circulatory system devices panel wednesday, april 21, 2004 cordis corporation precise 5.5f and 6.0f...

CIRCULATORY SYSTEMCIRCULATORY SYSTEMDEVICES PANELDEVICES PANEL

Wednesday, April 21, 2004Wednesday, April 21, 2004

Cordis Corporation

Precise 5.5F and 6.0F OTW and RX nitinol Stent System

Angioguard XP OTW and RX Emboli Capture Guidewire System

PMA P030047

Lead FDA Reviewer

Lisa Kennell

DHHS / FDA / CDRHDHHS / FDA / CDRH3

Introduction Introduction• Regulatory history of the Cordis

system

• Non-clinical study summary

• Statistical Summary

• Clinical Summary

• Panel Questions


FDA Review TeamFDA Review Team

Team Leader Lisa Kennell

Clinical Reviewers Ronald Weintraub, M.D.

Wolf Sapirstein, M.D.

Paul Chandeysson, M.D.

Statistics Heng Li

Engineering Deanna Busick

Vivianne Holt

Terry Woods

Animal data/remainder Lisa Kennell


Device Description/SizesDevice Description/Sizes

• PRECISE 5.5F OTW • 135 cm long• 0.018” guidewire• Sizes 5, 6, 7, and 8 mm x 20, 30, or 40 mm

straight and tapered 8-6 x 30 mm

• PRECISE 6.0F OTW• 135 cm long• 0.018” guidewire• Sizes 9 and 10mm x 20, 30, and 40 cm

straight and 9-7 and 10-7 x 30 cm tapered


Device Description/Sizes continuedDevice Description/Sizes continued

• PRECISE RX 5.5 and 6.0F

• 135 cm long

• 0.014” guidewire

• Same sizes as OTW but no tapered configurations

• RX not under consideration today


Device Description/Sizes continuedDevice Description/Sizes continued

• ANGIOGUARD XP OTW• 300 or 180 cm long• 0.014” guidewire• Filter diameters 4, 5, 6, 7, and 8 mm• For vessel diameters 3 - </= 7.5

• ANGIOGARD XP RX• 180 cm long• 0.014” guidewire• Filter diameters 4, 5, 6, 7, and 8 mm

• RX not under consideration today


Recent DevelopmentsRecent Developments

Cordis submitted unsolicited amendment to PMA 4/5/04

• problem with air entrained in the RX version when used “off label” in carotid and other non-approved indications

• Has resulted in adverse events from air embolism

• Event rate estimated at 0.14% for all procedures (carotid and others)


Recent Developments continuedRecent Developments continued

• Performed simulated bench testing to determine root cause, but this testing not optimal

• Corrective actions

• stipulate use of larger guiding catheters/introducer sheaths to potential for air entrapment

• Modify IFU prep procedure

• Did not perform animal testing to verify if corrective action corrected problem


Precise/AngioGuard IndicationPrecise/AngioGuard Indication

The proposed indication for use for the system is:“The Cordis PRECISE Nitinol Stent System used in conjunction with the ANGIOGUARD XP Emboli Capture Guidewire is indicated for use in the treatment of carotid artery disease in high-risk patients. High-risk is defined as patients with neurological symptoms (one or more TIA’ s or one or more completed strokes) AND >/= 50% atherosclerotic stenosis of the common or internal carotid artery by ultrasound or angiogram;

ORPatients without neurological symptoms AND >/= 80% atherosclerotic stenosis of the common or internal carotid artery by ultrasound or angiogram.

Symptomatic or asymptomatic patients must also have one or more condition(s) that place them at high-risk for carotid endarterectomy.”


Regulatory HistoryRegulatory History

• IDE submitted in 1998

• Many design changes to devices

• Most significant were addition of Angioguard, lowering profile and rapid exchange configuration


Regulatory History ContinuedRegulatory History Continued

• Sponsor terminated randomized study early. Sponsor states reasons for early termination being:

• too many competing studies,

• physicians reluctant to randomize,

• Surgeons unwilling to refer patients



• Competing studies involved Cordis’s own devices

• Competing studies were single-investigator sponsored studies authorized by Cordis, but not followed by Cordis

• Cordis supplied each investigator copy of feasibility (non-randomized) protocol, CRFs, consent, and letter of authorization to facilitate opening their own IDE



• Most single investigator-sponsors followed Cordis protocol, with little deviation, however Cordis not certain of exact protocol amendments

• Investigator-sponsored studies each approved for 50-100 subjects



• No contractual relationship between Cordis and investigator-sponsors for sharing data

HOWEVER

• PMA regulation stipulates that sponsor must report all data that they are aware of or should be aware of, so Cordis made effort to supplement PMA with this data



•Cordis did not fund, sponsor or monitor these studies

•34 sites contributed data in PMA, 2 did not participate

•Single investigator sites following to 12 months, but only 30 day data in PMA


Non-Clinical Study SummaryNon-Clinical Study Summary

• Sponsor conducted simulated use, fatigue and device specification and integrity tests on the bench and in animals for both the stent and the embolic protection device, with each iteration of the devices.

• RX iteration has only pre-clinical bench and animal testing; FDA agreed to allow clinical use without clinical data since “working end” not changed

• Still working with sponsor on RX validation; only OTW under consideration today


Non-Clinical Study Summary - Non-Clinical Study Summary - continuedcontinued

• Engineering reviews complete and satisfactory

• Biocompatibility review complete and satisfactory

• Sterilization review ongoing but do not anticipate issues


Other non-Clinical IssuesOther non-Clinical Issues

• FDA issued warning letter on April 1, 2004• Cited non conformance with the Current

Good Manufacturing Practice (CGMP) requirements

• “FDA is concerned with the breadth and scope of the …violations”

• “symptomatic of serious underlying problems in [Cordis’ s] manufacturing and quality systems”

• FDA sought Corporate Corrective and Preventive Action plan which ties all facilities


Statistical SummaryStatistical Summary

Heng Li, FDA Statistician


Statistical IssuesStatistical Issues

• SAPPHIRE Randomized Trial

• SAPPHIRE Stent Registry

• Propensity Score Analysis

• Conclusions


Randomized Trial:Randomized Trial:Study Protocol AdherenceStudy Protocol Adherence

• The randomized clinical study was originally designed as a group sequential clinical trial using the sequential triangular test.

• Interim analyses were scheduled every 100 patients.

• The expected sample size was 600 to 900, with a maximum sample size of 2400.


Randomized Trial:Randomized Trial:Study Protocol AdherenceStudy Protocol Adherence

• The randomized study was not conducted according to the original group sequential protocol

• An alternative protocol seems to have never been developed

• FDA was not informed of any change in protocol prior to PMA submission


Randomized Trial:Randomized Trial:Statistical InferenceStatistical Inference

• Statistical inferences (e.g., declaring non-inferiority) for designed studies should be made according to the study design.

• Since the initial protocol was neither followed nor replaced by an alternative one, a nominal protocol needs to be referred to when statistical inference is conducted.


Randomized Trial:Randomized Trial:Statistical InferenceStatistical Inference

• The nominal protocol used by the sponsor for this PMA submission is a fixed sample size design with the planned sample size equal to the sample size at which the trial was discontinued.

• This is probably the most favorable choice for declaring non-inferiority.


Randomized trial:Randomized trial:Pre-specified analysisPre-specified analysis

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Randomized trial:Randomized trial:Analysis at 334 patientsAnalysis at 334 patients

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Stent Registry:Stent Registry:Pre-specified analysisPre-specified analysis

• OPC=16.94%

• Observed 360 day MAE rate: 15.76%

• 95% CI = (12.36%, 19.68%)

• OPC not met


Stent Registry:Stent Registry:comparison with randomized CEAcomparison with randomized CEA

• The sponsor carried out a comparison of the stent registry versus the CEA arm of the randomized studies

• Since by definition the patient characteristics of the two groups are different, a simple comparison is not appropriate

• The sponsor used the propensity score method to compare the two groups


Propensity Score MethodPropensity Score Method

• A class of statistical procedures that can help evaluate difference in treatment effect when the treatment groups are not necessarily comparable (e.g., treatments are not randomly assigned).

• The propensity score methodology reduces bias by balancing (on average) a set of chosen covariates


Propensity Score MethodPropensity Score Method

• Propensity score method has the advantage of typically being able to simultaneously balance a large number of covariates.


Stent Registry:Stent Registry:Comparison with randomized CEAComparison with randomized CEA

• It is not clear whether the analysis that the sponsor performed has taken full advantage of the potential to balance all the clinically relevant covariates

• Key covariates such as baseline demographics and angiographic data were not considered


ConclusionsConclusions

• Randomized trial• Original group sequential protocol not

followed • A second protocol not developed• No evidence of crossing non-inferiority

boundary at termination of study


Randomized trial:Randomized trial:Analysis at 334 patientsAnalysis at 334 patients

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Conclusions continuedConclusions continued

• Randomized trial• Original group sequential protocol not

followed • A second protocol not developed• No evidence of crossing non-inferiority

boundary at termination of study• Registry

• Fails to meet original OPC• Propensity score analysis not adequate


Clinical ReviewClinical Review

Dr. Ronald Weintraub, FDA Consultant


OverviewOverview

• Randomized SAPPHIRE trial

• Stent Registry cohort

• Subgroup results

• Effectiveness results

• Historical surgical trials


SAPPHIRE Trial


Inclusion CriteriaInclusion Criteria

• Symptomatic patients (ipsilateral TIA or completed stroke) with >/= 50% stenosis

OR• Asymptomatic patients with >/= 80%

stenosis

AND• A co-morbid condition indicating higher

risk for CAE


Inclusion Criteria ContinuedInclusion Criteria ContinuedCo-Morbid RisksCo-Morbid Risks

• Significant Cardiac disease

• Severe pulmonary disease

• Contralateral carotid occlusion

• Contralateral laryngeal palsy

• Post radiation treatment

• Previous CEA/stent

• Other anatomic risk factors


Exclusion CriteriaExclusion Criteria

• Stroke-in-progress, or stroke within 48 hours

• Intracranial mass• stent in target vessel• Intraluminal thrombus visible• Total occlusion of target vessel site• Known PVD, supra-aortic or ICA

tortuosity precluding interventional approach


Exclusion Criteria ContinuedExclusion Criteria Continued

• Intracranial aneurysm >9mm

• Lesion requires >2 stents

• Stent in contralateral vessel <30 days

• Subclavian ostial lesion (added later)

• Percutaneous interventions planned <30 days after index procedure (initially one year)

• Staged procedure for bilateral disease <30 past index procedure


Protocol overviewProtocol overview

Sponsor contracted out some aspects, or had independent oversight:

• Clinical Events Committed to adjudicate adverse events

• Core lab for angiographic analyses• Core lab for ultrasound analyses• Core lab for analysis of filter baskets• Data analysis contracted to Harvard

Clinical Research Institute


Study EndpointsStudy Endpoints• Primary Endpoints

• Composite major adverse events (death, any stroke, and/or MI at 30-days)

• Composite MAE as above, plus death and/or ipsilateral stroke 31 days to 12 months


Study Endpoints ContinuedStudy Endpoints Continued

• Secondary Endpoints• Successful stent deployment• Successful filter deployment and retrieval• <30% residual stenosis by angiography

post-dilatation• Access site complications• Surgical site complications• Patency (>50% restenosis by US at 48

hours, 6, 12, 24, and 36 months


Study Endpoints ContinuedStudy Endpoints Continued

• Independent neurological assessments at 24 hours, 30 days, 6, 12, 24, 36 months

• 30-day and 6 month evaluation for stroke

• MAE composite at 6, 12, 24, and 36 months (death and ipsilateral stroke)

• Safety assessment of Angioguard XP

• Presence of trapped material in filter

• Laboratory analysis of trapped material


Enrollment DistributionEnrollment Distribution

Most patients were enrolled at 5 sites:

Cleveland Clinic 93 subjects (27.8%)

Prairie Cardiovascular 43 subjects (12.9%)

St. Luke’s Medical Center (WI) 30 subjects (9.0%)

St. Luke’s Medical Towers (AZ) 29 subjects (8.7%)

Midwest Card. Res. Found. 19 subjects (5.7%)

Total enrolled in these sites 214/334 (64%)


MAE Distribution by SiteMAE Distribution by Site

Site # Number Enrolled

360-Day MAE Rate

Cleveland Clinic

93 (27.8%) 14.0%

Prairie 43 (12.9%) 18.6%

St. Luke’s (WI) 30 (9.0%) 20.0%

St. Luke’s (AZ) 29 (8.7%) 6.9%

Midwest 19 (5.7%) 21.1%


Randomized Pivotal Trial Randomized Pivotal Trial 30 Day Major Adverse Event Rates30 Day Major Adverse Event Rates

Event RCT StentN=167

RCT CEAN=167

Difference [95% CI]

MAE 4.8% 9.6% -4.8% [-10.3%, 0.7%]

Death 1.2% 2.4% -1.2% [-4.0%, 1.6%]All stroke 3.6% 3.0% 0.6% [-3.2%, 4.4%]

Major ipsi stroke 0.0% 0.6% -0.6% [-1.8%, 0.6%]

Minor ipsi stroke 1.8% 0.6% 1.2% [-1.1%, 3.5%]

MI 2.4% 6.0% -3.6% [-7.9%, 0.7%]

Q-wave MI 0.0% 1.2% -1.2% [-2.8%, 0.5%]

Non-Q-wave 2.4% 4.8% -2.4% [-6.4%, 1.6%]



Event RCT StentN=157

RCT CEAN=146

Difference [95% CI]

MAE 12.0% 19.2% -7.2% [-14.9%, 0.6%]

Death 7.2% 12.6% -5.4% [-11.8%, 1.0%]

All Stroke 6.0% 7.2% -1.2% [-6.5%, 4.1%]

Major ipsi stroke 0.6% 3.0% -2.4% [-5.2%, 0.4%]

Minor ipsi stroke 3.6% 1.8% 1.8% [-1.7%, 5.3%]

MI 3.0% 7.2% -4.2% [-8.9%, 0.5%]

Q-wave MI 0.0% 1.2% -1.2% [-2.8%, 0.5%]

Non-Q-wave MI 3.0% 6.0% -3.0% [-7.4%, 1.4%]



Event RCT Stent

N=103

RCT CEA N=88

Difference [95% CI]

MAE 19.2% 26.7% -7.5% [-5.4%, 20.4%]

Death 14.4% 20.9% -6.5% [-5.0%, 18.0%]

All stroke to 30 days plus ipsi stroke >30 days

5.9% 5.8% 0.1% [-7.9%, 7.7%]

MI 6.0% 8.7% -2.7% [-6.1%, 11.5%]


30-day MAE Rates with and without 30-day MAE Rates with and without MI includedMI included

Study Cohort 30-Day Rate with MI 30-Day Rate w/out MIRCT Stent 4.8% 4.2%RCT CEA 9.6% 4.8%Registry 6.9% 5.9%RCT Symptomatic 2.0% CAS

10.9% CEA0.0% CAS 6.5% CEA

RCT Asymptomatic

6.0% CAS 9.2% CEA

6.0% CAS 4.2% CEA

Registry symptomatic

9.7% 8.1%

Registry Asymptomatic

5.7% 5.0%


MI DetailsMI Details

MI Type RCT Stent

N=167

RCT CEA

N=167

Difference [95% CI] Stent Registry

N=406Q wave 0% (0) 1.2% (2) -1.2% [-2.8%, 0.5%] 0.2% (1)

WHO non-Q wave

2.4% (4) 4.8% (8) -2.4% [-6.4%, 1.6%] 1.5% (6)

HCRI Type 1 3.6% (6) 4.2% (7) -0.6% [-4.8%, 3.6%] 3.9% (16)

HCRI Type 2 1.2% (2) 0.6% (1) 0.6% [-1.4%, 2.6%] 1.0% (4)

HCRI Type 3 1.8% (3) 2.4% (4) -0.6% [-3.7%, 2.5%] 0.2% (1)


Stent Registry CohortStent Registry Cohort


Stent Registry CohortStent Registry Cohort

• Patients entered into registry cohort prior to randomization• Total of 406 entered• Reasons for entry were given for 196/406 (48.3%). These

included:Prior CEA 62/406 (15.3%)Previous radiation 27/406 (6.7%)High Cervical Lesion 20/406 (4.9%)CAD 20/406 (4.9%)Age >80 15/406 (3.7%)COPD 11/406 (2.7%)Multiple co-morbidities 9/406 (2.2%)

• Unknown 210/406 (51.8%)• Asymptomatic 281/406 (69.2%)


Stent Registry CohortStent Registry CohortMajor Adverse Event RatesMajor Adverse Event Rates

Event 30 Day

N=406

360 Day

N=383

720 Day

N=239MAE 6.9% 15.8% 26.4%

Death 2.2% 10.1% 20.1%

All stroke 4.9% 9.1% 9.3%*

Major ipsi stroke

2.5% 3.2%

Minor ipsi stroke

1.7% 3.9%

MI 1.7% 2.7% 5.5%


Statistical InferenceStatistical Inference (Stent Registry) (Stent Registry)

OPC=12.94%δ=4%Observed 360 day MAE rate = 15.76%95% Confidence Interval for 360 day MAE (12.36%, 19.68%)p-value for H0: 360 day MAE=OPC+ δ p=0.29• Pre-specified criterion of non-inferiority: not met.

• It is not clear that the propensity score method has been thoroughly explored; questions remain about adequacy of analysis.


Subgroup Results


SymptomaticSymptomatic Subgroup Analysis Subgroup Analysis 30-Day Adverse Event Rates30-Day Adverse Event Rates

Event RCT Stent

N=50

RCT CEA

N=46

Difference [95% CI]

MAE 2.0% 10.9% -8.9% [-18.7%, .9%]

Death 0.0% 6.5% -6.5% [-13.7%, 0.6%]

All stroke 0.0% 2.2% -2.2% [-6.4%, 2.0%]

Major ipsi stroke

0.0% 0.0% 0.0% [-, -]

minor ipsi stroke

0.0% 0.0% 0.0% [-, -]

MI 2.0% 4.3% -2.3% [-9.4%, 4.7%]


SymptomaticSymptomatic Subgroup Analysis Subgroup Analysis360 Day Adverse Event Rates360 Day Adverse Event Rates

Event RCT Stent

N=50

RCT CEA

N=46

Difference [95% CI]

MAE 16.0% 19.6% -3.6% [-18.9%, 11.8%]

Death 12.0% 17.4% -5.4% [-19.6%, 8.8%]

All stroke 2.0% 6.5% -4.5% [-12.6%, 3.6%]0.0%

Major ipsi stroke

0.0% 0.0% 0.0% [-, -]

Minor ipsi stroke

2.0% 0.0% 2.0% [-1.9%, 5.9%]

MI 4.0% 4.3% -0.3% [-8.4%, 7.7%]


AAsymptomaticsymptomatic Subgroup Analysis Subgroup Analysis 30-Day Adverse Event Rates30-Day Adverse Event Rates

Event RCT Stent

N=117

RCT CEA

N=120

Difference [95% CI]

MAE 6.0% 9.2% -3.2% [-9.9%, 3.5%]

Death 1.7% 0.8% 0.9% [-2.0%, 3.7%]

All stroke 5.1% 3.3% 1.8% [-3.3%, 6.9%]

Major ipsi stroke

0.9% 1.7% -0.8% [-3.6%, 2.0%]

Minor ipsi stroke

3.4% 0.8% 2.6% [-1.1%, 6.3%]

MI 2.6% 6.7% -4/1% [-9.4%, 1.2%]


AAsymptomaticsymptomatic Subgroup Analysis Subgroup Analysis360 Day Adverse Event Rates360 Day Adverse Event Rates

Event RCT Stent

N=117

RCT CEA

N=120

Difference [95% CI]

MAE 10.3% 19.2% -8.9% [-17.8%, 0.0%]

Death 5.1% 10.8% -5.7% [-12.6%, 1.1%]

All stroke 7.7% 7.5% 0.2% [-6.6%, 6.9%]

Major ipsi stroke

0.9% 4.2% -3.3% [-7.3%, 0.6%]

Minor ipsi stroke

4.3% 2.5% 1.8% [-2.8%, 6.4%]

MI 2.6% 8.3% -5.8% [-11.5%, -0.1%]


MAE in Significant SubgroupsMAE in Significant SubgroupsOther than Symptomatic/AsymptomaticOther than Symptomatic/Asymptomatic

Subgroup 30-Day MAE 360-Day MAE

Male RCT CEA (N=108)

Male RCT Stent (N=111)

Male Registry (N=261)

12.0%

5.4%

5.0%

22.2%

12.6%

14.9%

Female RCT CEA (N=53)

Female RCT Stent (N=55)

Female Registry (N=145)

5.7%

3.6%

10.3%

15.1%

10.9%

17.2%

Diabetic RCT CEA (N=44)

Diabetic RCT Stent (N=42)

Diabetic Registry (N=125)

22.7%

4.8%

9.6%

31.8%

16.7%

20.0%


MAE in Significant SubgroupsMAE in Significant SubgroupsOther than Symptomatic/Asymptomatic Cont.Other than Symptomatic/Asymptomatic Cont.

Group 30-Day MAE 360-Day MAE

>80 Years RCT CEA (N=39)

>80 Years RCT Stent (N=37)

>80 Years Registry (N=92) 78

7.69%

8.11%

5.43%

25.64%

18.92%

21.74%

Recurrent Stenosis Post CEA RCT CEA (N=35)

Recurrent Stenosis Post CEA RCT Stent (N=37)

Recurrent Stenosis Post CEA Registry (N=151)

5.71%

2.70%

3.97%

11.43%

8.11%

9.93%


Effectiveness Results


Effectiveness ResultsEffectiveness ResultsSecondary EndpointsSecondary Endpoints

Parameter RCT Stent RCT CEA

Stent Reg

Feasibility Inv-Spon

Lesion success

91.8% N/A 90.4% 95.8% 94.7%

Procedure success

88.1% N/A 87.9% 90.4% 93.8%

Device success

91.2% N/A 89.6% 92.3% 94.3%

Angioguard success

95.6% N/A 91.6% 86.7% 95.7%


Effectiveness ResultsEffectiveness ResultsSecondary Endpoints ContinuedSecondary Endpoints Continued

Parameter RCT Stent

RCT CEA

Stent Reg

Feasibility Inv-Spon

Trapped material

N/A 56.0% 53.8% 99.8%

TLR free at 1 yr

99.4% 95.7% 99.3% 98.3% 95.7%

MAE free at 1 yr

87.8% 79.9% 84.2% 89.1%


Historical Surgical StudiesHistorical Surgical Studies


Historical Study BackgroundHistorical Study Background

• VA Cooperative (asymptomatic) Study

• ACAS (asymptomatic) study

• ECST (European) symptomatic study

• NASCET (North American) symptomatic study


Enrollment CriteriaEnrollment CriteriaHistorical ComparisonHistorical Comparison

NASCET/ACAS Exclusions• >79 yrs• Cardiac source emboli• Mental incapacity• MI <6mo.• Kidney/liver failure• Lung failure• Ipsilateral CEA• Contralateral CEA <4mo.• Unstable angina• Intracranial pathology• Life expectancy <5 yr• Ipsilateral CVA • Intolerance to anticoagulants

SAPPHIRE Inclusions• >79 yrs• Cardiac source emboli not addressed• Mental capacity not addressed• MI >24 hrs.• Kidney/liver failure excluded• Lung failure included• Ipsilateral stent excluded• Contralateral stent <30 day• Unstable angina• Intracranial disease excluded• Life expectancy <1yr• Ipsilateral CVA excluded• Intolerance to antiplatelet excluded


VA Cooperative StudyVA Cooperative Study

Asymptomatic, with >/=50% StenosisMAE (30 days): 4.7%• Risk of Ipsilateral stroke, TIA, Monocular

blindness markedly reduced (8% CEA v. 20% Med)

BUT• Long-term MAE (mean: 4 years; range: to 8

years) were equally high: (41% CEA v. 44% Med)

• High attrition from Stroke and Cardiac diseases • Cardiac Mortality 20% in both CEA and Med RX

Groups


ACASACAS

Asymptomatic, with >/=60% stenosisMAE (30 days): 1.5%, plus 1.2% TIA or stroke from Angiography

• Over 5 years, ~50% reduction in risk of stroke (5% CEA; 11% Med Rx)

• In asymptomatic patients with Moderate/Severe stenosis, CEA is indicated if it can be performed with a perioperative Stroke/Death rate < 3%


ECST (Europe)ECST (Europe)

• Symptomatic, with pts stratified by degree of stenosis

• MAE (30 days): 4.8%, but long-term MAE the same (~37%) for both CEA and Med

• In pts with >/=60% stenosis, risk of MAE at 3 yrs was 15% CEA and 26% Med

• 11% absolute (58% relative) benefit

• Pts with < 60% stenosis do not benefit

• Operative risk does not increase with degree of stenosis


NASCET (N American)NASCET (N American)Entire CohortEntire Cohort

Symptomatic, with pts stratified by degree of stenosis

MAE (30 days), entire cohort: 6.7%

MAE (30 days), 70-99% stenosis: 5.8%

At 2 years follow-up, study discontinued for pts with 70-99% stenosis


BENEFITS AND RISKS OF CEA (RCTs)BENEFITS AND RISKS OF CEA (RCTs)

TRIAL DEGREE

STENOS (%) n

RECENT

SX

ABSOLUTE MAE RISK

REDUCTION (%)

p VALUE V. MED

30 DAY MAE (%)

NASCET >/= 70 659 YES 16.5 @ 2 YR <0.001 5.8

ECST >/= 60 356 YES 11.6 @ 3YR 0.001 4.8

NASCET 50-69 430 YES 10.1 @ 5 YR 0.005 6.7

NASCET < 50 678 YES 0.8 @ 5 YR 0.97 6.7

ECST < 40 1455 YES SURG GROUP

WORSE @ 3 Y

<0.05 7.9

ACAS >/= 60 1662 NO 6.3 @ 5 YR 0.08 2.3

VA STUDY >/= 50 211 NO @ 7 YEARS

NEURO: 11.6

MAE: 0

@ 7 YEARS

NEUR: 0.001

MAE: 0.92

4.7

Modified from Chassin MR, NEJM 1998; 339:1468


Historical RCT Conclusions (1)Historical RCT Conclusions (1)Symptomatic PatientsSymptomatic Patients

• 70-99 % stenosis: CEA very effective (>50% reduction in risk of stroke and any death at 2 years) • Risk reduction varies with stenosis

• 50-69% stenosis: success less certain• 23 operations to prevent each

severe ipsilateral stroke at 5 years• Each 2% increase in 30 day MAE reduces 5-year benefit by 20%


Historic RCT Conclusions (2)Asymptomatic Patients

• > 60% stenosis: CEA Very Effective

(50% reduction in risk of ipsilateral stroke or peri-op stroke or death)

IF

Procedure can be performed with 30-day MAE < 3%


CAUTIONARY NOTES FOR ASYMPTOMATIC PATIENTS

(ALL RCTs and AHA)

• Risk of ipsilateral stroke is low (1-3%/year) in patients treated medically

• As many as 45% of strokes in such patients (NASCET) were found to be of lacunar or cardioembolic etiology

• Older patients and those with comorbidities should be carefully evaluated before CEA

• Asymptomatic patients with an expected lifespan < 5 years are not candidates for CEA


30-Day Adverse Event Rates-30-Day Adverse Event Rates-SymptomaticSymptomatic

Event Stent Reg

N=124

Stent RCT

N=50

CEA RCT

N=46

NASCET

N=326 >70% stenosis

Major ipsi stroke

3.2% 0.0% 0.0% 2.1%

Minor ipsi stroke

3.2% 0.0% 0.0% 3.7%

All ipsi stroke

6.4% 0.0% 0.0% 5.8%

All stroke and death

8.1% 0.0% 6.5% 5.8%

death 0.8% 0.0% 6.5% 0%


360-Day Major Adverse Event Rates360-Day Major Adverse Event Rates SymptomaticSymptomatic

Event Stent Reg

N=124

(%)

Stent RCT

N=50

(%)

CEA RCT

N=46

(%)

NASCET

N=328 >70% sten

Major ipsi stroke

3.2 0.0 0.0 ~2.0

Minor ipsi stroke

5.6 2.0 0.0

All ipsi stroke

8.8 2.0 0.0 ~7.5

MAE* without nonfatal MI

16.1 *11-12.9

16.0*14.0-16.0

19.6*17.4-19.6

* ~10.0

death 8.9 12.0 17.4


30-Day Major Adverse Event Rates-30-Day Major Adverse Event Rates-AsymptomaticAsymptomatic

Event Stent Reg

N=281

(%)

Stent RCT

N=117

(%)

CEA RCT

N=120

(%)

ACAS (all stroke)

N=825

(%)Major ipsi stroke

2.1 0.9 1.7 1.2

Minor ipsi stroke

1.1 3.4 0.8 1.2

All ipsi stroke

3.2 4.3 2.5 2.1

All stroke and death

5.0 6.0 4.2 2.3

death 2.8 1.7 0.8 0.4


360-Day Major Adverse Event Rates 360-Day Major Adverse Event Rates AsymptomaticAsymptomatic

Event Stent Reg

N=281

(%)

Stent RCT

N=117

(%)

CEA RCT

N=120

(%)

ACAS

N=825

(%)Major ipsi stroke

3.2 0.9 4.2

Minor ipsi stroke

3.2 4.3 2.5

All ipsi stroke

6.4 5.2 5.3

MAE* Without nonfatal MI

15.7*12.4-13.8

10.3*6.8-7.6

19.2*10.8-15.0

* ~6.5

Death 10.7 5.1 10.8


Study LimitationsStudy Limitations

• The pre-specified enrollment plan and study analysis was not carried to completion in the SAPPHIRE randomized study

• Resulted in a smaller size study with small sample sizes in important subsets of carotid populations


ConclusionsConclusions

• Randomized study suggests non-inferiority of stent to CEA

• Registry cohort failed to meet the OPC

• Comparability of the registry to the control CEA patients has not been optimally defined/conducted

circulatory system devices panel wednesday, april 21, 2004 cordis corporation precise 5.5f and 6.0f...

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