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

2. 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 TIA’s or one or more completed strokes) and >50% atherosclerotic stenosis of the common or internal carotid artery by ultrasound or angiogram; and Patients without neurological symptoms and >80% 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. 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. 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. 5 BACKGROUND Stroke & Carotid Disease >700,000 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 disease 2 Stroke is the number 1 cause of disability in the U.S. 1 Health care costs for stroke in excess of $53.6 billion/year 1 Over 50% of people under age 65 who have a stroke die within 8 years 1 Older population with co-morbid disease 1 1. Heart Disease and Stroke Statistics – 2004 Update, American Heart Association 2. ACAS Executive Committee JAMA 273:1421-1428, 1995

6. 6 BACKGROUND Carotid 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 33:728-732, 2001

7. 7BACKGROUND Carotid Endarterectomy - cont Randomized clinical studies –Superiority of CEA vs. best medical therapy NASCET 1 –Symptomatic >50% diameter stenosis ACAS 2 –Asymptomatic >60% diameter stenosis ECST 3 –Symptomatic >50% diameter stenosis VA Cooperative Study 4 –Symptomatic >50% diameter stenosis “Standard of Care” for interventional treatment of symptomatic and asymtomatic carotid artery disease 1. NASCET Trial Collaborators NEJM 325:445-453, 1991 2. ACAS Executive Committee JAMA 273:1421-1428, 1995 3. Rothwell et al., Stroke 34: 514-523, 2003 4. Hobson et al., NEJM 328:221-227, 1993

8. 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 patient 1 NASCET 1 out of every 3 treated patients enrolled 1 –Patients considered high risk for CEA as defined by trial ineligibility comprise up to 50% of patients in published series: Ochsner Clinic – 46.2% 2 CCF Registry – 19.4% 3 1.Wennberg et al., JAMA 279:1278-1281, 1998. 2. Leporre et al., J Vasc Surg 34: 581-586, 2001. 3. Ouriel et al., J Vasc Surg 33: 728-732, 2001.

9. 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 >79 Previous CVA with profound deficit MI within 6 months (NASCET) Unstable angina Atrial fibrillation Symptomatic CHF Valvular heart disease Cancer with <50% 5 year survival Renal/pulmonary/liver failure

10. 10 Wennberg, et al., JAMA, 279: 1278-1281, 1998 CEA MORTALITY 113,000 Medicare Patients (1992-1993) 30-Day Follow up Mortality %

11. 11 PUBLISHED 30-DAY CEA EVENT RATES % 1. Leporre et al., J Vasc Surg 34:581-586, 2001. 2. Cebul et al., JAMA 279:1282-1287, 1998 3. Halm et al., Stroke 34: 14264-1472, 2003 1 2 3 3

12. 12 IN-HOSPITAL CEA OUTCOMES US ACADEMIC CENTERS Retrospective analysis 1160 patients 12 academic centers in US 1988-90 In-hospital Death + MI +Stroke McCrory DC et al. Stroke 1993;24:1285-1291 Death + MI + Stroke

13. 13 IN-HOSPITAL CEA OUTCOMES US ACADEMIC CENTERS McCrory DC et al. Stroke 1993;24:1285-1291 Death + MI + Stroke

14. 14 PERCENT ASYMTOMATIC PATIENTS UNDERGOING CEA IS UP TO 75% 19982001 2003 % 1. Cebul et al., JAMA 279:1282-1287, 1998 2. Leporre et al., J Vasc Surg 34:581-586, 2001 3. Ouriel et al., J Vasc Surg 33: 728-732, 2001 4. Halm et al., Stroke 34: 14264-1472, 2003 1 2 3 4

15. 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 6 5 4 3 2 1 0 0-19%20-29%30-39%40-49%50-59%60-69%70-79%80-89%90-99% Stroke Incidence (%) Carotid Artery Stenosis INCIDENCE OF STROKE AT 360-DAYS Asymptomatic Patients

16. 16 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 TYPE OF PATIENTS CURRENTLY TREATED WITH CEA

17. 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. 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. 19 Includes a system consisting of 2 devices: –Stent Delivery System Stent Delivery catheter –Emboli Protection Device CAROTID ARTERY STENTING

20. 20 Cordis PRECISE™ Nitinol Stent

21. 21 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 Cordis PRECISE™ Nitinol Stent System 5.5F (5 – 8 mm) 6F (9 – 10 mm) 5F

22. 22 CAROTID ARTERY STENT SYSTEM 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” Emboli Protection: ANGIOGUARD™ XP Emboli Capture Guidewire

23. 23 CAS SYSTEM ANIMATION

24. 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. 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 n=121 1-year follow up –US FEASIBILITY Study CAS, non-randomized n=261 3-year follow up

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

27. 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. 28 CASCADE STUDY Overview 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: >70% stenosis if symptomatic by U/S or angiography >85% stenosis if asymptomatic by U/S or angiography Stenosis between origin of CCA and extracranial segment of the ICA

29. 29 CASCADE STUDY 30-Day Data % n=121

30. 30 CASCADE STUDY 30-Day Outcomes With/Without ANGIOGUARD™ % P=0.45 P>0.99 P=0.68

31. 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. 32 US FEASIBILITY STUDY The Cordis Nitinol Carotid Stent and Delivery System (SDS) in Patients with de novo or Restenotic Native Carotid Artery Lesions Trial

33. 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. 34 US FEASIBILITY STUDY Overview 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 >60% stenosis by U/S or angiography Asymptomatic >80% stenosis by U/S or angiography Native Common or Internal Carotid Artery

35. 35 US FEASIBILITY STUDY Overview - 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. 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 (< 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. 37 % US FEASIBILITY STUDY 30-Day Events n=261

38. 38 US FEASIBILITY STUDY 30-Day Events With/Without ANGIOGUARD™ P = 1.00 P = 0.31 P= 0.51 P = 0.19 % P = 0.10

39. 39 US FEASIBILITY STUDY Cumulative Percentage of MAE to 1080 Days 6.9% 30 10.9% 16.8% 21.8% Days:303607201080 N at Risk:247218177113 Error bars are 1.5 X S.E. Time After Initial Procedure (days) Cumulative Percentage of MAE

40. 40 US FEASIBILITY STUDY Cumulative Percentage of All Stroke to 30 Days and Ipsilateral Stroke from 31-1080 Days 6.1% 7.3% 8.7% 30 Days:303607201080 N at Risk:247218176113 Time After Initial Procedure (days) Cumulative Percentage of Stroke

41. 41 US FEASIBILITY STUDY Cumulative Percentage of Death to 1080 Days 9.0% 13.9% 4.0% 0.8% 30 Days:303607201080 N at Risk:258234192127 Time After Initial Procedure (days) Cumulative Percentage of Death

42. 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. 43 CAROTID STENT 30-Day Stroke Rates by Study and ANGIOGUARD™ P=0.10 P=0.45 P=0.02 %

44. 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. 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. 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. 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. 48 Patients Referred for Evaluation of Carotid Disease Screened for SAPPHIRE Inclusion/Exclusion Criteria 2294 patients SAPPHIRE STUDY Trial Design and Patient Flow Evaluated by panel of physicians (interventionalist, surgeon, neurologist) who concur on qualification of patient n = 747

49. 49 RCT 334 Randomized (310 Treated) Stent Treatment n=167 CEA Treatment n=167 Surgeon & Interventionalist will treat patient SAPPHIRE STUDY Trial Design and Patient Flow Evaluated by panel of physicians (interventionalist, surgeon, neurologist) who concur on qualification of patient n = 747

50. 50 Non-Randomized Stent Arm n=406 RCT 334 Randomized (310 Treated) Surgeon: unacceptable risk for CEA Stent Treatment n=167 CEA Treatment n=167 Surgeon & Interventionalist will treat patient SAPPHIRE STUDY Trial Design and Patient Flow Evaluated by panel of physicians (interventionalist, surgeon, neurologist) who concur on qualification of patient n = 747

51. 51 Non-Randomized Stent Arm n=406 Non-Randomized CEA Arm n=7 RCT 334 Randomized (310 Treated) Interventionalist: unacceptable risk for stenting Surgeon: unacceptable risk for CEA Stent Treatment n=167 CEA Treatment n=167 Surgeon & Interventionalist will treat patient SAPPHIRE STUDY Trial Design and Patient Flow Evaluated by panel of physicians (interventionalist, surgeon, neurologist) who concur on qualification of patient n = 747

52. 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. 53 SAPPHIRE STUDY Differences 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. 54 SAPPHIRE STUDY Relevance 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 mo 1 –Perioperative MI predicts mortality at one-year 2 –27-fold increased risk of another MI over the next 6 mo 1 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) 1 Kim et al. Circulation 2002;106:2366-2371 2 McFalls et al. Chest 1998;113:681-686

55. 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 >2, CK-MB >1 in the absence of new, pathological Q waves.

56. 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. 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 on 360 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. 58 SAPPHIRE STUDY Diminishing Enrollment (Randomized) Competing CAS registries Stop Enrollment

59. 59 SAPPHIRE STUDY Key Inclusion Criteria Patients referred for treatment of Carotid Artery Disease –Symptomatic >50% stenosis by U/S or angiography –Asymptomatic >80% 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. 60 Anatomic factors: –Contralateral carotid occlusion –Contralateral laryngeal nerve palsy –Radiation therapy to neck –Previous CEA with recurrent stenosis –Difficult surgical access –Severe tandem lesions SAPPHIRE STUDY Key Inclusion Criteria - cont

61. 61 Medical Co-morbidities: –CHF (class III/IV) &/or severe LV dysfunction (LVEF <30%) –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 SAPPHIRE STUDY Key Inclusion Criteria - cont

62. 62 RCT 334 Randomized (310 Treated) Stent Treatment n=167 CEA Treatment n=167 Surgeon & Interventionalist will treat patient SAPPHIRE STUDY Trial Design and Patient Flow Non-Randomized Stent Arm n=406 Non-Randomized CEA Arm n=7 Evaluated by panel of physicians (interventionalist, surgeon, neurologist) who concur on qualification of patient n = 747

63. 63 SAPPHIRE STUDY Demographics – Randomized Patients

64. 64 SAPPHIRE STUDY Acute Procedure & Device Outcomes* Stent Delivery Success**: -Randomized Stent:99.4% -Non-Randomized Stent:99.8% Device Success (Stent): <30% DS *** <50% 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. 65 SAPPHIRE STUDY OUTCOMES Data Presented Are Based on Intent-to-Treat Analyses (unless otherwise specified)

66. 66 RCT 334 Randomized (310 Treated) Stent Treatment n=167 CEA Treatment n=167 SAPPHIRE STUDY Trial Design and Patient Flow Clinical 93.5% Ultrasound 80.6%Ultrasound 69.2% Clinical 85.6% 1 Year Compliance All events adjudicated by independent CEC Angiograms and ultrasounds reviewed by independent core labs

67. 67 SAPPHIRE All Randomized Patients at 30 Days % P=0.68 P=1.00 P=0.17 P=0.14

68. 68 SAPPHIRE STUDY Primary Endpoint at 360 Days Randomized Patients – Overall Rates

69. 69 SAPPHIRE STUDY Primary Endpoint – 360-day MAE Non-Inferiority Statistics StentCEA%Difference [95% C.I.] 12.0% (20/167)19.2% (32/167) – 7.2%[ – 14.9%, 0.6%] Margin of Non-inferiority Stent Non-inferior to CEA 3% % Difference (Stent – CEA)

70. 70 SAPPHIRE STUDY Primary Endpoint at 360 Days P=0.14 P=0.83 P=0.17 P=0.10 (30 day) %

71. 71 SAPPHIRE STUDY Primary Endpoint at 360 Days % P=0.21 P=0.50 P=0.83

72. 72 SAPPHIRE STUDY Cumulative % of MAE to 360 Days Randomized Patients – Kaplan Meier Analysis CEA 20.1% Stent 12.2% LR p = 0.053 9.8% 4.8% Time After Initial Procedure (days) Cumulative Percentage of MAE

73. 73 9.8% 4.8% 30 12.2% 20.1% Days:30360720 N at Risk (CEA):16112559 N at Risk (Stent):16314788 CEA 26.7% Stent 19.2% SAPPHIRE STUDY Cumulative % of MAE to 720 Days Randomized Patients – Kaplan Meier Analysis Time After Initial Procedure (days) Cumulative Percentage of MAE 9.8% 4.8% 12.2% 20.1% CEA 26.7% Stent 19.2%

74. 74 Days:30360720 N at Risk (CEA):15913059 N at Risk (Stent):16214588 3.6% Stent 3.1% CEA 30 5.8% CEA 5.9% Stent 4.9% Stent * All Stroke to 30 days and ipsilateral stroke from 31-720 Days SAPPHIRE STUDY Cumulative % of Stroke* to 720 Days Randomized Patients - Kaplan Meier Analysis Time After Initial Procedure (days) Cumulative Percentage of Stroke

75. 75 1.2% Stent 2.5% CEA 30 7.4% Stent 13.5% CEA 20.9% CEA 14.4% Stent Days:30360720 N at Risk (CEA):16213764 N at Risk (Stent):16615393 SAPPHIRE STUDY Cumulative % of Death to 720 Days Randomized Patients - Kaplan Meier Analysis Time After Initial Procedure (days) Cumulative Percentage of Death

76. 76 Total Deaths: 33 –CEA: 21 –Stent:12 Total Number of Neurologic Deaths: 4 –CEA: 3 –Stent: 1 Non-Neurologic Deaths 29 SAPPHIRE STUDY Cause of Death at 360 Days - R andomized

77. 77 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 –Cardiac18 10 8 –Respiratory Failure 4 3 1 –Cancer 3 1 2 –Renal Failure 1 1 0 –Multi-system Failure 3 3 0 SAPPHIRE STUDY Cause of Death at 360 Days - Randomized

78. 78 SAPPHIRE STUDY Complications Stent (n=167) CEA (n=167) P-value Target Lesion Revascularization (TLR) 1 (0.6%)6 (3.6%)0.12 Vessel Thrombosis0 (0.0%) --- Major Bleeding15 (9.0%)17 (10.2%)0.85 Cranial Nerve Injury0 (0.0%)8 (4.8%)0.01

79. 79 SAPPHIRE STUDY Restenosis Rates and TLR at 360 Days In-Vessel Restenosis by U/SStent (n=167) CEA (n=167) P-value >50% Diameter Stenosis* 19.7% (24/122)31.3% (30/96)0.06 >70% Diameter Stenosis 0.8% (1/122)5.2% (5/96)0.09 >80% 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. 80 SAPPHIRE STUDY Analysis of the Evaluable (Treated) Patients

81. 81 SAPPHIRE STUDY Randomized Patients Who Were Not Treated StentCEA Subsequent to randomization found to not meet Inclusion Criteria: 24 Patient Withdrew Consent:38 Patient Condition Deteriorated/Too High a Risk:32 Other:02 TOTAL: 8 16

82. 82 SAPPHIRE STUDY Primary Endpoint 360 Days – Randomized TREATED Patients

83. 83 SAPPHIRE STUDY Cumulative % of MAE to 360 Days Randomized TREATED Patients – Kaplan Meier Analysis Time After Initial Procedure (days) LR p = 0.048 CAS: 12.0% CEA: 20.1% Cumulative Percentage of MAE

84. 84 Non-Randomized Stent Arm n=406 Non-Randomized CEA Arm n=7 RCT 334 Randomized (310 Treated) Stent Treatment n=167 CEA Treatment n=167 Surgeon & Interventionalist will treat patient SAPPHIRE STUDY Trial Design and Patient Flow Surgeon: unacceptable risk for CEA Evaluated by panel of physicians (interventionalist, surgeon, neurologist) who concur on qualification of patient n = 747

85. 85 SAPPHIRE STUDY Non-Randomized Stent Arm vs. CEA Randomized Demographic Characteristics

86. 86 SAPPHIRE STUDY MAE at 360 Days Rand CEA: 20.1% Non-Rand Stent: 16.0% Rand Stent: 12.2% Non-Randomized Stent Arm vs. Randomized Stent & CEA Time After Initial Procedure (days) Cumulative Percentage of MAE Rand CEA: 9.8% Non-Rand Stent: 6.9% Rand Stent: 4.8%

87. 87 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 SAPPHIRE STUDY Non-Randomized Stent Arm

88. 88 %Difference [95% C.I.] –5.3%[–13.4%, 3.0%] Margin of Non-inferiority % Difference (Non-randomized Stent – Randomized CEA) Stent Non-inferior to CEA 3% Non-Inferiority Statistics SAPPHIRE STUDY Primary Endpoint – 360-day MAE Adjusted for Baseline Characteristics

89. 89 SAPPHIRE STUDY Complications Randomized Stent (n = 167) Randomized CEA (n = 167) Non-Rand Stent (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%) 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%)<0.01

90. 90 Non-Randomized Stent Arm n=406 Non-Randomized CEA Arm n=7 RCT 334 Randomized (310 Treated) Stent Treatment n=167 CEA Treatment n=167 Surgeon & Interventionalist will treat patient SAPPHIRE STUDY Trial Design and Patient Flow Interventionalist: unacceptable risk for stenting Surgeon: unacceptable risk for CEA Evaluated by panel of physicians (interventionalist, surgeon, neurologist) who concur on qualification of patient n = 747

91. 91 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 SAPPHIRE STUDY Subgroup Analyses

92. 92 SAPPHIRE STUDY 30-Day MAE Asymptomatic (ITT) % P=0.62 P=0.54 P=0.22 P=0.46

93. 93 SAPPHIRE STUDY 360-Day MAE Asymptomatic (ITT) % P=0.15 P=1.00 P=0.08 P=0.07

94. 94 SAPPHIRE STUDY Cumulative % of MAE Asymptomatic to 360 Days All Randomized Patients – Kaplan Meier Analysis Time After Initial Procedure (days) Cumulative Percentage of MAE LR p = 0.04 CEA: 20.3% Stent: 10.5%

95. 95 SAPPHIRE STUDY 30-Day MAE Symptomatic (ITT) P=0.10 P=0.61 P=0.48 P=0.11 %

96. 96 SAPPHIRE STUDY 360-Day MAE Symptomatic (ITT) % P=0.57 P=0.35 P=1.00

97. 97 SAPPHIRE STUDY Cumulative % of MAE Symptomatic to 360 Days All Randomized Patients – Kaplan Meier Analysis Time After Initial Procedure (days) Cumulative Percentage of MAE LR p = 0.58 CEA: 20.0% Stent: 16.3%

98. 98 % P=0.07 SAPPHIRE STUDY 360-Day MAE Symptomatic vs. Asymptomatic (ITT) n=281n=46n=124n=120 n=117n=50

99. 99 SAPPHIRE STUDY 360-Day MAE Symptomatic vs. Asymptomatic Treated (Evaluable) Patients P=0.02 % n=281n=124n=111n=48n=108n=43

100. 100 SAPPHIRE STUDY Surgeon Experience and Outcomes Experience and outcomes for surgeons in SAPPHIRE trial are consistent with previous surgical data –CEA volume –Outcomes –Complication rates

101. 101 Pre-study survey conducted 53 SAPPHIRE surgeons – Mean of 36.3 procedures per year – Median of 28 procedures per year SAPPHIRE STUDY Surgeon Experience & Judgment

102. 102 CEA OUTCOMES BY VOLUME Wennberg, JAMA 289: 1278-1281, 1998 Annualized Volume Tercile - # Procedures in Medicare Treated Patients Tercile of cases per year – all CEA surgeons Mortality (%)

103. 103 CEA OUTCOMES BY VOLUME Wennberg, JAMA 289: 1278-1281, 1998 Annualized Volume Tercile - # Procedures in Medicare Treated Patients Tercile of cases per year – all CEA surgeons Mortality (%) SAPPHIRE 1 4 48 Cases/Surgeon

104. 104 CRANIAL NERVE INJURY Comparison with Other Studies SAPPHIRE Randomized CEA: 4.8% NASCET:7.2% VA Cooperative Study:3.8% ACAS: NA NASCET AND VA STUDY EXCLUDED REPEAT CEA

105. 105 30-Day Ipsilateral Stroke SURGICAL OUTCOMES vs. OTHER TRIALS Error Bar = 95% CI %

106. 106 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 CAS OUTCOMES TO OTHER SURGICAL TRIALS

107. 107 30-Day Ipsilateral Stroke CAS OUTCOMES TO OTHER SURGICAL TRIALS Symptomatic Patients Error Bar = 95% CI %

108. 108 30-Day Ipsilateral Stroke CAS OUTCOMES TO OTHER SURGICAL TRIALS Asymptomatic Patients Error Bar = 95% CI %

109. 109 SAPPHIRE STUDY CAS 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. 110 SAPPHIRE STUDY Conclusions

111. 111 SAPPHIRE STUDY Conclusions: 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 (>50% DS) Significant decrease in cranial nerve injuries

112. 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. 113 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 SAPPHIRE STUDY Conclusions: Non-Randomized Stent Arm

114. 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. 115 PROFESSIONAL EDUCATION Carotid Artery Stent Education System

116. 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. 117 On-lineDidacticOn-lineDidactic Observation Observation SimulationSimulationStaffIn-ServiceStaffIn-ServiceProctorNetworkProctorNetwork Step 1 Step 2 Step 3 Step 4Step 5 InternetDeliveryInternetDelivery Regional Education Regional EducationCenter Center On-site Training at Physician’s Facility On-site Training at Physician’s Facility PatientOutcomesPatientOutcomes StaffTrainingStaffTraining DELIVERY PROCESS Proficiency Measurement

118. 118  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 CAROTID ARTERY STENT TRAINING SYSTEM

119. 119 On-site training at physician’s 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 CAROTID ARTERY STENT TRAINING SYSTEM

120. 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. 121 % INSTITUTIONAL IDEs 30-Day Events - Site Reported

122. 122 COMPARISON OF 30-DAY EVENT RATES Treated Patients with ANGIOGUARD ™ Only %

123. 123 Carotid Stenting With Emboli Protection For The Treatment of Obstructive Carotid Artery Disease POST-MARKETING SURVEILLANCE

124. 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. 125 Study Population: High Risk patients with de novo or restenotic lesions > 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 POST-MARKETING SURVEILLANCE

126. 126 CAROTID ARTERY STENTING WITH EMBOLI PROTECTION Summary and Conclusions

127. 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. 128 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 TIA’s or one or more completed strokes) and >50% atherosclerotic stenosis of the common or internal carotid artery by ultrasound or angiogram; and Patients without neurological symptoms and >80% 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. SUMMARY AND CONCLUSIONS

129. 129 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 CONCLUSION

130. 130 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 SUMMARY AND CONCLUSIONS

131. 131 THANK YOU