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

2. © 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)

3. © 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.

4. © 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.

5. © 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.

6. © 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

7. © 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).

8. © 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

9. © 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

10. © 2005 American Academy of NeurologyFebruary 25, 2004 Clinical Question Does CE benefit symptomatic and asymptomatic patients?

11. © 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

12. © 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

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 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

14. © 2005 American Academy of NeurologyFebruary 25, 2004 Clinical Question Does CE benefit asymptomatic patients?

15. © 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

16. © 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

17. © 2005 American Academy of NeurologyFebruary 25, 2004 Analysis of the Evidence Asymptomatic patients Asymptomatic Carotid Atherosclerosis Study (ACAS) –5 year projected rate of ipsilateral stroke medically treated patients 11.0% surgically treated patients 5.1% relative risk reduction 53%

18. © 2005 American Academy of NeurologyFebruary 25, 2004 Clinical Question Is emergent CE beneficial in patients with progressing stroke of <24 hours?

19. © 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

20. © 2005 American Academy of NeurologyFebruary 25, 2004 Clinical Question What are the most important clinical variables that impact the risk/benefit ratio?

21. © 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

22. © 2005 American Academy of NeurologyFebruary 25, 2004 Clinical Question What are the most important radiologic factors that impact the risk/benefit ratio?

23. © 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)

24. © 2005 American Academy of NeurologyFebruary 25, 2004 Clinical Question What is the ideal dose of aspirin preoperatively in patients undergoing CE?

25. © 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

26. © 2005 American Academy of NeurologyFebruary 25, 2004 Clinical Question How long should one wait after a stroke to perform CE?

27. © 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.

28. © 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).

29. © 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.

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

31. © 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).

32. © 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.

33. © 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).

34. © 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

35. © 2005 American Academy of NeurologyFebruary 25, 2004 COMMENT THANK YOU Published in Neurology 2005;65:794-801