Siegburg / Stanford

BMS and DES Thrombosis

Differences among DES

Eberhard Grube MDFSCAI, FACC

HELIOS Heart Center Siegburg, Siegburg, GermanyStanford University, School of Medicine, CA, USAHospital Israelita Albert Einstein, São Paulo, Brazil

SCAI 30th Annual Scientific SessionsOrlando/Fla

Siegburg / Stanford

BMS and DES Thrombosis

Differences in DESEberhard Grube MD, FSCAI

The following relationships exist related to this presentation:

Grant support (GS), consultant (C), speakers bureau (SB), stock options (SO), equity interest (EI):

Boston Scientific: GS, C, SBCordis: C, SBBiosenors: GS, C, SB, EIAbbott: C, SB, Medtronic: C, SB

Off label use of products will be discussed in this presentation.

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Contributing FactorsHonda Y et al., Circulation, 2003, 8;108(1):2-5

Stent factorsDesign/Length

PolymerSurfaceDrugs

Patient factorsGene polymorphism

LV functionACS

Lesion factorsVessel sizeThrombus

Plaque characteristics

Blood factorsCoagulation activity

Platelet inhibition

Procedural factorsResidual dissection

Incomplete stent appositionAntithrombotic/anticoagulation therapy

STENT THROMBOSIS

AntiplateletTreatment

ResistanceDrug-drug interactionDuration of therapy

Siegburg / Stanford

Contributing FactorsHonda Y et al., Circulation, 2003, 8;108(1):2-5

Patient factorsGene polymorphism

LV functionACS

Lesion factorsVessel sizeThrombus

Plaque characteristics

Blood factorsCoagulation activity

Platelet inhibition

Procedural factorsResidual dissection

Incomplete stent appositionAntithrombotic/anticoagulation therapy

STENT THROMBOSIS

AntiplateletTreatment

ResistanceDrug-drug interactionDuration of therapy

Stent factorsDesign/Length

PolymerSurfaceDrugs

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TAXUS

TAXUS

Polyolefin derivative Polyolefin derivative PaclitaxelPaclitaxel ExpressExpress22

DrugDrug PolymerPolymer StentStentCYPHER

CYPHER

PEVA + PBMA blendPEVA + PBMA blendSirolimusSirolimus BX VelocityBX Velocity

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Localized Hypersensitivity Related to Sirolimus Eluting Stent

Marked Chronic Inflammation and Medial Destruction

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Inflammation in DES

Conclusions:

• DES delays arterial healing and promotes inflammation

Compared to SES, PES induce greater:

• Fibrin deposition

• Medial cell loss

• WBC Infiltration

• Late Neointimal Hyperplasia

Overlapping SES vs PES

Finn, A. V. et al. Circulation 2005;112:270-278

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Overlapping SES vs PESOverlapping SES vs PESBMS PESSESBMS

Overlap Overlap

Conclusions:• BMS showed far greater endothelialization than DES• Lack of coverage highlighted in areas of overlap• Less surface coverage by endothelial cells in PES than SES

DES Delayed Endothelialization

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REALITY

0,6

1,6

0,4

1,7

0,4

1,8

0,0

0,5

1,0

1,5

2,0

2,5

Intention-to-Treat Per-Protocol Actually-Treated*

CYPHER® TAXUS™

0,6

1,6

0,4

1,7

0,4

1,8

0,0

0,5

1,0

1,5

2,0

2,5

Intention-to-Treat Per-Protocol Actually-Treated*

CYPHER® TAXUS™

PP=0.0723=0.0723 PP=0.0333=0.0333 PP=0.0196=0.0196

111144 111133 121233

% of % of PatientsPatients

Stent Thrombosis (Acute + Subacute)

Per protocol analysis: CYPHERPer protocol analysis: CYPHER ®® 0.4, TAXUS0.4, TAXUS™™ 1.7: P=0.0331.7: P=0.033* 1 patient randomized to CYPHER* 1 patient randomized to CYPHER ®® actually treated with a TAXUSactually treated with a TAXUS ™™ stentstent

Stent Thrombosis: DES vs. BMSPer Protocol Analysis

Mauri L et al. N Engl J Med 2007;356:1020-9

1.3

0.5

0.2

0.6

0.8

0.5

0.10.2

0

0.5

1

1.5

2

OverallST

Early ST Late ST VeryLate ST

PES (N=1,400) BMS (N=1,397)

P=0.24

TAXUS I, II, IV, VEvents to 4 Years (N=2,797)

RAVEL, SIRIUS, E-SIRIUS, C-SIRIUSEvents to 4 Years (N=1,748)

%

1.2

0.5

0.1

0.60.6

0.1

0.5

0.00

0.5

1

1.5

2

OverallST

Early ST Late ST VeryLate ST

SES (N=878) BMS (N=870)

%

P=0.20

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Time after Initial Procedure (years)Time after Initial Procedure (years)

TAXUS I, II, IV, VTAXUS I, II, IV, V--SRSR

(N=2,797)(N=2,797)

00 11 22 33 44

TAXUS Stent (N=1,400)

Bare Metal Stent (N=1,397)

p=0.2499.2% (10)

98.7% (16)

6 vs.1, p=0.057 log-rank

After 1 yearAfter 1 year

Time after Initial Procedure (years)Time after Initial Procedure (years)

00 11 22 33 44

RAVEL, SIRIUS, ERAVEL, SIRIUS, E--SIRIUS, and CSIRIUS, and C--SIRIUSSIRIUS

(N=1,748)(N=1,748)

CYPHER Stent (N=870)

Bare Metal Stent (N=878)

P=0.2099.4% (5)

98.8% (10)

5 vs.0,p=0.025 log-rank

After 1 yearAfter 1 year

+0.48%

CRF analysis presented by Dr. Gregg Stone and Dr. Martin Leon, TCT 2006. TAXUS Stent data presented by Dr. Don Baim, December 7, 2006. TAXUS 4-year meta-analysis includes

TAXUS I (5 yr), II-SR cohort I (4 yr), IV (4 yr), V (2 yr) (N=2,797). The safety and effectiveness of the TAXUS®Stent have not been established in patients for longer than 12 months.

FDA Requested Analysis (Commercial TAXUS ® Stent SR Only)Freedom From (Protocol) Stent Thrombosis

+ 0.57%

95

96

97

98

99

100

95

96

97

98

99

100

Siegburg / Stanford

Different Definitions of Stent Thrombosis

0.57%

(5/878)

0.45%

(6/1401)“Confirmed”

(Angiographically)

“Presumed”(Sudden death within 30 days

or MI without angiographic confirmation)

TAXUS Trials(TAXUS I, II-SR, IV, V*)

(to 3 years)

Cypher Trials(RAVEL, SIRIUS, E&C-SIRIUS*)

(to 4 years)

1.03%

(9/878)1.00%

(10/1401)Total Reported

Thrombosis

?%

0.46%

(4/878)0.19%

(7/1401)SAT (1 - 30 days)

?%

Late ST (>30 days)

0.08%1/1401

• *TAXUS I 3-year data presented at TCT 2004 by Dr. E berhard Grube. TAXUS II 2-year data presented at TC T 2004 by Dr. Antonio Colombo. TAXUS IV 2-year data presented at TCT 2004 by Dr. Gregg W. Stone. TAXUS V 9-month data pr esented at ACC 2005 by Dr. Gregg W. Stone. RAVEL 4- year data presented at PCR 2005 by Dr. J. Eduardo S ousa. SIRIUS 3-year data presented at ACC 2005 by Dr. Martin B. Le on. E-Sirius 3-year data presented at ESC 2005 by D r. Vieter Legrand. C-SIRIUS presented at ACC 2003 b y Dr. Erick Schampaert.

Included per Protocol Protocol does not include “Presumed”Protocol does not include “Presumed”

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Pooled Meta-Analysis

Mauri et al. N Engl J Med 2007;356:1020-9.

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2229 patients after successful DES implantation 2229 patients after successful DES implantation

PESPES1167 pts1167 pts

2223 stents 2223 stents

SATSAT4 (0.4%)4 (0.4%)

SATSAT10 (0.9%)10 (0.9%)

LSTLST5 (0.5%)5 (0.5%)

LSTLST10 (0.9%)10 (0.9%)

Total SESTotal SES9 (0.9%) 9 (0.9%)

Total PESTotal PES20 (1.7%)20 (1.7%)

9.3 9.3 ±±±±±±±± 5.6 months 5.6 months Total DES 29/2229 Total DES 29/2229 (1.3%)(1.3%)

P=0.5P=0.5

P=0.3P=0.3

P=0.09P=0.09

10.2 10.2 ±±±±±±±± 4.44.4 mm 7.9 7.9 ±±±±±±±± 3.63.6 mm

Stent Thrombosis after DES

SESSES1062 pts 1062 pts

2272 stents 2272 stents

Iakovou et al, JAMA 2006

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Solutions to Avoid Stent ThrombosisSolutions to Avoid Stent Thrombosis

Improved SAFETYImproved SAFETYImproved SAFETY

Optimal Stent DesignOptimal Stent Design

Drug DurationDrug Duration Optimal Procedural ResultOptimal Procedural Result

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DES on the US Market – Forecast

TAXUS® Liberté™

2007 2008

JNJ

BSC

ABT

As of January, 2007. TAXUS, Liberté and PROMUS are trademarks of Boston Scientific Corporation or its affiliates. PROMUS Stent is a private-labeled XIENCE™ V Everolimus Eluting Coronary

Stent System manufactured by Abbott and distributed by Boston Scientific Corporation. XIENCE is a trademark of Abbott Laboratories group of companies. Cypher, Cypher-Mini and Cypher-Max

are trademarks of Cordis Corporation. CoStar is a registered trademark of Conor Medsystems Inc. Endeavor is a trademark of Medtronic Vascular, Inc. Caution- TAXUS Liberté, TAXUS Atom,

TAXUS 4.0mm, PROMUS, Xience V, Endeavor, CoStar, Cypher Mini and Max are investigational devices. Not currently available for sale in the US.

PROMUS™

Xience™ V

MDT

Endeavor®

Cypher® \ CoStar®

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EfficacySafety

Device Introduction

Generation of Evidence after Device IntroductionGeneration of Evidence after Device Introduction

FIM Pivotal Post approval studies

Early Safety

To assess stent thrombosis differences one needs large patient populations as well as

long-term follow-up

Siegburg / Stanford

1 yr 2 yrs 3 yrs 5 yrs4 yrs

TAXUS II (n=536)TAXUS IV (n=1314)TAXUS V (n=1156)TAXUS VI (n=448)RAVEL (n=238)SIRIUS (n=1058)E-SIRIUS (n=352)C-SIRIUS (n=100)ENDEAVOR I (n=100)ENDEAVOR II (n=1197)ENDEAVOR III (n=436)

~3,500 patients

~1,800 patients

~1,700 patients

Colombo et al. Circulation. 2003;108:788; Stone et al. N Engl Med. 2004;350:221; Stone et al. JAMA. 2005;294:1215; Dawkins et al. Circulation. 2005;112:3306; Morice et al. N Engl J Med.

2002;346:1773; Moses et al. N Engl J Med. 2003;349:1315; Schofer et al. Lancet. 2003;3362:1093; Schampaert et al. JACC. 43:1110; Dr. Meredith, EuroPCR 2006; Dr. Kandzari, ACC 2006; Dr.

Serruys, ESC 2006. Dr. Stone, ACC 2007

SPIRIT I (n=54)

SPIRIT II (n=300)~ 1334 patients

TAXUS I (n=61)

Currently Available Drug-Eluting Stent Pivotal Clinical Trial Data

SPIRIT III (n=980)

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Endeavor Shows More CompleteEndothelization than Cypher and Taxus

0

25

50

75

100

Mean % Endothel

Cypher

Taxus

Endeavor

% of Struts Endothelialized

Virmani et. al; PCR 2006

CypherCypher TaxusTaxus EndeavorEndeavor

Rabbit model at 21 days

Siegburg / Stanford

Defined as angiographic thrombus or subacute closur e within the stented vessel at the time of the clin ically driven angiographicrestudy for documented ischaemia (chest pain and ECG changes). Any death not attributed to a non-cardi ac cause within the first 30 days is considered a surrogate for stent t hrombosis in the absence of documented angiographic stent patency .

EIEIn=100n=100

1 2 3 12 13 14Days Post ProcedureDays Post Procedure

30 100 150 270 200 360 720

EIIEIIn=598n=598

EII CAEII CAn=296n=296

EIIIEIIIn=323n=323

= 1%

= 0.5%

= 0.0%

= 0.0%

Overall Thrombosis = 0.3%Overall Thrombosis = 0.3%

ENDEAVOR IENDEAVOR I--III Clopidogrel Therapy for III Clopidogrel Therapy for ≥≥ 3 months3 months

10801 year 2 years 3 years

Endeavor Clinical ProgramRate of Protocol Defined Stent Thrombosis by Study

Siegburg / Stanford

Different Definitions of Stent Thrombosis

0

0.57%

(5/878)

0.45%

(6/1401)“Confirmed”

(Angiographically)

“Presumed”(Sudden death within 30 days

or MI without angiographic confirmation)

TAXUS Trials(TAXUS I, II-SR, IV, V*)

(to 3 years)

ENDEAVOR Trials(ENDEAVOR I & II*)

(2 years)

Cypher Trials(RAVEL, SIRIUS, E&C-SIRIUS*)

(to 4 years)

1.03%

(9/878)1.00%

(10/1401)Total Reported

Thrombosis

?%

0.6%

(4/691)

0.46%

(4/878)0.19%

(7/1401)SAT (1 - 30 days)

?%

?%

?%

Late ST (>30 days)

0.08%1/1401

0.6%

(4/691)• *TAXUS I 3-year data presented at TCT 2004 by Dr. E berhard Grube. TAXUS II 2-year data presented at TC T 2004 by Dr. Antonio Colombo. TAXUS IV 2-year data presented at TCT

2004 by Dr. Gregg W. Stone. TAXUS V 9-month data pr esented at ACC 2005 by Dr. Gregg W. Stone. RAVEL 4- year data presented at PCR 2005 by Dr. J. Eduardo S ousa. SIRIUS 3-year data presented at ACC 2005 by Dr. Martin B. Le on. E-Sirius 3-year data presented at ESC 2005 by D r. Vieter Legrand. C-SIRIUS presented at ACC 2003 b y Dr. Erick Schampaert. ENDEAVOR I data presented at ESC 2005 b y Dr. Wijns. ENDEAVOR II data presented at PCR 2005 by Dr.J. Fajadet. Data from trials that are not he ad-to-head are not intended to be comparative.

Included per Protocol Protocol does not include “Presumed”Protocol does not include “Presumed”

Cypher is registered trademarks of Cordis Corporation, Endeavor is trademarks of Medtronic Corporation, NIR® is a registered trademark of Medinol Ltd. - Jerusalem

Siegburg / Stanford

Examples of Next Generation Stents

2. Generation DESXience V: Everolimus – Durable PolymerBioMatrix: Biolimus – Absorbable PolymerConor: Paclitaxel – Absorbable Polymer ??ZoMaxx: Zotarolimus – Durable Polymer

Drug Combo… and many more …

Lesion Dedicated DESDevax – BifurcationsXtent – Multi-lesion

Absorbable DES

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ML VISION®

Stent Delivery System

Everolimus

ML VISION®

Platform

Durable Polymer

XIENCE V® DES Everolimus Eluting Coronary Stent System

Everolimus – Durable PolymerXience V (SPIRIT Trials)

Siegburg / Stanford

XIENCE V Stent Thrombosis

1.30.5Late stent thrombosis (%)(>30days)

0.00.0Early stent thrombosis (%)(<30days)

TAXUS®

77 patientsXIENCE™ V223 patientsSPIRIT II

0.00.15Late stent thrombosis (%)(>30days)

0.00.3Early stent thrombosis (%)(<30days)

TAXUS®

322 patientsXIENCE™ V658 patientsSPIRIT III

Siegburg / Stanford

S-Stent™ (stainless steel)

Biolimus A9™(rapamycinderivative)

BioMatrixStent

BioMatrixStent

Biolimus – Absorbable PolymerBioMatrix Stent (STEALTH Trial)

PLA PolymerAsymmetrical bioresorbablecoating

Siegburg / Stanford

0.160.15

0.28

0.07 0.07

0.14

0.24

0.04

0.23

0.13

0.34

0.0

0.1

0.2

0.3

0.4

Late

Los

s (m

m)

6 mos.9 mos. 8 mos. 6 mos. 8 mos.8 mos. 8 mos. 8 mos.

TAXUS™ Stent

CYPHER™ Stent

ENDEAVOR™ Stent

XIENCE™ V Stent(PROMUS™ Stent)

In-Segment Late Loss Across Multiple Randomized Clinical Trials

ENDEAVOR III

REALITY

TAXUS IV

REALITY

SPIRIT

II

SPIRIT

I

SIRIU

S

SPIRIT

II

Data from trials that are not head-to-head are not intended to be comparative. SPIRIT is sponsored by Abbott. PROMUS Stent is a private-labeled XIENCE V Everolimus Eluting Coronary Stent System manufactured by Abbott and distributed by Boston Scientific Corporation. XIENCE is a trademark of Abbott Laboratories group of companies. PROMUS, TAXUS and Express2 are trademarks of Boston Scientific Corporation or its affiliates. Cypher is a trademark of Cordis Corp. Endeavor is a trademark of Medtronic Vascular, Inc. For products, sponsors, and publications, refer to the Clinical Trial Glossary.

6 mos.ENDEAVOR II

I

PSST 4128

8 mos.

SPIRIT

III

SPIRIT

III

8 mos.

0.09

STEALT

H

BioMATRIX ™

Stent

Siegburg / Stanford

STEALTH I Cumulative Hierarchical MACE

0.0%0.0%0.0%0.0%Stent thrombosis

0.0%0.0%0.0%0.0%TLR-CABG

1.3%0.0%1.3%0.0%TLR-PTCA

24 Months6 MonthsRESULTS

2.5%

0.0%

2.5%

5.0%

S-Stent

1.3%1.3%2.5%Non-Q Wave MI

5.1%3.8%2.5%MACE

1.3%0.0%0.0%Death*

1.3%1.3%0.0%Q Wave MI

BioMatrixBioMatrixS-Stent

*Death events were noncardiac: 1 diabetic foot syndrome (S-Stent) and 1 acute leukemia (BioMatrix)

Siegburg / Stanford

10 µg Paclitaxel With Controlled Mural Release

Conor/JnJ(CoStar)

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Discrete MicroDrop Structures (Labcoat)

Siegburg / Stanford

BioMatrix Freedom StentBiolimus A9 ® Drug

• Abluminal drug coating targets blood vessel walls• Small amounts are released into circulation

Bloodstream

Pure Biolimus A9 impregnated in metal stent surface

Siegburg / Stanford

28-DAY Porcine Histology Results

BARE Control BA9/PLA POLYMER BA9 MicroStruct.

Drug 225µg/Poly 225µg 225µg drug

Siegburg / Stanford

BioMatrix Freedom StentBiolimus A9 ® Drug

First-in-man: Baseline, Oct 2006

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BioMatrix Freedom StentBiolimus A9 ® DrugFirst-in-man: 6 Months Follow-up, March 2007

Siegburg / Stanford

The STENT Thrombosis Study

10,000 consecutive pts receiving DES at up to 12 sites

10,000 consecutive pts receiving DES 10,000 consecutive pts receiving DES at up to 12 sitesat up to 12 sites

Aspirin and Clopidogrel responsiveness evaluatedAspirin and Clopidogrel responsiveness evaluated(Accumetrics VerifyNow system)(Accumetrics VerifyNow system)

Clinical FU for 2-5 yearsClinical FU for 2Clinical FU for 2 --5 years5 years

Angiographic core lab assessment of all Angiographic core lab assessment of all stent thromboses and 1:3 matching controlsstent thromboses and 1:3 matching controls

PIs: Gregg W. Stone and Chuck SimontonPIs: Gregg W. Stone and Chuck SimontonSponsors: CRF and the Dickinson Inst.Sponsors: CRF and the Dickinson Inst.Principal study group: STENT Registry investigatorsPrincipal study group: STENT Registry investigators

Funded by grants from Boston Scientific Funded by grants from Boston Scientific (lead supporter), Accumetrics, Abbott (lead supporter), Accumetrics, Abbott

Vascular, Cordis, and MedtronicVascular, Cordis, and Medtronic

Siegburg / Stanford

The PROTECT Randomized Trial

Global randomized trial 8,000 patients

Endeavor vs. Cypher stent

Primary endpoint = stent thrombosisPI: W. Wijns

Sponsor: Medtronic Corp.

Siegburg / Stanford

ThankThank youyou