Anthony J. Comerota, MD, FACS, FACC Carotids Are We There Yet? Anthony J. Comerota, MD, FACS, FACC Jobst Vascular Center Toledo, Ohio USA Adjunct Professor of Surgery, University of Michigan

Anthony J. Comerota, MD, RVT DISCLOSURES Anthony J. Comerota, MD, RVT Consulting Fees Aastrom, Cook Medical, Covidien, Bristol-Myers Squibb, sanofi-aventis U.S. LLC, Talecris Biotherapeutics, Inc. Honoraria Bristol-Myers Squibb, Covidien, Otsuka, sanofi-aventis U.S. LLC, Servier, ZymoGenetics Grants/Contracted Research Aastrom Biosciences, Inc., Abbott Vascular, Baxter Healthcare, Bristol-Myers Squibb, Boehringer Ingelheim, BSN, Colorado Prevention Center, CVRx, ev3, Inc., Lombard Medical, Medtronic CardioVascular, Inc., National Institutes of Health, Pfizer, sanofi-aventis U.S. LLC, Schering-Plough Corp. / Merck & Co., Inc., Talecris Biotherapeutics, Inc.

Stroke Brain Infarction Can this be avoided? What are the data?

Carotid Artery Disease

When should this plaque be removed? Symptomatic Carotid Lesion Hemispheric Stroke or TIA Ulcer Subintimal Hemorrhage When should this plaque be removed? Luminal Thrombus (platelet-rich)

Early Carotid Endarterectomy Questions What is the purpose of CEA? To prevent a Stroke! Who is at greatest risk? Patients with symptomatic lesions, especially stroke! When is the patient at greatest risk of stroke? Soon after the first ischemic event! Do we need to reassess the risk of stroke from asymptomatic carotid disease? First Slide after Title Slide only (or first slide with title)! Use only once. For sure!

Current preoccupation… Carotid Artery Disease Fact Current preoccupation… Treat vast number of ASX patients Assume that… All 60-99% ASX carotid stenosis identified All Rx’ed with ≤ 2.3% procedure risk …Outcome… Will do little to reduce overall burden of stroke …97% of strokes will still occur!! Naylor AR Eur J Vas Endovas Surg 2008;35:383

Risk of Stroke After TIA or Minor Stroke Recurrent Stroke 70% of strokes after symptomatic disease occurred within 14 days 80% of those…within 4 days Strokes clustered soon after TIA/Stroke Coull A et al BMJ 2004;328:326-328

Soon After The Initial Event! Early Carotid Endarterectomy Acute Stroke When is the patient at higher risk for recurrence? Soon After The Initial Event! First Slide after Title Slide only (or first slide with title)! Use only once.

Symptomatic Carotid Disease Acute Stroke Why are there proponents of delayed intervention? Fear… Hemorrhagic conversion… Procedure related stroke… First Slide after Title Slide only (or first slide with title)! Use only once. Any Data to Justify this Fear?

No increased morbidity from early CEA Early Carotid Endarterectomy Acute Stroke Early vs. Late Days to CEA Stroke Rate Whittemore et al 11 0 Rosenthal et al <3 weeks 3% Sbarigia et al 1.5 days 0% Alesic et al 4 days 6% Ballotta et al <30 days 2% Paty et al 1 week 2.8% * First Slide after Title Slide only (or first slide with title)! Use only once. * 3% had symptomatic deterioration but unchanged CT No increased morbidity from early CEA

228 patients with acute stroke having CEA within 4 weeks Early Carotid Endarterectomy:21 Year Review Acute Stroke 228 patients with acute stroke having CEA within 4 weeks Results Interval (weeks) 0-1* 1-2 2-3 3-4 Op stroke 2.8% 3.4% 3.4% 2.6% First Slide after Title Slide only (or first slide with title)! Use only once. 71% op strokes due to thrombosed ICA Only one hemorrhage Significantly greater NIHSS score Paty PSK, et al J Vasc Surg 2004;39:148

Early Carotid Endarterectomy Ischemic Stroke: Prospective Study 96 patients having very early CEA after completed stroke Protocol: NIHSS ≤22 Brain infarct <2/3 MCA territory Carotid stenosis Mean time to CEA 1.5 days 50% within 24 hrs 98% within 1 week 60% had CT infarct @ time of CEA First Slide after Title Slide only (or first slide with title)! Use only once. Sbargia E et al Eur J Vasc Endovasc Surg 2006;32:22

96 patients having very early CEA after completed stroke Early Carotid Endarterectomy Ischemic Stroke: Prospective Study 96 patients having very early CEA after completed stroke Results 30-day morbidity/mortality 7.3% 2 deaths: Heart Failure Aspiration Worsening neuro status 3.1% No new infarcts on CT scan No intracranial hemorrhage First Slide after Title Slide only (or first slide with title)! Use only once. Sbargia E et al Eur J Vasc Endovasc Surg 2006;32:22

YES! Symptomatic Carotid Disease Consistent Observations Delaying therapy expose patient to unnecessary risk! No increased risk of early CEA… Stroke Intracranial hemorrhage First Slide after Title Slide only (or first slide with title)! Use only once. However… …has risk of delayed CEA or benefit of early CEA been quantified? YES!

Strokes Prevented at 5 Years Carotid Endarterectomy Trialists Collaboration Symptomatic Patients: NASCET & ECST Stenosis N CEA Risk 5 Year Risk Surg Med RRR NNT Strokes Prevented at 5 Years (1000 CEA’s) <30% 1746 18.4% 15.7% - None 30-49% 1429 6.7% 22.4% 25.5% 10% 38 26 50-69% 1549 8.4% 20.0% 27.8% 28% 13 78 70-99% 1095 6.2% 17.1% 32.7% 48% 6 156 String 262 5.4% 22.3% 0% Lancet 2004 Stroke 2004

Pooled data from NASCET and ECST CEA for Symptomatic Carotid Stenosis Timing of Procedure Pooled data from NASCET and ECST 5,893 patients 33,000 patient years of follow-up Benefit of CEA Males P =0.003 Age ≥75 P =0.03 <2 weeks from event P =0.009 First Slide after Title Slide only (or first slide with title)! Use only once. Rothewell PM et al Lancet 2004;363:915

Strokes prevented at 5 years/1000CEAs Symptomatic Carotid Disease ARR of Ipsilat Ischemic Stroke at 5yrs by CEA Stratified by Time to Randomization Strokes prevented at 5 years/1000CEAs Symptomatic Carotid Disease All 50-99% Stenosis Time to Randomization ARR NNT CVA/1000* < 2 Weeks 18.5 5 185 2 - 4 Weeks 9.8 10 98 4 - 12 Weeks 5.5 18 55 > 12 Weeks 0.8 125 8 Waiting ≥ 4 weeks reduces benefit by 70% Naylor AR Eur J Vas Endovas Surg 2008;35:383

Strokes prevented at 5 years/1000CEAs Symptomatic Carotid Disease ARR of Ipsilat Ischemic Stroke at 5yrs by CEA Stratified by Time to Randomization Strokes prevented at 5 years/1000CEAs Symptomatic Carotid Disease All 70-99% Stenosis Time to Randomization ARR NNT CVA/1000* < 2 Weeks 23.0 4 230 2 - 4 Weeks 15.9 6 159 4 - 12 Weeks 7.9 13 79 > 12 Weeks 7.4 14 74 Waiting ≥ 4 weeks reduces benefit by 66% Naylor AR Eur J Vas Endovas Surg 2008;35:383

CEA for Symptomatic Carotid Stenosis Timing of Procedure Pooled data from NASCET and ECST Number of patients requiring CEA to prevent one stroke in 5 years Subgroup NNT CEA < 2 weeks 5 Age ≥75 5 Males 9 Age <65 18 Women 36 CEA at 6 weeks 62 CEA ≥12 weeks 125 No signal that hemorrhage occurred… …only benefit to early CEA! First Slide after Title Slide only (or first slide with title)! Use only once. Rothewell PM et al Lancet 2004;363:915

Symptomatic Carotid Disease 61 yo. man with nondisabling stroke and carotid stenosis (NASCET patient) How long would you wish to wait after a stroke to have this lesion removed?

Symptomatic carotid artery disease should be treated as a Symptomatic Carotid Disease Symptomatic carotid artery disease should be treated as a Vascular Emergency!

Non Disabling Stroke/TIA Carotid Endarterectomy (within 48 hours) Symptomatic Carotid Disease Non Disabling Stroke/TIA Carotid Duplex CT/MRI Brain ≥50% Carotid Stenosis …and… ≤67% MCA Territory Infarct URGENT CEA PROTOCOL • ASA 81mg • Clopidogrel 600mg • Atorvastatin 80mg • Glucose ≤ 120 • BP ≤ 135/85 Carotid Endarterectomy (within 48 hours)

Asymptomatic Carotid Disease Optimal Treatment Question: Is risk of stroke from asymptomatic carotid disease changing?

Asymptomatic Carotid Artery Disease Principles of Care! Caveat #1 Any procedure offered to patients should reduce the risk of a stroke… … compared to best medical care. Caveat #2 If procedure related-stroke/death is not less than best medical care… … procedure should not be performed. Are these reasonable?

Treated an average of 17 years ago ACAS: Asymptomatic Atherosclerosis Procedure Related Stroke/Death and Stroke to 5 Years Randomized 42 Days 5 Years Treated an average of 17 years ago CEA 2.3% 5.1% MED Rx 0.4% 11.0% JAMA 1995; 273:1421

5 Year Risk of Cerebral Events RRR: Approx 30-50% for stroke endpoints Asymptomatic Carotid Stenosis Randomized Trials 5 Year Risk of Cerebral Events ACAS ACST BMT CEA ARR Ipsilat Stroke 11.0% 5.1% 5.9% 4.4% 1.1% Any Stroke 17.5% 12.4% 11.8% 6.4% 5.4% Major Stroke 9.1% 2.7% 6.1% 3.5% 2.6% RRR: Approx 30-50% for stroke endpoints Naylor A R et al EJVES 2009.01.026 (epub 4/09)

1000 CEA’s with procedural risk - 2.3% Asymptomatic Carotid Disease Patient Implications 1000 CEA’s with procedural risk - 2.3% …will prevent 59 ipsilateral strokes in 5 years (according to medical risk 15-20 years ago) ACAS JAMA 1995; 273:1421

Asymptomatic Carotid Disease Observation If it were possible to identify and operate on all asymptomatic 60 - 99% stenoses… …with a procedural risk of 2.3% …fewer than 5% of all strokes would be prevented Naylor A R Surgeon 2007; 5:23 Hankey G J Med J Aust 1995; 163:197

Asymptomatic Carotid Disease Randomized Trials ACAS & ACST Relationship of carotid stenosis to stroke None Benefit to women None* *unless operative stoke/death were excluded JAMA 1995 Lancet 2004

Randomized Trials: Asymptomatic Disease Risk of Stroke: Medical Care No definition of “best medical care” No defined pharmacotherapy No treatment targets Therefore … this was not “best” medical Rx … … and probably not good medical Rx!

Asymptomatic Carotid Disease Risk of Stroke and Medical Rx Has the risk of stroke and death from atherosclerotic carotid artery disease decreased in the past 15-20 years? …If yes, we cannot accept historical medical controls for comparators to today’s procedures. Therefore…the current controversy regarding management of asymptomatic carotid disease

135,701 Carotid Revascularizations Carotid Procedures in the USA 2005 135,701 Carotid Revascularizations 90% CEA 92% Asymptomatic 10% CAS 8% Symptomatic McPhee J T et al J Vasc Surg 2005; 48:1442

Extrapolating ACAS to 2005 (Same Medical Risk) Carotid Endarterectomy in the USA Extrapolating ACAS to 2005 (Same Medical Risk) 122,986 Procedures (2.3% Procedural Risk) 7,256 Strokes Prevented at 5 Years …but Conversely 115,730 Unnecessary Procedures 21 billion dollars on unnecessary procedures $369,685 to prevent any stroke in 5 years McPhee J T et al J Vasc Surg 2005; 48:1442

Carotid Endarterectomy in the USA US Multistate CEA Audit Procedural Risk (Stroke/Death) - 3.8% “? Real-World Results” 44 ipsilateral strokes prevented per 1000 procedures at 5 years 5,411 strokes prevented from 122,986 procedures $428,510 per stroke prevented Based on medical Rx 20 years ago Kresowik T F J Vasc Surg 2004; 39:372

Asymptomatic Carotid Disease What evidence is there that improvements in medical therapy are reducing the annual stroke risk?

Asymptomatic Carotid Disease Randomized Trials Best Medical Care ACAS - No data re: Changing trends in therapy, compliance or medical outcome ACST - Considerable data on changes in medical Rx during the 10 year trial ie: Statins… 17% - 1996 58% - 2000 70% - 2003 90% - 2008 JAMA 1995 Lancet 2004

* = derived from oral presentations of the 10-year ACST data Asymptomatic Carotid Disease ACAS and ACST: Medical Care Temporal changes in the 5-year risk of “any” stroke and “ipsilateral” stroke Stroke Trial Years Pub Year ‘Any’ ‘Ipsilateral’ ACAS 1 - 5 1995 17.5% 11.0% ACST 2004 11.8% 5.3%* 6 - 10 2009 7.2% 3.6%* * = derived from oral presentations of the 10-year ACST data Naylor A R J.EJVS 2009.01.026

Carotid Artery Disease Current Best Medical Care Includes: Platelet inhibition Statins Ace inhibitors/ARBS Control of hypertension Glucose control Diet Exercise Smoking cessation

Effects of Platelet Inhibition Stroke and TIA Effects of Platelet Inhibition 22% reduction of stroke/MI/death with platelet inhibition (18 trials) …32% reduction with low-dose ASA Antiplatelet Trialists Collaboration BMJ 1994 BMJ 2002 DYP/ASA vs. Placebo – 37% RRR of stroke DYP/ASA vs. ASA – 23% RRR of stroke (p<.001) (p=.006) J Neurological Sciences 1996;143:1 Significant reduction of stroke in high risk patients with ASA/clopidogrel vs. ASA (p=0.02) CHARISMA Investigators NEJM 2006;354:1706-17.

Statins and Risk of Stroke Statins vs. Placebo Patients No. F/U RRR Diabetics1 2,828 3.9 yrs 46% High Risk2 20,536 5.0 yrs 25% Calhoun HM Lancet 2004; 364: 685 MRC/BHF HPS Investigators, Lancet 2002; 360:7

Risk Reduction with Statin SPARCL Trial Risk Reduction with Statin 4731 stroke / TIA patients Randomized: atorvastatin 80mg vs. placebo Results at 4.9 years Endpoint RRR P-value Stroke (any) Stroke/TIA Any CV event Major CV event 16% 35% 26% 23% .03 <.001 SPARCL Investigators NEJM 2006;355:549

Suggesting Improvement in Medical Care Asymptomatic Carotid Disease Annual rates of “ipsilateral” and “any” stroke by date Suggesting Improvement in Medical Care Naylor A R J.EJVS 2009.01.026

Second Manifestation of ARTerial Disease The SMART Study (2007) Prospective 2684 consecutive patients Clinical manifestations of arterial disease, or Type II diabetes No history of cerebral ischemia Carotid duplex 221 (8%) ≥50% carotid stenosis Follow-up to 5 years (mean 3.6 years) Evaluated for ischemic events Bertine M B et al Stroke 2007; 38:1470

H R Adjusted for Age/Gender The SMART Study Asymptomatic Carotid Stenosis Risk of Stroke* H R Adjusted for Age/Gender Degree of Stenosis Ischemic Stroke All Events 30 - 49% 0.7 1.0 50 - 69% 0.6 1.4 70 - 99% Occlusion 2.6 1.5 * vs. no stenosis Bertine M B et al Stroke 2007; 38:1470

Asymptomatic Carotid Disease SMART Study Annual risk of “ipsilateral” or “any” stroke with 50 - 99% stenosis was <1% Goessens B M B et al Stroke 2007; 38:1470

Asymptomatic Carotid Disease Future Trials Should (must) contain a “best medical therapy” arm, with enough patients to obtain an answer. …who will fund such trials?

Implications for Current Care Asymptomatic Carotid Disease Implications for Current Care Require appropriate medical care…to target! Need to select patients for CEA: Biomarkers (hsCRP, MMPs…..) Plaque composition TCD - embolic signals Contralateral symptomatic disease or occlusion

Limited Indication for CAS Carotid Artery Disease Symptomatic: - Urgent CEA Asymptomatic: - Aggressive Medical Care - Selective CEA Limited Indication for CAS

End Slide

US Hospital Discharge Database CEA vs CAS (N=135,701) US Hospital Discharge Database Symptomatic (N=10,495) CEA CAS p-value In-Hosp Mortality 1.4% 4.6% 0.0002 PostOp Stroke 2.5% 4.1% 0.15 LOS (Median) 4 Days 5 Days <0.0001 Hosp Charges $29,894 $49,535 <0.001 McPhee J T et al JVS 2008; 48:1442

US Hospital Discharge Database CEA vs CAS (N=135,701) US Hospital Discharge Database Asymptomatic (N=125,216) CEA CAS p-value In-Hosp Mortality 0.38% 0.57% 0.18 PostOp Stroke 0.88% 1.6% 0.001 LOS (Median) 1 Day <0.001 Hosp Charges $16,956 $28,853 McPhee J T et al JVS 2008; 48:1442