Alison Halliday, Professor of Vascular Surgery, University of Oxford 4 th April 2013 Trial update – 1169 Patients so far- Well done, what’s next? 1

40 years of carotid surgery trials Carotid endarterectomy [CEA] vs no intervention s: “symptomatic” patients s: asymptomatic patients CEA vs carotid stenting[CAS] s: symptomatic patients -2010s: asymptomatic patients 2

1990s: what about asymptomatic patients? 3

ACST % Years ACST-1: 10-year stroke risk reduced by surgery (CEA) CEA 10% Control 15% 2p =

Surgery reduces 10-year stroke risk for men & women under 75 years 5

ACST-1 changed practice worldwide (Lancet 2004, 2010) Over 1000 citations so far…. 6

Wide variation in current practice North America60% surgery, 40% stenting Continental Europe50% surgery, 50% stenting United Kingdom90% surgery, 10% stenting 7

North America >100,000 pa, 95% asymptomatic Continental Europe + UK >100,000 pa, 60% asymptomatic Annual numbers of carotid procedures (CEA or CAS) 8

Poor outcomes after endovascular treatment of symptomatic carotid stenosis: time for a moratorium Lancet Neurology 2009 ….Most stenting for symptomatic stenosis (has) a greater procedural risk of stroke and a worse long-term outcome than..endarterectomy ……….Routine use of stenting in (symptomatic) patients suitable for endarterectomy can no longer be justified… …Vague and non-evidence-based categorisations, such as “high risk for surgery,” which have been systematically misused to justify the uncontrolled roll-out of carotid stenting in many centres, must stop…….. 9

Meta-analysis Symptomatic Stenting vs Surgery trials (Lancet 2010) EventCAS (n=1649)CEA (n=1645)Risk Ratio (95% CI) P value Any stroke or death130 (7.7%)73 (4.4%)1.74 ( ) Disabling stroke or death 65 (3.9%)43 (2.6%)1.48 ( )0.04 Non-disabling stroke 66 (3.9%)31 (1.9%)2.09 (1.37–3.19) All Ischaemic stroke118 (7.0%)57 (3.5%)2.02 ( ) Ipsilateral carotid territory stroke 113 (6.7%)66 (4.0%)1.67 ( ) MI (all)4 (0.2%)7 (0.4%) Cranial nerve damage7 (0.4%)99 (6.0%)0.07 ( )<

Carotid artery stenting versus surgery: adequate comparisons? Lancet Neurology 2010, 339–341 Correspondence ‘As randomised clinical trials are the gold standard of clinical investigation, it seems unwise to challenge them. However, for the comparison of CAS versus CEA, most of the randomised trials should be considered not only scientifically but also ethically questionable because the endovascular experience required for interventionalists to be eligible for the studies was minimal’ 11

Carotid artery stenting versus surgery: adequate comparisons? – the Trials’ experience Lancet Neurology, April 2010, Pages 341–342 Martin M Brown, Jean-Louis Mas, Peter A Ringleb, Werner Hacke Martin M BrownJean-Louis MasPeter A RinglebWerner Hacke YearNumberLifetime endovascular experience CAVATAS Training in neuroradiology and angioplasty (but not necessarily in the carotid artery); tutor-assisted procedures allowed SAPPHIRE Procedures submitted to an executive review committee; CAS periprocedural death or stroke rate had to be <6%; no tutor- assisted procedures allowed SPACE At least 25 successful CAS or assistance of a tutor for interventionalists who have done at least 10 CAS EVA-3S ≥12 CAS cases or ≥5 CAS and ≥30 cases of endovascular treatment of supra-aortic trunks; tutor-assisted CAS allowed for centres not fulfilling minimum requirements ICSS A minimum of 50 total stenting procedures, of which at least ten should be in the carotid artery; tutor-assisted procedures allowed for interventionalists with insufficient experience 12

After the symptomatic trials CAS may be getting better – but what has changed? Experience, time and devices Open vs closed cell stents (ICSS data) Filters vs no filters New devices – direct puncture, reverse flow, others arriving (And possibly MEDICAL treatments are better) 13

Years of experience – lower risk Meta-regression analysis 14

More Procedures – lower risk 15

Muller-Hulsbeck S et al. JEVT 2009;16:

Does Free Cell Area Influence the Outcome in Carotid Artery Stenting ? ( N =3179 X-act, Nexstent, Wallstent, Precise, Protégé, Acculink, Exponent) Bosiers M e al EJVES 2007;33:

After the symptomatic trials CAS may be getting better – but what has changed? The CREST Trial (NEJM 2010) 2500 patients About half were asymptomatic No significant differences found overall Symptomatic patients still higher risk from CAS Asymptomatic = similar risks (but numbers too small) So ACST-2 (CAS vs CEA) is important for the FUTURE 18

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CREST: Major Stroke/Death (CAS) during Enrollment 50% Trial Enrollment CAS = 0.4% CEA = 0.4% 20

Statins lower stroke risk in CEA (J Vasc Surg 2005;42: ) 21

Future of CEA vs CAS trials - Reducing procedural hazards (stent design, insertion, drug elution) - Changing spectrum of patients (older, chronically ill, screen-detected) And.. -Improving medical treatments Trials will need VERY large numbers of patients, because they study moderate effects BUT their results can change future treatments worldwide 22

If a patient with no recent symptoms has 70-99% carotid stenosis should any carotid procedure be done? If Yes: Consider ACST-2 A large simple trial of CEA vs CAS (where both procedures are appropriate) planning to recruit 5000 patients by 2019, and follow to

Stenting Surgery When intervention seems clearly needed and, after arch imaging, both procedures are appropriate Consider patients for ACST-2 24

ACST-2 – current status 1169 patients recruited (April 2013) Soon will have more asymptomatic patients randomised than any other trial Many more Centres and Patients needed – we welcome our first from Japan! 25

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Patient Characteristics - Balance at trial entry CEA (n=570) CAS (n=570) CharacteristicFemale (33%) Atrial fibrillation (5%) 3231 Diabetes (30%) Age (years)< (34%) Median71 28

Patient Characteristics - Balance at trial entry CEA (n=570) CAS (n=570) Echolucent plaque No181 Yes Unknown

Patient Characteristics - Balance at trial entry CEA (n=570) CAS (n=570) Contralateral stenosis (%) < Median30 Ipsilateral stenosis (%) Median80 30

Patient Characteristics - Balance at trial entry CEA (n=570) CAS (n=570) Systolic BP (mm Hg) <= > Renal impairment 5269 Ischaemic heart disease

If Procedure not yet done…. Return 1 Month Follow-up Form recording why procedure not done or delayed Once the procedure has been done, please return a 1 Month Form to us with the details 32

Type of stent used in CAS (Any CE-approved device allowed) StentStraightTaperedTotal Cristallo Ideale Precise50151 Protégé RX RX Acculink83442 Wallstent1190 XAct56873 Other6814 Total443 33

Straight (54%)Tapered (46%) 34

Cerebral protection (CP) devices used in ACST-2 Device typeDevice nameProcedures Distal balloonTwin One2 FilterAccunet26 FilterAngioGuard29 FilterEmboshield115 FilterFilterwire80 FilterSpider46 Proximal occlusionGore Flow Reversal28 Proximal occlusionMoma52 None used54 TOTAL443 35

ACST-2 Medical treatment one month after Intervention Anti-hypertensive 85% Lipid- Lowering 85% Anti-platelet or anti-coagulant 99% 36

Future of carotid surgery trials - Improving medical treatments - Reducing procedural hazards (stent design, insertion, drug elution) - Different spectrum of patients (older, chronically ill, screen-detected) - Collaboration – with SPACE-2, ECST-2 and CREST-2 37

ACST-2 is funded by the UK Health Technology Assessment Programme and the BUPA Charitable Foundation and organised within 38