where outcome is independently assessed, or independently derived by ob- effect of endarterectomy in patients with symptomatic severe carotid jective outcome measurement.
stenosis and contralateral carotid stenosis or occlusion: results from Class IV: Evidence from uncontrolled studies, case series, case reports, or NASCET. J Neurosurg 1995;83:778–782.
18. Baker WH, Howard VJ, Howard G, Toole JF, Investigators ftA.Effect of contralateral occlusion on long-term efficacy of endarterectomy in theAsymptomatic Carotid Atherosclerosis Study (ACAS). Stroke 2000;31: Appendix 2
Classification of recommendations 19. Lindblad B, Persson N, Takolander R, Bergqvist D. Does low-dose ace- tylsalicylic acid prevent stroke after carotid surgery? A double-blind, A ⫽ Established as effective, ineffective, or harmful for the given condition placebo-controlled randomized trial. Stroke 1993;24:1125–1128.
in the specified population. (Level A rating requires at least two con- 20. Biller J, Feinberg WM, Castaldo JE, et al. Guidelines for carotid endar- sistent Class I studies.) terectomy: A statement for healthcare professionals from a special writ- B ⫽ Probably effective, ineffective, or harmful for the given condition in the ing group of the Stroke Council, American Heart Association. Stroke specified population. (Level B rating requires at least one Class I study or at least two consistent Class II studies.) 21. CAVATAS Investigators. Endovascular versus surgical treatment in C ⫽ Possibly effective, ineffective, or harmful for the given condition in the patients with carotid stenosis in the Carotid and Vertebral Artery specified population. (Level C rating requires at least one Class IIstudy or two consistent Class III studies.) Transluminal Angioplasty Study (CAVATAS): a randomised trial. Lan- U ⫽ Data inadequate or conflicting given current knowledge, treatment is 22. Yadav JS, Wholey MH, Kuntz RE, et al. Protected carotid-artery stent- ing versus endarterectomy in high-risk patients. N Engl J Med 2004;351:1493–1501.
23. Hobson RW. CREST (Carotid Revascularization Endarterectomy versus Stent Trial): background, design, and current status. Semin Vasc Surg Therapeutics and Technology Assessment Subcommittee Members: DouglasS. Goodin, MD (Chair); Yuen T. So, MD, PhD (Vice-Chair); Carmel Armon, MD, MHS; Richard M. Dubinsky, MD, MPH; Mark Hallett, MD; David 24. Silvestrini M, Vernieri F, Pasqualetti P, et al. Impaired cerebral vaso- Hammond, MD; Cynthia Harden, MD; Chung Hsu, MD, PhD (ex-officio); reactivity and risk of stroke in patients with asymptomatic carotid Andres M. Kanner, MD (ex-officio); David S. Lefkowitz, MD; Janis Mi- artery stenosis. JAMA 2000;283:2122–2127.
yasaki, MD; Michael A. Sloan, MD, MS; James C. Stevens, MD.
25. Expert Panel on Detection Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of theNational Cholesterol Education Program (NCEP) Expert Panel on De- tection, Evaluation, and Treatment of High Blood Cholesterol in Adults 1. Interim assessment: carotid endarterectomy. Report of the American (Adult Treatment Panel III). JAMA 2001;285:2486–2497.
Academy of Neurology, Therapeutics and Technology Assessment Sub- 26. Grundy SM, Cleeman JI, Merz CNB, et al. Implications of recent clini- committee. Neurology 1990;40:682–683.
cal trials for the National Cholesterol Education Program Adult Treat- 2. Barnett HJM, Taylor DW, Eliasziw M, et al. Benefit of carotid endarter- ment Panel III Guidelines. Circulation 2004;110:227–239.
ectomy in patients with symptomatic moderate or severe stenosis. N 27. Chaturvedi S. Should the multicenter carotid endarterectomy trials be Engl J Med 1998;339:1415–1425.
repeated? Arch Neurol 2003;60:774–775.
September (2 of 2) 2005
Carotid endarterectomy—An evidence-based review: Report of the Therapeutics
and Technology Assessment Subcommittee of the American Academy of Neurology
S. Chaturvedi, A. Bruno, T. Feasby, R. Holloway, O. Benavente, S. N. Cohen, R. Cote, D. Hess, J. Saver, J. D. Spence, B. Stern and J. Wilterdink Neurology 2005;65;794-801 DOI: 10.1212/01.wnl.0000176036.07558.82 This information is current as of October 7, 2007
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