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Second Generation DES: Are New DES Really Better? Encore Seoul 2007 Mitchell W.

Krucoff MD, FACC


Professor of Medicine // Cardiology Professor of Medicine Cardiology Duke University Medical Center Duke University Medical Center Director, Cardiovascular Devices Unit Director, Cardiovascular Devices Unit Duke Clinical Research Institute Duke Clinical Research Institute

Conflict of Interest: Conflict of Interest:


Grants and consulting: All Grants and consulting: All Equity, advisory boards etc: None Equity, advisory boards etc: None
Abbott Abbott Boston Scientific Boston Scientific Biosensors Biosensors Terumo Terumo Conor Medsystems Conor Medsystems Cordis/J&J Cordis/J&J Medtronic Medtronic Orbus Neich Orbus Neich St. Jude St. Jude Special Government Employee, Special Government Employee, U.S. FDA: U.S. FDA:
Circulatory Devices Circulatory Devices Advisory Panel Advisory Panel Global Harmonization Task Global Harmonization Task Force WG5 Force WG5 Duke-FDA Cardiac Safety Duke-FDA Cardiac Safety Critical Path Stent Critical Path Stent Thrombosis Initiative Thrombosis Initiative Japan-USA Harmonization Japan-USA Harmonization by Doing by Doing

Looking Forward: 2nd Generation DES: Looking Forward: 2nd Generation DES: Exciting potential, challenging evaluations! Exciting potential, challenging evaluations!
DES platforms: Combination product DES platforms: Combination product A priori rule ofwhich delivers aTechnologies: Device which delivers a drug Device Breakthrough drug Components: TheComponents: is the worst generation. first generation Stent platform Stent platform Polymer coating Near Polymer coating Horizon Second Generation DES: Drug Drug ENDEAVOR/RESOLUTE (MEDTRONIC)
COSTAR (CONOR/J&J) Implantation technique Implantation technique XIENCE (ABBOT)

Drug adjunct: dual antiplatelet therapy Drug adjunct: dual antiplatelet therapy BIOSENSORS/TERUMO etc. Patient substrate(s) Patient substrate(s)

Components of the Endeavor Stent Components of the Endeavor Stent

Cobalt Alloy Modular stent Strut thickness 0.0036

Delivery based on Discrete, Secure Technology

ABT-578 (Zotarolimous) 10 g/mm stent dosage

Biocompatible PC Technology (phosphorylcholine polymer)

Zotarolimous (ABT-578): Mechanism of Action Zotarolimous (ABT-578): Mechanism of Action

Complex blocks mTOR signal transduction ABT-578

ABT-578 binds with FKBP12 protein

Antiproliferative mode of action by inhibiting mTOR.

ENDEAVOR: PC Technology ENDEAVOR: PC Technology

Strut Coverage and Endothelization


Driver Endeavor
% of Struts Endothelialized
100 90 80 70 60 50 40 30 20 10 0
Mean % Endothel

Driver Endeavor

Virmani et. al; PCR 2006

ENDEAVOR II ENDEAVOR II

In-Stent Late Loss Distribution


LL Relationship to TLR Probability

TLR Probability
50 45 40 35

Endeavor

Driver
1.00 0.90 0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00

TLR Probability

Frequency

30 25 20 15 10 5 0 -0.40 -0.20 0.00 0.20 0.40 0.60 0.80 1.00 1.20 1.40 1.60 1.80 2.00 2.20 2.40 2.60 2.80

3.00

In-Stent Late Loss (mm)

ENDEAVOR III: Angiographic and IVUS Results at 8 Months ENDEAVOR III: Angiographic and IVUS Results at 8 Months
Endeavor n=282
Angiographic f/u % (N) RVD (mm) MLD (mm) In-Stent In-Segment DS (%) BAR (%) In-Stent In-Segment In-Stent In-Segment 87.3 (323) 2.74 2.08 1.92 24.3 29.9 9.2 11.7 0.60 0.34

Cypher n=94
83.2 (113) 2.84 2.52 2.16 11.0 23.9 2.1 4.3 0.15 0.13

pvalue
0.27 0.07 <0.001 <0.001 <0.001 <0.001 0.02 0.04 <0.001 <0.001

Late Loss (mm) In-Stent In-Segment

Endeavor: Complete NIH


Smooth Lumen, Even Neointimal Distribution

Proximal (mm3/mm) 2 Neointimal Volume Index

Distal

0 Proximal

18 mm ZES

Distal

ENDEAVOR II: Stent Thrombosis & Timing ENDEAVOR II: Stent Thrombosis & Timing
No Stent Thrombosis After 14 Days
Driver

1.2% (7)

1 2 3

12 13 14

30

100

150

200

270

300

325

360 Days

Endeavor

0.5% (3)

ENDEAVOR III

What About Negative Late Loss?


Percent of Patients 30 25 20 15 10 5 0
-0.6 -0.2 0.2 0.6 1.0

Endeavor

Cypher

1.4

1.8

2.2

2.6

In-Stent Late Loss

% of patients 0 mm In-Segment LL

9.6% Endeavor

46.8% Cypher

RESOLUTE: The BioLinx Polymer


Cell Membrane BioLinx Polymer

Hydrophilic

Zotarolimus Hydrophobic Hydrophobic and hydrophilic groups

Hydrophilic polymer: Polyvinyl pyrrolidinone (PVP) for initial drug burst and enhanced biocompatibility Hydrophobic polymer: based upon hydrophobic butyl methacrylate (C10) for combining with zotarolimus and uniform drug dispersion Combination polymer: hydrophobic hexyl methacrylate, hydrophilic vinyl pyrrolidinone and vinyl acetate (C19) to support delayed drug elution and biocompatibility

RESOLUTE: Angiographic Results 4 Month Subset


n=30
RVD (mm) Lesion Length (mm) MLD (mm) pre post Acute Gain MLD (mm) 4 mo f/u Late Loss (mm) Late Loss Index % DS ABR (%) 2.810.36 1.980.45 2.680.39 0.120.26 0.06+0.17 7.187.86 0

In-stent

In-segment
2.900.38 15.16+5.38 0.83+0.34 2.430.45 1.610.59 2.380.40 0.050.20 0.01+0.18 17.747.57 0

CoStar Paclitaxel-Eluting Coronary Stent System CoStar Paclitaxel-Eluting Coronary Stent System
A Stent Specifically Designed for Controlled Drug Delivery from a Bioresorbable Polymer

The First Second-Generation DES


Reservoir Technology Bioresorbable Polymer Cobalt Chromium

Discrete Reservoir Technology Discrete Reservoir Technology


Bi-Directional Uni-Directional

Single Drug Structure

Single

Drug Delivery Reservoirs

Adjacent

Multiple Drug Structures

CoStar Bioresorbable Polymer CoStar Bioresorbable Polymer


PLGA (Polylactide-co-glycolide) PLGA (Polylactide-co-glycolide) Widely used bioresorbable surgical suture material Widely used bioresorbable surgical suture material Mechanism of bio-degradation well characterized Mechanism of bio-degradation well characterized Degrades by random hydrolytic scission into Lactate Degrades by random hydrolytic scission into Lactate & Glycolate & Glycolate
7 Day Porcine Explant
Following Tissue Removal Showing Signs of Polymer Bioresorption

180 Day Porcine Explant


Following Tissue Removal Showing No Residual Polymer

Conor Clinical Trials Dose Formulations Conor Clinical Trials Dose Formulations

Formulations
D1 D2
10g / 10D

D3
10g / 10D

D4
30g / 10D

D5
10g / 30D

D6
30g / 30D

D11
3g / 30D

Stent Platform
Stainless Steel with Paclitaxel Cobalt Chromium with Paclitaxel Cobalt Chromium with Paclitaxel Cobalt Chromium with Paclitaxel

Trial

10g / 5D

Bi-Direct*

Bi-Direct*

Mural

Bi-Direct*

Mural

Mural

Mural

Group 1

Group 2

Group 3

Arm 1

Arm 2

CoStar +

* Bi-Directional = direction of paclitaxel elution is both mural and luminal Bi+ CoStar Stent randomized against TAXUS Stent in a 3:2 ratio.

Caution: CoStar is an investigational device in the U.S. and not available for sale. sale. Limited by law to investigational use in the U.S.
Conor Medsystems and CoStar are trademarks of Conor Medsystems. Conor Medsystems, Inc. 2005

EuroSTAR Angiographic Follow-Up EuroSTAR Angiographic Follow-Up


Late Loss at 6 Months Late Loss at 6 Months
Arm 1 (N=149 lesions) Arm 1 (N=149 lesions) Arm 2 (N=116 lesions) Arm 2 (N=116 lesions)
P = 0.011 P = 0.003

0.80 0.80
P = 0.008 P = 0.19

Late Loss (mm)

0.60 0.60 0.40 0.40 0.26 0.26 0.20 0.20 0.06 0.06 0.00 0.00 In-Stent In-Stent -0.20 -0.20 Prox Edge Prox Edge Distal Edge Distal Edge In-Segment In-Segment -0.04 -0.04 0.08 0.08 0.07 0.07 0.39 0.39 0.44 0.44 0.22 0.22

COSTAR II Trial COSTAR II Trial


Study Design & Patient Follow-Up Study Design & Patient Follow-Up
A Prospective, Asymmetrically Randomized, Single-Blind, Non-Inferiority Study comparing the Conor CoStar Paclitaxel-Eluting Coronary Stent System with the TAXUS Drug-Eluting Coronary Stent System for the treatment of de novo lesions in patients with single or multi-vessel coronary artery disease.
Baseline Angiography & COSTAR II Principal Investigators & QCA Cardiac Enzymes

CoStar Arm

10 m / 30 days / Mural

Mitchell W. Krucoff M.D. N = 900 patients


Randomized in 3:2 Ratio

Post-Procedure ECG

1 Month Clinical F/U

1,700 Total Patients *


N = 1500 Patients (to be evaluated)

William Wijns M.D. 8 Month Clinical F/U* Dean Kereiakes M.D. QCA and IVUS* with
TAXUS Arm
N = 600 patients
5 Year Clinical F/U - Conducted Yearly
* Primary Endpoint - 8-Month MACE

Subset: 9 Month Angiographic


1 Year Clinical F/U

COSTAR II: Not Just Another DES Study **


First real clinical endpoint pivotal DES trial First real clinical endpoint pivotal DES trial First real world randomized MV DES study First real world randomized MV DES study Evaluation of HgA1c in all patients Evaluation of HgA1c in all patients Largest pivotal DES study Largest pivotal DES study

Enrollment completed: May 2006 1,700 patients in 322 days!


* Wang et al, Am Heart J 2007;153:743-8

MACE Through 270 Days Kaplan-Meier


100%
Freedom from Event to 270 Days

98% 96% 94% 92% 90% 88% 86% 84% 0 30 60 90 120 150 180 HR (95% CI)=0.622 (0.423-0.915) HR (95% CI)=0.612 (0.433-0.865)

P-value=0.005 P-value=0.015 94.4%

91.2% 92.0%

CoStar (n = 972)

Taxus (n = 670)
210 240

87.5%

270

Days from Procedure


MACE: A composite of adjudicated death, MI, and and clinically driven TVR

Death or Q-Wave MI 270 Days Kaplan-Meier


100%
Freedom from Event to 270 Days

98% 96% 94% 92% 90% 88%

P-value=0.645

P-value=0.645

99.0% 98.9%

HR (95% CI)=0.792 (0.293-2.141)

CoStar (n = 972)
86% 84% 0 30 60 90

Taxus (n = 670)
210 240 270

120 150 180 Days from Procedure

Clinically-Driven TLR Through 270 Days Kaplan-Meier


100%
Freedom from Event to 270 Days

P-value=0.002

98% 96% 94% 92% 90% 88% 86% 84% 0 30 HR (95% CI)=0.468 (0.286-0.766) 92.2% 96.3%

CoStar (n = 972)
60 90 120

Taxus (n = 670)
150 180 210 240 270

Days from Procedure

8-Month MACE Prespecified Subgroup Analysis


Diabetic IDDM NIDDM Non-diabetics MVD SVD Overlap Non-overlap Anticoagulation Rx Anticoagulation Rx D/C Lesion Length (mm): <=12 12-15 >15 RVD (mm): <=2.5 2.5-3.0 >3.0 LAD Target Vessel Non-LAD Target Vessel -2 -1

OR (95% CI)

CoStar better Taxus better


MACE: A composite of adjudicated death, MI, and and clinically driven TVR

XIENCE V Everolimus Eluting CSS Components XIENCE V Everolimus Eluting CSS Components
MULTI-LINK VISION Stent MULTI-LINK VISION Stent Delivery System

Everolimus

Fluoropolymer

Minimal Injury Minimal Injury


Minimizing Strut and Polymer Thickness Minimizing Strut and Polymer Thickness

Acute Long-Term

CYPHER

TAXUS

ENDEAVOR

XIENCE V

Strut Thickness:

Strut Thickness:

Strut Thickness:

Strut Thickness:

140 um
Polymer Thickness:

132 um
Polymer Thickness:

91 um
Polymer Thickness:

81 um
Polymer Thickness:

12.6 um
Total:

16 um
Total:

5.3 um
Total:

7.6 um
Total:

152.6 um

148 um

96.3 um

88.6 um

3.0 mm diameter stents, 500x magnification

Everolimus Everolimus
Developed by Novartis Developed by Novartis Immunosuppressant drug Immunosuppressant drug
M

G1 1

G2 2

Cell cycl e
S

G0 0

Targets primary causes of chronic rejection in Targets primary causes of chronic rejection in heart, renal, and lung transplant patients heart, renal, and lung transplant patients

Proliferation inhibitor Proliferation inhibitor


Inhibits growth factor-stimulated cell proliferation by Inhibits growth factor-stimulated cell proliferation by causing cell cycle arrest in the late G1 stage causing cell cycle arrest in the late G1 stage

Active ingredient in CERTICAN (Novartis) Active ingredient in CERTICAN (Novartis)


Approved for prevention of rejection of heart and kidney Approved for prevention of rejection of heart and kidney transplant in over 60 countries transplant in over 60 countries Investigational drug; Novartis received approvable letter Investigational drug; Novartis received approvable letter from FDA from FDA

XIENCE V Fluoropolymer XIENCE V Fluoropolymer


Biocompatible with a proven history in blood Biocompatible with a proven history in blood contacting applications contacting applications Haemodialysis machines Haemodialysis machines Cardiac sutures Cardiac sutures Vascular grafts Vascular grafts Guide catheters Guide catheters High drug loading High drug loading Minimize coating thickness Minimize coating thickness Good physical coating integrity Good physical coating integrity Excellent adhesion to metal Excellent adhesion to metal Good ductility and flexibility Good ductility and flexibility

14-Day Rabbit Iliac Re-endothelialization Study: 14-Day Rabbit Iliac Re-endothelialization Study:
Representative Photomicrographs of Competitive Stents Representative Photomicrographs of Competitive Stents
XIENCE V CYPHER TAXUS ENDEAVOR

Photos on file at Abbott Vascular, Shown with permission from Dr. Renu Virmani

Consistency of Everolimus Consistency of Everolimus


6-month follow-up

SPIRIT First .10


.09 0%

SPIRIT II .11
.07 1.3%

FUTURE I FUTURE II .11


.19 0%

Late Loss in stent (mm) Late Loss in segment (mm) Binary Restenosis stent Binary Restenosis segment MACE Platform in

.12
.16 0%

in

<5% 7.7%
ML VISION

3.4% 2.7%*
ML VISION

<5% 7.4%
S Stent

<5% 4.7%
S Stent

Source: Eberhard Grube, MD., TCT 2004; Patrick Serruys, MD., TCT 2004; MACE defined as cardiac death, MI, all TLR and TVR-CABG *SPIRIT II MACE Definition: cardiac death, MI and ischemia driven TLR

Study Algorithm
1002 pts enrolled at 65 U.S sites
RVD 2.5 mm - 3.75 mm; Lesion length 28 mm Max. 2 lesions each in a different epicardial vessel
Pre-rand: ASA 300 mg, clopidogrel 300 mg load unless on chronic Rx

Randomized 2:1 XIENCE V:TAXUS


Stratified by diabetes and intent for 1 vs. 2 lesion treatment Pre-dilatation mandatory

Everolimus-eluting

Paclitaxel-eluting

XIENCE V

TAXUS

Aspirin 80 mg QD for 5 years; Clopidogrel 75mg QD for 6 months

Clinical f/u: 1, 6, 9 months and yearly for 1-5 years Angio f/u (N=564) @ 8 mos; IVUS f/u (N=240) @ 8 mos

Primary Endpoint: In-segment LL at 8 Months*


(Analysis Lesion)
100% 90% 80%

% of Lesions

70% 60% 50% 40% 30% 20% 10% 0% -1 -0.5 0 0.5

TAXUS: 0.28 0.48 (n=134) XIENCE V: 0.14 0.41 (n=301)

PNI < 0.0001 PSUP = 0.004

1.5

2.5

In-segment Late Loss (mm)


*F/U window 28 days.

MACE Through 284 Days


8.1%

HR=0.56 [0.33 0.94] MACE (%)

Plogrank = 0.03 4.6%

Days

Safety Endpoints at 270 Days*


XIENCE V (658 pts)
P=0.55 P=1.0

TAXUS (322 pts)


P=0.64 P=0.55

3.4% 2.7% < 1,000 pts, <1 year 2.5% 2.0%


Q=0.2 Q=0

1.0% 0.9% 0.46%


L=0.15 E=0.30 C=0.5 C=0.6 NQ=1.8 NQ=2.5

NC=0.5 NC=0.3

Stent thrombosis

Death

MI

Death or MI

*F/U window 14 days. E = early (30d); L = late (>30d-9mo); C = cardiac; NC = non cardiac; Q = Q-wave; NQ = non Q-wave

Biolimus A9 Eluting Stents

January 25, 2007


Not available for sale in the United Sates.

S-Stent Bare Metal Stent and Tiger Delivery System


Biosensors International

QUADRATURE LINKTM FOR FLEXIBILITY BEFORE AND AFTER STENT PLACEMENT

Stent: Polymer: Drug: Delivery System: Sizes:

S-Stent Proprietary biodegradable PLA Biolimus A9 Tiger Rx balloon catheter 6-cell: 2.5-3.25mm / 8-28mm 9-cell: 3.5-4.0mm / 8-28mm
Not available for sale in the United Sates.

Biolimus A9
12 10

CH3 3 O

Sirolimus Everolimus Zotarolimus Biolimus A9 G0 G0 G1 G1

S S

H3C 3

16

OH N H O
1

OCH3 O 3

Resting Cell division


37 39 40

Cell cycle

G2 G2

O
35

H3C 3

22

OH
32 28

34

OCH3 3 O

X M M

Paclitaxel

CH3 3 O

Ethoxy ethyl modification

CH3 OCH3 3 3

CH3 CH3 3 3

Rapamycin Derivative C55H87NO14 (MW=986Da) More lipophilic than Sirolimus / Everolimus Immunosuppressant

Mechanism of Action Antiproliferative agent Binds to FKBP-12 Inhibits mTOR activity


Not available for sale in the United Sates.

PLA Metabolic Pathway


H2O Hydrolysis

PLA

Molecular weight Mass loss Lactic acid Mass transport of lactic acid

Krebs cycle

CO2+H2O
Not available for sale in the United Sates.

BioMatrix Stent Platform


Biodegradable Drug/Carrier: - Biolimus A9 / Poly (Lactic Acid) 50:50 mix
BIOFLEX I

- abluminal surface only (contacts vessel wall) - 10 microns coating thickness - degrades in 9 months releasing CO2+ water

BioFlex I stent

Stent Platform:
- stainless steel (112 microns) - corrugated ring, quadrature-link design - radius link enhances axial fatigue resistance

Parylene Durable Primer Coating:


- 5 microns thick, encapsulates stent - prevents surface metal ion migration - biostable + athrombogenic*
Not available for sale in the United Sates.

*Data per NHLBI sponsored study, available from BSI

STEALTH I FIM Trial


Percent Intimal Volume
p>0.99

40 35 30 25 20 15 10 5 0

32.818.3 31.44.6

S-Stent

BioMatrix BioMatrix

p=0.06 3.22.5 6.25.6

th on 6-m

th on 2-m

th on 6-m

th on 2-m

*20 Serial Volumetric Analysis cases (S-Stent 8, BioMatrix 12)


Not available for sale in the United Sates.

Krucoff et al, Circulation. 2007.

Evaluation of Second Generation DES Evaluation of Second Generation DES


More complex, real world patients More complex, real world patients Clinical outcomes not surrogate endpoints Clinical outcomes not surrogate endpoints Clinical outcome before protocol angiograms Clinical outcome before protocol angiograms Longer primary follow up: 12-24 months Longer primary follow up: 12-24 months Better detail on anti-platelet therapy: Better detail on anti-platelet therapy: Duration Duration Compliance Compliance Interruption Interruption Larger cohorts, 5 year follow up (post-market) Larger cohorts, 5 year follow up (post-market)

Clinical Evaluation of New Medical Devices Global Clinical Evaluation


Iceland Canada Norway Finland
Estonia

Russia

United States

Latvia U.K. Denmark Lithuania Netherlands Poland Ireland Germany Belgium Czech Rep. Austria Slovenia Ukraine Switz. France Hungary Romania Bulgaria Georgia Spain Italy Portugal GreeceTurkey

China

Japan

Mexico Dominica Guatemala Guatemala El Salvador

Israel Egypt Egypt United Arab Emirates India

Taiwan Hong Kong Thailand Malaysia Singapore Indonesia

Redundancy
Venezuela Columbia Brazil

Panama

Added Cost
Paraguay Chile Uruguay Argentina South Africa Australia

Time Delay Limited knowledge

New Zealand

October 2002

Second Generation DES: Are New DES Really Better? Encore Seoul 2007 Mitchell W. Krucoff MD, FACC
Professor of Medicine // Cardiology Professor of Medicine Cardiology Duke University Medical Center Duke University Medical Center Director, Cardiovascular Devices Unit Director, Cardiovascular Devices Unit Duke Clinical Research Institute Duke Clinical Research Institute

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