Alison Halliday, Professor of Vascular Surgery, University of Oxford
4th April 2013
Trial update – 1169 Patients so far-Well done, what’s next?
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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
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1990s: what about asymptomatic patients?
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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
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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
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ACST-1 changed practice worldwide(Lancet 2004, 2010)
Over 1000 citations so far….
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Wide variation in current practice
North America 60% surgery, 40% stenting
Continental Europe 50% surgery, 50% stenting
United Kingdom 90% surgery, 10% stenting
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North America >100,000 pa,95% asymptomatic
Continental Europe + UK >100,000 pa,60% asymptomatic
Annual numbers of carotid procedures(CEA or CAS)
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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……..
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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
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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’
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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
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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)
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Years of experience – lower riskMeta-regression analysis
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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
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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
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CREST: Major Stroke/Death (CAS) during Enrollment
50% Trial Enrollment
CAS = 0.4%CEA = 0.4%
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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
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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!
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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
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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
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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
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Patient Characteristics - Balance at trial entry
CEA(n=570)
CAS(n=570)
Echolucent plaque
No 181 181
Yes 149 148
Unknown 240 241
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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
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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
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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
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ACST-2 Medical treatment one month after Intervention
Anti-hypertensive 85%
Lipid-Lowering 85%
Anti-platelet or anti-coagulant 99%
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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
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ACST-2 is funded by the UK Health Technology Assessment Programme and the BUPA Charitable
Foundation and organised within
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