1. © 2005 American Academy of NeurologyFebruary 25, 2004 Assessment: Carotid Endarterectomy― An Evidence-Based Review Report 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

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3. © 2005 American Academy of NeurologyFebruary 25, 2004 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.

4. © 2005 American Academy of NeurologyFebruary 25, 2004 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.

5. © 2005 American Academy of NeurologyFebruary 25, 2004 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.

6. © 2005 American Academy of NeurologyFebruary 25, 2004 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.

7. © 2005 American Academy of NeurologyFebruary 25, 2004 AAN Strength of Evidence Class IClass 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

8. © 2005 American Academy of NeurologyFebruary 25, 2004 AAN Strength of Evidence Class IIIClass 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).

9. © 2005 American Academy of NeurologyFebruary 25, 2004 Translation of Evidence to Recommendation Level Level ALevel B Level A = Established as useful/predictive or not useful/predictive for the given condition in the specified population Level 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 population Level B rating requires at least one convincing class II study or at least three consistent class III studies

10. © 2005 American Academy of NeurologyFebruary 25, 2004 Translation of Evidence to Recommendation Level Level CLevel U Level C = Possibly useful/predictive or not useful/predictive for the given condition in the specified population Level 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

11. © 2005 American Academy of NeurologyFebruary 25, 2004 Clinical Question Does CE benefit symptomatic and asymptomatic patients?

12. © 2005 American Academy of NeurologyFebruary 25, 2004 Analysis of the Evidence Symptomatic patients Author/ YearIpsilateral 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% 12.6 27.6 8.0% 18.1% ECST Collab. Group 1991 Stenosis= 70-99% CE+BMT=9.5% BMT = 13.6% 7.5% NA 3.7% NA 4.8% 8.4% BMT = best medical therapy

13. © 2005 American Academy of NeurologyFebruary 25, 2004 Author/ YearIpsilateral Stroke risk plus periop stroke & death Periop stroke & death Periop disabling stroke & death Any stroke Major stroke or death Mayberg 1991 Stenosis= 50-99% CE + BMT=4.4% BMT=7.1% 6.5% 2.2% 4.4% 0% NA ECST Collab. Group 1996 Stenosis= 50-69% CE + BMT=NA BMT=NA NA 7.9%16.8% 14.2% NA NASCET collab.1998 Stenosis= 50-69% CE + BMT=1.9% BMT=7.0% 22.2% 15.7% NA 19.8% 26.4% 14.9% 20.1% Analysis of the Evidence Symptomatic patients

14. © 2005 American Academy of NeurologyFebruary 25, 2004 Author/ YearIpsilateral Stroke risk plus periop stroke & death Periop stroke & death Periop disabling stroke & death Any stroke Major stroke or death ECST Collab. Group 1996 Stenosis= 30-49% CE + BMT=NA BMT=NA NA 8.0% NA 16.2% 10.4% NA ECST Collab. Group 1991, 1998 Stenosis= 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 Analysis of the Evidence Symptomatic patients

15. © 2005 American Academy of NeurologyFebruary 25, 2004 Clinical Question Does CE benefit asymptomatic patients?

16. © 2005 American Academy of NeurologyFebruary 25, 2004 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

17. © 2005 American Academy of NeurologyFebruary 25, 2004 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

18. © 2005 American Academy of NeurologyFebruary 25, 2004 Analysis of the Evidence Asymptomatic 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

19. © 2005 American Academy of NeurologyFebruary 25, 2004 Analysis of the Evidence Asymptomatic patients 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%

20. © 2005 American Academy of NeurologyFebruary 25, 2004 Analysis of the Evidence Asymptomatic patients 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%)

21. © 2005 American Academy of NeurologyFebruary 25, 2004 Analysis of the Evidence Asymptomatic patients 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

22. © 2005 American Academy of NeurologyFebruary 25, 2004 Analysis of the Evidence Asymptomatic patients Asymptomatic Carotid Surgery Trial (ACST) –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

23. © 2005 American Academy of NeurologyFebruary 25, 2004 Analysis of the Evidence Asymptomatic patients Asymptomatic Carotid Surgery Trial (ACST) –Subgroup analyses showed benefits were significant 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)

24. © 2005 American Academy of NeurologyFebruary 25, 2004 Clinical Question Is emergent CE beneficial in patients with progressing stroke of <24 hours?

25. © 2005 American Academy of NeurologyFebruary 25, 2004 Analysis of the Evidence Emergent 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

26. © 2005 American Academy of NeurologyFebruary 25, 2004 Clinical Question What are the most important clinical variables that impact the risk/benefit ratio?

27. © 2005 American Academy of NeurologyFebruary 25, 2004 Analysis of the Evidence Clinical 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

28. © 2005 American Academy of NeurologyFebruary 25, 2004 Clinical Question What are the most important radiologic factors that impact the risk/benefit ratio?

29. © 2005 American Academy of NeurologyFebruary 25, 2004 Analysis of the Evidence Radiologic 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)

30. © 2005 American Academy of NeurologyFebruary 25, 2004 Analysis of the Evidence Radiologic 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.

31. © 2005 American Academy of NeurologyFebruary 25, 2004 Clinical Question What is the ideal dose of aspirin preoperatively in patients undergoing CE?

32. © 2005 American Academy of NeurologyFebruary 25, 2004 Analysis of the Evidence Aspirin 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

33. © 2005 American Academy of NeurologyFebruary 25, 2004 Analysis of the Evidence Aspirin 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

34. © 2005 American Academy of NeurologyFebruary 25, 2004 Clinical Question What are the data regarding CE concurrent with or prior to CABG?

35. © 2005 American Academy of NeurologyFebruary 25, 2004 Analysis of the Evidence CABG 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.

36. © 2005 American Academy of NeurologyFebruary 25, 2004 Analysis of the Evidence CABG Author/ YearGroupPeriop stroke % Periop MI % Periop death % Long- term survival Ennix, 1979 Class III Simultaneous CE-CABG 03.95.9NR Ennix, 1979 Class III Staged CABG then CE 02.41.2NR Carrel, 1992 Class III Simultaneous CE-CABG 1.903.891 at 6 yrs Carrel, 1992 Class III Staged CE then CABG 08.84.487 at 6 yrs Takach, 1997 Class III Simultaneous CE-CABG 3.94.73.5NR Takach, 1997 Class III Staged CE then CABG 1.94.71.6NR

37. © 2005 American Academy of NeurologyFebruary 25, 2004 Analysis of the Evidence CABG Author/ YearGroupPeriop stroke % Periop MI % Periop death % Long- term survival Hertzer, 1997 Class IV Simultaneous CE-CABG 4.305.3NR Kaul, 2000 Class IV Simultaneous CE-CABG 1.4 within 3 Months NA3.4NR Minami, 2000 Class IV Simultaneous CE-CABG 3.20.62.679 at 5 yrs Evageloupoulos, 2000 Class IV Simultaneous CE-CABG 2.23.28.9NR

38. © 2005 American Academy of NeurologyFebruary 25, 2004 Clinical Question How long should one wait after a stroke to perform CE?

39. © 2005 American Academy of NeurologyFebruary 25, 2004 Analysis of the Evidence Time 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.

40. © 2005 American Academy of NeurologyFebruary 25, 2004 Recommendations Use 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).

41. © 2005 American Academy of NeurologyFebruary 25, 2004 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.

42. © 2005 American Academy of NeurologyFebruary 25, 2004 Recommendations Patient Variables to Consider in Carotid Endarterectomy Decision-making Patient variables 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).

43. © 2005 American Academy of NeurologyFebruary 25, 2004 Recommendations Radiologic Factors to Consider in Carotid Endarterectomy Decision-making Radiologic FactorsRecommendation 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).

44. © 2005 American Academy of NeurologyFebruary 25, 2004 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.

45. © 2005 American Academy of NeurologyFebruary 25, 2004 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).

46. © 2005 American Academy of NeurologyFebruary 25, 2004 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.

47. © 2005 American Academy of NeurologyFebruary 25, 2004 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.

48. © 2005 American Academy of NeurologyFebruary 25, 2004 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.

49. © 2005 American Academy of NeurologyFebruary 25, 2004 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.

50. © 2005 American Academy of NeurologyFebruary 25, 2004 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

51. © 2005 American Academy of NeurologyFebruary 25, 2004 To view the entire guideline and additional AAN guidelines visit: www.aan.com/guidelines Published in Neurology 2005;65:794-801