STENT Feature & Benefit

Learning Objectives Drawbacks of traditional POBA Advantages of Stents in treatment of CAD Manufacturing of Stents Terminology: Deliverability and Deployment Terminology: Implant Performance

Plain Old Balloon Angioplasty (POBA) Goal: Get the artery open (first procedure in 1977) BEFORE DURING When Balloon expands: Plaque is compressed against vessel wall Blood flow is restored Vessel wall is stretched How does this process work? Balloon travels to target vessel on catheter: Balloon is rapidly inflated at site of blockage PLAQUE IN TARGET VESSEL: RESTRICTED BLOOD FLOW www.enh.org

Implications of POBA: Side Effects x Lumen Lumen Disease State Plaque x Post POBA Elastic Recoil Neointimal Formation Observations Post POBA: Pronounced Elastic Recoil and Neointimal Hyperplasia Restenosis likely (40-60%) Procedure results in minimal increase in lumen diameter

How Can Elastic Recoil be Reduced? Stents: Hollow Metal Tubes Implanted in target vessel to provide permanent support Delivered to target vessel using catheter system – balloon expanded Reduces recoil to ensure a larger lumen than with POBA

How Stents Work - Introduction Stent positioned on balloon catheter BEFORE DEPLOYMENT AFTER DEPLOYMENT Small Vessel 2.25-2.5 mm diameter MAX: 3.0 mm diameter BEFORE DEPLOYMENT AFTER DEPLOYMENT Large Vessel 4.0 - 5.0 mm diameter MAX: 5.75 mm diameter

Bare Metal Stents: Reduced Recoil EVIDENCE OF RESTENOSIS: Lumen Lumen Lumen Plaque Disease State Post BMS Minimal Pronounced Elastic Recoil Neointimal Formation Observations Post-BMS Deployment: Reduced Elastic Recoil and Neointimal Hyperplasia Restenosis pronounced (immune response leads to proliferation of ussmooth muscle cells) Procedure results in minimal increase in lumen diameter

DES: Reduced Recoil and Restenosis RESTENOSIS LIMITED Lumen Lumen Lumen Plaque Disease State Post DES Minimal Pronounced Elastic Recoil Neointimal Formation Observations Post-DES Deployment: Reduced Elastic Recoil and Neointimal Hyperplasia Restenosis reduced considerably Procedure results in marked increase in lumen diameter

Deliverability and Deployment Characteristics of Implant What Makes a Good Stent? Deliverability and Deployment Characteristics of Implant

Demonstration: What are You Holding? You have an entire stent delivery system Guide Wire balloon expanded stent balloon catheter

Deliverability and Deployment What Makes a Good Stent? Deliverability and Deployment 1.) The ability to get the stent to the target vessel 2.) To safely and accurately deploy the stent 3.) Remove the delivery system from the patient Implant Performance 1.) Physical characteristics of the device (construction) 2.) The ability of the device to “match” the target vessel. 3.) Measurement of long term safety and effectiveness (data)

Deliverability and Deployment – 1 of 3 CROSSABILITY: The degree to which a stent can be maneuvered past various lesions Balloon and Stent SYSTEM PROFILE TIP PROFILE PUSHABILITY: A measure of how accurately movement of the system outside the body translates to movement of the stent. FLEXIBILITY: How readily a stent can be manipulated on while being delivered to a lesion. Structural stiffness can be a factor. TRACKABILITY: How easily the catheter travels along the guide wire to the site of the lesion. Less friction is more desirable.

Deliverability and Deployment – 2 of 3 DELIVERABILITY: The general term physicians use to indicate the overall ease with which a stent system can be “delivered” to the lesion site. Trackability: How easily the catheter travels along the guide wire to the site of the lesion. Less friction is more desirable. Crossability: The degree to which a stent can be maneuvered past various lesions (profile of stent is critical.) Determined by: Flexibility: How readily a stent can be manipulated on while being delivered to a lesion. Structural stiffness can be a factor. Pushability: A measure of how accurately movement of the system outside the body translates to movement of the stent.

Deliverability and Deployment – 3 of 3 MINIMAL BALLOON OVERHANG limits damage to tissue beyond target lesion. RADIOPACITY: Stent should be visible under fluoroscopy Markers will improve PLACEMENT ACCURACY on target lesion (critical) Length before deployment Difference is due to FORESHORTENING Length after deployment

Implant Performance – 1 of 3 STENT DESIGN offers unique properties to suit varied target vessels. METAL TYPE can impact strength, flexibility, radiopacity. CONFORMABILITY is the ability of a stent to take the shape of the target vessel. STRUT THICKNESS determines strength of stent, may also limit flexibility.

Implant Performance: 2 of 3 If the struts touch the vessel walls, the implant is said to have good STRUT APPOSITION SCAFFOLDING offers uniform support of vessel wall: Considerable Risks associated with Poor Strut Apposition, called MALAPPOSITION closely related METAL TO ARTERY RATIO determines coverage of target vessel: Can limit likelihood of PLAQUE PROLAPSE RADIAL STRENGTH keeps the target vessel open, also called COMPRESSION RESISTANCE.

Implant Performance – 3 of 3 LONG TERM CLINICAL DATA is also an important measure of implant safety and efficacy. This is another important consideration during stent selection. RESTENOSIS RATE TLR (TARGET LESION REVASCULARIZATION) MACE (MAJOR ADVERSE CARDIAC EVENT) SUBACUTE STENT THROMBOSIS (SAT) LATE LOSS (see next slide)

In-Stent Late Loss Limitations of Measurement In-Segment All of these vessels have the same in-stent late loss In-stent Late Loss = .6 mm Late loss is not sensitive to patterns of restenosis In-stent Late Loss = .6 mm One of the major limitations in assessing late lumen loss, is measurement itself. In this slide, while all vessels have a late loss of .6mm, patterns of restenosis are not identified. Areas outside of the stent including the edges are not taken into consideration. The edges are excluded from analysis In-stent Late Loss = .6 mm

In-Segment Late Loss In-segment late loss may allow a more complete evaluation of the treated segment because it looks at the margins In-segment Late Loss provides a more detailed understanding of the entire lesion by including the analysis segment In-segment In-stent 5mm

In-stent Late loss levels below .6mm may not predict TLR Late Loss Below a Certain Level May Not Be A Strong Predictor of TLR In-stent Late loss levels below .6mm may not predict TLR Source: Dr. Jeffrey Popma, MD Director of Interventional Cardiology, Brigham and Womens Hospital Cypher is a trademark of Cordis Corporation

DES VS BMS

One Company’s Experience The Stent Drug Eluting Stents – The New Paradigm The Carrier Matrix The Stent Mechanical integrity Mechanical Scaffolding Carrier Dose Kinetic Release Rate (KDR) Vascular Compatibility The Drug (Chemical Entity) The Tissue Tissue Pharmacokinetics

One Company’s Experience The Stent Mechanical scaffolding, mechanical integrity, vascular compatibility were considered when selecting the best stent design and material. Current Technology 2nd & 3rd Generation Early Technology • Good scaffolding/ vessel support • Increased flexibility • Increased deliverability • Good scaffolding/ vessel support • Good flexibility • Good deliverability • Minimal scaffolding/ vessel support • Minimally flexible • Minimally deliverable Result: Stainless Steel Stent = Vascular Compatibility & good mechanical scaffolding/integrity

One Company’s Experience The Carrier Matrix - Polymer Polymer: poly (styrene-b-isobutylene-b-styrene) (SIBS) Why Polymer? Dose Control - uniform drug distribution - ability to modify release rate - consistent release Protect the Drug - no loss in handling or delivery - consistent dose Versatile - one polymer can be used for a portfolio of drugs - can be applied to various device geometries - manufacturing processes are compatible w/ pharmaceuticals

One Company’s Experience The Carrier Matrix - Dose Pre-clinical Dosing studies: The Approach Evaluate Maximum Possible Dose - Loading capacity of polymer/stent system Identify the Maximum Tolerable Dose - Understand “The Window” (safety margin) Identify Minimum Effective Dose FDA requirement: to demonstrate safety of 3x overdose

One Company’s Experience The Carrier Matrix - Dose Dosing Range – Preclinical Study 4 ug/mm2 2 ug/mm2 1ug/mm2 0.5 ug/mm2 345 ug 175 ug 85 ug 50 ug Medial Thinning Drug Effect Thrombus No Medial Thinning Drug Effect No Thrombus Result: Determined the Safe & Potentially Therapeutic Range for the Artery

One Company’s Experience BSC - Brief History BSC has cumulated more than a decade of experience in developing Drug-eluting stent technologies Known proven chemical entity Determined Dose & mechanism of action Developed aggressive Vigilance program & complete product validation Selected Drug platform 1995 1997 1999 2001 2003 2005 Conducted product Clinical Trials Searched & validated the Polymer Carrier Determined & Validated Dose Release Test Method (KDR) Conducted Post-Market Trials (28,000 +)

DES Efficacy Roiron C. et al, Heart 2006;92:641–649

TAXUS® Stent 4-Year Meta-Analysis reinforces the positive benefit / risk profile TAXUS I, II-SR, IV, V (N=2,797) Risk Benefit p=0.17 p=0.24 p=0.78 p=0.87 p=0.83 p=0.86 p<0.0001 20.2 n=266 10.5 n=133 8.3 n=89 7.9 n=86 4-Yr Cumulative Events (%) 7.4 n=79 7.1 n=75 6.4 n=80 6.9 n=82 1.1 n=13 1.8 n=21 0.8 n=10 1.3 n=16 1.1 n=12 1.0 n=13 Primary ARC ST Def/Prob Protocol ST All Death All MI Q Wave MI Death or Q Wave MI TLR Bare Metal Stent (N=1,397) TAXUS® Stent (N=1,400) *TAXUS Stent 4-year meta-analysis includes TAXUS I (5 yr), II-SR cohort I (4 yr), IV (4 yr), V (2 yr) (N=2,797). Kaplan Meier estimate and p values from log rank

Clear Benefit of the TAXUS™ Stent Subset Data: Stent TLR Rates TAXUS I, II-SR, IV, V Studies (N=2,797) p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 31.3% 35.9% 27.7% 24.9% TLR Rate (%) 20.2% 14.5% 13.4% 13.1% 12.8% 10.5% N=2,797 n=715 n=965 n=341 ™ n=497 Adapted from Don Baim M.D. - FDA Panel Presentation December 2006. TAXUS™ Stent is not approved for use in patients with coronary artery reference vessel diameters < 2.25mm or in patients with lesions longer than 32mm. TAXUS Stent 4-year meta-analysis: See Glossary. Kaplan Meier estimate and p values from log rank

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