columbia university medical center the cardiovascular research foundation state of the art review:...

Columbia University Medical CenterColumbia University Medical CenterThe Cardiovascular Research FoundationThe Cardiovascular Research Foundation

State of the Art Review:State of the Art Review:Carotid Stenting, Patient Selection, Carotid Stenting, Patient Selection,

and Clinical Trial Results and Clinical Trial Results

William A. Gray MDWilliam A. Gray MDDirector of Endovascular ServicesDirector of Endovascular Services

Associate Professor of Clinical MedicineAssociate Professor of Clinical Medicine

DisclosuresDisclosures

• ConsultantConsultant Abbott VascularAbbott Vascular Cordis/J&JCordis/J&J BSCBSC MedtronicMedtronic ContegoContego Silk RoadSilk Road

OverviewOverview• Large scale CEA dataLarge scale CEA data

LandmarkLandmark Recent validation of high risk population and Recent validation of high risk population and

differential outcomesdifferential outcomes

• What has the evolution in CAS data been?What has the evolution in CAS data been?

• What predicts stroke in CAS?What predicts stroke in CAS?

• What are the data for outcomes as regards:What are the data for outcomes as regards: ExperienceExperience DevicesDevices

95

89

91

74

50

60

70

80

90

100

110

0 1 2 3 4 5Year of study

% w

ithou

t st

roke

Surgical-ACAS

Medical-ACAS

Surgical-NASCET

Medical-NASCET

Surgical-ACST

Medical-ACST

17%

6%

ACST crossover

Landmark CEA studiesLandmark CEA studiesACAS, ACST and NASCET: ACAS, ACST and NASCET:

Comparative ResultsComparative Results

NY State Registry ResultsNY State Registry ResultsState of the state of CEAState of the state of CEA

Stroke. 2009;40:221-229

Validation of high-risk

CEA subsets.

Conclusions from these recent dataConclusions from these recent data

• Although limited in terms of surveillance Although limited in terms of surveillance for events (retrospective, not neurologist for events (retrospective, not neurologist evaluated):evaluated): Confirmatory data on the outcomes after Confirmatory data on the outcomes after

CEA, though probably underestimates CEA, though probably underestimates eventsevents

Clearly identifies subgroups at increased Clearly identifies subgroups at increased riskrisk• Including patients >80 years Including patients >80 years

Evolution in CAS OutcomesEvolution in CAS Outcomes

Incidence of stroke and death in high risk Incidence of stroke and death in high risk carotid stent IDE trials: 2002-2008carotid stent IDE trials: 2002-2008

Incidence of stroke and death in high risk Incidence of stroke and death in high risk carotid stent IDE trials: 2002-2008carotid stent IDE trials: 2002-2008

0

1

2

3

4

5

6

7

8

9S

AP

PH

IRE

200

2

AR

CH

eR 2

003

SE

CuR

ITY

200

3

BE

AC

H 2

004

MA

VeR

IC 2

004

CA

BE

RN

ET

2004

CR

EA

TE 2

005

EM

PIR

E (2

008)

EP

IC (2

008)

PR

OTE

CT

(200

8)

% M

AE

0

1

2

3

4

5

6

7

8

9S

AP

PH

IRE

200

2

AR

CH

eR 2

003

SE

CuR

ITY

200

3

BE

AC

H 2

004

MA

VeR

IC 2

004

CA

BE

RN

ET

2004

CR

EA

TE 2

005

EM

PIR

E (2

008)

EP

IC (2

008)

PR

OTE

CT

(200

8)

% M

AE

ARMOUR results: 1° EndpointARMOUR results: 1° Endpoint

2.3% 2.1%2.3% 2.1%2.3% 2.7%

0.0% 0.0%

3.2%2.7%

0%

3%

6%

ALL Asymptomatics Symptomatics Age >75 Symptomatics &Age >75

30d Strokes 30d MACCE

30d Results (ITT & Full Population)30d Results (ITT & Full Population)

30d Results by Symptoms and Age (ITT)30d Results by Symptoms and Age (ITT)

ARMOUR 30d

0.0%0.9%

2.7%

0.0%1.2%

2.3%0.9%1.4%0.9% 0.8% 1.2% 0.8%

0%

2%

4%

6%

Major Stroke Minor Stroke Death MI TIA 1° Endpointcumulative

MACCE

ITT (220) ITT + Roll-in (257)

Predictors of OutcomesPredictors of Outcomes

VariableVariable

Symptomatic Symptomatic

Pre-dilatation w/o EPD Pre-dilatation w/o EPD (n=143)(n=143)

Age ≥ 80 (n=788)Age ≥ 80 (n=788)

Multiple stents per Multiple stents per procedure (n=196)procedure (n=196)

CAPTURE 3500: CAPTURE 3500: Predictors of CAS OutcomesPredictors of CAS Outcomes

All Patients (3307) Symptomatic (479) Asymptomatic (2517) >80 (809) <80 (2611)

2.46

2.19

3.09

3.154.972.21

1.842.002.53

2.42

2.44

2.17

2.93

Odds Ratio

CAS Outcomes by age and symptomsCAS Outcomes by age and symptoms

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16

0.18

0.20

0.22

0.24

0.26

0.28

0.30

40 50 60 70 80 90 100

Age

Pre

dic

ted

Str

oke

Rat

e

Symptomatic

Asymptomatic

CAPTURE 3500

CAPTURE 3500: CAPTURE 3500: Stroke by Location Stroke by Location

1.7%

2.2%

0.2%

0.7%

0.0

1.0

2.0

3.0

4.0

% o

f p

ati

en

ts

Ipsilateral (3.9%) Non-Ipsi ( 0.9%)

Minor

Major

44% 22

%

• 18% of all strokes in CAPTURE are non-ipsilateral

• More non-ipsilateral strokes were minor c/w ipsilateral

Experience and OutcomesExperience and Outcomes

ExperienceExperience

• Preface (assumption: volume equals experience)Preface (assumption: volume equals experience)• Trial-based outcome data supporting experience Trial-based outcome data supporting experience

as a determinant of outcomesas a determinant of outcomes SurgicalSurgical Pro-CASPro-CAS EVA-3SEVA-3S SPACESPACE PMS registriesPMS registries

Retrospective CEA Survey Demonstrates Inverse Retrospective CEA Survey Demonstrates Inverse Relationship between Volume and Neurologic and Relationship between Volume and Neurologic and

Mortality Outcome Mortality Outcome

Maryland state 1998Maryland state 1998

J Vasc Surg. 1998;27:25-33

……More CEA Volume DataMore CEA Volume Data

Mortality

Stroke

Length of stay

J Vasc Surg. 1998;27:25-33

Pro-CAS: Prospective registry of CASPro-CAS: Prospective registry of CAS• Prospective, multi-center German registryProspective, multi-center German registry

25 sites/6 year enrollment (July 1999-June 2005)25 sites/6 year enrollment (July 1999-June 2005) 5341 interventions (outcomes of first 3267 5341 interventions (outcomes of first 3267

published 2004)published 2004)• Median # of center CAS before enrollment: 38 (0-1200)Median # of center CAS before enrollment: 38 (0-1200)• Median # of center CAS SPACE enrollment: 140 (10-806)Median # of center CAS SPACE enrollment: 140 (10-806)• No learning curve data availableNo learning curve data available

No defined inclusions or exclusions, or procedural No defined inclusions or exclusions, or procedural methodsmethods

No angiographic core labNo angiographic core lab Voluntary independent neurologic assessment (no Voluntary independent neurologic assessment (no

stroke scales or CEC)stroke scales or CEC) Primary endpoint: in-hospital death and stroke Primary endpoint: in-hospital death and stroke

Stroke 2008;39;2325-2330;

Pro-CAS: Overall outcomesPro-CAS: Overall outcomes

• Median age: 70 years (32-96)Median age: 70 years (32-96)

• In-hospital stoke and death: 3.6%In-hospital stoke and death: 3.6%

Pro-CAS: Effect of experience*Pro-CAS: Effect of experience*

*Univariate analysis

Pro-CAS: effect of age and gender*Pro-CAS: effect of age and gender*


Pro-CAS: effect of symptom status*Pro-CAS: effect of symptom status*


Pro-CAS: Multivariate analysis of predictorsPro-CAS: Multivariate analysis of predictors

The trouble with (European) The trouble with (European) randomized CAS datarandomized CAS data

• Trial analysis in CAS using ICSS as a primerTrial analysis in CAS using ICSS as a primer

Columbia University Medical CenterColumbia University Medical CenterThe Cardiovascular Research FoundationThe Cardiovascular Research Foundation

EVA-3S EVA-3S

Randomized CEA vs CASRandomized CEA vs CAS

RR 2.5 (95% CI, 1.2-5.1) P=0.01

262262 265265

Mas JL, et al. New Engl J Med. 2006;355:1661-1671Mas JL, et al. New Engl J Med. 2006;355:1661-1671

EVA-3S: Trial designEVA-3S: Trial design

• Randomized, multicenter, non-inferiority trial of Randomized, multicenter, non-inferiority trial of standard surgical risk patients with symptomatic standard surgical risk patients with symptomatic carotid stenosis >60%carotid stenosis >60% Primary endpoint: 30-day death and strokePrimary endpoint: 30-day death and stroke Secondary endpoint: 30-day MAE plus ipsilateral Secondary endpoint: 30-day MAE plus ipsilateral

stroke to 4 yearsstroke to 4 years

• 30 centers in France30 centers in France

• 527 patients527 patients

Lancet Neurol 2008; 7: 885–92

EVA-3S critiqueEVA-3S critique• Slow enrollment resulted in limited investigator experienceSlow enrollment resulted in limited investigator experience

1.7 CAS patients/year/site1.7 CAS patients/year/site

• Early and/or non-standard technique resulted in Early and/or non-standard technique resulted in unnecessary morbidityunnecessary morbidity Use of EPD not widespread or familiarUse of EPD not widespread or familiar

• Lack of use in the early phase of the trial likely responsible for 4-5 Lack of use in the early phase of the trial likely responsible for 4-5 excess strokes (~20% of all strokes in the CAS arm)excess strokes (~20% of all strokes in the CAS arm)

5% 5% stent procedure failure requiring emergency surgery in stent procedure failure requiring emergency surgery in this trial resulting in 2 strokes in the CAS groupthis trial resulting in 2 strokes in the CAS group

– Major pivotal trials in this country (e.g., SAPPHIRE, ARCHeR) have not Major pivotal trials in this country (e.g., SAPPHIRE, ARCHeR) have not reported reported anyany emergent surgical conversions emergent surgical conversions

No pre-dilation in >80% of procedures (standard in US)No pre-dilation in >80% of procedures (standard in US) Significant (beyond local) anesthesia was employed in ~30% Significant (beyond local) anesthesia was employed in ~30%

of procedures (estimated <5% in US)of procedures (estimated <5% in US)

EVA-3S critiqueEVA-3S critique

• Limited investigator experience and number of trained Limited investigator experience and number of trained sites/operatorssites/operators Experienced operators defined by 12 Experienced operators defined by 12 lifetime lifetime CAS CAS

procedures or 5 CAS procedure if 35 supra-aortic procedures or 5 CAS procedure if 35 supra-aortic procedure procedure

• These operators were deemed experienced and allowed to These operators were deemed experienced and allowed to tutor the non-experiencedtutor the non-experienced

No centralized training qualification process (local No centralized training qualification process (local proctors pronounced the operators qualified)proctors pronounced the operators qualified)

Approximately 2/3 of sites were under tutelage at the Approximately 2/3 of sites were under tutelage at the beginning of their beginning of their randomized randomized participation.participation.

EVA 3SEVA 3S

• Prototypical low operator experience multi-Prototypical low operator experience multi-center trialcenter trial

• Outcomes for CAS in EVA-3S for Outcomes for CAS in EVA-3S for symptomatic standard risk patients are higher symptomatic standard risk patients are higher than the contemporary cohortsthan the contemporary cohorts

SPACE: an incomplete studySPACE: an incomplete study• Randomized, multicenter non-inferiority study of CEA Randomized, multicenter non-inferiority study of CEA

vs. CAS in standard surgical risk symptomatic vs. CAS in standard surgical risk symptomatic patients with 70% carotid stenosispatients with 70% carotid stenosis Primary endpoint 30-day ipsilateral stroke and Primary endpoint 30-day ipsilateral stroke and

deathdeath Only 27% EPD useOnly 27% EPD use Stopped before non-inferiority was proven ($$$)Stopped before non-inferiority was proven ($$$) Pre-specified secondary analyses include:Pre-specified secondary analyses include:

• AgeAge• SexSex• Type of eventType of event• Side of interventionSide of intervention• Degree of stenosisDegree of stenosis• High-grade contralateral stenosisHigh-grade contralateral stenosis

6.34 6.84

0

5

10

15

20

Primary Endpoint

30 d

ay d

eath

an

d s

tro

ke (

%)

CEA CAS

6.34 6.84

0

5

10

15

20

Primary Endpoint

30 d

ay d

eath

an

d s

tro

ke (

%)

CEA CAS

SPACE SPACE Randomized CEA vs. CAS symptomatic patientsRandomized CEA vs. CAS symptomatic patients

SPACE collaborators. Lancet 2006;368:1239-47SPACE collaborators. Lancet 2006;368:1239-47

Abs diff: 0.51, 90%CI 1.89-2.91, P=0.09 (non-inferiority)

595595 605605

SPACE: Effect of volumes on outcomeSPACE: Effect of volumes on outcome

Neuroradiology, Sept 2008

SPACE: sub-group analysis (PP)SPACE: sub-group analysis (PP)

SPACE: Hazard ratio for 30-day MAE plus SPACE: Hazard ratio for 30-day MAE plus ipsilateral stroke to 2 yearsipsilateral stroke to 2 years

The evolution of CAS in symptomatic patients:The evolution of CAS in symptomatic patients:EVA-3S, SPACE, ICSS vs. the worldEVA-3S, SPACE, ICSS vs. the world

0

2

4

6

8

10

12

EVA-3S (265) ICSS (853) SPACE (599) CREST Lead-in (343)

CAPTURE 2/EXACT

(589)

EMPIRE (78) EPIC (47) PROTECT (35)

30-day death and stroke for CAS in symptomatic patients trial (n)

AHA guideline limit

Long-term CAS efficacy for stroke preventionLong-term CAS efficacy for stroke prevention

EVA-3S: 4-year outcomesEVA-3S: 4-year outcomes

Any ipsilateral stroke Any stroke Any stroke or death

SPACE: K-M plots of 2-year outcomesSPACE: K-M plots of 2-year outcomes

Ipsilateral stroke and vascular death

30-day stroke/deathplus ipsilateral stroke

to 2 years

SPACE and Pro-CAS: conclusionsSPACE and Pro-CAS: conclusions

• Experience determines outcomes in CASExperience determines outcomes in CAS

• Age related gradient for outcomes in CAS, Age related gradient for outcomes in CAS, favoring the younger patient (even over favoring the younger patient (even over surgery)surgery)

• Long-term efficacy of CAS similar to CEALong-term efficacy of CAS similar to CEA

Post-market US registriesPost-market US registries

5.5

9.9

4.93.8

8.1

3.44.0

7.4

3.6

0

2

4

6

8

10

12

All Patients Symptomatic Asymptomatic

% o

f a

ll p

ati

en

ts

CAPTURE (4225) CAPTURE 2 (1987) EXACT (2124)

CAS after device approval: CAS after device approval: Increasingly safe in the “real world”Increasingly safe in the “real world”

* Hierarchical Events – Includes only the most serious event for each patient and includes only each patient’s first occurrence of each event

C: n=573; E#: n=204 C2#: n=197 C: n= 3574; E: n=1917; C2: n=1788

All stroke/death*

#Small symptomatic cohorts preclude any comparisons

2004 2007

ARCHeR 8.3%

0.8 0.6

2.42.9 3.3

2.0

0.9

5.4

6.7 7.0

0

2

4

6

8

10

Death MI Stroke Stroke orDeath

MAE

(%)

Pat

ien

ts

Asymptomatic (n= 1,446)

Symptomatic (n = 555)

MAE defined as any death, MI or stroke

SAPPHIRE WW: 30 day major adverse events Asymptomatic vs. Symptomatic

P=0.0010

P=NS

P=0.0005P=0.0003P=0.0286

3% AHA Asx

6% AHA Sx

CAPTURE: CAPTURE: Asymptomatic Patients <80 Years Asymptomatic Patients <80 Years

No stroke/death at 43% (61/143) of sites

30 day stroke/death distribution by site30 day stroke/death distribution by site

N=2764

3%3%

CAPTURE 2: Asymptomatic <80 PatientsCAPTURE 2: Asymptomatic <80 Patients

N=1372

30 day stroke/death distribution by site30 day stroke/death distribution by site

No stroke or death in 81% (134/166) of sites

Outcome Improvements with Increasing Outcome Improvements with Increasing Experience in CASExperience in CAS

% of sites with 0% 30-day MAE% of sites with 0% 30-day MAE

2004 2008

The Influence of Experience: The Influence of Experience: PMS OutcomesPMS Outcomes

*Hierarchical events – Includes only the most serious event for each patient and includes only each patient’s first occurrence of each event.

Level I CAPTURE: n=210

EXACT: n=267 CAPTURE 2: n=83

Level 2 CAPTURE: n=1879 EXACT: n=776 CAPTURE 2: n=1026

Level 3 CAPTURE: n=735


Asymptomatic patients <80 years old

2.5%3.4%

3.8%

0%1%2%3%4%5%6%7%8%

Str

oke

deat

h ra

tes

The Influence of Experience: The Influence of Experience: PMS OutcomesPMS Outcomes

* Hierarchical events – Includes only the most serious event for each patient and includes only each patient’s first occurrence of each event.

Level I CAPTURE: n=52


Level 2 CAPTURE: n= 282 EXACT: n=87 CAPTURE 2: n=105

Level 3 CAPTURE: n=93


Symptomatic patients <80 years old

4.8%

7.6%

8.8%

0%

2%

4%

6%

8%

10%

Str

oke

deat

h ra

tes

EXACT and CAPTURE 2EXACT and CAPTURE 230-day Composite Endpoint of Death and Stroke 30-day Composite Endpoint of Death and Stroke

Hierarchical- Includes only the most serious event for each patient and includes only each patient first occurrence of Hierarchical- Includes only the most serious event for each patient and includes only each patient first occurrence of each event. each event.

*

EXACT (N=2145)*CAPTURE 2 (N=4175)Combined (N=6320)

EXACT (N=213)CAPTURE 2 (N=548)Combined (N=761)

EXACT (N=1931)CAPTURE 2 (N=3627)Combined (N=5558)

EXACT/CAPTURE 2 (combined): EXACT/CAPTURE 2 (combined): 30-day major adverse events 30-day major adverse events

symptomatic patients <80 years symptomatic patients <80 years


Symptomatic patients

N=589

5.3

2.21.0 1.4

3.1

012345678

Death/Stroke Death/Major Stroke Death Stroke Minor (3.1%)Stroke Major (1.4%)

(%)

Su

bje

cts

6% AHA guideline


N=4282

2.91.1 0.8 0.6

1.8

012345678

Death/Stroke Death/Major Stroke Death Stroke Minor (1.8%)Stroke Major (0.6%)

(%)

Su

bje

cts

3% AHA guideline

EXACT/CAPTURE 2 (combined): EXACT/CAPTURE 2 (combined): 30-day major adverse events 30-day major adverse events

asymptomatic patients <80 years asymptomatic patients <80 years

Devices and OutcomesDevices and Outcomes

1.1 0.9 1.4

3.03.1 3.04.3

5.4

0

2

4

6

8

10

12

C2<80 E<80 C2 >/=80 E >/=80

% o

f a

ll p

ati

en

tsmajor stroke/death all stroke/death

CAS outcomes: No differences by deviceCAS outcomes: No differences by device30 day Outcomes30 day Outcomes

• Hierarchical Events – Includes only the most serious event for each patient and includes only each patient’s first occurrence of each event• Clinical Studies are not directly comparable by methodology presented. -Data from respective studies are presented for educational purposes



<80 years >80 years

3%

Future Data SetsFuture Data Sets

• CREST: February 2010CREST: February 2010• ACT I: Lead-in phaseACT I: Lead-in phase

Event 30 days, N=118

Death, Stroke, and MI* 1.7%

All Stroke and Death* 1.7%

Major Stroke and Death* 0.0%

Death 0.0%

All Stroke 1.7%

Major Stroke 0.0%

Minor Stroke 1.7%

MI 0.0%

ConclusionsConclusions

• A relationship of experience to outcomes in CAS A relationship of experience to outcomes in CAS appears to be present based on indirect evidence:appears to be present based on indirect evidence: Generally improving outcomes for the fieldGenerally improving outcomes for the field Operator disparityOperator disparity

• ……and direct evidenceand direct evidence EVA-3S vs. “the world”EVA-3S vs. “the world” IDE and PMS registriesIDE and PMS registries

• No convincing evidence of device influenceNo convincing evidence of device influence

• Future trials will deliver more prospective, and likely Future trials will deliver more prospective, and likely confirmatory, dataconfirmatory, data

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