Guidelines in the Management of Carotid Stenosis

Professor Alun H DaviesAcademic Section of Vascular Surgery,

Imperial College,Charing Cross & St Mary’s Hospital,

London

Stroke

• Each year 120,000 people suffer 1st stroke• Within 1 year 33% dead• 3rd most common cause of death (UK)

Symptoms due to:- Critical Stenosis- Occlusion- Unstable plaque

Aetiology of Stroke

• Ischaemic (80%)- 75% Carotid territory

- 50% thrombo-embolism of ICA or MCA- 25% small vessel disease- 15% cardiac embolus,- 10% other: Takayasu’s arteritis, FMD

- 15% Vertebrobasillar features- 10% unknown

• Haemorrhagic (20%) Under-perform by 2-3 fold CEA/CAS

Natural history of severe symptomatic and asymptomatic

carotid artery stenosis

50

60

70

80

90

100

Golledge J, Greenhalgh RM, Davies AH. Stroke 2000

6 12 18

Time (months)

Freedom from ipsilateral stroke (%)

ACAS (60-99%)

ECST symptomless vessel (70-99%)

ECST (80-99%)

NASCET (70-99%)

Life-table analysis of stroke related to presentation

0102030405060708090

100

0 6 12 18 24 30 36

AmaurosisTIATransient strokeEstablished strokeProgressive strokeCrescendo TIA

Avoidance of stroke (%)

Time (months)

Golledge J, Cuming R, Beattie DK,

Davies AH, Greenhalgh RM JVS 1996

Life-table analysis of survival related to presenting symptom

0102030405060708090

100

0 6 12 18 24 30 36

AmaurosisTIATransient strokeEstablished strokeProgressive strokeCrescendo TIA

Survival (%)

Time (months)

Golledge J, Cuming R, Beattie DK, Davies AH, Greenhalgh RM

JVS 1996

Stroke Risk: NASCET and ECST

• 13.1% major ipsilateral stroke at 2 years

• 13%/yr for ANY ipsilateral stroke

• ECST - 16.2% for ANY ipsilateral stroke at 3 years

• Most strokes occur within first year of signal event

• Risk is directly proportional to degree of stenosis

Stroke, 1999

30 Day stoke and death rates following carotid surgery at Charing Cross (CX)

and Leicester Royal Infirmary (L)

0

1

2

3

4

5 Pre 1996 1996-2000

CX

CX

LL

Number 460 494 291 500 823

% 2001-8

Risk of Stroke

Naylor 2007

Number of stokes saved at 5 yearsPer 1000 CEAs in 50-99% stenosis

Naylor 2007

Benefit of Urgent Treatment

Naylor 2007

Natural history - stroke rate in asymptomatic carotid artery

stenosis

Patients with <75% stenosis - annual stroke rate 1.3%

Patients with >75% stenosis - annual stroke rate 3.3%

Chambers BR, Norris JW Stroke 1991

Asymptomatic Disease• Stroke risk with asymptomatic stenosis

(NASCET)> 60% is 9.9% at 5 yrs < 60% risk stroke 5.4% at 5 yrs

• ACST : DEGREE OF STENOSIS 60%-80% = 9.5% risk stroke at 5 yrs 80%-99% = 9.6% risk stroke at 5 yrs

• NO INCREASE IN STROKE WITH INCREASE IN STENOSIS

• THEREFORE There is NO high risk subgroup of asymptomatic patients based on degree of stenosis

Asymptomatic stenosis

0

1

2

3

4

5

6

7

8

9

VA ACAS ACE ACST

Trial

% risk of stroke

% medical risk

% surgical risk 2004

ACST

Carotid angioplasty

Single center studies 1990-1999

Studies Number of arteries

PTA 13 714

Endarterectomy 20 6970

Stent used in 44% of patients with cerebral

protection in 11%

Technical failure in 37 Cases (7%)

Golledge J, Mitchell A, Greenhalgh RM, Davies AH Stroke 2000

30 Day Stroke or Death Rate

0

1

2

3

4

5

6

7

8

9Angioplasty

Endarterectomy

Any stroke

or death

Disabling stroke

or death

%

Golledge J, Mitchell A, Greenhalgh RM, Davies AH Stroke 2000

Odds ratio for outcome

Any stroke

Disabling or fatal stroke

TIA

Death

Any stroke or death

Disabling stroke or death

1 2 3 4 5 6 70

Relative odds

2.22

2.09

4.02

0.68

Surgery Angioplasty

Golledge J, Mitchell A, Greenhalgh RM, Davies AH Stroke 2000

CAVATAS

CAVATAS trial compared carotid

endarterectomy with carotid angioplasty.

The rate of any stroke lasting more than

7 days, or death were 9.9% and

10% respectively. CAVATAS investigators Lancet June 2001

Sapphire

Archer

Crest

Caress

“High Risk”

The Rest

EVAS -3

• RCT• N=527

Stoke/Death Rates• 30 day CEA 1.5 % vs CAS 3.4% RR 2.2• 6/12 CEA 6.1% vs CAS 11.7% p<0.02• 4 yrs CEA 6.2% vs CAS 11.1% RR 1.97

p<0.03

Mas et al, 2006 ,2008

SPACE Trial

• n=1200

• CAS n=605 or CEA n=595

• 30 days CAS 6.84% vs CEA 6.34% SPACE failed to prove non-inferiority of CAS compared

to CEA. Results do not justify the widespread use in the short term of CAS for treatment of carotid- artery

stenosis. Reingleb et al 2006 The incidence of recurrent carotid stenosis at 2 years,

as defined by ultrasound, is significantly higher after carotid artery stenting. Older patients do worse with CAS.

Eckstein et al 2008

Carotid endarterectomy was performed with lower stroke and death rates than carotid artery stenting

in the USA in 2003 and 2004

• During the calendar years 2003 and 2004, an estimated 259,080 carotid revascularization procedures were performed in the United States. CAS had a higher rate of in-hospital postoperative stroke (2.1% vs 0.88%, P < .0001) and higher postoperative mortality (1.3% vs 0.39%) than CEA.

• For symptomatic patients (8%), the rates for postoperative stroke (4.2% vs 1.1%, P < .0001) and mortality (7.5% vs 1.0%, P < .0001) were significantly higher after CAS

McPhee et al, 2007

Clinical results of carotid artery stenting

compared with carotid endarterectomy

• Ten trials encompassing 3580 patients were analyzed. Patients who underwent CAS had a higher risk of 30-day stroke/death relative to patients who underwent CEA (risk ratio [RR], 1.30; 95% CI, 1.01-1.67).

• Subgroup analysis of trials enrolling only symptomatic patients showed higher risk of 30-day stroke/death (RR, 1.63; 95% CI, 1.18-2.25), but trials enrolling both symptomatic and asymptomatic patients showed no significant differences (RR, 0.89; 95% CI, 0.59-1.35).

Brahmandam et al 2008

Risk-adjusted 30-day outcomes of carotid stenting and endarterectomy: results from the

SVS Vascular Registry.

• When CAS and CEA were compared in the treatment of atherosclerotic disease only, the difference in outcomes between the two procedures was more pronounced, with death/stroke/MI

6.42% after CAS vs 2.62% following CEA, P < .0001.

• Following best possible risk adjustment of these unmatched groups, symptomatic and asymptomatic CAS patients had significantly higher 30-day postprocedure incidence of death/stroke/MI when compared with CEA patients.

Sidway et al 2009

Further on Going Trials

• Various RCTs on CEA vs PTA + Stent

CAVATAS IIACST IITACITSPACE II

Equipoise!

Timing of Angioplasty Many suggest wait 6 weeks

Assuming similar stroke rate CEA still prevents 170 more strokes per 1000 interventions

Better out than in !

Candidates for PTA

30 Day Stroke Rate

0

1

2

3

4

5

6

7

8

Angioplasty

Endarterectomy

Any stroke Disabling/

fatal stroke

TIA Death

%

Golledge J, Mitchell A, Greenhalgh RM,

Davies AH Stroke 2000

2009

CREST Study Design

• RCT of CAS vs CEA• 1:1 randomisation, stratified by centre and

symptomatic status• Lead-in credentialing for CAS

– N=20 CAS– 427 applicants, 224 (52%) approved to randomise

• Primary end-point – composite:– Any stroke, MI (including biochemical) or death within

30 days– Ipsilateral stroke to 4 years

• Target recruitment 2,500• Industry sponsored

NEJM 2010;363(1):11-23

p=0.51

NEJM 2010;363(1):11-23

NEJM 2010;363(1):11-23

CREST at 4 Years

CREST• symptomatic (n=1,321) or asymptomatic (n=1,181)

• At 30 days, the rate of stroke was significantly higher with stenting, at 4.1% vs. 2.3% with surgery.

• Myocardial infarction was higher with carotid endarterectomy, at 2.3% vs. 1.1% with stenting.

• when death and stroke are considered alone, there are almost twice as many events with carotid stenting/angioplasty as there are with carotid endarterectomy.

“I do not believe the results of CREST should alter the conclusion that endarterectomy remains the treatment of choice for symptomatic patients”

Moore 2010, PI CREST

CREST Limitations

• Composite endpoint• Biochemical MI• Underpowered to show difference in death and major

ipsilateral stroke• Heterogeneity of symptomatic and asymptomatic patients• Not all patients on statins • More lipid lowering in CEA• More anti-platelets in CAS• Advances in BMT, CEA stent and embolic protection

since CREST commenced in 2000• Can CREST CAS results be reproduced in wider

practice?• Left to interpretation based on personal bias?

Identify at risk asymptomatic patients

• NNT

• Degree of stenosis

• Plaque type

Is asymptomatic carotid endarterectomy a good use of

resources?

Are stroke rates changing over time?

SMART

ASED

Johnson

ACAS

VA

CHS

ACBS

To estimate the lifetime cost-effectiveness of early endarterectomy in the UK based on the Asymptomatic

Carotid Surgery Trial

ACST, Lancet 2010

Markov transition state model

HenrikksonBJS 2005

Event rates taken from ACST

Halliday et al, Lancet 2010

Costs standardised to 2010

CEA £33451

Disabling stroke Year 1 £29,3122

Disabling stroke Year 2+ £14,8462

Non-disabling stroke Year 1 £4,9382

Non-disabling stroke Year 2 £1,1522

Medical therapy equivalent both arms

Costs

1 NHS HRG Tariff 2010-2011 2 NHS HTA 2006

?

?

Assessing cost-effectiveness

Additional cost (£)

Additional effect (QALYs)

Results

-0.1 0.1 0.2

-2000

2000

4000

6000

£20, 000 per QALY

£30, 000 per QALY

Women > 75y

Men > 75y

Men < 75y

Women < 75y

BASE CASE

CEA more costly

CEA more effective

Restriction of crossovers

Incremental effectiveness / QALYs

Incr

emen

tal c

ost /

£

Base case ICER = £7584/QALY

Reduced stroke rates

Limitations

• Previous US trials with higher stroke rates, shorter follow up and fewer patients excluded

• TIA not included as endpoint• Loss of productivity from stroke not included in costs• Informal care not included in costs• Stenting not considered following interim guidance from

NICE

Interpretation

• Endarterectomy was likely to be cost-effective in under 75s• Especially so in young women• Late crossovers to endarterectomy did not improve cost-

effectiveness• With lower background stroke rates, endarterectomy may soon

become borderline cost-effective, even if it becomes safer

• Maintaining cost-effectiveness relies on:• Identification of patients with high risk carotid plaque• Maintaining low rates of operative stroke• Prevention of cardiac death for men in their 70s

X

XX

?

NEJM 2010;363(1):11-23

Effect of Age

NEJM 2010;363(1):11-23

Lancet Neurol 2011;10:530-537

Effect of Gender

Impact at 1 Year

JACC 2011;58:1557-1565

Impact of Events – SF36

NEJM 2010;363(1):11-23

Time from Symptoms to Surgery

Naylor 2007

ACST

Effect of Symptomatic Status

Stroke 2011;42:675-680