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  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 <ul><li>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; </li></ul><ul><li>  and  </li></ul><ul><li>Patients without neurological symptoms and > 80% atherosclerotic stenosis of the common or internal carotid artery by ultrasound or angiogram. </li></ul><ul><li>  </li></ul><ul><li>Symptomatic and asymptomatic patients must also have one or more condition(s) that place them at high-risk for carotid endarterectomy. </li></ul>
  3. 3. AGENDA <ul><li>Project Overview & CAS Background </li></ul><ul><li>Description of Devices </li></ul><ul><li>Overview of PMA Clinical Data (Total of 1619 Pts) </li></ul><ul><ul><li>1. Non-Randomized CAS Clinical Trials – Supportive data </li></ul></ul><ul><ul><ul><li>CASCADE (European) Study </li></ul></ul></ul><ul><ul><ul><li>US FEASIBILITY Study </li></ul></ul></ul><ul><li> 2. SAPPHIRE Pivotal Trial – Ken Ouriel, M.D. </li></ul><ul><ul><ul><li>Randomized Arm: CAS vs. CEA </li></ul></ul></ul><ul><ul><ul><li>Non-Randomized Arms: CAS and CEA </li></ul></ul></ul><ul><li>Overview of Training </li></ul><ul><li>Post-Market Surveillance Study </li></ul>
  4. 4. PROJECT OVERVIEW <ul><li>US FEASIBILITY Study start date - September 1998 </li></ul><ul><li>SAPPHIRE Pivotal Study start date – August 2000 </li></ul><ul><li>PMA filed on October 8, 2003 </li></ul><ul><ul><li>Achieved primary endpoint of non-inferiority of CAS to CEA for 1-year </li></ul></ul><ul><ul><li>CAS - improved outcomes for MI and re-interventions with a significant decrease in cranial nerve injuries </li></ul></ul><ul><ul><li>Sustained benefit of CAS treatment demonstrated through 3-years follow up </li></ul></ul><ul><li>PMA granted Expedited Review Status November 14, 2003 </li></ul><ul><ul><li>Significant therapeutic advance </li></ul></ul>
  5. 5. BACKGROUND Stroke & Carotid Disease <ul><li>> 700,000 strokes occur annually in the U.S. 1 </li></ul><ul><li>Stroke is the third leading cause of death with an estimated 164,000 deaths per year 1 </li></ul><ul><li>Up to 30% of strokes are caused by carotid artery disease 2 </li></ul><ul><li>Stroke is the number 1 cause of disability in the U.S. 1 </li></ul><ul><li>Health care costs for stroke in excess of $53.6 billion/year 1 </li></ul><ul><li>Over 50% of people under age 65 who have a stroke die within 8 years 1 </li></ul><ul><li>Older population with co-morbid disease 1 </li></ul>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 <ul><li>50 year history of technique development and refinement </li></ul><ul><li>CEA is the current interventional standard of care in treating carotid artery disease to reduce the risk of stroke </li></ul><ul><li>Up to 200,000 CEAs performed per year in the U.S. 1 </li></ul><ul><li>Estimated that 20% of CEAs are performed on “high surgical-risk” patients annually in the U.S. 2 </li></ul><ul><li>High surgical risk defined: </li></ul><ul><ul><li>Anatomic - increased procedure risk </li></ul></ul><ul><ul><li>Medical Co-morbidities - increased risk MI and death </li></ul></ul>1. Heart Disease and Stroke Statistics – 2004 Update, American Heart Association 2. Ouriel et al., J Vasc Surg 33:728-732, 2001
  7. 7. <ul><li>Randomized clinical studies </li></ul><ul><ul><li>Superiority of CEA vs. best medical therapy </li></ul></ul><ul><ul><ul><li>NASCET 1 </li></ul></ul></ul><ul><ul><ul><ul><li>Symptomatic > 50% diameter stenosis </li></ul></ul></ul></ul><ul><ul><ul><li>ACAS 2 </li></ul></ul></ul><ul><ul><ul><ul><li>Asymptomatic > 60% diameter stenosis </li></ul></ul></ul></ul><ul><ul><ul><li>ECST 3 </li></ul></ul></ul><ul><ul><ul><ul><li>Symptomatic > 50% diameter stenosis </li></ul></ul></ul></ul><ul><ul><ul><li>VA Cooperative Study 4 </li></ul></ul></ul><ul><ul><ul><ul><li>Symptomatic > 50% diameter stenosis </li></ul></ul></ul></ul><ul><li>“ Standard of Care” for interventional treatment of symptomatic and asymtomatic carotid artery disease </li></ul>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. 8. TYPE OF PATIENTS CURRENTLY TREATED WITH CEA <ul><li>CEA treatment of patients clearly extends beyond </li></ul><ul><li>NASCET/ACAS inclusion criteria: </li></ul><ul><ul><li>NASCET/ACAS studied a relatively healthy subset of patients: </li></ul></ul><ul><ul><ul><li>ACAS screened 25 to enroll 1 patient 1 </li></ul></ul></ul><ul><ul><ul><li>NASCET 1 out of every 3 treated patients enrolled 1 </li></ul></ul></ul><ul><ul><li>Patients considered high risk for CEA as defined by trial ineligibility comprise up to 50% of patients in published series: </li></ul></ul><ul><ul><ul><li>Ochsner Clinic – 46.2% 2 </li></ul></ul></ul><ul><ul><ul><li>CCF Registry – 19.4% 3 </li></ul></ul></ul><ul><li>Wennberg et al., JAMA 279:1278-1281, 1998. 2. Leporre et al., J Vasc Surg 34: 581-586, 2001. </li></ul><ul><li>3. Ouriel et al., J Vasc Surg 33: 728-732, 2001. </li></ul>
  9. 9. NASCET/ACAS EXCLUSION CRITERIA <ul><li>Anatomic Risks </li></ul><ul><li>Tandem lesions </li></ul><ul><li>Previous CEA </li></ul><ul><li>Radiation therapy to neck (ACAS) </li></ul><ul><li>Status post radical neck dissection </li></ul><ul><li>Medical Co-morbidities </li></ul><ul><li>Age >79 </li></ul><ul><li>Previous CVA with profound deficit </li></ul><ul><li>MI within 6 months (NASCET) </li></ul><ul><li>Unstable angina </li></ul><ul><li>Atrial fibrillation </li></ul><ul><li>Symptomatic CHF </li></ul><ul><li>Valvular heart disease </li></ul><ul><li>Cancer with <50% 5 year survival </li></ul><ul><li>Renal/pulmonary/liver failure </li></ul>
  10. 10. CEA MORTALITY Wennberg, et al., JAMA, 279: 1278-1281, 1998 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 <ul><li>Retrospective analysis </li></ul><ul><li>1160 patients </li></ul><ul><li>12 academic centers in US </li></ul><ul><li>1988-90 </li></ul><ul><li>In-hospital Death + MI +Stroke </li></ul>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% 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. 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. <ul><li>In US, standard of care for interventional treatment includes: </li></ul><ul><ul><li>NASCET/ACAS eligible & ineligible patients </li></ul></ul><ul><ul><li>Symptomatic and asymptomatic patients </li></ul></ul><ul><ul><li>Higher risk patients </li></ul></ul><ul><ul><ul><li>Anatomic </li></ul></ul></ul><ul><ul><ul><li>Medical Co-morbidities </li></ul></ul></ul><ul><li>SAPPHIRE trial studied patients who currently are referred for treatment of their carotid disease </li></ul>TYPE OF PATIENTS CURRENTLY TREATED WITH CEA
  17. 17. RATIONALE FOR TREATMENT OF “HIGH SURGICAL-RISK” PATIENTS <ul><li>Initial evaluation of new technology (CAS) in cohort of patients where CEA is technically demanding </li></ul><ul><ul><li>Anatomic: difficult access that may lead to local tissue and nerve injury </li></ul></ul><ul><ul><li>Medical Co-morbidities: patients less tolerant of general anesthesia & surgery </li></ul></ul><ul><li>CAS studied as an alternative and less invasive method of therapy </li></ul>
  18. 18. AGENDA <ul><li>Project Overview & CAS Background </li></ul><ul><li>Description of Devices </li></ul><ul><li>Overview of PMA Clinical Data (Total of 1619 Pts) </li></ul><ul><ul><li>1. Non-randomized CAS Clinical Trials – Supportive data </li></ul></ul><ul><ul><ul><li>CASCADE (European) Study </li></ul></ul></ul><ul><ul><ul><li>US FEASIBILITY Study </li></ul></ul></ul><ul><li> 2. SAPPHIRE Pivotal Trial – Ken Ouriel, M.D. </li></ul><ul><ul><ul><li>Randomized Arm: CAS vs. CEA </li></ul></ul></ul><ul><ul><ul><li>Non-Randomized Arms: CAS and CEA </li></ul></ul></ul><ul><li>Overview of Training </li></ul><ul><li>Post-Market Surveillance Study </li></ul>
  19. 19. <ul><li>Includes a system consisting of 2 devices: </li></ul><ul><ul><li>Stent Delivery System </li></ul></ul><ul><ul><ul><li>Stent </li></ul></ul></ul><ul><ul><ul><li>Delivery catheter </li></ul></ul></ul><ul><ul><li>Emboli Protection Device </li></ul></ul>CAROTID ARTERY STENTING
  20. 20. Cordis PRECISE ™ Nitinol Stent
  21. 21. Cordis PRECISE ™ Nitinol Stent System <ul><li>Stent Delivery System: </li></ul><ul><ul><li>5.5F Cordis PRECISE Nitinol Stent System </li></ul></ul><ul><ul><li>6F Cordis PRECISE Nitinol Stent System </li></ul></ul><ul><ul><li>Usable Length: 135 cm </li></ul></ul><ul><ul><li>Guidewire Lumen: 0.018” compatible </li></ul></ul>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 <ul><li>Project Overview & CAS Background </li></ul><ul><li>Description of Devices </li></ul><ul><li>Overview of PMA Clinical Data (Total of 1619 Pts) </li></ul><ul><ul><li>1. Non-Randomized CAS Clinical Trials – Supportive data </li></ul></ul><ul><ul><ul><li>CASCADE (European) Study </li></ul></ul></ul><ul><ul><ul><li>US FEASIBILITY Study </li></ul></ul></ul><ul><li> 2. SAPPHIRE Pivotal Trial – Ken Ouriel, M.D. </li></ul><ul><ul><ul><li>Randomized Arm: CAS vs. CEA </li></ul></ul></ul><ul><ul><ul><li>Non-randomized Arms: CAS and CEA </li></ul></ul></ul><ul><li>Overview of Training </li></ul><ul><li>Post-Market Surveillance Study </li></ul>
  25. 25. CLINICAL TRIALS Supportive Data <ul><li>Purpose </li></ul><ul><ul><li>Gain experience: </li></ul></ul><ul><ul><ul><li>Carotid stent system </li></ul></ul></ul><ul><ul><ul><li>Learning curve for investigators </li></ul></ul></ul><ul><ul><li>Refine the stent delivery system </li></ul></ul><ul><ul><li>Evaluate the advantage of adding ANGIOGUARD ™ </li></ul></ul><ul><li>Two Studies </li></ul><ul><ul><li>CASCADE (European) Study </li></ul></ul><ul><ul><ul><li>CAS, non-randomized </li></ul></ul></ul><ul><ul><ul><li>n=121 </li></ul></ul></ul><ul><ul><ul><li>1-year follow up </li></ul></ul></ul><ul><ul><li>US FEASIBILITY Study </li></ul></ul><ul><ul><ul><li>CAS, non-randomized </li></ul></ul></ul><ul><ul><ul><li>n=261 </li></ul></ul></ul><ul><ul><ul><li>3-year follow up </li></ul></ul></ul>
  26. 26. CASCADE STUDY The C ordis Sm a rt Self-Expandable S tent in Ca rotid Artery D iseas e
  27. 27. CASCADE STUDY <ul><li>Objective: </li></ul><ul><li>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 </li></ul><ul><li>Primary Endpoint: Ipsilateral stroke or procedural related death within 30 days of stent implantation </li></ul>
  28. 28. CASCADE STUDY Overview <ul><li>Design: </li></ul><ul><ul><li>Multi-center, prospective, non-randomized study </li></ul></ul><ul><ul><li>Nine centers across Europe </li></ul></ul><ul><ul><li>7F SMART Stent Delivery System </li></ul></ul><ul><ul><li>121 patients enrolled (31 with ANGIOGUARD ™ ) </li></ul></ul><ul><ul><li>Conducted from September 1998 until May 2002 </li></ul></ul><ul><li>Inclusion Criteria: </li></ul><ul><ul><li>>70% stenosis if symptomatic by U/S or angiography </li></ul></ul><ul><ul><li>>85% stenosis if asymptomatic by U/S or angiography </li></ul></ul><ul><ul><li>Stenosis between origin of CCA and extracranial segment of the ICA </li></ul></ul>
  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 <ul><li>Conclusion: </li></ul><ul><ul><li>Carotid artery stenting was found to be feasible for the treatment of carotid stenosis </li></ul></ul><ul><ul><li>The ANGIOGUARD ™ distal protection device functioned well and reduced the risk of distal embolization, resulting in fewer strokes. </li></ul></ul><ul><ul><ul><li>30-day stroke rate of 3.2%, with no major strokes </li></ul></ul></ul>
  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 <ul><li>Objective: </li></ul><ul><ul><li>Primary: Assess the feasibility of carotid artery stenting in the treatment of obstructive carotid artery disease </li></ul></ul><ul><ul><li>Secondary: Assess and standardize optimal operator techniques for pivotal trial </li></ul></ul>
  34. 34. US FEASIBILITY STUDY Overview <ul><li>Design: </li></ul><ul><li>Non-randomized, prospective, 33 center trial </li></ul><ul><li>6/7F SMART ™ and 5.5F PRECISE ™ SDS </li></ul><ul><li>261 patients enrolled </li></ul><ul><ul><li>176 stent </li></ul></ul><ul><ul><li>85 stent plus ANGIOGUARD ™ </li></ul></ul><ul><li>Sept 1998 through July 2001 </li></ul><ul><li>Follow up to 3 years </li></ul><ul><li>Key Inclusion Criteria: </li></ul><ul><li>Symptomatic > 60% stenosis by U/S or angiography </li></ul><ul><li>Asymptomatic > 80% stenosis by U/S or angiography </li></ul><ul><li>Native Common or Internal Carotid Artery </li></ul>
  35. 35. US FEASIBILITY STUDY Overview - cont <ul><li>Key Inclusion Criteria: (cont) </li></ul><ul><li>High Risk for Surgical Endarterectomy </li></ul><ul><li>Anatomic risk factors (not ACAS eligible): </li></ul><ul><ul><ul><li>Restenosis after CEA </li></ul></ul></ul><ul><ul><ul><li>Radical neck dissection </li></ul></ul></ul><ul><ul><ul><li>Contralateral carotid artery occlusion </li></ul></ul></ul><ul><ul><ul><li>Ostial lesion of the common carotid </li></ul></ul></ul><ul><ul><ul><li>High take-off carotid bifurcation disease </li></ul></ul></ul>
  36. 36. US FEASIBILITY STUDY <ul><li>Primary Endpoint: </li></ul><ul><li>30-day MAE (death, any stroke, &/or MI) </li></ul><ul><li>  </li></ul><ul><li>Key Secondary Endpoints: </li></ul><ul><li>Major clinical events </li></ul><ul><ul><li>6 months, 1, 2, 3 years </li></ul></ul><ul><li>Patency (< 50% restenosis) by carotid U/S </li></ul><ul><ul><li>48 hours, 30 days, 6 months, 1, 2, & 3 years </li></ul></ul><ul><li>Neurological assessments </li></ul><ul><ul><li>28 hours, 30 days, 6 months, 1, 2, & 3 years </li></ul></ul>
  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% 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. 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. 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. 42. US FEASIBILITY STUDY <ul><li>Conclusion: </li></ul><ul><li>Demonstrated feasibility of carotid stenting with the Cordis PRECISE ™ Nitinol Stent System </li></ul><ul><li>ANGIOGUARD ™ emboli protection device reduced the incidence of stroke </li></ul><ul><ul><li>30-day stroke rate 2.4%, with no major strokes </li></ul></ul><ul><li>Provided run-in to pivotal study </li></ul>
  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 <ul><li>Refinement of CAS System </li></ul><ul><ul><li>Reduction in profile (7F to 5.5F) </li></ul></ul><ul><ul><li>Improvement in design </li></ul></ul><ul><li>Data supports benefit of ANGIOGUARD ™ emboli protection device in reducing stroke </li></ul><ul><li>Demonstrated the feasibility of CAS </li></ul>
  45. 45. AGENDA <ul><li>Project Overview & CAS Background </li></ul><ul><li>Description of Devices </li></ul><ul><li>Overview of PMA Clinical Data (Total of 1619 Pts) </li></ul><ul><ul><li>1. Non-Randomized CAS Clinical Trials – Supportive data </li></ul></ul><ul><ul><ul><li>CASCADE (European) Study </li></ul></ul></ul><ul><ul><ul><li>US FEASIBILITY Study </li></ul></ul></ul><ul><li> 2. SAPPHIRE Pivotal Trial – Ken Ouriel, M.D. </li></ul><ul><ul><ul><li>Randomized Arm: CAS vs. CEA </li></ul></ul></ul><ul><ul><ul><li>Non-Randomized Arms: CAS and CEA </li></ul></ul></ul><ul><li>Overview of Training </li></ul><ul><li>Post-Market Surveillance Study </li></ul>
  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. 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. 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. 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. 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. 52. SAPPHIRE STUDY <ul><li>Primary Endpoint: </li></ul><ul><ul><li>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. </li></ul></ul>
  53. 53. SAPPHIRE STUDY Differences Between SAPPHIRE and Previous Surgical Trials <ul><li>Primary endpoint included all-cause mortality for 1 year </li></ul><ul><li>MAE includes MI in addition to death/stroke </li></ul><ul><li>24-hour post procedure stroke evaluation performed by neurologist </li></ul><ul><li>Use of Stroke scales in addition to PEx </li></ul><ul><li>Objective vessel patency data obtained by duplex U/S </li></ul><ul><li>Different specialties providing input on treatment strategy (multi-disciplinary team) </li></ul>
  54. 54. SAPPHIRE STUDY Relevance of MI as Part of the Primary Endpoint <ul><li>MI leads to disability, death, prolonged hospitalization, and increased health care costs – key safety endpoint </li></ul><ul><li>In patients undergoing peripheral vascular surgery who sustain a non-Q wave MI: </li></ul><ul><ul><li>6-fold increase in mortality over 6 mo 1 </li></ul></ul><ul><ul><li>Perioperative MI predicts mortality at one-year 2 </li></ul></ul><ul><ul><li>27-fold increased risk of another MI over the next 6 mo 1 </li></ul></ul><ul><li>Thus, perioperative MI is a strong surrogate for long-term mortality after vascular surgical procedures </li></ul><ul><li>Perioperative MI is part of the primary endpoint for other CAS trials (e.g. CREST) </li></ul>1 Kim et al. Circulation 2002;106:2366-2371 2 McFalls et al. Chest 1998;113:681-686
  55. 55. DEFINITIONS <ul><li>Myocardial Infarction : </li></ul><ul><li>Q wave MI </li></ul><ul><li>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. </li></ul><ul><li>Non-Q wave MI </li></ul><ul><li>CK ratio >2, CK-MB >1 in the absence of new, pathological Q waves. </li></ul>
  56. 56. DEFINITIONS – (cont) <ul><li>Stroke : </li></ul><ul><li>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. </li></ul>
  57. 57. SAPPHIRE STUDY Statistical Analysis Plan (Randomized) <ul><li>Primary hypothesis: Non-inferiority of CAS to CEA </li></ul><ul><ul><li>Primary Endpoint: Composite 360-day MAE </li></ul></ul><ul><ul><li>3% non-inferiority delta assumed (i.e., Stent no more than 3% higher than CEA) </li></ul></ul><ul><ul><li>If non-inferiority demonstrated, then test for superiority (2 ° hypothesis) </li></ul></ul><ul><li>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) </li></ul><ul><li>Enrollment stopped for administrative reasons </li></ul><ul><li>First planned interim analysis at 300 patients was not done as it was already evident that enrollment would stop </li></ul><ul><li>Final analysis on the 1 ° endpoint utilized the interval censored survival analysis method designated in protocol </li></ul><ul><li>No adjustments were required since no interim analysis performed </li></ul>
  58. 58. SAPPHIRE STUDY Diminishing Enrollment (Randomized) Competing CAS registries Stop Enrollment
  59. 59. SAPPHIRE STUDY Key Inclusion Criteria <ul><li>Patients referred for treatment of Carotid Artery Disease </li></ul><ul><ul><li>Symptomatic > 50% stenosis by U/S or angiography </li></ul></ul><ul><ul><li>Asymptomatic > 80% stenosis by U/S or angiography </li></ul></ul><ul><li>Disease of Native Common or Internal Carotid Artery </li></ul><ul><li>Consensus agreement by multidisciplinary team </li></ul><ul><ul><li>Interventionalist, Consulting Neurologist, Surgeon </li></ul></ul><ul><li>Must also have at least 1 co-morbid condition which increases the risk of endarterectomy: </li></ul><ul><ul><li>Anatomic </li></ul></ul><ul><ul><li>Medical </li></ul></ul>
  60. 60. <ul><ul><li>Anatomic factors: </li></ul></ul><ul><ul><ul><li>Contralateral carotid occlusion </li></ul></ul></ul><ul><ul><ul><li>Contralateral laryngeal nerve palsy </li></ul></ul></ul><ul><ul><ul><li>Radiation therapy to neck </li></ul></ul></ul><ul><ul><ul><li>Previous CEA with recurrent stenosis </li></ul></ul></ul><ul><ul><ul><li>Difficult surgical access </li></ul></ul></ul><ul><ul><ul><li>Severe tandem lesions </li></ul></ul></ul>SAPPHIRE STUDY Key Inclusion Criteria - cont
  61. 61. <ul><li>Medical Co-morbidities: </li></ul><ul><ul><li>CHF (class III/IV) &/or severe LV dysfunction (LVEF <30%) </li></ul></ul><ul><ul><li>Open heart surgery within 6 weeks </li></ul></ul><ul><ul><li>Recent MI (1 day to 4 weeks prior) </li></ul></ul><ul><ul><li>Angina at low workload or unstable angina (CCS class III/IV) </li></ul></ul><ul><ul><li>Severe pulmonary disease </li></ul></ul><ul><ul><li>Age greater than 80 years </li></ul></ul>SAPPHIRE STUDY Key Inclusion Criteria - cont
  62. 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. 63. SAPPHIRE STUDY Demographics – Randomized Patients
  64. 64. SAPPHIRE STUDY Acute Procedure & Device Outcomes* <ul><li>Stent Delivery Success**: </li></ul><ul><ul><li>Randomized Stent: 99.4% </li></ul></ul><ul><ul><li>Non-Randomized Stent: 99.8% </li></ul></ul><ul><li>Device Success ( Stent): <30% DS *** <50% DS </li></ul><ul><ul><li>Randomized Stent: 91.2% 99.4% </li></ul></ul><ul><ul><li>Non-Randomized Stent: 89.6% 98.5% </li></ul></ul><ul><li>ANGIOGUARD ™ Success (Deployment and Retrieval) </li></ul><ul><li>Initial Attempt *** Ultimate Placement </li></ul><ul><ul><li>Randomized Stent: 95.6% 98.1% </li></ul></ul><ul><ul><li>Non-Rand Stent: 91.6% 95.1% </li></ul></ul>* 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. 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. 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 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. 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. 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. 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. 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. 76. <ul><li>Total Deaths: 33 </li></ul><ul><ul><li>CEA: 21 </li></ul></ul><ul><ul><li>Stent: 12 </li></ul></ul><ul><li>Total Number of Neurologic Deaths: 4 </li></ul><ul><ul><li>CEA: 3 </li></ul></ul><ul><ul><li>Stent: 1 </li></ul></ul><ul><li>Non-Neurologic Deaths 29 </li></ul>SAPPHIRE STUDY Cause of Death at 360 Days - R andomized
  77. 77. <ul><li>Total Deaths: 33 </li></ul><ul><ul><li>CEA: 21 </li></ul></ul><ul><ul><li>Stent: 12 </li></ul></ul><ul><li>Total Number of Neurologic Deaths: 4 </li></ul><ul><ul><li>CEA: 3 </li></ul></ul><ul><ul><li>Stent: 1 </li></ul></ul><ul><li>Non-Neurologic Deaths CEA Stent </li></ul><ul><li>29 18 11 </li></ul><ul><ul><li>Cardiac 18 10 8 </li></ul></ul><ul><ul><li>Respiratory Failure 4 3 1 </li></ul></ul><ul><ul><li>Cancer 3 1 2 </li></ul></ul><ul><ul><li>Renal Failure 1 1 0 </li></ul></ul><ul><ul><li>Multi-system Failure 3 3 0 </li></ul></ul>SAPPHIRE STUDY Cause of Death at 360 Days - Randomized
  78. 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. 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. 80. SAPPHIRE STUDY Analysis of the Evaluable (Treated) Patients
  81. 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. 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. 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. 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. <ul><li>Original non-inferiority analysis based on OPC ~12-14% plus 4% delta </li></ul><ul><ul><li>Weighted OPC calculated at 12.94 was not met </li></ul></ul><ul><ul><li>OPC estimated (1999) without benefit of multi-center randomized data from high-surgical risk studies </li></ul></ul><ul><ul><ul><li>SAPPHIRE CEA arm </li></ul></ul></ul><ul><ul><ul><ul><li>1 year MAE rate of 19.2% </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Has  frequency of high surgical-risk characteristics </li></ul></ul></ul></ul><ul><li>Agency consulted in March 2003 </li></ul><ul><ul><li>FDA suggested supplemental non-inferiority analysis </li></ul></ul><ul><ul><ul><li>Non-Randomized Stent Arm to the Randomized CEA Arm </li></ul></ul></ul><ul><ul><ul><li>Adjustment for differences in baseline demographics </li></ul></ul></ul>SAPPHIRE STUDY Non-Randomized Stent Arm
  88. 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. 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. 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. 91. <ul><li>Study is not powered for subgroup analyses </li></ul><ul><li>Symptomatic/Asymptomatic: </li></ul><ul><ul><li>Randomization stratified by +/- symptoms </li></ul></ul><ul><ul><li>Subgroup analyses pre-specified </li></ul></ul><ul><li>Subgroup sample sizes </li></ul><ul><ul><li>Symptomatic Patients: 96 </li></ul></ul><ul><ul><li>Asymptomatic Patients: 237 </li></ul></ul>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. 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. 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. 100. SAPPHIRE STUDY Surgeon Experience and Outcomes <ul><li>Experience and outcomes for surgeons in SAPPHIRE trial are consistent with previous surgical data </li></ul><ul><ul><li>CEA volume </li></ul></ul><ul><ul><li>Outcomes </li></ul></ul><ul><ul><li>Complication rates </li></ul></ul>
  101. 101. SAPPHIRE STUDY Surgeon Experience & Judgment <ul><li>Pre-study survey conducted </li></ul><ul><ul><li>53 SAPPHIRE surgeons </li></ul></ul><ul><ul><ul><li>Mean of 36.3 procedures per year </li></ul></ul></ul><ul><ul><ul><li>Median of 28 procedures per year </li></ul></ul></ul>
  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. SURGICAL OUTCOMES vs. OTHER TRIALS 30-Day Ipsilateral Stroke Error Bar = 95% CI %
  106. 106. <ul><li>Comparison of 30-day ipsilateral stroke rates </li></ul><ul><li>SAPPHIRE randomized and non-randomized symptomatic stent patients vs. NASCET </li></ul><ul><li>SAPPHIRE randomized and non-randomized asymptomatic stent patients vs. ACAS </li></ul>CAS OUTCOMES TO OTHER SURGICAL TRIALS
  107. 107. CAS OUTCOMES TO OTHER SURGICAL TRIALS Symptomatic Patients 30-Day Ipsilateral Stroke Error Bar = 95% CI %
  108. 108. CAS OUTCOMES TO OTHER SURGICAL TRIALS Asymptomatic Patients 30-Day Ipsilateral Stroke Error Bar = 95% CI %
  109. 109. SAPPHIRE STUDY CAS 30-Day Mortality <ul><li>CAS 30-day all cause mortality </li></ul><ul><ul><li>Symptomatic </li></ul></ul><ul><ul><ul><li>Randomized – 0.0% </li></ul></ul></ul><ul><ul><ul><li>Non-randomized – 0.8% </li></ul></ul></ul><ul><ul><li>Asymptomatic </li></ul></ul><ul><ul><ul><li>Randomized – 1.7% </li></ul></ul></ul><ul><ul><ul><li>Non-randomized – 2.8% </li></ul></ul></ul>
  110. 110. SAPPHIRE STUDY Conclusions
  111. 111. SAPPHIRE STUDY Conclusions: Randomized Arm <ul><li>The primary endpoint of the study was achieved demonstrating CAS is non-inferior to CEA </li></ul><ul><li>Trends favoring CAS over CEA </li></ul><ul><ul><li>Major Ipsilateral stroke </li></ul></ul><ul><ul><li>MI </li></ul></ul><ul><ul><li>TLR </li></ul></ul><ul><ul><li>Restenosis (>50% DS) </li></ul></ul><ul><li>Significant decrease in cranial nerve injuries </li></ul>
  112. 112. SAPPHIRE STUDY Conclusions: Randomized Arm <ul><li>Symptomatic and asymptomatic subgroups </li></ul><ul><ul><li>ITT Asymptomatic: Significant improvement at 360 days in favor of CAS compared to CEA with 50% reduction in MAE rate </li></ul></ul><ul><ul><li>ITT Symptomatic: MAE rates at 360 days were similar between CAS and CEA </li></ul></ul><ul><ul><li>Outcomes for ipsilateral stroke overlap those from NASCET and ACAS </li></ul></ul>
  113. 113. <ul><li>Risk factors contributing to “too high risk for CEA”: </li></ul><ul><ul><li>Anatomic </li></ul></ul><ul><ul><ul><ul><li>Prior CEA </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Prior radiation therapy </li></ul></ul></ul></ul><ul><ul><ul><ul><li>High cervical ICA lesion </li></ul></ul></ul></ul><ul><ul><li>Medical </li></ul></ul><ul><ul><ul><ul><li>Angina Class CCS III or IV </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Previous stroke </li></ul></ul></ul></ul><ul><ul><li>Non-inferior to randomized CEA </li></ul></ul><ul><li>Surgeons in SAPPHIRE were experienced in CEA and had outcomes similar to referenced literature </li></ul><ul><li>Too high risk for surgery  Too high risk for stenting </li></ul><ul><ul><li>True for symptomatic and asymptomatic patients </li></ul></ul>SAPPHIRE STUDY Conclusions: Non-Randomized Stent Arm
  114. 114. AGENDA <ul><li>Project Overview & CAS Background </li></ul><ul><li>Description of Devices </li></ul><ul><li>Overview of PMA Clinical Data (Total of 1619 Pts) </li></ul><ul><ul><li>1. Non-Randomized CAS Clinical Trials – Supportive data </li></ul></ul><ul><ul><ul><li>CASCADE (European) Study </li></ul></ul></ul><ul><ul><ul><li>US FEASIBILITY Study </li></ul></ul></ul><ul><li> 2. SAPPHIRE Pivotal Trial – Ken Ouriel, M.D. </li></ul><ul><ul><ul><li>Randomized Arm: CAS vs. CEA </li></ul></ul></ul><ul><ul><ul><li>Non-Randomized Arms: CAS and CEA </li></ul></ul></ul><ul><li>Overview of Training </li></ul><ul><li>Post-Market Surveillance Study </li></ul>
  115. 115. Carotid Artery Stent Education System PROFESSIONAL EDUCATION
  116. 116. CAROTID ARTERY STENT TRAINING SYSTEM <ul><li>Training system is intended to build upon already existing endovascular expertise to develop a physicians knowledge and technical expertise in performing CAS </li></ul><ul><li>System was developed using a variety of consultants: </li></ul><ul><ul><li>SAPPHIRE Investigators </li></ul></ul><ul><ul><li>Internet based training </li></ul></ul><ul><ul><li>Simulator modeling </li></ul></ul><ul><ul><li>Proficiency measurements </li></ul></ul>
  117. 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. 118. <ul><li>On-line didactic training: </li></ul><ul><ul><li>Transferring Expert Knowledge </li></ul></ul><ul><ul><ul><li>Through doing and decision making </li></ul></ul></ul><ul><ul><li>Goal </li></ul></ul><ul><ul><ul><li>Assure Procedural Success </li></ul></ul></ul><ul><ul><ul><ul><li>Detailed understanding of anatomy </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Appropriate case selection </li></ul></ul></ul></ul><ul><ul><ul><ul><li>High performance technical execution </li></ul></ul></ul></ul><ul><li>Training at Regional Education Center: </li></ul><ul><ul><li>Small group setting – review 4 Modules Over 2 Days </li></ul></ul><ul><ul><ul><li>Didactic Review, Case Observation, Simulation Lab, Product Lab </li></ul></ul></ul><ul><ul><li>Physicians </li></ul></ul><ul><ul><ul><li>interact with realistic graphical simulations </li></ul></ul></ul><ul><ul><ul><li>assess task performance </li></ul></ul></ul><ul><ul><ul><li>demonstrate understanding of the learning objectives </li></ul></ul></ul>CAROTID ARTERY STENT TRAINING SYSTEM
  119. 119. <ul><li>On-site training at physician’s facility by physician proctors: </li></ul><ul><ul><li>Network of CAS experienced physician proctors </li></ul></ul><ul><ul><li>Proctor Sign Off or Additional Training Recommendations Based on Proficiency Standards </li></ul></ul><ul><li>Training Program: </li></ul><ul><ul><li>34 Hours of Training with exposure to a minimum of 15 Cases </li></ul></ul><ul><ul><li>Serves as the foundation for hospital credentialing </li></ul></ul>CAROTID ARTERY STENT TRAINING SYSTEM
  120. 120. INITIAL ASSESSMENT OF TRAINING Institutional IDEs <ul><li>36 centers ( 30 non-Sapphire Investigators) </li></ul><ul><li>All investigators were trained and proctored on use of the stent and the emboli protection system </li></ul><ul><li>Patient selection criteria similar to the US FEASIBILITY Study </li></ul><ul><li>Neurologist evaluation 24 hours and 30 days post-procedure </li></ul><ul><li>Data are site reported and unadjudicated </li></ul>
  121. 121. INSTITUTIONAL IDEs 30-Day Events - Site Reported %
  122. 122. COMPARISON OF 30-DAY EVENT RATES Treated Patients with ANGIOGUARD ™ Only %
  123. 123. <ul><li>Carotid Stenting With Emboli Protection For The Treatment of Obstructive Carotid Artery Disease </li></ul>POST-MARKETING SURVEILLANCE
  124. 124. POST-MARKETING SURVEILLANCE <ul><li>Objective : </li></ul><ul><li>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 </li></ul><ul><li>Design: </li></ul><ul><li>Multicenter, prospective, non-randomized, open label </li></ul><ul><li>Primary Endpoint: </li></ul><ul><li>30-day composite of major adverse clinical events </li></ul><ul><li>(MAE = all death and all stroke) </li></ul>
  125. 125. <ul><li>Study Population: </li></ul><ul><li>High Risk patients with de novo or restenotic lesions </li></ul><ul><li>> 1000 patients </li></ul><ul><li>Inclusion Criteria: Per Label Indications </li></ul><ul><li>Follow-up: </li></ul><ul><li>Neurologic examinations at discharge and 30 days (Neurologist) </li></ul><ul><li>Clinical events tracking through discharge </li></ul><ul><ul><ul><li>30-day office visit </li></ul></ul></ul><ul><ul><ul><li>9-month telephone contact </li></ul></ul></ul><ul><li>Monitoring with built in stopping rule: </li></ul><ul><li>Electronic data capture to expedite review of outcomes </li></ul>POST-MARKETING SURVEILLANCE
  126. 126. CAROTID ARTERY STENTING WITH EMBOLI PROTECTION Summary and Conclusions
  127. 127. SUMMARY AND CONCLUSIONS <ul><li>Stroke </li></ul><ul><ul><li>Significant morbidity and mortality </li></ul></ul><ul><ul><li>Due to carotid disease in up to 30% of patients </li></ul></ul><ul><ul><li>Goal of Tx: to prevent stroke and improve quality of life </li></ul></ul><ul><li>CEA is the standard of care in: </li></ul><ul><ul><li>NASCET/ACAS eligible and ineligible patients </li></ul></ul><ul><ul><li>Symptomatic and asymptomatic patients </li></ul></ul><ul><ul><li>Low, intermediate, and high risk </li></ul></ul><ul><li>There are no multi-center randomized studies that define outcomes in high medical- or surgical-risk patients </li></ul><ul><li>SAPPHIRE is an objective comparison of CEA, the current interventional standard of care, with CAS, a less invasive approach to therapy </li></ul>
  128. 128. <ul><li>Cordis is seeking the following indication: </li></ul><ul><li>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; </li></ul><ul><li>  and  </li></ul><ul><li>Patients without neurological symptoms and > 80% atherosclerotic stenosis of the common or internal carotid artery by ultrasound or angiogram. </li></ul><ul><li>  </li></ul><ul><li>Symptomatic and asymptomatic patients must also have one or more condition(s) that place them at high-risk for carotid endarterectomy. </li></ul>SUMMARY AND CONCLUSIONS
  129. 129. <ul><li>This indication is supported by: </li></ul><ul><li>SAPPHIRE </li></ul><ul><ul><li>Achieved primary endpoint of non-inferiority of CAS to CEA for MAE at 1-year </li></ul></ul><ul><ul><li>CAS - improved outcomes for MI and re-interventions with a significant decrease in cranial nerve injuries </li></ul></ul><ul><li>SUPPORTIVE STUDIES </li></ul><ul><ul><li>CAS treatment demonstrated sustained benefit through 3-year follow up </li></ul></ul>CONCLUSION
  130. 130. <ul><li>Cordis will institute a training program to ensure outcomes of carotid stenting in non-trial setting replicates safety and effectiveness demonstrated in SAPPHIRE </li></ul><ul><li>Cordis will conduct a post-marketing surveillance study with the goal of </li></ul><ul><ul><li>quantifying patient outcomes </li></ul></ul><ul><ul><li>confirming the adequacy of physician training </li></ul></ul>SUMMARY AND CONCLUSIONS
  131. 131. THANK YOU
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