# Presentation: 102254

## CAROTID ARTERY STENTING WITH EMBOLI PROTECTION

**PMA # P030047**

- Cordis Presentation
- Sidney A. Cohen, M.D., Ph.D.
- Group Director, Clinical Research

## 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.

## 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**

## 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

## 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 disease2
- Stroke is the number 1 cause of disability in the U.S. 1
- Health care costs for stroke in excess of $53.6 billion/year1
- Over 50% of people under age 65 who have a stroke die within 8 years1
- Older population with co-morbid disease1

**1. Heart Disease and Stroke Statistics – 2004 Update, American Heart Association   ****2. ACAS Executive Committee JAMA 273:1421-1428, 1995**

## 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**

## 
Randomized clinical studies 
Superiority of CEA vs. best medical therapy 
NASCET1
Symptomatic >50% diameter stenosis
ACAS2 
Asymptomatic >60% diameter stenosis 
ECST3
Symptomatic >50% diameter stenosis
VA Cooperative Study4
Symptomatic >50% diameter stenosis

“Standard of Care” for interventional treatment of symptomatic and asymtomatic carotid artery disease

**Carotid Endarterectomy - cont**

- Randomized clinical studies
- Superiority of CEA vs. best medical therapy
- NASCET1
- Symptomatic _>_50% diameter stenosis
- ACAS2
- Asymptomatic _>_60% diameter stenosis
- ECST3
- Symptomatic _>_50% diameter stenosis
- VA Cooperative Study4
- Symptomatic _>_50% diameter stenosis
- “Standard of Care” for interventional treatment of symptomatic and asymtomatic carotid artery disease

**        ****1.   NASCET Trial Collaborators NEJM 325:445-453, 1991     2. ACAS Executive Committee JAMA****     273:1421-1428, 1995     3.  Rothwell et al., Stroke 34: 514-523, 2003      4.  Hobson et al., NEJM ****     328:221-227, 1993**

## TYPE OF PATIENTS CURRENTLY TREATED WITH CEA

**CEA treatment of patients clearly extends beyond**
**NASCET/ACAS inclusion criteria:**
- NASCET/ACAS studied a relatively healthy subset of patients:** **
- ACAS screened 25 to enroll 1 patient1
- NASCET 1 out of every 3 treated patients enrolled1
- Patients considered high risk for CEA as defined by trial ineligibility comprise up to 50% of patients in published series:
- Ochsner Clinic – 46.2%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.  **

## 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

## CEA MORTALITY

**CEA MORTALITY**

**113,000 Medicare Patients (1992-1993)**

- 30-Day Follow up

**Mortality %**

## 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

## 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**

## IN-HOSPITAL CEA OUTCOMES US ACADEMIC CENTERS

**McCrory DC et al. Stroke 1993;24:1285-1291**

**Death + MI + Stroke**

## 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

## INCIDENCE OF STROKE AT 360-DAYS

**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

## 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

- 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**

## 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

## 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

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

- Stent Delivery System
- Stent
- Delivery catheter
- Emboli Protection Device

**CAROTID ARTERY STENTING**

## Cordis PRECISETM Nitinol Stent

## Cordis PRECISETM 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

**Cordis PRECISE****TM**** Nitinol Stent System**

**5.5F (5 – 8 mm)**
**6F (9 – 10 mm)**

**5F**

## CAROTID ARTERY STENT SYSTEM

**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:** **ANGIOGUARDTM XP Emboli Capture Guidewire

## CAS SYSTEM ANIMATION

## 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**

## CLINICAL TRIALS Supportive Data

**Purpose**
- Gain experience:
- Carotid stent system
- Learning curve for investigators
- Refine the stent delivery system
- Evaluate the advantage of adding ANGIOGUARDTM
**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

## CASCADE STUDY

***The ***_***C***_***ordis Sm***_***a***_***rt Self-Expandable ***_***S***_***tent in ***_***Ca***_***rotid Artery ***_***D***_***iseas***_***e***_

## CASCADE STUDY

**Objective:**
-  To evaluate the safety and performance of the   SMART Stent with or without ANGIOGUARDTM   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

## CASCADE STUDYOverview

-   **Design:**
-   Multi-center, prospective, non-randomized study
-   Nine centers across Europe
-   7F SMART Stent Delivery System
-   121 patients enrolled (31 with ANGIOGUARDTM)
-   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

## CASCADE STUDY 30-Day Data 

**CASCADE STUDY ****30-Day Data**** **

- %

- n=121

## CASCADE STUDY  30-Day Outcomes With/Without ANGIOGUARDTM

**%**

- P=0.45

- P>0.99

- P=0.68

## CASCADE STUDY

**Conclusion:**
- Carotid artery stenting was found to be feasible for the treatment of carotid stenosis
- The ANGIOGUARDTM 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

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

## 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

## US FEASIBILITY STUDYOverview

**Design:**
- Non-randomized, prospective, 33 center trial
- 6/7F SMARTTM and 5.5F PRECISETM SDS
- 261 patients enrolled
- 176 stent
- 85 stent plus ANGIOGUARDTM
- 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

## 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

## 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

## US FEASIBILITY STUDY30-Day Events

**%**

**US FEASIBILITY STUDY****30-Day Events**

- n=261

## US FEASIBILITY STUDY30-Day Events With/Without ANGIOGUARDTM

- P = 1.00

- P = 0.31

- P= 0.51

- P = 0.19

**%**

- P = 0.10

## 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**

## 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**

## 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**

## US FEASIBILITY STUDY

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

## CAROTID STENT30-Day Stroke Rates by Study and ANGIOGUARDTM

**CAROTID STENT****30-Day Stroke Rates by Study and ANGIOGUARD****TM**

- P=0.10

- P=0.45

- P=0.02

**%**

## CONCLUSIONS FROM SUPPORTIVE STUDIES

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

## 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**

## 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*

## 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.

## SAPPHIRE STUDYTrial Design and Patient Flow

- Patients Referred for Evaluation of Carotid Disease
- Screened for SAPPHIRE Inclusion/Exclusion Criteria
- 2294 patients
** **

**SAPPHIRE STUDY****Trial Design and Patient Flow**

- Evaluated by panel of physicians (interventionalist, surgeon, neurologist) who **concur on qualification of patient**
**n = 747**

## SAPPHIRE STUDYTrial Design and Patient Flow

**334 Randomized  (310 Treated)**

**Stent**
**Treatment**
**n=167**

**CEA**
**Treatment**
**n=167**

**Surgeon & Interventionalist **_**will**_** treat patient**

**SAPPHIRE STUDY****Trial Design and Patient Flow**

- Evaluated by panel of physicians (interventionalist, surgeon, neurologist) who **concur on qualification of patient**
**n = 747**

## SAPPHIRE STUDYTrial Design and Patient Flow

**n=406**

**RCT **
**334 Randomized  (310 Treated)**

**Surgeon: ****unacceptable  risk for CEA**

**Stent**
**Treatment**
**n=167**

**CEA**
**Treatment**
**n=167**

**Surgeon & Interventionalist **_**will**_** treat patient**

**SAPPHIRE STUDY****Trial Design and Patient Flow**

- Evaluated by panel of physicians (interventionalist, surgeon, neurologist) who **concur on qualification of patient**
**n = 747**

## SAPPHIRE STUDYTrial Design and Patient Flow

**n=406**

**Non-Randomized CEA Arm **
**n=7**

**RCT **
**334 Randomized  (310 Treated)**

**Interventionalist: unacceptable risk for stenting**

**Surgeon: ****unacceptable risk for CEA**

**Stent**
**Treatment**
**n=167**

**CEA**
**Treatment**
**n=167**

**Surgeon & Interventionalist **_**will**_** treat patient**

**SAPPHIRE STUDY****Trial Design and Patient Flow**

- Evaluated by panel of physicians (interventionalist, surgeon, neurologist) who **concur on qualification of patient**
**n = 747**

## 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.

## 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)

## 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 mo1
- Perioperative MI predicts mortality at one-year2
- 27-fold increased risk of another MI over the next 6 mo1
- Thus, perioperative MI is a strong surrogate for long-term mortality after vascular surgical procedures
- Perioperative MI is part of the primary endpoint for other CAS trials (e.g. CREST)

***1******Kim et al. Circulation 2002;106:2366-2371***
***2******McFalls et al. Chest 1998;113:681-686***

## 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.

## 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.

## SAPPHIRE STUDY Statistical Analysis Plan (Randomized)

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

## SAPPHIRE STUDYDiminishing Enrollment (Randomized)

**Competing CAS registries **

**Stop Enrollment**

## 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

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

- 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**** **

## 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

- 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**** **

## SAPPHIRE STUDYTrial Design and Patient Flow

**334 Randomized  (310 Treated)**

**Stent Treatment**
**n=167**

**CEA Treatment**
**n=167**

**Surgeon & Interventionalist **_**will**_** treat patient**

**SAPPHIRE STUDY****Trial Design and Patient Flow**

**Non-Randomized Stent Arm  **
**n=406**

**Non-Randomized CEA Arm **
**n=7**

- Evaluated by panel of physicians (interventionalist, surgeon, neurologist) who **concur on qualification of patient**
**n = 747**

## SAPPHIRE STUDYDemographics – Randomized Patients

## 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****TM**** 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**

## SAPPHIRE STUDY OUTCOMES

***Data Presented Are Based on ******Intent-to-Treat Analyses******(unless otherwise specified)***

## SAPPHIRE STUDYTrial Design and Patient Flow

**334 Randomized  (310 Treated)**

**Stent Treatment**
**n=167**

**CEA Treatment**
**n=167**

**SAPPHIRE STUDY****Trial Design and Patient Flow**

- Clinical 93.5%

- Ultrasound 80.6%

- Ultrasound 69.2%

- Clinical 85.6%

- 1 Year Compliance

- All events adjudicated by independent CEC
- Angiograms and ultrasounds reviewed by independent core labs

## SAPPHIRE All Randomized Patients at 30 Days

**SAPPHIRE**** ****All Randomized Patients at 30 Days**

**%**

- P=0.68

- P=1.00

- P=0.17

- P=0.14

## SAPPHIRE STUDY Primary Endpoint at 360 Days 

**SAPPHIRE STUDY**** ****Primary Endpoint at 360 Days **

- Randomized Patients – Overall Rates

## SAPPHIRE STUDYPrimary Endpoint – 360-day MAE

- Non-Inferiority Statistics

| Stent | CEA | %Difference [95% C.I.] |
| --- | --- | --- |
| 12.0% (20/167) | 19.2% (32/167) | –7.2%[–14.9%, 0.6%] |

- Margin of Non-inferiority

***Stent Non-inferior to CEA***

**3%**

- % Difference (Stent – CEA)

## SAPPHIRE STUDY Primary Endpoint at 360 Days 

- P=0.14

- P=0.83

- P=0.17

- P=0.10

**(30 day)**

**%**

## SAPPHIRE STUDY Primary Endpoint at 360 Days 

**%**

- P=0.21

- P=0.50

- P=0.83

## 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**

## 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%**

**SAPPHIRE STUDY****Cumulative % of MAE to 720 Days****Randomized Patients – Kaplan Meier Analysis**

**Time After Initial Procedure (days)**

**Cumulative Percentage of MAE**

**9.8%**

**4.8%**

**12.2%**

**20.1%**

**CEA 26.7%**

**Stent 19.2%**

## 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**

**SAPPHIRE STUDY****Cumulative % of Stroke* to 720 Days****Randomized Patients - Kaplan Meier Analysis**

**Time After Initial Procedure (days)**

**Cumulative Percentage of Stroke**

## 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**

**SAPPHIRE STUDY****Cumulative % of Death to 720 Days****Randomized Patients - Kaplan Meier Analysis**

**Time After Initial Procedure (days)**

**Cumulative Percentage of Death**

## Total Deaths: 				33
CEA:				 	21
Stent:					12					
Total Number of Neurologic Deaths:	  4 
CEA:					  3
Stent:					  1

Non-Neurologic Deaths 		           29

- 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**

## 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

- 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**

## SAPPHIRE STUDYComplications

|  | Stent (n=167) | CEA 
(n=167) | P-value |
| --- | --- | --- | --- |
| Target Lesion Revascularization (TLR) | 1 (0.6%) | 6 (3.6%) | 0.12 |
| Vessel Thrombosis | 0 (0.0%) | 0 (0.0%) | --- |
| Major Bleeding | 15 (9.0%) | 17 (10.2%) | 0.85 |
| Cranial Nerve Injury | 0 (0.0%) | 8 (4.8%) | 0.01 |

## SAPPHIRE STUDYRestenosis Rates and TLR at 360 Days

| In-Vessel Restenosis by U/S | Stent
(n=167) | CEA
(n=167) | P-value |
| --- | --- | --- | --- |
| >50% Diameter Stenosis*
 | 19.7% (24/122) | 31.3% (30/96)
 | 0.06 |
| >70% Diameter Stenosis
 | 0.8% (1/122) | 5.2% (5/96)
 | 0.09
 |
| >80% Diameter Stenosis
 | 0.8% (1/122) | 4.2% (4/96) | 0.17 |
| TLR – Clinically driven 
            (to 360 days) | 0.6% (1/167) | 3.6% (6/167) | 0.12 |

*** Protocol Definition**

## SAPPHIRE STUDY

***Analysis of the Evaluable (Treated) Patients***

## SAPPHIRE STUDYRandomized Patients Who Were Not Treated

|  | Stent | CEA |
| --- | --- | --- |
| Subsequent to randomization found to not meet Inclusion Criteria: | 2 | 4 |
| Patient Withdrew Consent: | 3 | 8 |
| Patient Condition Deteriorated/Too High a Risk: | 3 | 2 |
| Other: | 0 | 2 |
| TOTAL: |       8 |  |
|  |  |  |

- 16

## SAPPHIRE STUDY Primary Endpoint 360 Days – Randomized TREATED Patients 

**SAPPHIRE STUDY**** ****Primary Endpoint 360 Days – Randomized *****TREATED***** Patients**** **

## 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**

## SAPPHIRE STUDYTrial Design and Patient Flow

**n=406**

**Non-Randomized CEA Arm **
**n=7**

**RCT **
**334 Randomized  (310 Treated)**

**Stent**
**Treatment**
**n=167**

**CEA**
**Treatment**
**n=167**

**Surgeon & Interventionalist **_**will**_** treat patient    **

**SAPPHIRE STUDY****Trial Design and Patient Flow**

**Surgeon: ****unacceptable risk for CEA**

- Evaluated by panel of physicians (interventionalist, surgeon, neurologist) who **concur on qualification of patient**
**n = 747**

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

## 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%

##  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

-   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 **

## SAPPHIRE STUDYPrimary Endpoint – 360-day MAE Adjusted for Baseline Characteristics

| %Difference
[95% C.I.] |
| --- |
| –5.3%[–13.4%, 3.0%] |

- Margin of Non-inferiority

- % Difference (Non-randomized Stent – Randomized CEA)

***Stent Non-inferior to CEA***

**3%**

- Non-Inferiority Statistics

**SAPPHIRE STUDY****Primary Endpoint – 360-day MAE Adjusted for Baseline Characteristics**

## SAPPHIRE STUDYComplications

|  | Randomized Stent 
(n = 167) | Randomized CEA 
(n = 167) | Non-RandStent
(n = 406) | P-value 
(CEA vs. Non-Rand) |
| --- | --- | --- | --- | --- |
| TLR | 1 (0.6%) | 6 (3.6%) | 3 (0.7%) | 0.02 |
| Vessel Thrombosis | 0 (0.0%) | 0 (0.0%) | 3 (0.7%) | 0.56 |
| Major Bleeding | 15 (9.0%) | 17 (10.2%) | 54 (13.3%) | 0.33 |
| Cranial Nerve Injury | 0 (0.0%) | 8 (4.8%) | 0 (0.0%) | <0.01 |

## SAPPHIRE STUDYTrial Design and Patient Flow

**n=406**

**Non-Randomized CEA Arm **
**n=7**

**RCT **
**334 Randomized  (310 Treated)**

**Stent**
**Treatment**
**n=167**

**CEA**
**Treatment**
**n=167**

**Surgeon & Interventionalist **_**will**_** treat patient    **

**SAPPHIRE STUDY****Trial Design and Patient Flow**

**Interventionalist: unacceptable risk for stenting**

**Surgeon: ****unacceptable risk for CEA**

- Evaluated by panel of physicians (interventionalist, surgeon, neurologist) who **concur on qualification of patient**
**n = 747**

## 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

- Symptomatic/Asymptomatic:
- Randomization stratified by +/- symptoms
- Subgroup analyses pre-specified
- Subgroup sample sizes
- Symptomatic Patients:          96
- Asymptomatic Patients:      237

**SAPPHIRE STUDY**** ****Subgroup Analyses**

## SAPPHIRE STUDY30-Day MAE Asymptomatic (ITT)

**%**

- P=0.62

- P=0.54

- P=0.22

- P=0.46

## SAPPHIRE STUDY360-Day MAE Asymptomatic  (ITT) 

**SAPPHIRE STUDY****360-Day MAE Asymptomatic  (ITT) **

**%**

- P=0.15

- P=1.00

- P=0.08

- P=0.07

## 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%**

## SAPPHIRE STUDY30-Day MAE Symptomatic  (ITT)

**SAPPHIRE STUDY****30-Day MAE Symptomatic  (ITT)**

- P=0.10

- P=0.61

- P=0.48

- P=0.11

**%**

## SAPPHIRE STUDY360-Day MAE Symptomatic  (ITT)

**SAPPHIRE STUDY****360-Day MAE Symptomatic  (ITT)**

**%**

- P=0.57

- P=0.35

- P=1.00

## 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%**

## SAPPHIRE STUDY360-Day MAE Symptomatic vs. Asymptomatic (ITT)

- %

- P=0.07

**SAPPHIRE STUDY****360-Day MAE Symptomatic vs. Asymptomatic (ITT)**

- n=281

- n=46

- n=124

- n=120

- n=117

- n=50

## SAPPHIRE STUDY360-Day MAE Symptomatic vs. Asymptomatic Treated (Evaluable) Patients

**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

## 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

## SAPPHIRE STUDYSurgeon Experience & Judgment

-   53 SAPPHIRE surgeons
-  Mean of 36.3 procedures per year
-  Median of 28 procedures per year

**SAPPHIRE STUDY****Surgeon Experience & Judgment**

## 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 (%)

## 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**

## 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**

## SURGICAL OUTCOMES vs. OTHER TRIALS

**SURGICAL OUTCOMES vs. OTHER TRIALS**

- Error Bar = 95% CI

**%**

## 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

- 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**

## CAS OUTCOMES TO OTHER SURGICAL TRIALSSymptomatic Patients

- 30-Day Ipsilateral Stroke

**CAS OUTCOMES TO OTHER SURGICAL TRIALS****Symptomatic Patients**

- Error Bar = 95% CI

**%**

## CAS OUTCOMES TO OTHER SURGICAL TRIALSAsymptomatic Patients

- 30-Day Ipsilateral Stroke

**CAS OUTCOMES TO OTHER SURGICAL TRIALS****Asymptomatic Patients**

- Error Bar = 95% CI

**%**

## 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%

## SAPPHIRE STUDY

***Conclusions***

## 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

## 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

## 
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

- 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**

## 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**

## Carotid Artery Stent Education System

**PROFESSIONAL EDUCATION**

***Carotid Artery Stent Education System***

## 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

## DELIVERY PROCESS

**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

## 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

- 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**

## 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

- 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**

## 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

## INSTITUTIONAL  IDEs 30-Day Events - Site Reported 	

**%**

**INSTITUTIONAL  IDEs ****30-Day Events - Site Reported**** ****	**

## COMPARISON OF 30-DAY EVENT RATESTreated Patients with ANGIOGUARDTM Only

**%**

##    

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

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

**POST-MARKETING SURVEILLANCE**

## 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)

## 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 

- 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**

## CAROTID ARTERY STENTING WITH EMBOLI PROTECTION

***Summary and Conclusions***

## 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

## 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. 

- 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**

## 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

- 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**

## 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

- Cordis will conduct a post-marketing surveillance study with the goal of
- quantifying patient outcomes
- confirming the adequacy of physician training

**SUMMARY AND CONCLUSIONS**

## THANK YOU