Endovascular Management of Intracranial and Extracranial Atherosclerosis Rishi Gupta, MD Associate Professor of Neurology, Neurosurgery, and Radiology Emory University School of Medicine Director,Multi-Center Acute Stroke Network Marcus Stroke and Neuroscience Center Grady Memorial Hospital

Extracranial Carotid Artery Disease 700,000 Strokes annually in the US 1 Extracranial carotid artery disease accounts for % of Ischemic Cerebral Infarctions 2 Causes cognitive impairment Ovbiagele et al., Stroke Whisnant Rao et al., Stroke 1999

Natural History of Carotid Disease Strongest predictors of future events 1 Prior ipsilateral hemispheric symptoms Degree of stenosis Other predictors of future events Unstable plaque 2 (ulceration, intraplaque hemorrhage, intraluminal thrombus) Hemodynamic impairment 3,4,5 Coexistence of both 6 1 Rothwell, Stroke 2000, 2 Rothwell, Cerebrovasc. Dis. 2001, 3 Silvestrini JAMA 2000, 4 Markus, Brain 2001, 5 Yonas, J Neurosurg 1993, 6 Caplan, Arch Neurol 1999

Carotid Endarterectomy for Symptomatic High Grade Carotid Stenosis (NASCET) 659 patients with ischemic stroke or TIA and Carotid stenosis 70%-99% Carotid Endarterectomy (n=328) Medical management (n=331) 9%26% Ipsilateral stroke 2 years P < NNT=8 NASCET investigators, NEJM 1991 Complications: stroke/death 5.8%

Carotid Endarterectomy for Symptomatic Moderate Grade Carotid Stenosis (NASCET) 858 patients with ischemic stroke or TIA And Carotid stenosis 50%-69% Carotid Endarterectomy (n=428) Medical management (n=430) 15.7% 22.2% Ipsilateral stroke 5 years P = Barnett et al, NEJM 1998 NNT=20 Complications: stroke/death 6.7%

Carotid Endarterectomy for Asymptomatic Moderate-Severe Carotid Stenosis (ACAS) 1662 patients with asymptomatic Carotid stenosis 60%-99% Carotid Endarterectomy (n=825) Medical management (n=834) 5.1%11% Ipsilateral Stroke, Death 5 years P = ACAS investigators, JAMA 1995 NNT= 48 Complications: stroke/death 2.3%

Asymptomatic Carotid Surgery Trial (ACST) 3120 patients with asymptomatic Carotid stenosis 60%-99% Carotid Endarterectomy Medical management 6.4%11.8% Stroke, Death 5 years P = ACST Investigators, Lancet 2004

Asymptomatic Carotid Stenosis Interestingly, with a decade between ACAS and ACST, natural history of asymptomatic carotid stenosis did not change Rates of anti-platelet therapy use higher in ACAS and statin implementation higher compared to ACAS

High Surgical Risk for CEA Risk factors – –Age > 75 – –Ipsilateral carotid occlusion – –Carotid siphon stenosis – –Intraluminal thrombus Not considered – –MI within 6 months – –Severe hypertension – –CHF – –COPD – –Severity of stenosis – –Contralateral carotid stenosis – –Ulceration Goldstein et al. Stroke 25;1116, 1994

High Surgical Risk for CEA 1160 CEAs at 12 hospitals - Retrospective review Goldstein et al. Stroke 25;1116, 1994

Carotid Artery Stenting/Angioplasty (CAS) First performed in the 1980’s Early clinical trials for high risk CEA patients - Clinical registries, SAPPHIRE More recently, RCT comparing to CEA in low risk patients

SAPPHIRE: Study Design Randomized, multi-center trial comparing carotid stenting with protection vs. endarterectomy in high surgical risk patients Prove Non-Inferiority of Stenting with EDP vs. CEA 80% Asymptomatic carotid stenosis or 50% symptomatic carotid stenosis Non-randomized patients entered in stent registry or surgical registry Stroke, MI and Death (Composite outcome) – –30-day post- procedure

Key Inclusion Criteria: > 1 Comorbidity (Systemic) Congestive heart failure (class III/IV) and/or known severe LV dysfunction (LVEF <30%) Open heart surgery needed within six weeks Recent MI (>24 hrs. and <4 weeks) Unstable angina (CCS class III/IV) Severe pulmonary disease Age greater than 80 years

Randomized Study-All Patients 30 Days Events (N= 156 vs 151) P=0.047

Randomized trial Randomized trial 1:1 CEA vs CAS 1:1 CEA vs CAS Designed to prove non-inferiority Designed to prove non-inferiority Symptomatic patients with  60% Symptomatic patients with  60% 524 patients enrolled 524 patients enrolled Stopped prematurely due to safety and futility Stopped prematurely due to safety and futility EVA 3S

EVA 3S - Issues Operator experience: Operator experience: –12 carotid stents does not require 014 experience –35 supraaortic stents (of which 5 carotids) or –performance of stenting under supervision by proctor who fullfills above criteria No requirement for : No requirement for : - dual antiplatelet therapy (15% without) - dual antiplatelet therapy (15% without) - uniform stent/protection device - uniform stent/protection device - use of protection device (10% without) - use of protection device (10% without)

SPACE -Randomized trial -1:1 CEA vs CAS - Designed to prove non-inferiority - Symptomatic patients with  50% (NASCET) patients enrolled -Stopped prematurely due to lack of funding

SX ICA WITH LARGE ULCERATION TREATED WITH EMBOLI PREVENTION FILTER Filter PRE FILTER POST EMBOLIZED PLAQUE EMBOLIZED PLAQUE

CREST Randomized controlled study of 2502 patients with conventional risk 1:1 randomization to CAS vs. CEA Included symptomatic and Asymptomatic patients Primary endpoint of any stroke, death or MI Rigorous vetting process with a lead in phase for investigators and prior experience with a pre-defined 6% complication rate in the past

Peri-procedural Stroke and MI CAS vs. CEAHazard Ratio 95% CI P- Value Stroke vs. 2.3 % HR = 1.79; 95% CI: MI vs. 2.3 % HR = 0.50; 95% CI:

Primary Endpoint ≤ 4 years (any stroke, MI, or death within peri-procedural period plus ipsilateral stroke thereafter) CAS vs. CEAHazard Ratio, 95% CIP-Value % 7.2 vs. 6.8 % HR = 1.11; 95% CI:

Primary outcome – 4 year

Study # Patients Tutor Allowed Stent TypeDual Anti- platelet EPD Use30 day stroke CAVATAS504NoAngioplastyAspirin0%8% EVA 3S527YesMultiple15% not on dual anti- platelets 91%8.8% SPACE1200YesMultipleMandated27%6.5% ICSS1710YesMultipleRecommended72%6.3% CREST2502NoAcculinkMandated 4.1% SAPPHIRE334NoPreciseMandated 3.6% Summary of Randomized CAS Studies

Summary of Carotid Treatment Carotid revascularization recommended for patients with moderate to severe stenosis: - If Sx and survival > 2 years - If ASx and survival > 5 years CEA and CAS are both options available for revascularization Multidisciplinary approach with surgery, endovascular specialist and neurologist will likely yield best clinical outcome As with ICAD, maximal medical therapy important towards reducing risk of stroke, MI long term

Conclusions Medical management pre and post carotid revascularization may impact safety, durability of treatment CAS will likely have a larger role in carotid revascularization after CREST. Interest in cognitive differences between CAS and CEA, also ? if distal vs. proximal protection leads to reduced downstream emboli