- 1. CAROTID ARTERY STENTING WITH EMBOLI PROTECTION PMA # P030047
Cordis Presentation Sidney A. Cohen, M.D., Ph.D. Group Director,
Clinical Research
2. REQUESTED INDICATION
- The Cordis [Carotid Stent System is] indicated for use in the
treatment of carotid artery disease in high-risk patients.High-risk
is defined as patients with neurological symptoms (one or more TIAs
or one or more completed strokes) and> 50% atherosclerotic
stenosis of the common or internal carotid artery by ultrasound or
angiogram;
- 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
- Overview of PMA Clinical Data (Total of 1619 Pts)
-
- 1. Non-Randomized CAS Clinical Trials Supportive data
- 2. SAPPHIRE Pivotal Trial Ken Ouriel, M.D.
-
-
- Randomized Arm: CAS vs. CEA
-
-
- Non-Randomized Arms: CAS and CEA
- 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 year1
- 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 Association2. 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 Association2.Ouriel et al., J Vasc Surg 33:728-732, 2001
7.
- Randomized clinical studies
-
- Superiority of CEA vs. best medical therapy
-
-
-
- Symptomatic> 50% diameter stenosis
-
-
-
- Asymptomatic> 60% diameter stenosis
-
-
-
- Symptomatic> 50% diameter stenosis
-
-
-
- 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, 19912. ACAS Executive Committee
JAMA 273:1421-1428, 19953.Rothwell et al., Stroke 34: 514-523,
20034.Hobson et al., NEJM328:221-227, 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:
- 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
- Radiation therapy to neck (ACAS)
- Status post radical neck dissection
- Previous CVA with profound deficit
- MI within 6 months (NASCET)
- Cancer with 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 segmentof the
ICA
29. CASCADE STUDY30-Day Data % n=121 30. CASCADE STUDY30-Day
Outcomes With/Without ANGIOGUARD % P=0.45 P>0.99 P=0.68 31.
CASCADE STUDY
-
- Carotid artery stentingwas 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
-
- 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
- Non-randomized, prospective, 33 center trial
- 6/7F SMART and 5.5F PRECISE SDS
- Sept 1998 through July 2001
- 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):
-
-
- Contralateral carotid artery occlusion
-
-
- Ostial lesion of the common carotid
-
-
- High take-off carotid bifurcation disease
36. US FEASIBILITY STUDY
- 30-day MAE (death, any stroke, &/or MI)
- Patency (< 50% restenosis) by carotid U/S
-
- 48 hours, 30 days, 6 months, 1, 2, & 3 years
-
- 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 STUDYCumulative Percentage of All
Stroke to 30 Days andIpsilateral 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
- 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 SUPPORTIVESTUDIES
-
- Reduction in profile (7F to 5.5F)
- Data supports benefit of ANGIOGUARD emboli protection device in
reducing stroke
- Demonstrated the feasibility of CAS
45. AGENDA
- Project Overview & CAS Background
- Overview of PMA Clinical Data(Total of 1619 Pts)
-
- 1. Non-Randomized CAS Clinical Trials Supportive data
- 2. SAPPHIRE Pivotal Trial Ken Ouriel, M.D.
-
-
- Randomized Arm: CAS vs. CEA
-
-
- Non-Randomized Arms: CAS and CEA
- 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 Criteria2294
patients Evaluated by panel of physicians (interventionalist,
surgeon, neurologist) whoconcur on qualification of patient n = 747
49. SAPPHIRE STUDY Trial Design and Patient Flow RCT334
Randomized(310 Treated) Stent Treatment n=167 CEA Treatment n=167
Surgeon & Interventionalistwilltreat patient Evaluated by panel
of physicians (interventionalist, surgeon, neurologist) whoconcur
on qualification of patient n = 747 50. SAPPHIRE STUDY Trial Design
and Patient Flow Non-Randomized Stent Armn=406 RCT334
Randomized(310 Treated) Surgeon:unacceptablerisk for CEA Stent
Treatment n=167 CEA Treatment n=167 Surgeon &
Interventionalistwilltreat patient Evaluated by panel of physicians
(interventionalist, surgeon, neurologist) whoconcur on
qualification of patient n = 747 51. SAPPHIRE STUDY Trial Design
and Patient Flow Non-Randomized Stent Armn=406 Non-Randomized CEA
Armn=7 RCT334 Randomized(310 Treated) Interventionalist:
unacceptable risk for stenting Surgeon:unacceptable risk for CEA
Stent Treatment n=167 CEA Treatment n=167 Surgeon &
Interventionalistwilltreat patient Evaluated by panel of physicians
(interventionalist, surgeon, neurologist) whoconcur on
qualification of patient n = 747 52. SAPPHIRE STUDY
-
- 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 mortalityfor 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 byduplex U/S
- Different specialties providing input on treatment strategy
(multi-disciplinary team)
54. SAPPHIRE STUDY Relevance of MI as Part ofthe 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
- 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.
- CK ratio >2, CK-MB >1 in the absence of new,
pathologicalQ waves.
56. DEFINITIONS (cont)
- 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 registriesStop Enrollment 59. SAPPHIRE STUDYKey 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:
60.
-
-
- Contralateral carotid occlusion
-
-
- Contralateral laryngeal nerve palsy
-
-
- Radiation therapy to neck
-
-
- Previous CEA with recurrent stenosis
-
-
- Difficult surgical access
SAPPHIRE STUDY Key Inclusion Criteria - cont 61.
-
- CHF (class III/IV) &/or severe LV dysfunction(LVEF 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
RandomizedTREATEDPatients 83. SAPPHIRE STUDY Cumulative % of MAE to
360 DaysRandomizedTREATEDPatients 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
Armn=7 RCT334 Randomized(310 Treated) Stent Treatment n=167 CEA
Treatment n=167 Surgeon & Interventionalistwilltreat
patientSurgeon:unacceptable risk for CEA Evaluated by panel of
physicians (interventionalist, surgeon, neurologist) whoconcur on
qualification of patient n = 747 85. SAPPHIRE STUDY Non-Randomized
Stent Arm vs. CEA RandomizedDemographic 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
-
-
-
- Hasfrequency 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 50% DS)
- Significant decrease in cranial nerve injuries
112. SAPPHIRE STUDYConclusions: 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:
-
-
-
- Angina Class CCS III or IV
-
- 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
- Overview of PMA Clinical Data(Total of 1619 Pts)
-
- 1. Non-Randomized CAS Clinical Trials Supportive data
- 2. SAPPHIRE Pivotal Trial Ken Ouriel, M.D.
-
-
- Randomized Arm: CAS vs. CEA
-
-
- Non-Randomized Arms: CAS and CEA
- 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:
117. On-lineDidactic Observation Simulation StaffIn-Service
ProctorNetwork Step 1 Step 2 Step 3 Step 4 Step 5 Internet Delivery
Regional EducationCenter On-site Training atPhysicians Facility
Patient Outcomes StaffTraining DELIVERY PROCESS Proficiency
Measurement 118.
- On-line didactic training:
-
- Transferring Expert Knowledge
-
-
- Through doing and decision making
-
-
- 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
-
-
- interact with realistic graphical simulations
-
-
- demonstrate understanding of the learning objectives
CAROTID ARTERY STENT TRAINING SYSTEM 119.
- On-site training at physicians facility by physician
proctors:
-
- Network of CAS experienced physician proctors
-
- Proctor Sign Off or Additional Training Recommendations Based
on Proficiency Standards
-
- 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 InstitutionalIDEs
- 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. INSTITUTIONALIDEs30-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 ArteryDisease
POST-MARKETING SURVEILLANCE 124. POST-MARKETING SURVEILLANCE
- 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
- Multicenter, prospective, non-randomized, open label
- 30-day composite of major adverse clinical events
- (MAE = all death and all stroke)
125.
- High Risk patients withde novoor restenotic lesions
- Inclusion Criteria: Per Label Indications
- Neurologic examinations at discharge and 30 days
(Neurologist)
- Clinical events tracking through discharge
-
-
- 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
-
- 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 TIAs
or one or more completed strokes) and> 50% atherosclerotic
stenosis of the common or internal carotid artery by ultrasound or
angiogram;
- 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:
-
- 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
-
- 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