Alison Halliday, Professor of Vascular Surgery, University of Oxford

4th 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

- 1980s: “symptomatic” patients- 1990s: asymptomatic patients

CEA vs carotid stenting[CAS] - 2000s: symptomatic patients-2010s: asymptomatic patients

2

1990s: what about asymptomatic patients?

3

ACST-1

0 5 100

5

10

15

20

%

Years

ACST-1: 10-year stroke risk reduced by surgery (CEA)

CEA 10%

Control 15%

2p = 0.0006

4

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

0 5 100

10

20%

YearsPerioperative + other events

Years 0-4 Years 5+16 + 7 0 + 9 Immediate4 + 28 1 + 17 Deferred

(c) Any type of stroke or perioperative death(Female, Age <75)

Immediate

Deferred

5.9%

10.2%

8.4%

16.0%Gain at5 yr: 2.5% (1.9), p > 0.1; NS

10 yr: 5.8% (2.9), p = 0.05

0 5 100

10

20%

YearsPerioperative + other events

Years 0-4 Years 5+17 + 28 0 + 25 Immediate8 + 84 1 + 21 Deferred

(a) Any type of stroke or perioperative death(Male, Age <75)

Immediate

Deferred

5.8%

12.7%

12.3%

18.1%Gain at

5 yr: 6.5% (1.5), p = 0.0000110 yr: 5.5% (2.3), p = 0.02

5

ACST-1 changed practice worldwide(Lancet 2004, 2010)

Over 1000 citations so far….

6

Wide variation in current practice

North America 60% surgery, 40% stenting

Continental Europe 50% surgery, 50% stenting

United Kingdom 90% 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)

Event CAS (n=1649) CEA (n=1645) Risk Ratio (95% CI)

P value

Any stroke or death 130 (7.7%) 73 (4.4%) 1.74 (1.32-2.30) 0.0001

Disabling stroke or death 65 (3.9%) 43 (2.6%) 1.48 (1.01-2.15) 0.04

Non-disabling stroke 66 (3.9%) 31 (1.9%) 2.09 (1.37–3.19) 0.0004

All Ischaemic stroke 118 (7.0%) 57 (3.5%) 2.02 (1.48-2.75) 0.0001

Ipsilateral carotid territory stroke

113 (6.7%) 66 (4.0%) 1.67 (1.24-2.25) 0.0005

MI (all) 4 (0.2%) 7 (0.4%)

Cranial nerve damage 7 (0.4%) 99 (6.0%) 0.07 (0.03-0.15) <0.0001

10

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 341–342Martin M Brown, Jean-Louis Mas, Peter A Ringleb, Werner Hacke

Year Number Lifetime endovascular experience

CAVATAS 2001 504 Training in neuroradiology and angioplasty (but not necessarily in the carotid artery); tutor-assisted procedures allowed

SAPPHIRE 2004 334Procedures submitted to an executive review committee; CAS periprocedural death or stroke rate had to be <6%; no tutor-assisted procedures allowed

SPACE 2006 1200 At least 25 successful CAS or assistance of a tutor for interventionalists who have done at least 10 CAS

EVA-3S 2006 527≥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 2010 1710A 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 riskMeta-regression analysis

14

0

1

2

3

4

5

6

7

8

9

0 100 200 300 400 500 600 700 800 900

Neg

ative

Eve

nt R

ate

(%)

Number of Procedures Performed

R2 = 0.834

Negative Event Rate = 7.70 x Exp(-0.00220 x Number of Procedures Performed)

More Procedures – lower risk

15

Muller-Hulsbeck S et al. JEVT 2009;16:168-177 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;33:135 - 14117

After the symptomatic trials CAS may be getting better– but what has changed?

The CREST Trial (NEJM 2010)

2500 patientsAbout half were asymptomatic

No significant differences found overallSymptomatic patients still higher risk from CAS

Asymptomatic = similar risks (but numbers too small)

So ACST-2 (CAS vs CEA) is importantfor the FUTURE

18

19

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;42:829-836)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 worldwide22

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 2025 23

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

Mar-1

0

May-1

0Jul-1

0

Sep-10

Nov-10

Jan-11

Mar-1

1

May-1

1Jul-1

1

Sep-11

Nov-11

Jan-12

Mar-1

2

May-1

2Jul-1

2

Sep-12

Nov-12

Jan-130

10

20

30

40

50

60

0

200

400

600

800

1000

1200

Active centres and Trial recruitment (Mar 2010-Feb 2013)

Num

ber o

f acti

ve c

entr

esN

umber of patients recruited

26

Italy

United Kingdom

SwedenSerb

ia

Belgium

Germany

France

Czech

Republic

The Netherlands

Spain

Poland

Greece

Hungary

Slovenia

Switzerla

ndIsr

ael

Slovak RepublicChina

Norway

Canada0

50

100

150

200

250

300

Patients recruited by countryPa

tient

s re

crui

ted

27

Patient Characteristics - Balance at trial entry

CEA(n=570)

CAS(n=570)

Characteristic Female (33%) 173 171Atrial fibrillation (5%)

32 31

Diabetes (30%) 174 175

Age (years) <65 137 13065-74 223 24775+ (34%) 210 193Median 71 71

28

Patient Characteristics - Balance at trial entry

CEA(n=570)

CAS(n=570)

Echolucent plaque

No 181 181

Yes 149 148

Unknown 240 241

29

Patient Characteristics - Balance at trial entry

CEA(n=570)

CAS(n=570)

Contralateral stenosis (%)

<50 357 35550-79 148 14980-99 22 22100 43 44Median 30 30

Ipsilateralstenosis (%) 50-69 23 26

70-79 175 17380-89 232 23190-99 140 140

Median 80 8030

Patient Characteristics - Balance at trial entry

CEA(n=570)

CAS(n=570)

Systolic BP(mm Hg)

<=140 330 325141-160 186 189>160 64 56

Renal impairment 52 69

Ischaemic heart disease

200 203

31

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)

Stent Straight Tapered Total

Cristallo Ideale 10 72 82Precise 50 1 51

Protégé RX 11 34 46RX Acculink 8 34 42Wallstent 119 0 119

XAct 5 68 73Other 6 8 14

Total 44333

Straight (54%) Tapered (46%) 34

Cerebral protection (CP) devices used in ACST-2

Device type Device name ProceduresDistal balloon Twin One 2Filter Accunet 26Filter AngioGuard 29Filter Emboshield 115Filter Filterwire 80Filter Spider 46Proximal occlusion Gore Flow Reversal 28Proximal occlusion Moma 52None used 54TOTAL 443

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