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  • 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 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. 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. 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. 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.
    • 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
    BACKGROUND Carotid Endarterectomy - cont 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. 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
    • 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. 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. CEA MORTALITY Wennberg, et al., JAMA, 279: 1278-1281, 1998 113,000 Medicare Patients (1992-1993) 30-Day Follow up Mortality %
  • 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. 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. IN-HOSPITAL CEA OUTCOMES US ACADEMIC CENTERS McCrory DC et al. Stroke 1993;24:1285-1291 Death + MI + Stroke
  • 14. PERCENT ASYMTOMATIC PATIENTS UNDERGOING CEA IS UP TO 75% 1998 2001 2001 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.
    • 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. 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.
    • Includes a system consisting of 2 devices:
      • Stent Delivery System
        • Stent
        • Delivery catheter
      • Emboli Protection Device
    CAROTID ARTERY STENTING
  • 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 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. 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
        • n=121
        • 1-year follow up
      • US FEASIBILITY Study
        • CAS, non-randomized
        • n=261
        • 3-year follow up
  • 26. CASCADE STUDY The C ordis Sm a rt Self-Expandable S tent in Ca rotid Artery D iseas e
  • 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 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. CASCADE STUDY 30-Day Data % n=121
  • 30. CASCADE STUDY 30-Day Outcomes With/Without ANGIOGUARD ™ % P=0.45 P>0.99 P=0.68
  • 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 STUDY The 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 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. 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. 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. US FEASIBILITY STUDY 30-Day Events % n=261
  • 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. US FEASIBILITY STUDY Cumulative Percentage of MAE to 1080 Days 6.9% 30 10.9% 16.8% 21.8% Error bars are 1.5 X S.E. Time After Initial Procedure (days) Cumulative Percentage of MAE Days: 30 360 720 1080 N at Risk: 247 218 177 113
  • 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% 8.7% 30 Time After Initial Procedure (days) Cumulative Percentage of Stroke Days: 30 360 720 1080 N at Risk: 247 218 176 113
  • 41. US FEASIBILITY STUDY Cumulative Percentage of Death to 1080 Days 9.0% 13.9% 4.0% 0.8% 30 Time After Initial Procedure (days) Cumulative Percentage of Death Days: 30 360 720 1080 N at Risk: 258 234 192 127
  • 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 STENT 30-Day Stroke Rates by Study and ANGIOGUARD ™ P=0.10 P=0.45 P=0.02 %
  • 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 STUDY Trial 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 STUDY Trial Design and Patient Flow RCT 334 Randomized (310 Treated) Stent Treatment n=167 CEA Treatment n=167 Surgeon & Interventionalist will treat patient Evaluated by panel of physicians (interventionalist, surgeon, neurologist) who concur on qualification of patient n = 747
  • 50. SAPPHIRE STUDY Trial Design and Patient Flow 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 Evaluated by panel of physicians (interventionalist, surgeon, neurologist) who concur on qualification of patient n = 747
  • 51. SAPPHIRE STUDY Trial Design and Patient Flow 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 Evaluated by panel of physicians (interventionalist, surgeon, neurologist) who concur on qualification of patient n = 747
  • 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 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. 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. 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. 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 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. SAPPHIRE STUDY Diminishing Enrollment (Randomized) Competing CAS registries Stop Enrollment
  • 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.
      • 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.
    • 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. SAPPHIRE STUDY Trial Design and Patient Flow RCT 334 Randomized (310 Treated) Stent Treatment n=167 CEA Treatment n=167 Surgeon & Interventionalist will treat patient 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. SAPPHIRE STUDY Demographics – Randomized Patients
  • 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. SAPPHIRE STUDY OUTCOMES Data Presented Are Based on Intent-to-Treat Analyses (unless otherwise specified)
  • 66. SAPPHIRE STUDY Trial Design and Patient Flow RCT 334 Randomized (310 Treated) Stent Treatment n=167 CEA Treatment n=167 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. SAPPHIRE All Randomized Patients at 30 Days % P=0.68 P=1.00 P=0.17 P=0.14
  • 68. SAPPHIRE STUDY Primary Endpoint at 360 Days Randomized Patients – Overall Rates
  • 69. SAPPHIRE STUDY Primary Endpoint – 360-day MAE   Non-Inferiority Statistics Margin of Non-inferiority Stent Non-inferior to CEA 3% % Difference (Stent – CEA) – 7.2%[–14.9%, 0.6%] 19.2% (32/167) 12.0% (20/167) %Difference [95% C.I.] CEA Stent
  • 70. SAPPHIRE STUDY Primary Endpoint at 360 Days P=0.14 P=0.83 P=0.17 P=0.10 (30 day) %
  • 71. SAPPHIRE STUDY Primary Endpoint at 360 Days % P=0.21 P=0.50 P=0.83
  • 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. SAPPHIRE STUDY Cumulative % of MAE to 720 Days Randomized Patients – Kaplan Meier Analysis 9.8% 4.8% 30 12.2% 20.1% CEA 26.7% Stent 19.2% Time After Initial Procedure (days) Cumulative Percentage of MAE 9.8% 4.8% 12.2% 20.1% CEA 26.7% Stent 19.2% Days: 30 360 720 N at Risk (CEA): 161 125 59 N at Risk (Stent): 163 147 88
  • 74. SAPPHIRE STUDY Cumulative % of Stroke* to 720 Days Randomized Patients - Kaplan Meier Analysis 3.6% Stent 3.1% CEA 30 5.8% CEA 5.8% CEA 5.9% Stent 4.9% Stent * All Stroke to 30 days and ipsilateral stroke from 31-720 Days Time After Initial Procedure (days) Cumulative Percentage of Stroke Days: 30 360 720 N at Risk (CEA): 159 130 59 N at Risk (Stent): 162 145 88
  • 75. SAPPHIRE STUDY Cumulative % of Death to 720 Days Randomized Patients - Kaplan Meier Analysis 1.2% Stent 2.5% CEA 30 7.4% Stent 13.5% CEA 20.9% CEA 14.4% Stent Time After Initial Procedure (days) Cumulative Percentage of Death Days: 30 360 720 N at Risk (CEA): 162 137 64 N at Risk (Stent): 166 153 93
  • 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.
    • 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
    SAPPHIRE STUDY Cause of Death at 360 Days - Randomized
  • 78. SAPPHIRE STUDY Complications 0.01 8 (4.8%) 0 (0.0%) Cranial Nerve Injury 0.85 17 (10.2%) 15 (9.0%) Major Bleeding --- 0 (0.0%) 0 (0.0%) Vessel Thrombosis 0.12 6 (3.6%) 1 (0.6%) Target Lesion Revascularization (TLR) P-value CEA (n=167) Stent (n=167)
  • 79. SAPPHIRE STUDY Restenosis Rates and TLR at 360 Days * Protocol Definition 0.12 3.6% (6/167) 0.6% (1/167) TLR – Clinically driven (to 360 days) 0.17 4.2% (4/96) 0.8% (1/122) >80% Diameter Stenosis 0.09 5.2% (5/96) 0.8% (1/122) >70% Diameter Stenosis 0.06 31.3% (30/96) 19.7% (24/122) >50% Diameter Stenosis* P-value CEA (n=167) Stent (n=167) In-Vessel Restenosis by U/S
  • 80. SAPPHIRE STUDY Analysis of the Evaluable (Treated) Patients
  • 81. SAPPHIRE STUDY Randomized Patients Who Were Not Treated 16 CEA Stent 8 TOTAL: 2 0 Other : 2 3 Patient Condition Deteriorated/Too High a Risk: 8 3 Patient Withdrew Consent: 4 2 Subsequent to randomization found to not meet Inclusion Criteria:
  • 82. SAPPHIRE STUDY Primary Endpoint 360 Days – Randomized TREATED Patients
  • 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. SAPPHIRE STUDY Trial Design and Patient Flow 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 Surgeon: unacceptable risk for CEA Evaluated by panel of physicians (interventionalist, surgeon, neurologist) who concur on qualification of patient n = 747
  • 85. SAPPHIRE STUDY Non-Randomized Stent Arm vs. CEA Randomized Demographic Characteristics
  • 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.
    • 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. SAPPHIRE STUDY Primary Endpoint – 360-day MAE Adjusted for Baseline Characteristics   Margin of Non-inferiority % Difference (Non-randomized Stent – Randomized CEA) Stent Non-inferior to CEA 3% Non-Inferiority Statistics – 5.3%[–13.4%, 3.0%] %Difference [95% C.I.]
  • 89. SAPPHIRE STUDY Complications <0.01 0 (0.0%) 8 (4.8%) 0 (0.0%) Cranial Nerve Injury 0.33 54 (13.3%) 17 (10.2%) 15 (9.0%) Major Bleeding 0.56 3 (0.7%) 0 (0.0%) 0 (0.0%) Vessel Thrombosis 0.02 3 (0.7%) 6 (3.6%) 1 (0.6%) TLR P-value (CEA vs. Non-Rand) Non-Rand Stent (n = 406) Randomized CEA (n = 167) Randomized Stent (n = 167)
  • 90. SAPPHIRE STUDY Trial Design and Patient Flow 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 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.
    • 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. SAPPHIRE STUDY 30-Day MAE Asymptomatic (ITT) % P=0.62 P=0.54 P=0.22 P=0.46
  • 93. SAPPHIRE STUDY 360-Day MAE Asymptomatic (ITT) % P=0.15 P=1.00 P=0.08 P=0.07
  • 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. SAPPHIRE STUDY 30-Day MAE Symptomatic (ITT) P=0.10 P=0.61 P=0.48 P=0.11 %
  • 96. SAPPHIRE STUDY 360-Day MAE Symptomatic (ITT) % P=0.57 P=0.35 P=1.00
  • 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. SAPPHIRE STUDY 360-Day MAE Symptomatic vs. Asymptomatic (ITT) % P=0.07 n=281 n=46 n=124 n=120 n=117 n=50
  • 99. SAPPHIRE STUDY 360-Day MAE Symptomatic vs. Asymptomatic Treated (Evaluable) Patients P=0.02 % n=281 n=124 n=111 n=48 n=108 n=43
  • 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. SAPPHIRE STUDY Surgeon 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 Wennberg, JAMA 289: 1278-1281, 1998 Annualized Volume Tercile - # Procedures in Medicare Treated Patients Tercile of cases per year – all CEA surgeons Mortality (%)
  • 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. 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. SURGICAL OUTCOMES vs. OTHER TRIALS 30-Day Ipsilateral Stroke Error Bar = 95% CI %
  • 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. CAS OUTCOMES TO OTHER SURGICAL TRIALS Symptomatic Patients 30-Day Ipsilateral Stroke Error Bar = 95% CI %
  • 108. CAS OUTCOMES TO OTHER SURGICAL TRIALS Asymptomatic Patients 30-Day Ipsilateral Stroke Error Bar = 95% CI %
  • 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. SAPPHIRE STUDY Conclusions
  • 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. 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.
    • 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. 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. On-line Didactic Observation Simulation Staff In-Service Proctor Network Step 1 Step 2 Step 3 Step 4 Step 5 Internet Delivery Regional Education Center On-site Training at Physician’s Facility Patient Outcomes Staff Training DELIVERY PROCESS Proficiency Measurement
  • 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.
    • 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. 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 RATES Treated Patients with ANGIOGUARD ™ Only %
  • 123.
    • Carotid Stenting With Emboli Protection For The Treatment of Obstructive Carotid Artery Disease
    POST-MARKETING SURVEILLANCE
  • 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.
    • 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. 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.
    • 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.
    • 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.
    • 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. THANK YOU