Carotid Trials in Progress and Predictions on Outcomes Kenneth Rosenfield, MD, FACC, FAHA Section Head, Vascular Medicine and Intervention Massachusetts General Hospital Boston, Massachusetts, U.S.A.

Kenneth Rosenfield, MD Conflicts of Interest Consultant Abbott Vascular Baxter Harvard Clinical Research Institute Micell Complete Conference Management Vortex Endospan Equity Icon CardioMEMs Medical Simulation Corporation Primacea Research or Fellowship Support Abbott Vascular Cordis Lutonix/Bard Boston Scientific Baxter Atrium IDEV Board Member VIVA Physicians www.vivapvd.com

Carotid Trials – Where have we come from?

Stroke Prevention by Intervention Summary of what evidence we have… RCT’s: CEA vs. OMT completed* Symptomatic High-risk Asymptomatic High-risk None None Symptomatic Standard-risk Asymptomatic Standard-risk NASCET ACAS VA Trial ECST ACST 1

Benefit of medical Rx with revascularization over Med Rx alone ACST - Early vs. Deferred Carotid Endarterectomy in Asymptomatic Patients with ICA Stenosis Any Stroke or Perioperative Death Time (years)  Benefit of medical Rx with revascularization over Med Rx alone ACST Investigators. Lancet 2004;363:1491-1502

RCT’s: CAS vs. OMT for stroke prevention Symptomatic High-risk Asymptomatic High-risk None None Symptomatic Standard-risk Asymptomatic Standard-risk None None In absence of “head to head” trials vs. OMT, can only infer ability of CAS to prevent stroke based on: a) registry studies of CAS and b) RCT’s comparing it to CEA!

Carotid Artery Disease RCT’s: CAS vs. CEA completed* SAPPHIRE * ongoing Symptomatic High-risk Asymptomatic High-risk None None KENTUCKY * Symptomatic Standard-risk Asymptomatic Standard-risk EVA3s, SPACE 1 * ACT1, SPACE2, ACST2 CREST

We should have refused more patients! SAPPHIRE >50% Stenosis Sx 80% Stenosis Asx One or More Comorbidity Conditions Physician Team: Neurologist, Surgeon, Interventionalist CONSENSUS: 747 pts enrolled RANDOMIZED 334 SURGICAL REFUSAL INTERVENTIONAL REFUSAL TREATED 310 Stent Registry n=409 Surgical Registry n=7 We should have refused more patients! CEA n=151 STENT n=159

SAPPHIRE Trial: 1-Year Outcome - sxatic and asxatic high surgical risk patients 20.1% p=0.048 12.0% 30 25 20 15 10 60 90 120 150 180 210 240 270 300 330 360 Time after Initial Procedure (days) Cumulative Percentage of MAE Nitinol Stent Carotid Endarterectomy 5 In high risk patients, carotid stenting with distal embolic prevention is associated with fewer deaths, myocardial infarctions or strokes at 30 days than carotid endarterectomy, and these differences persist at 1 year.

SAPPHIRE 3-Year Outcomes Freedom from MAE N Engl J Med 2008;358:1572-9

30 Day Event Rates (2000--->2008) All Stroke - Stenting Trials for High Risk Surgical Patients This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) Factors: embolic protection, experience, case selection 11

Protect  Stroke and Death 1.8%

Carotid Disease - Natural History Unanswered Questions Effect of... Sxatic status Degree of narrowing Morphology and consistency Location Patient substrate – standard or high surgical risk patient Clinical consequences Benign or not (stroke, MI, death)

Carotid Disease - Revascularization Unanswered Questions Effect of... Patient substrate Standard or high surgical risk patient Sxatic status Age Lesion status Degree of narrowing Location Morphology and consistency

Carotid Revascularization Unanswered Questions Optimal lesion characterization Severity DUS CTA MRA Angiography Embolic potential (risk stratification) DWI Plaque characterization (e.g. ulceration) Biological plaque imaging

Carotid Revascularization Unanswered Questions Selection of optimal revascularization modality CEA Stenting

Carotid Stenting Unanswered Questions Equipment Embolic protection Proximal Distal Stent Closed-cell Open-cell Covered or “meshed” Access site Femoral Upper extremity Direct carotid - cutdown or puncture

Carotid Disease Adding to the evidence base… Randomized Controlled Trials in Progress SPACE 2 ACST 2 ACT 1 Randomized Controlled Trials Planned CREST 2 Single Arm Trials and Registries NCDR CARE and SVS Gore and MDT Prox protection

SPACE 2 – “Stent-protected angioplasty in Asymptomatic Carotid Artery Stenosis” Funding – German Research Council Start date – original 1/07; revised 11/09 Countries – Austria, Germany, Switzerland Hypothesis Superiority of revasc (CAS or CEA) c/t OMT CAS not inferior to CEA Primary Outcome Death or any stroke w/n 30 days Ipsilat stroke within 5 yrs. Design – RCT – three open arms OMT OMT plus CAS OMT plus CEA Inclusion <86 y.o.; 6 mos w/o sx’s

SPACE 2 Asymptomatic (no ipsilateral symptoms within previous 180 days) Carotid artery stenosis >/= 70% Ultrasound proven by certified study personal Informed consent Randomisation CEA CAS conservative n=1550 n=1550 n=540 Procedure within 30 days Procedure within 30 days Optimal medical treatment up to 5 years

SPACE 2 – “Stent-protected angioplasty in Asymptomatic Carotid Artery Stenosis” Progress # Pts to be randomized - 3523 patients Currently – <300 (after two years) Randomization scheme altered to: Asx patient <86 y.o. Asx patient <86 y.o. From: To: * * CAS CEA Best Medical Tx Revasc- either CEA or CAS Best Medical Tx

The HTA/BUPA Foundation ACST-2 A large simple randomised trial of CEA (carotid endarterectomy) vs CAS (carotid stenting) for the prevention of stroke Aims to randomise 5000+ patients with asymptomatic carotid stenosis in whom intervention is thought to be clearly needed, but where there is substantial uncertainty as to which procedure is best

ACST-2 Subjects in whom CEA and CAS are anatomically suitable are randomized 1:1 to CEA or CAS. The main outcomes are 1-month stroke/MI/death and long term stroke (5 or more years). Randomization and 1-month evaluations are performed by the study doctor, and long term follow up is primarily though direct contact from the ACST office.

Asymptomatic Carotid Stenosis Trial (ACST-2) Randomisation to Stenting or Surgery Funded to 2014 - Plans 200 centres to randomise at least 5000 patients Experience with more devices, longer follow up, determine groups who may/ may not benefit Since randomisation started (2 years) 45 Centres (16 countries) have entered patients 127 centres have joined or are joining

16 Countries Randomising in ACST-2 Belgium Czech Republic France Germany Greece Ireland Israel Italy Netherlands Norway Poland Serbia Slovenia Spain Sweden United Kingdom

ACST-2 UK 25 centres (Mar 2010) Centre open Joining Belfast Newcastle Hospitals Joining Sunderland Royal Infirmary James Cook Hospital Royal Preston Hospital Univ Hospital North Durham Bishop Auckland General Hospital Univ Hospital of South Manchester Manchester Royal Infirmary Hull Royal Infirmary Sheffield Vascular Institute Norfolk and Norwich Univ Hospital Queens Medical Centre, Nottingham Addenbrookes Hospital Southend Univ Hospital of North Staffordshire St Mary’s London Sandwell and West Birmingham St Georges, London East Kent and Canterbury Bristol Royal Infirmary Belfast Bournemouth Royal Sussex, Brighton

Centre Recruitment 125 62 Mar 2010

CREST 2 950 patients at ~70 centers Power ~90% to detect 4.8% treatment difference (1.2% per year) Primary Endpt – Composite of stroke or death within 30 days or ipsilat stroke up to 4 years SAMMPRIS – style Intensive medical management Criteria >35 y.o.; asymptomatic for 180 days >70% stenosis (det by DUS, CAT, MRA, CBA) Series of exclusion criteria each for CEA and CAS

Asymptomatic Carotid stenosis, stenting versus endarterectomy Trial Carotid stenting is not currently approved by the FDA for asymptomatic patients who are at standard risk for surgery. CAUTION: Investigational device. Limited by Federal (or United States) law to investigational use. Confidential: This information is confidential and is intended for distribution to ACT I Study Site participants ONLY. This document contains Abbott Laboratories and Abbott Vascular proprietary information and shall not be duplicated, disclosed to others, or used for purposes other than to carry out the intent for which this material is delivered. ©2008 VIVA 2008 ( Las Vegas, NV) September 22nd 2008 39 AP2928021 Rev A 39

Summary - ACT 1 Focus only on asymptomatic patients excludes high risk for CEA--protocol defined excludes high risk for CAS--protocol defined surgeon and interventionalist criteria are strict and verified (IMC and SMC) Independent neuro assessment embolic protection required central core labs, independent audit

ACT I: Study Design Prospective, randomized, 2-arm, multicenter trial 3:1 randomization CAS to CEA Lead-in enrollment of up to 400 subjects Maximum of 1658 pivotal subjects Followed at 1, 6, 12 months & annually for 5 yrs Contemporary medical therapy for all patients VIVA 2007 ( Las Vegas, NV) September 25th 2007

Key Inclusion Criteria • Subject > 18 and  80 years of age. • Subject asymptomatic no stroke or TIA (hemispheric or ocular) within 180 days prior to procedure neurologist must confirm status Carotid stenosis >70% and <99% by carotid duplex (accredited lab) or angiography (visual estimate)

Key Exclusion Criteria Clinical • Bilateral significant carotid stenosis (contralateral stenosis > 60% by duplex or angiography) • High risk surgical candidate • Known cardiac sources of emboli

Primary Endpoint Composite • Any stroke*, myocardial infarction and death during 30-day post procedural period Ipsilateral stroke* between 31 and 365 days post procedure *Independent neurologic assessment

Summary - ACT 1 ACT 1 will focus on evaluating CAS in asymptomatic patients excludes high risk for CEA--protocol defined excludes high risk for CAS--protocol defined surgeon and interventionalist criteria are strict and verified standardized protocol: embolic protection central corelabs, independent audit

ACT 1 - Enrolling Sites as of September 2008 Dartmouth Massachusetts General Hospital St. Francis, NY St. Luke’s Milwaukee Deaconess Medical Center University of Rochester William Beaumont Hospital NYU Medical Center Albany Medical Center Oregon Health & Science University Rush University Medical Center Lenox Hill Hospital Our Lady of Lourdes St. John’s Hospital / Prairie Medical Columbia Presbyterian Millard Fillmore Hospital North Central Heart Institute Detroit Medical Center Hospital of Univ. of Pennsylvania Allegheny General Hospital Washington Hospital Center El Camino Hospital Northwestern University Memorial Hospital Cleveland Clinic Foundation Riverside Methodist Hospital Harrisburg Hospital / Pinnacle Health Hoag Memorial Hospital Presbyterian Parkview Hospital Berks Cardiology Chesapeake General Hospital Kaiser Foundation Hospital – San Diego Wellmont Holston Valley St. Mary’s Hospital/ VA Cardiovascular Specialists St. Joseph Hospital Wellness Center Stern Cardiovascular Center Wake Medical Center St. Luke’s Hospital, Phoenix Presbyterian Heart Institute-Dallas Providence Medical Center Duke University Austin Heart P.A. Baptist Hospital of East Tennessee Westlake Medical Center Kaiser Permanente Hawaii St. Luke’s Episcopal Hospital, Houston Cardiovascular Inst. of the South Forsyth Medical Center VIVA 2007 ( Las Vegas, NV) September 25th 2007 Ochsner Clinic Foundation BCVI

ACT I: Outcomes Lead In Patients Event 30 days, N=180 Death, Stroke and MI 1.7% (3/180) All Stroke and Death 1.7% Major Stroke and Death 0.0% Death All Stroke Major Stroke Minor Stroke MI 31-365 days, N=157 Ipsilateral Stroke Updated Source: 2009 IDE Annual Report ACT I Study Sept 2009. Source: IDE Annual Progress Report ACT I Study Sep 2008 2 minor ipsi strokes within 30 days.

Therapy for Carotid Stenosis Conclusions IV The Future - better definition of patients appropriate for… Medical Therapy CEA only Stenting only Patients in “gray zone” between revasc or no revasc Patients who could benefit equally from either CEA or CAS and are appropriate for both