CAROTID ARTERY STENTING WITH EMBOLI PROTECTION

1
CAROTID ARTERY STENTING WITH EMBOLI PROTECTION
PMA P030047
Cordis Presentation Sidney A. Cohen, M.D.,
Ph.D. Group Director, Clinical Research
2
REQUESTED INDICATION

• The Cordis Carotid Stent System 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 TIAs or one or more completed
  strokes) and gt50 atherosclerotic stenosis of the
  common or internal carotid artery by ultrasound
  or angiogram
•  and 
• Patients without neurological symptoms and gt80
  atherosclerotic stenosis of the common or
  internal carotid artery by ultrasound or
  angiogram.
•  
• Symptomatic and asymptomatic patients must also
  have one or more condition(s) that place them at
  high-risk for carotid endarterectomy.

3
AGENDA

• Project Overview CAS Background
• Description of Devices
• Overview of PMA Clinical Data (Total of 1619 Pts)
• 1. Non-Randomized CAS Clinical Trials
  Supportive data
• CASCADE (European) Study
• US FEASIBILITY Study
• 2. SAPPHIRE Pivotal Trial Ken Ouriel, M.D.
• Randomized Arm CAS vs. CEA
• Non-Randomized Arms CAS and CEA
• Overview of Training
• Post-Market Surveillance Study

4
PROJECT OVERVIEW

• US FEASIBILITY Study start date - September 1998
• SAPPHIRE Pivotal Study start date August 2000
• PMA filed on October 8, 2003
• Achieved primary endpoint of non-inferiority of
  CAS to CEA for 1-year
• CAS - improved outcomes for MI and
  re-interventions with a significant decrease in
  cranial nerve injuries
• Sustained benefit of CAS treatment demonstrated
  through 3-years follow up
• PMA granted Expedited Review Status November 14,
  2003
• Significant therapeutic advance

5
BACKGROUNDStroke Carotid Disease

• gt700,000 strokes occur annually in the U.S.1
• Stroke is the third leading cause of death with
  an estimated 164,000 deaths per year 1
• Up to 30 of strokes are caused by carotid artery
  disease2
• Stroke is the number 1 cause of disability in the
  U.S. 1
• Health care costs for stroke in excess of 53.6
  billion/year1
• Over 50 of people under age 65 who have a stroke
  die within 8 years1
• Older population with co-morbid disease1

1. Heart Disease and Stroke Statistics 2004
Update, American Heart Association 2. ACAS
Executive Committee JAMA 2731421-1428, 1995
6
BACKGROUNDCarotid Endarterectomy

• 50 year history of technique development and
  refinement
• CEA is the current interventional standard of
  care in treating carotid artery disease to reduce
  the risk of stroke
• Up to 200,000 CEAs performed per year in the
  U.S.1
• Estimated that 20 of CEAs are performed on high
  surgical-risk patients annually in the U.S.2
• High surgical risk defined
• Anatomic - increased procedure risk
• Medical Co-morbidities - increased risk MI and
  death

1. Heart Disease and Stroke Statistics 2004
Update, American Heart Association 2. Ouriel
et al., J Vasc Surg 33728-732, 2001
7
BACKGROUND Carotid Endarterectomy - cont

• Randomized clinical studies
• Superiority of CEA vs. best medical therapy
• NASCET1
• Symptomatic gt50 diameter stenosis
• ACAS2
• Asymptomatic gt60 diameter stenosis
• ECST3
• Symptomatic gt50 diameter stenosis
• VA Cooperative Study4
• Symptomatic gt50 diameter stenosis
• Standard of Care for interventional treatment
  of symptomatic and asymtomatic carotid artery
  disease

1. NASCET Trial Collaborators NEJM
325445-453, 1991 2. ACAS Executive Committee
JAMA 2731421-1428, 1995 3. Rothwell et
al., Stroke 34 514-523, 2003 4. Hobson et
al., NEJM 328221-227, 1993
8
TYPE OF PATIENTS CURRENTLY TREATED WITH CEA

• CEA treatment of patients clearly extends beyond
• NASCET/ACAS inclusion criteria
• NASCET/ACAS studied a relatively healthy subset
  of patients
• ACAS screened 25 to enroll 1 patient1
• NASCET 1 out of every 3 treated patients
  enrolled1
• Patients considered high risk for CEA as defined
  by trial ineligibility comprise up to 50 of
  patients in published series
• Ochsner Clinic 46.22
• CCF Registry 19.43

• Wennberg et al., JAMA 2791278-1281, 1998. 2.
  Leporre et al., J Vasc Surg 34 581-586, 2001.
  
• 3. Ouriel et al., J Vasc Surg 33 728-732,
  2001.

9
NASCET/ACAS EXCLUSION CRITERIA

• Anatomic Risks
• Tandem lesions
• Previous CEA
• Radiation therapy to neck (ACAS)
• Status post radical neck dissection

• Medical Co-morbidities
• Age gt79
• Previous CVA with profound deficit
• MI within 6 months (NASCET)
• Unstable angina
• Atrial fibrillation
• Symptomatic CHF
• Valvular heart disease
• Cancer with lt50 5 year survival
• Renal/pulmonary/liver failure

10
CEA MORTALITY
113,000 Medicare Patients (1992-1993)
30-Day Follow up
Mortality
Wennberg, et al., JAMA, 279 1278-1281, 1998
11
PUBLISHED 30-DAY CEA EVENT RATES
1
2
3
3

1. Leporre et al., J Vasc Surg 34581-586, 2001.
2. Cebul et al., JAMA 2791282-1287, 1998 3.
Halm et al., Stroke 34 14264-1472, 2003
12
IN-HOSPITAL CEA OUTCOMES US ACADEMIC CENTERS
Death MI Stroke

• Retrospective analysis
• 1160 patients
• 12 academic centers in US
• 1988-90
• In-hospital Death MI Stroke

McCrory DC et al. Stroke 1993241285-1291
13
IN-HOSPITAL CEA OUTCOMES US ACADEMIC CENTERS
Death MI Stroke
McCrory DC et al. Stroke 1993241285-1291
14
PERCENT ASYMTOMATIC PATIENTS UNDERGOING CEA IS UP
TO 75
1
2
3
4

1998
2001
2001
2003
1. Cebul et al., JAMA 2791282-1287, 1998 2.
Leporre et al., J Vasc Surg 34581-586, 2001 3.
Ouriel et al., J Vasc Surg 33 728-732, 2001
4. Halm et al., Stroke 34 14264-1472, 2003
15
INCIDENCE OF STROKE AT 360-DAYS
6
Asymptomatic Patients
5
4
3
Stroke Incidence ()
2
1
0
0-19
20-29
30-39
40-49
50-59
60-69
70-79
80-89
90-99
Carotid Artery Stenosis
Chambers New England Journal of Medicine.
315(14)860-5, 1986 Norris Stroke.
22(12)1485-90, 1991 Mendelsohn Yadav,
Management of Atherosclerotic Carotid Disease,
Remedica Publishing, 2000
16
TYPE OF PATIENTS CURRENTLY TREATED WITH CEA

• In US, standard of care for interventional
  treatment includes
• NASCET/ACAS eligible ineligible patients
• Symptomatic and asymptomatic patients
• Higher risk patients
• Anatomic
• Medical Co-morbidities
• SAPPHIRE trial studied patients who currently are
  referred for treatment of their carotid disease

17
RATIONALE FOR TREATMENT OF HIGH SURGICAL-RISK
PATIENTS

• Initial evaluation of new technology (CAS) in
  cohort of patients where CEA is technically
  demanding
• Anatomic difficult access that may lead to
  local tissue and nerve injury
• Medical Co-morbidities patients less tolerant
  of general anesthesia surgery
• CAS studied as an alternative and less invasive
  method of therapy

18
AGENDA

• Project Overview CAS Background
• Description of Devices
• Overview of PMA Clinical Data (Total of 1619 Pts)
• 1. Non-randomized CAS Clinical Trials
  Supportive data
• CASCADE (European) Study
• US FEASIBILITY Study
• 2. SAPPHIRE Pivotal Trial Ken Ouriel, M.D.
• Randomized Arm CAS vs. CEA
• Non-Randomized Arms CAS and CEA
• Overview of Training
• Post-Market Surveillance Study

19
CAROTID ARTERY STENTING

• Includes a system consisting of 2 devices
• Stent Delivery System
• Stent
• Delivery catheter
• Emboli Protection Device

20
Cordis PRECISE Nitinol Stent
21
Cordis PRECISE Nitinol Stent System

• Stent Delivery System
• 5.5F Cordis PRECISE Nitinol Stent System
• 6F Cordis PRECISE Nitinol Stent System
• Usable Length 135 cm
• Guidewire Lumen 0.018 compatible

5.5F (5 8 mm) 6F (9 10 mm)
5F
22
CAROTID ARTERY STENT SYSTEM
Emboli Protection ANGIOGUARD XP Emboli Capture
Guidewire
Polyurethane filter on a Nitinol frame Basket
Diameter 4 - 8 mm Oversize basket 0.5 1.5
mm vs. RVD Filter Pore Size 100 microns
Crossing Profile 3.5F Wire Diameter 0.014
23
CAS SYSTEM ANIMATION
24
AGENDA

• Project Overview CAS Background
• Description of Devices
• Overview of PMA Clinical Data (Total of 1619 Pts)
• 1. Non-Randomized CAS Clinical Trials
  Supportive data
• CASCADE (European) Study
• US FEASIBILITY Study
• 2. SAPPHIRE Pivotal Trial Ken Ouriel, M.D.
• Randomized Arm CAS vs. CEA
• Non-randomized Arms CAS and CEA
• Overview of Training
• Post-Market Surveillance Study

25
CLINICAL TRIALS Supportive Data

• Purpose
• Gain experience
• Carotid stent system
• Learning curve for investigators
• Refine the stent delivery system
• Evaluate the advantage of adding ANGIOGUARD
• Two Studies
• CASCADE (European) Study
• CAS, non-randomized
• n121
• 1-year follow up
• US FEASIBILITY Study
• CAS, non-randomized
• n261
• 3-year follow up

26
CASCADE STUDY
The Cordis Smart Self-Expandable Stent in Carotid
Artery Disease
27
CASCADE STUDY

• Objective
• To evaluate the safety and performance of the
  SMART Stent with or without ANGIOGUARD emboli
  capture device in patients with high grade
  carotid artery stenosis
• Primary Endpoint Ipsilateral stroke or
  procedural related death within 30 days of stent
  implantation

28
CASCADE STUDYOverview

• Design
• Multi-center, prospective, non-randomized study
  
• Nine centers across Europe
• 7F SMART Stent Delivery System
• 121 patients enrolled (31 with ANGIOGUARD)
• Conducted from September 1998 until May 2002
• Inclusion Criteria
• gt70 stenosis if symptomatic by U/S or
  angiography
• gt85 stenosis if asymptomatic by U/S or
  angiography
• Stenosis between origin of CCA and extracranial
  segment of the ICA

29
CASCADE STUDY 30-Day Data
n121

30
CASCADE STUDY 30-Day Outcomes With/Without
ANGIOGUARD
P0.45
P0.68

Pgt0.99
31
CASCADE STUDY

• Conclusion
• Carotid artery stenting was found to be feasible
  for the treatment of carotid stenosis
• The ANGIOGUARD distal protection device
  functioned well and reduced the risk of distal
  embolization, resulting in fewer strokes.
• 30-day stroke rate of 3.2, with no major
  strokes

32
US FEASIBILITY STUDYThe Cordis Nitinol Carotid
Stent and Delivery System (SDS) in Patients with
de novo or Restenotic Native Carotid Artery
Lesions Trial
33
US FEASIBILITY STUDY

• Objective
• Primary Assess the feasibility of carotid artery
  stenting in the treatment of obstructive carotid
  artery disease
• Secondary Assess and standardize optimal
  operator techniques for pivotal trial

34
US FEASIBILITY STUDYOverview

• Design
• Non-randomized, prospective, 33 center trial
• 6/7F SMART and 5.5F PRECISE SDS
• 261 patients enrolled
• 176 stent
• 85 stent plus ANGIOGUARD
• Sept 1998 through July 2001
• Follow up to 3 years
• Key Inclusion Criteria
• Symptomatic gt60 stenosis by U/S or angiography
• Asymptomatic gt80 stenosis by U/S or angiography
• Native Common or Internal Carotid Artery

35
US FEASIBILITY STUDYOverview - cont

• Key Inclusion Criteria (cont)
• High Risk for Surgical Endarterectomy
• Anatomic risk factors (not ACAS eligible)
• Restenosis after CEA
• Radical neck dissection
• Contralateral carotid artery occlusion
• Ostial lesion of the common carotid
• High take-off carotid bifurcation disease

36
US FEASIBILITY STUDY

• Primary Endpoint
• 30-day MAE (death, any stroke, /or MI)
•  
• Key Secondary Endpoints
• Major clinical events
• 6 months, 1, 2, 3 years
• Patency (lt 50 restenosis) by carotid U/S
• 48 hours, 30 days, 6 months, 1, 2, 3 years
• Neurological assessments
• 28 hours, 30 days, 6 months, 1, 2, 3 years

37
US FEASIBILITY STUDY30-Day Events
n261

38
US FEASIBILITY STUDY30-Day Events With/Without
ANGIOGUARD
P 0.19
P 0.51

P 0.10
P 0.31
P 1.00
39
US FEASIBILITY STUDY Cumulative Percentage of
MAE to 1080 Days
21.8
16.8
10.9
Cumulative Percentage of MAE
6.9
Error bars are 1.5 X S.E.
30
Time After Initial Procedure (days)
40
US FEASIBILITY STUDY Cumulative Percentage of
All Stroke to 30 Days and Ipsilateral Stroke
from 31-1080 Days
8.7
8.7
Cumulative Percentage of Stroke
7.3
6.1
30
Time After Initial Procedure (days)
41
US FEASIBILITY STUDY Cumulative Percentage of
Death to 1080 Days
13.9
9.0
Cumulative Percentage of Death
4.0
0.8
30
Time After Initial Procedure (days)
42
US FEASIBILITY STUDY

• Conclusion
• Demonstrated feasibility of carotid stenting with
  the Cordis PRECISE Nitinol Stent System
• ANGIOGUARD emboli protection device reduced the
  incidence of stroke
• 30-day stroke rate 2.4, with no major strokes
• Provided run-in to pivotal study

43
CAROTID STENT30-Day Stroke Rates by Study and
ANGIOGUARD

P0.10
P0.45
P0.02
44
CONCLUSIONS FROM SUPPORTIVE STUDIES

• Refinement of CAS System
• Reduction in profile (7F to 5.5F)
• Improvement in design
• Data supports benefit of ANGIOGUARD emboli
  protection device in reducing stroke
• Demonstrated the feasibility of CAS

45
AGENDA

• Project Overview CAS Background
• Description of Devices
• Overview of PMA Clinical Data (Total of 1619 Pts)
• 1. Non-Randomized CAS Clinical Trials
  Supportive data
• CASCADE (European) Study
• US FEASIBILITY Study
• 2. SAPPHIRE Pivotal Trial Ken Ouriel, M.D.
• Randomized Arm CAS vs. CEA
• Non-Randomized Arms CAS and CEA
• Overview of Training
• Post-Market Surveillance Study

46
SAPPHIRE PIVOTAL STUDY

• Ken Ouriel, M.D., F.A.C.S, F.A.C.C.
• Chairman, Division of Surgery
• Chairman, Department of Vascular Surgery
• Cleveland Clinic Foundation

47
SAPPHIRE STUDY
Objective To compare the safety and
effectiveness of carotid stenting with emboli
protection to endarterectomy in the treatment of
carotid artery disease in high-risk patients.
48
SAPPHIRE STUDYTrial Design and Patient Flow
Patients Referred for Evaluation of Carotid
Disease Screened for SAPPHIRE Inclusion/Exclusion
Criteria 2294 patients
Evaluated by panel of physicians
(interventionalist, surgeon, neurologist) who
concur on qualification of patient n 747
49
SAPPHIRE STUDYTrial Design and Patient Flow
Evaluated by panel of physicians
(interventionalist, surgeon, neurologist) who
concur on qualification of patient n 747
Surgeon Interventionalist will treat patient
RCT 334 Randomized (310 Treated)
Stent Treatment n167
CEA Treatment n167
50
SAPPHIRE STUDYTrial Design and Patient Flow
Evaluated by panel of physicians
(interventionalist, surgeon, neurologist) who
concur on qualification of patient n 747
Surgeon unacceptable risk for CEA
Surgeon Interventionalist will treat patient
Non-Randomized Stent Arm n406
RCT 334 Randomized (310 Treated)
Stent Treatment n167
CEA Treatment n167
51
SAPPHIRE STUDYTrial Design and Patient Flow
Evaluated by panel of physicians
(interventionalist, surgeon, neurologist) who
concur on qualification of patient n 747
Surgeon unacceptable risk for CEA
Interventionalist unacceptable risk for stenting
Surgeon Interventionalist will treat patient
Non-Randomized Stent Arm n406
Non-Randomized CEA Arm n7
RCT 334 Randomized (310 Treated)
Stent Treatment n167
CEA Treatment n167
52
SAPPHIRE STUDY

• Primary Endpoint
• Death (all-cause), any stroke, and MI to 30 days
  post-procedure plus death (all-cause) and
  ipsilateral stroke between days 31 and 360
  post-procedure.

53
SAPPHIRE STUDYDifferences Between SAPPHIRE and
Previous Surgical Trials

• Primary endpoint included all-cause mortality
  for 1 year
• MAE includes MI in addition to death/stroke
• 24-hour post procedure stroke evaluation
  performed by neurologist
• Use of Stroke scales in addition to PEx
• Objective vessel patency data obtained by duplex
  U/S
• Different specialties providing input on
  treatment strategy (multi-disciplinary team)

54
SAPPHIRE STUDYRelevance of MI as Part of the
Primary Endpoint

• MI leads to disability, death, prolonged
  hospitalization, and increased health care costs
  key safety endpoint
• In patients undergoing peripheral vascular
  surgery who sustain a non-Q wave MI
• 6-fold increase in mortality over 6 mo1
• Perioperative MI predicts mortality at one-year2
• 27-fold increased risk of another MI over the
  next 6 mo1
• Thus, perioperative MI is a strong surrogate for
  long-term mortality after vascular surgical
  procedures
• Perioperative MI is part of the primary endpoint
  for other CAS trials (e.g. CREST)

1Kim et al. Circulation 20021062366-2371 2McFall
s et al. Chest 1998113681-686
55
DEFINITIONS

• Myocardial Infarction
• Q wave MI
• Chest pain or other acute symptoms consistent
  with myocardial ischemia and new pathological Q
  waves in two or more contiguous ECG leads as
  determined by an ECG Core Laboratory or
  independent review by the CEC, in the absence of
  timely cardiac enzyme data.
• Non-Q wave MI
• CK ratio gt2, CK-MB gt1 in the absence of new,
  pathological Q waves.

56
DEFINITIONS (cont)

• Stroke
• Any non-convulsive, focal neurological
  deficit of abrupt onset persisting more than 24
  hours was a stroke. The deficit must correspond
  to a vascular territory. Strokes were classified
  as major or minor using the NIH Stroke, Rankin
  and Barthel scales.For a stroke to be minor, it
  must be minor on all three scales. A stroke
  rated as major on any scale was considered major
  if the deficit persisted more than 3 months.
  Disabilities or impairments attributed to medical
  conditions that were non-neurological in origin
  were not considered strokes.

57
SAPPHIRE STUDY Statistical Analysis Plan
(Randomized)

• Primary hypothesis Non-inferiority of CAS to CEA
• Primary Endpoint Composite 360-day MAE
• 3 non-inferiority delta assumed (i.e., Stent no
  more than 3 higher than CEA)
• If non-inferiority demonstrated, then test for
  superiority (2 hypothesis)
• Study was designed to stop enrollment based on
  interim analysis of 30-day MAE (2 endpoint) with
  final analysis on360 day data (1 endpoint)
• Enrollment stopped for administrative reasons
• First planned interim analysis at 300 patients
  was not done as it was already evident that
  enrollment would stop
• Final analysis on the 1 endpoint utilized the
  interval censored survival analysis method
  designated in protocol
• No adjustments were required since no interim
  analysis performed

58
SAPPHIRE STUDYDiminishing Enrollment (Randomized)
Competing CAS registries
Stop Enrollment
59
SAPPHIRE STUDY Key Inclusion Criteria

• Patients referred for treatment of Carotid Artery
  Disease
• Symptomatic gt50 stenosis by U/S or angiography
• Asymptomatic gt80 stenosis by U/S or angiography
  
• Disease of Native Common or Internal Carotid
  Artery
• Consensus agreement by multidisciplinary team
• Interventionalist, Consulting Neurologist,
  Surgeon
• Must also have at least 1 co-morbid condition
  which increases the risk of endarterectomy
• Anatomic
• Medical

60
SAPPHIRE STUDYKey Inclusion Criteria - cont

• Anatomic factors
• Contralateral carotid occlusion
• Contralateral laryngeal nerve palsy
• Radiation therapy to neck
• Previous CEA with recurrent stenosis
• Difficult surgical access
• Severe tandem lesions

61
SAPPHIRE STUDYKey Inclusion Criteria - cont

• Medical Co-morbidities
• CHF (class III/IV) /or severe LV dysfunction
  (LVEF lt30)
• Open heart surgery within 6 weeks
• Recent MI (1 day to 4 weeks prior)
• Angina at low workload or unstable angina (CCS
  class III/IV)
• Severe pulmonary disease
• Age greater than 80 years

62
SAPPHIRE STUDYTrial Design and Patient Flow
Evaluated by panel of physicians
(interventionalist, surgeon, neurologist) who
concur on qualification of patient n 747
Surgeon Interventionalist will treat patient
Non-Randomized Stent Arm n406
Non-Randomized CEA Arm n7
RCT 334 Randomized (310 Treated)
Stent Treatment n167
CEA Treatment n167
63
SAPPHIRE STUDYDemographics Randomized Patients
64
SAPPHIRE STUDY Acute Procedure Device Outcomes

• Stent Delivery Success
• Randomized Stent 99.4
• Non-Randomized Stent 99.8
• Device Success (Stent) lt30 DS
  lt50 DS
• Randomized Stent 91.2 99.4
• Non-Randomized Stent 89.6
  98.5
• ANGIOGUARD Success (Deployment and Retrieval)
• Initial Attempt Ultimate Placement
• Randomized Stent 95.6 98.1
• Non-Rand Stent 91.6 95.1

Patients in whom treatment was attempted
Device Failures Tables Per Protocol
Definition
65
SAPPHIRE STUDY OUTCOMES
Data Presented Are Based on Intent-to-Treat
Analyses(unless otherwise specified)
66
SAPPHIRE STUDYTrial Design and Patient Flow
RCT 334 Randomized (310 Treated)
Stent Treatment n167
CEA Treatment n167
1 Year Compliance
Clinical 85.6
Clinical 93.5
Ultrasound 80.6
Ultrasound 69.2
All events adjudicated by independent
CEC Angiograms and ultrasounds reviewed by
independent core labs
67
SAPPHIRE All Randomized Patients at 30 Days

P0.14
P0.17
P1.00
P0.68
68
SAPPHIRE STUDY Primary Endpoint at 360 Days
Randomized Patients Overall Rates
69
SAPPHIRE STUDYPrimary Endpoint 360-day MAE
Non-Inferiority Statistics
 
Margin of Non-inferiority
Stent Non-inferior to CEA
3
Difference (Stent CEA)
Stent CEA Difference 95 C.I.
12.0 (20/167) 19.2 (32/167) 7.214.9, 0.6
70
SAPPHIRE STUDY Primary Endpoint at 360 Days
P0.10
P0.14

P0.83
P0.17
(30 day)
71
SAPPHIRE STUDY Primary Endpoint at 360 Days

P0.83
P0.50
P0.21
72
SAPPHIRE STUDYCumulative of MAE to 360
DaysRandomized Patients Kaplan Meier Analysis
LR p 0.053
CEA 20.1
Cumulative Percentage of MAE
Stent 12.2
9.8
4.8
Time After Initial Procedure (days)
73
SAPPHIRE STUDYCumulative of MAE to 720
DaysRandomized Patients Kaplan Meier Analysis
CEA 26.7
CEA 26.7
20.1
20.1
Stent 19.2
Stent 19.2
Cumulative Percentage of MAE
12.2
12.2
9.8
9.8
4.8
4.8
Time After Initial Procedure (days)
30
74
SAPPHIRE STUDYCumulative of Stroke to 720
DaysRandomized Patients - Kaplan Meier Analysis
All Stroke to 30 days and ipsilateral stroke
from 31-720 Days
Cumulative Percentage of Stroke
4.9 Stent
5.9 Stent
3.6 Stent
3.1 CEA
5.8 CEA
5.8 CEA
30
Time After Initial Procedure (days)
75
SAPPHIRE STUDYCumulative of Death to 720
DaysRandomized Patients - Kaplan Meier Analysis
20.9 CEA
Cumulative Percentage of Death
13.5 CEA
14.4 Stent
2.5 CEA
7.4 Stent
1.2 Stent
30
Time After Initial Procedure (days)
76
SAPPHIRE STUDYCause of Death at 360 Days -
Randomized

• Total Deaths 33
• CEA 21
• Stent 12
• Total Number of Neurologic Deaths 4
• CEA 3
• Stent 1
• Non-Neurologic Deaths 29

77
SAPPHIRE STUDYCause of Death at 360 Days -
Randomized

• Total Deaths 33
• CEA 21
• Stent 12
• Total Number of Neurologic Deaths 4
• CEA 3
• Stent 1
• Non-Neurologic Deaths
  CEA Stent
• 29 18 11
• Cardiac 18 10 8
• Respiratory Failure 4 3 1
• Cancer 3 1 2
• Renal Failure 1 1 0
• Multi-system Failure 3 3 0

78
SAPPHIRE STUDYComplications
Stent (n167) CEA (n167) P-value
Target Lesion Revascularization (TLR) 1 (0.6) 6 (3.6) 0.12
Vessel Thrombosis 0 (0.0) 0 (0.0) ---
Major Bleeding 15 (9.0) 17 (10.2) 0.85
Cranial Nerve Injury 0 (0.0) 8 (4.8) 0.01
79
SAPPHIRE STUDYRestenosis Rates and TLR at 360
Days
In-Vessel Restenosis by U/S Stent (n167) CEA (n167) P-value
gt50 Diameter Stenosis 19.7 (24/122) 31.3 (30/96) 0.06
gt70 Diameter Stenosis 0.8 (1/122) 5.2 (5/96) 0.09
gt80 Diameter Stenosis 0.8 (1/122) 4.2 (4/96) 0.17
TLR Clinically driven (to 360 days) 0.6 (1/167) 3.6 (6/167) 0.12
Protocol Definition
80
SAPPHIRE STUDY
Analysis of the Evaluable (Treated) Patients
81
SAPPHIRE STUDYRandomized Patients Who Were Not
Treated
Stent CEA
Subsequent to randomization found to not meet Inclusion Criteria 2 4
Patient Withdrew Consent 3 8
Patient Condition Deteriorated/Too High a Risk 3 2
Other 0 2
TOTAL 8 8

16
82
SAPPHIRE STUDY Primary Endpoint 360 Days
Randomized TREATED Patients
83
SAPPHIRE STUDYCumulative of MAE to 360 Days
Randomized TREATED Patients Kaplan Meier
Analysis
LR p 0.048
CEA 20.1
CAS 12.0
Cumulative Percentage of MAE
Time After Initial Procedure (days)
84
SAPPHIRE STUDYTrial Design and Patient Flow
Evaluated by panel of physicians
(interventionalist, surgeon, neurologist) who
concur on qualification of patient n 747
Surgeon unacceptable risk for CEA
Surgeon Interventionalist will treat patient
Non-Randomized CEA Arm n7
Non-Randomized Stent Arm n406
RCT 334 Randomized (310 Treated)
Stent Treatment n167
CEA Treatment n167
85
SAPPHIRE STUDYNon-Randomized Stent Arm vs. CEA
Randomized Demographic Characteristics
86
SAPPHIRE STUDYMAE at 360 Days
Non-Randomized Stent Arm vs. Randomized Stent
CEA
Rand CEA 20.1
Non-Rand Stent 16.0
Rand CEA 9.8
Cumulative Percentage of MAE
Non-Rand Stent 6.9
Rand Stent 12.2
Rand Stent 4.8
Time After Initial Procedure (days)
87
SAPPHIRE STUDYNon-Randomized Stent Arm

• Original non-inferiority analysis based on OPC
  12-14 plus 4 delta
• Weighted OPC calculated at 12.94 was not met
• OPC estimated (1999) without benefit of
  multi-center randomized data from
  high-surgical risk studies
• SAPPHIRE CEA arm
• 1 year MAE rate of 19.2
• Has ? frequency of high surgical-risk
  characteristics
• Agency consulted in March 2003
• FDA suggested supplemental non-inferiority
  analysis
• Non-Randomized Stent Arm to the Randomized CEA
  Arm
• Adjustment for differences in baseline
  demographics

88
SAPPHIRE STUDYPrimary Endpoint 360-day MAE
Adjusted for Baseline Characteristics
Non-Inferiority Statistics
 
Margin of Non-inferiority
Stent Non-inferior to CEA
3
Difference (Non-randomized Stent Randomized
CEA)
Difference 95 C.I.
5.313.4, 3.0
89
SAPPHIRE STUDYComplications
Randomized Stent (n 167) Randomized CEA (n 167) Non-RandStent (n 406) P-value (CEA vs. Non-Rand)
TLR 1 (0.6) 6 (3.6) 3 (0.7) 0.02
Vessel Thrombosis 0 (0.0) 0 (0.0) 3 (0.7) 0.56
Major Bleeding 15 (9.0) 17 (10.2) 54 (13.3) 0.33
Cranial Nerve Injury 0 (0.0) 8 (4.8) 0 (0.0) lt0.01
90
SAPPHIRE STUDYTrial Design and Patient Flow
Evaluated by panel of physicians
(interventionalist, surgeon, neurologist) who
concur on qualification of patient n 747
Interventionalist unacceptable risk for stenting
Surgeon unacceptable risk for CEA
Surgeon Interventionalist will treat patient
Non-Randomized CEA Arm n7
Non-Randomized Stent Arm n406
RCT 334 Randomized (310 Treated)
Stent Treatment n167
CEA Treatment n167
91
SAPPHIRE STUDY Subgroup Analyses

• Study is not powered for subgroup analyses
• Symptomatic/Asymptomatic
• Randomization stratified by /- symptoms
• Subgroup analyses pre-specified
• Subgroup sample sizes
• Symptomatic Patients 96
• Asymptomatic Patients 237

92
SAPPHIRE STUDY30-Day MAE Asymptomatic (ITT)

P0.46
P0.22
P0.54
P0.62
93
SAPPHIRE STUDY360-Day MAE Asymptomatic (ITT)
P0.07
P0.15

P1.00
P0.08
94
SAPPHIRE STUDYCumulative of MAE Asymptomatic
to 360 DaysAll Randomized Patients Kaplan
Meier Analysis
LR p 0.04
Cumulative Percentage of MAE
CEA 20.3
Stent 10.5
Time After Initial Procedure (days)
95
SAPPHIRE STUDY30-Day MAE Symptomatic (ITT)
P0.10

P0.11
P0.61
P0.48
96
SAPPHIRE STUDY360-Day MAE Symptomatic (ITT)
P0.57

P0.35
P1.00
97
SAPPHIRE STUDYCumulative of MAE Symptomatic to
360 DaysAll Randomized Patients Kaplan Meier
Analysis
LR p 0.58
Cumulative Percentage of MAE
CEA 20.0
Stent 16.3
Time After Initial Procedure (days)
98
SAPPHIRE STUDY360-Day MAE Symptomatic vs.
Asymptomatic (ITT)
P0.07

n281
n46
n124
n120
n117
n50
99
SAPPHIRE STUDY360-Day MAE Symptomatic vs.
Asymptomatic Treated (Evaluable) Patients
P0.02

n281
n124
n111
n48
n108
n43
100
SAPPHIRE STUDYSurgeon Experience and Outcomes

• Experience and outcomes for surgeons in SAPPHIRE
  trial are consistent with previous surgical data
• CEA volume
• Outcomes
• Complication rates

101
SAPPHIRE STUDYSurgeon Experience Judgment

• Pre-study survey conducted
• 53 SAPPHIRE surgeons
• Mean of 36.3 procedures per year
• Median of 28 procedures per year

102
CEA OUTCOMES BY VOLUME
Annualized Volume Tercile - Procedures in
Medicare Treated Patients
Wennberg, JAMA 289 1278-1281, 1998
Mortality ()
Tercile of cases per year all CEA surgeons
103
CEA OUTCOMES BY VOLUME
Annualized Volume Tercile - Procedures in
Medicare Treated Patients
Wennberg, JAMA 289 1278-1281, 1998
Mortality ()
Tercile of cases per year all CEA surgeons
SAPPHIRE 1
4 48 Cases/Surgeon
104
CRANIAL NERVE INJURYComparison with Other Studies
SAPPHIRE Randomized CEA 4.8 NASCET 7.2 V
A Cooperative Study 3.8 ACAS NA
NASCET AND VA STUDY EXCLUDED REPEAT CEA
105
SURGICAL OUTCOMES vs. OTHER TRIALS
30-Day Ipsilateral Stroke
Error Bar 95 CI

106
CAS OUTCOMES TO OTHER SURGICAL TRIALS

• Comparison of 30-day ipsilateral stroke rates
• SAPPHIRE randomized and non-randomized
  symptomatic stent patients vs. NASCET
• SAPPHIRE randomized and non-randomized
  asymptomatic stent patients vs. ACAS

107
CAS OUTCOMES TO OTHER SURGICAL TRIALSSymptomatic
Patients
30-Day Ipsilateral Stroke
Error Bar 95 CI

108
CAS OUTCOMES TO OTHER SURGICAL TRIALSAsymptomatic
Patients
30-Day Ipsilateral Stroke
Error Bar 95 CI

109
SAPPHIRE STUDYCAS 30-Day Mortality

• CAS 30-day all cause mortality
• Symptomatic
• Randomized 0.0
• Non-randomized 0.8
• Asymptomatic
• Randomized 1.7
• Non-randomized 2.8

110
SAPPHIRE STUDY

• Conclusions

111
SAPPHIRE STUDYConclusions Randomized Arm

• The primary endpoint of the study was achieved
  demonstrating CAS is non-inferior to CEA
• Trends favoring CAS over CEA
• Major Ipsilateral stroke
• MI
• TLR
• Restenosis (gt50 DS)
• Significant decrease in cranial nerve injuries

112
SAPPHIRE STUDY Conclusions Randomized Arm

• Symptomatic and asymptomatic subgroups
• ITT Asymptomatic Significant improvement at 360
  days in favor of CAS compared to CEA with 50
  reduction in MAE rate
• ITT Symptomatic MAE rates at 360 days were
  similar between CAS and CEA
• Outcomes for ipsilateral stroke overlap those
  from NASCET and ACAS

113
SAPPHIRE STUDYConclusions Non-Randomized Stent
Arm

• Risk factors contributing to too high risk for
  CEA
• Anatomic
• Prior CEA
• Prior radiation therapy
• High cervical ICA lesion
• Medical
• Angina Class CCS III or IV
• Previous stroke
• Non-inferior to randomized CEA
• Surgeons in SAPPHIRE were experienced in CEA and
  had outcomes similar to referenced literature
• Too high risk for surgery ? Too high risk for
  stenting
• True for symptomatic and asymptomatic patients

114
AGENDA

• Project Overview CAS Background
• Description of Devices
• Overview of PMA Clinical Data (Total of 1619 Pts)
• 1. Non-Randomized CAS Clinical Trials
  Supportive data
• CASCADE (European) Study
• US FEASIBILITY Study
• 2. SAPPHIRE Pivotal Trial Ken Ouriel, M.D.
• Randomized Arm CAS vs. CEA
• Non-Randomized Arms CAS and CEA
• Overview of Training
• Post-Market Surveillance Study

115
Carotid Artery Stent Education System
PROFESSIONAL EDUCATION

116
CAROTID ARTERY STENT TRAINING SYSTEM

• Training system is intended to build upon
  already existing endovascular expertise to
  develop a physicians knowledge and technical
  expertise in performing CAS
• System was developed using a variety of
  consultants
• SAPPHIRE Investigators
• Internet based training
• Simulator modeling
• Proficiency measurements

117
DELIVERY PROCESS
Step 3
Step 4
Step 5
Step 1
Step 2
Patient Outcomes
Staff In-Service
On-line Didactic
Observation
Simulation
Proctor Network
Staff Training
Internet Delivery
Regional Education Center
On-site Training at Physicians Facility
Proficiency Measurement
118
CAROTID ARTERY STENT TRAINING SYSTEM

• On-line didactic training
• Transferring Expert Knowledge
• Through doing and decision making
• Goal
• Assure Procedural Success
• Detailed understanding of anatomy
• Appropriate case selection
• High performance technical execution
• Training at Regional Education Center
• Small group setting review 4 Modules Over 2
  Days
• Didactic Review, Case Observation, Simulation
  Lab, Product Lab
• Physicians
• interact with realistic graphical simulations
• assess task performance
• demonstrate understanding of the learning
  objectives

119
CAROTID ARTERY STENT TRAINING SYSTEM

• On-site training at physicians facility by
  physician proctors
• Network of CAS experienced physician proctors
• Proctor Sign Off or Additional Training
  Recommendations Based on Proficiency Standards
• Training Program
• 34 Hours of Training with exposure to a minimum
  of 15 Cases
• Serves as the foundation for hospital
  credentialing

120
INITIAL ASSESSMENT OF TRAINING Institutional IDEs

• 36 centers (30 non-Sapphire Investigators)
• All investigators were trained and proctored on
  use of the stent and the emboli protection system
• Patient selection criteria similar to the US
  FEASIBILITY Study
• Neurologist evaluation 24 hours and 30 days
  post-procedure
• Data are site reported and unadjudicated

121
INSTITUTIONAL IDEs 30-Day Events - Site
Reported

122
COMPARISON OF 30-DAY EVENT RATESTreated Patients
with ANGIOGUARD Only

123
POST-MARKETING SURVEILLANCE

• Carotid Stenting With Emboli Protection For The
  Treatment of Obstructive Carotid Artery Disease

124
POST-MARKETING SURVEILLANCE

• Objective
• To compare clinical outcomes with historical
  control data from SAPPHIRE in the early time
  period following approval and assess the
  effectiveness of the training program
• Design
• Multicenter, prospective, non-randomized, open
  label
• Primary Endpoint
• 30-day composite of major adverse clinical events
• (MAE all death and all stroke)

125
POST-MARKETING SURVEILLANCE

• Study Population
• High Risk patients with de novo or restenotic
  lesions
• gt 1000 patients
• Inclusion Criteria Per Label Indications
• Follow-up
• Neurologic examinations at discharge and 30 days
  (Neurologist)
• Clinical events tracking through discharge
• 30-day office visit
• 9-month telephone contact
• Monitoring with built in stopping rule
• Electronic data capture to expedite review of
  outcomes

126
CAROTID ARTERY STENTING WITH EMBOLI PROTECTION
Summary and Conclusions
127
SUMMARY AND CONCLUSIONS

• Stroke
• Significant morbidity and mortality
• Due to carotid disease in up to 30 of patients
• Goal of Tx to prevent stroke and improve quality
  of life
• CEA is the standard of care in
• NASCET/ACAS eligible and ineligible patients
• Symptomatic and asymptomatic patients
• Low, intermediate, and high risk
• There are no multi-center randomized studies that
  define outcomes in high medical- or surgical-risk
  patients
• SAPPHIRE is an objective comparison of CEA, the
  current interventional standard of care, with
  CAS, a less invasive approach to therapy

128
SUMMARY AND CONCLUSIONS

• Cordis is seeking the following indication
• The Cordis Carotid Stent System 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 TIAs or one or more completed
  strokes) and gt50 atherosclerotic stenosis of the
  common or internal carotid artery by ultrasound
  or angiogram
•  and 
• Patients without neurological symptoms and gt80
  atherosclerotic stenosis of the common or
  internal carotid artery by ultrasound or
  angiogram.
•  
• Symptomatic and asymptomatic patients must also
  have one or more condition(s) that place them at
  high-risk for carotid endarterectomy.

129
CONCLUSION

• This indication is supported by
• SAPPHIRE
• Achieved primary endpoint of non-inferiority of
  CAS to CEA for MAE at 1-year
• CAS - improved outcomes for MI and
  re-interventions with a significant decrease in
  cranial nerve injuries
• SUPPORTIVE STUDIES
• CAS treatment demonstrated sustained benefit
  through 3-year follow up

130
SUMMARY AND CONCLUSIONS

• Cordis will institute a training program to
  ensure outcomes of carotid stenting in non-trial
  setting replicates safety and effectiveness
  demonstrated in SAPPHIRE
• Cordis will conduct a post-marketing surveillance
  study with the goal of
• quantifying patient outcomes
• confirming the adequacy of physician training

131
THANK YOU