Carotid Endarterectomy versus Stenting: Where do we stand today?

1. Carotid Endarterectomy versus Stenting:Where do we stand today? Vascular Conference March 23, 2010

2. Landmark NIH Clinical Trial Comparing Two Stroke Prevention Procedures Shows Surgery and Stenting Equally Safe and Effective Opportunities Exist to Target the Treatment to the Patient ASA: Stenting Carotid on a Par with Endarterectomy SVS Responds to the Role of Carotid Studies, CREST and ICSS, in Stroke Prevention

3. Cerebrovascular disease affects 750,000 people in US each year Stroke is 3rd leading cause of death in North America 168,000 deaths in US/year Treatment: Medical therapy Aspirin, plavix, statins Risk factor modification Carotid Endarterectomy (CEA) Carotid artery stenting (CAS) Carotid Artery Atherosclerotic Disease

4. Randomized trial of CEA vs anti-platelet therapy 50 centers in US and Canada 1987-1996 659 patients with stenosis >70% 2226 patients with stenosis < 70% Patients: <80 years old Non-disabling stroke or retinal or hemispheric TIA within 120 days Exclusion: Disease limiting life expectancy to <5 years Carotid artery stenosis: 30-69% or 70-99% Defined by angiography Medical treatment: Anti-thrombotic medication Mostly aspirin (dose not specified) Anti-hypertensive and lipid lowering agents at the discretion of the treating physician Surgical treatment: Medical treatment as above CEA Peri-operative stroke or death: Net increase in surgical risk of any stroke or death of 4.3% 1.4% net increase in disabling stroke or death Long-term Result: 70-99% group: CEA had 17% absolute risk reduction for stroke at 2 years 50-69% group: CEA had a 7% absolute risk reduction at 5 years 30-49% group: No difference Conclusions: CEA recommended for symptomatic carotid artery stenosis of 70-99% In centers with low peri-operative stroke rate and in select patients, CEA can be utilized for symptomatic stenosis of 50-69% North American Symptomatic Carotid Endarterectomy Trial (NASCET) NEJM 1991 & 1998

5. Randomized trial of CEA vs anti-platelet therapy 39 centers in US and Canada 1988-1993 1662 patients Patients Age 40-79 Exclusion criteria: Severe comorbidities disease likely to cause death w/in 5 yrs Any cerebrovascular event Contra-indication to aspirin Carotid artery stenosis >60% stenosis Defined by angiography or doppler US Same angiographic definition as NASCET Medical treatment: 325mg aspirin daily Recommendations on risk factor reduction No angiography required Surgical treatment: Aspirin & risk reduction Angiography required CEA Peri-operative risk of stroke or death: Surgery: 2.3% 5 strokes secondary to angiography Medical: 0.4% 5-year results: 6% absolute risk reduction for stroke Conclusions: CEA recommended for patients with > 60% stenosis In centers with low peri-operative mortality and stroke rates (<3%) In patients with good overall health Asymptomatic Carotid Atherosclerosis Study (ACAS) JAMA 1995

7. Prospective non-randomized cohort study 14 centers in US 397 patients 254 CEA, 143 CAS Standard CEA versus CAS with cerebral protection device Patients: Similar patient demographics 68% asymptomatic >90% with >75% stenosis Significantly more prior CEA or stent in the CAS arm Peri-operative stroke or death: CEA: 2.4% CAS: 2.1% 4 year follow up results: Any stroke: CEA 9.6%, CAS 8.6% Death/ non-fatal stroke: CEA 26.5%, CAS 21.8% Restenosis: Significantly higher in CAS arm Conclusion: Proof of principle that CAS with distal protection should be compared to CEA in a broad patient sample in a randomized trial Carotid Revascularization Using Endarterectomy or Stenting Systems (CaRESS) J Endovasc Ther 2003 & 2009

8. Principle: The NASCET and ACAS trials exclude high risk patients These patients are being operated on in clinical practice Multi-center randomized trial 29 centers 334 patients randomized Patients: Patients were randomized if the team agreed that either CEA or CAS was appropriate At least one comorbidity that would deem them high risk for CEA Duplex US: Symtomatic patients: >50% Asymptomatic patients: >80% Procedures: All patients started on aspirin Plavix: CAS: plavix 24hrs pre-op & for 2-4wks CEA: No plavix CAS: Nitinol stent with distal cerebral protection device CEA: Not standardized Results: Primary end point (death/ stroke/ MI at 30 days or death from neurologic cause w/in 1 yr) CAS 12% vs. CEA 20.1% (p=0.05) Conventional end-point (as above subtracting MI data) No difference Conclusion: CAS is not inferior to CEA for patients considered high risk for CEA Protected Carotid-Artery Stenting versus Endarterectomy in High-Risk Patients (SAPPHIRE) NEJM 2004

9. Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Senting Study) • Randomized controlled trial multicenter trial • 50 centers from Europe/ Australia/ Canada/ New Zealand • 1713 patients randomized • Patients: • Included if >50% stenosis w/ symptoms attributable to the carotid disease • Exclusion: • Massive stroke • Previous CEA or stent on affected side • Planned CABG or other surgery or contraindication to treatment • Treating physicians had to agree that either method would be suitable • Procedures: • CAS: • Any trademarked device could be used • Embolic protection device recommended but not mandatory • Use of aspirin/ plavix and heparinization recommended • CEA: • Technique at the discretion of surgeon Lancet 2010

10. Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Senting Study) Outcomes between initiation of treatment and 30 days Outcomes between randomization of treatment and 120 days

12. Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Senting Study) • Conclusions: • Carotid endarterectomy is safer than carotid stenting in patients being treated for symptomatic carotid artery stenosis • 3.3% higher risk of stroke, death, or procedural MI within 120 days • This is mainly due to a higher risk of non-disabling strokes • Rate of disabling stroke or death not significantly different • More cranial nerve palsy and hematoma formation in CEA group

13. Multi-center randomized trial comparing CEA to CAS in severe carotid stenosis 117 sites in North America 2522 patients randomized Patients: Symptomatic with >50% by angio or >70% by US/ CTA/ MRI Asymptomatic with >60% by angio, >70% by US, or >80% by CTA/ MRI High risk patients remain eligible for the study; however, 4 year life expectancy required Octogenarians excluded in mid-trial due to stroke/ death rate Outcomes released in press release form Composite endpoint (stroke, death, or MI w/in 30 days) CEA 6.8%, CAS 7.2% Any stroke w/in 30 days: CEA 2.3%, CAS 4.1% Major stroke < 1% for both MI CEA 2.3%, CAS 1.1% MI resulted in better quality of life than stroke Ipsilateral stroke w/in 2 yrs Equivalent CEA 2.4%, CAS 2.0% The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) J Stroke & Cerebrovasc Dis 2010, Stroke 2010

14. Conclusions • Carotid endarterectomy has been established as the gold standard for treatment of carotid artery stenosis • NASCET and ACAS trials • Carotid stenting remains to be proven as a viable alternative to endarterectomy in all patients • SAPPHIRE results suggest that CAS is at least equivalent to CEA in high risk patients • ICSS results suggest that CAS may cause higher peri-operative morbidity in symptomatic patients • CREST results suggest equivalency of CAS to CEA for all patients with carotid stenosis for composite endpoint of death / stroke/ MI • However, stroke is more common in CAS, and has a greater impact on quality of life, that MI

15. Future Directions • NASCET and ACAS studies compared CEA to “best medical treatment” • Aspirin utilized in both • Plavix and statins used at the discretion of the treating physician • Statins in only 14% of patients in NASCET • Statins have subsequently been associated with decreased incidence of stroke • 29% relative reduction in stroke in one large meta-analysis • JAMA 1997 • Risk ratio of 0.82 [95% CI 0.76 – 0.90] for fatal or non-fatal stroke in another large meta-analysis • Am J Med 2004 • Future studies needed to re-assess CEA and CAS in light of optimal medical management

16. References • Barnett et. al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. NEJM 1998; 339: 1415-1425. • Briel et. al. Effects of statins on stroke prevention in patients with and without coronary heart disease: a meta-analysis of randomized controlled trials. Am J Med 2004; 117(8): 596-606. • CaRESS Steering Committee. Carotid Revascularization Using Endarterectomy or Stenting Systems (CaRESS): Phase I Clinical Trial. J Endovasc Ther 2003; 10: 1021-1030. • Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic Carotid Artery Stenosis. JAMA; 273(18): 1421-1428. • Hebert et al. Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials. JAMA 1997; 278(4): 313-321. • Hopkins et. al. The Carotid Revascularization Endarterectomy versus Stenting Trial: Credentialling of Interventionalists and Final Results of Lead-in Phase. Journal of Cerebrovascular Diseases 2010; 19(2): 153-162 • International Carotid Stenting Study Investigators. Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Senting Study): an interim analysis of a randomized controlled trial. Lancet 2010; 375: 985-997 • North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effects of carotid endarterectomy in symptomatic patients with high grade carotid stenosis. NEJM 1991; 325: 445-453. • Sheffet et al. Design of the Carotid Revascularization Endarterectomy versus Stenting Trial. Stroke 2010; 5: 40-46. • Yadev et al. Protected Carotid-Artery Stenting versus Endarterectomy in High-Risk patients. NEJM 2004; 351: 1493-1501. • Zarin et al. Carotid Revascularization Using Endarterectomy or Stenting Systems (CaRESS): Four year outcomes. J Endovasc Ther 2009; 16: 397-409.