PPT

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

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.

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

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

> 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

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

Randomized clinical studies

Superiority of CEA vs. best medical therapy

NASCET 1

Symptomatic> 50% diameter stenosis

ACAS 2

Asymptomatic> 60% diameter stenosis

ECST 3

VA Cooperative Study 4

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

CEA treatment of patients clearly extends beyond

NASCET/ACAS inclusion criteria:

NASCET/ACAS studied a relatively healthy subset of patients:

ACAS screened 25 to enroll 1 patient 1

NASCET 1 out of every 3 treated patients enrolled 1

Patients considered high risk for CEA as defined by trial ineligibility comprise up to 50% of patients in published series:

Ochsner Clinic 46.2% 2

CCF Registry 19.4% 3

Wennberg et al., JAMA 279:1278-1281, 1998.2. Leporre et al., J Vasc Surg 34: 581-586, 2001.

3.Ouriel et al.,J Vasc Surg 33: 728-732, 2001.

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 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

Conclusion:

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

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

Design:

Non-randomized, prospective, 33 center trial

6/7F SMART and 5.5F PRECISE SDS

261 patients enrolled

176 stent

85 stent plus ANGIOGUARD

Sept 1998 through July 2001

Follow up to 3 years

Key Inclusion Criteria:

Symptomatic> 60% stenosis by U/S or angiography

Asymptomatic> 80% stenosis by U/S or angiography

Native Common or Internal Carotid Artery

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

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

Conclusion:

Demonstrated feasibility of carotid stenting with the Cordis PRECISE Nitinol Stent System

ANGIOGUARD emboli protection device reduced the incidence of stroke

30-day stroke rate 2.4%, with no major strokes

Provided run-in to pivotal study

Refinement of CAS System

Reduction in profile (7F to 5.5F)

Improvement in design

Data supports benefit of ANGIOGUARD emboli protection device in reducing stroke

Demonstrated the feasibility of CAS

Overview of PMA Clinical Data(Total of 1619 Pts)

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.

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)

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)

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, pathologicalQ waves.

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.

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

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

Medical Co-morbidities:

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

SAPPHIRE CEA arm

1 year MAE rate of 19.2%

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

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

Overview of PMA Clinical Data(Total of 1619 Pts)

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

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

Physicians

interact with realistic graphical simulations

assess task performance

demonstrate understanding of the learning objectives

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

Training Program:

34 Hours of Training with exposure to a minimum of 15 Cases

Serves as the foundation for hospital credentialing

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

Carotid Stenting With Emboli Protection For The Treatment of Obstructive Carotid ArteryDisease

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 withde novoor 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

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 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.

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

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

PPT

Documents

Transcript of PPT