Martin B. Leon, MD Martin B. Leon, MD

Columbia University Medical CenterColumbia University Medical CenterCardiovascular Research FoundationCardiovascular Research Foundation

New York CityNew York City

SOLACI 2009SOLACI 2009June 10-12, Rio de Janeiro, BrazilJune 10-12, Rio de Janeiro, Brazil

Sustained Polymer Technology Sustained Polymer Technology Should Remain the Gold StandardShould Remain the Gold Standard

Presenter Disclosure Information for Presenter Disclosure Information for SOLACI 2009SOLACI 2009

Martin B. Leon, M.D.Martin B. Leon, M.D. Scientific Advisory Board or Consultant:Scientific Advisory Board or Consultant: Abbott, Boston Scientific, Cordis, Abbott, Boston Scientific, Cordis, and Medtronic and Medtronic

Scientific Advisory Board or Consultant:Scientific Advisory Board or Consultant: Abbott, Boston Scientific, Cordis, Abbott, Boston Scientific, Cordis, and Medtronic and Medtronic

The Holy Grail?The Holy Grail?The Holy Grail?The Holy Grail?

Optimal DESOptimal DES

• no restenosis!no restenosis!• no inflammation & normal healingno inflammation & normal healing• no clinical safety issues!!!no clinical safety issues!!!

Drug-eluting Stents 2003 - 2007Drug-eluting Stents 2003 - 2007T

AX

UT

AX

USS

Polyolefin derivative Polyolefin derivative PaclitaxelPaclitaxel ExpressExpress22

DrugDrug PolymerPolymer StentStent

Cyp

he

Cyp

he

rr

PEVA + PBMA blendPEVA + PBMA blendSirolimusSirolimus BX VelocityBX Velocity

The Sirolimus-Eluting StentThe Sirolimus-Eluting Stent

Bx VELOCITYBx VELOCITYTMTMStentStent

• Balloon expandable stainless steel stentBalloon expandable stainless steel stent

• Blend of components: Blend of components: 2 polymers (PEVA + PBMA) and sirolimus in a fixed ratio2 polymers (PEVA + PBMA) and sirolimus in a fixed ratio

• Thin uniform coating Thin uniform coating (~ 10um thick) (~ 10um thick)

In Vivo Release KineticsIn Vivo Release Kinetics

0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20

Time (days)

Fra

ctio

nal

Rel

ease

25 30

Sirolimus is released in a controlled manner from a Sirolimus is released in a controlled manner from a polymer matrix (PEVA + PBMA) bound to the stent; polymer matrix (PEVA + PBMA) bound to the stent;

ALL of the drug is released within 3 monthsALL of the drug is released within 3 months

Sirolimus is released in a controlled manner from a Sirolimus is released in a controlled manner from a polymer matrix (PEVA + PBMA) bound to the stent; polymer matrix (PEVA + PBMA) bound to the stent;

ALL of the drug is released within 3 monthsALL of the drug is released within 3 months

Topcoat Topcoat

StentStent

BasecoatBasecoat

Basecoat = polymer/sirolimus Basecoat = polymer/sirolimus ++

Topcoat = polymer only Topcoat = polymer only (diffusion barrier) (diffusion barrier)

Controlled Sirolimus Elution Controlled Sirolimus Elution from Cypherfrom CypherTMTM

50%

85%

The First Generation TAXUS StentThe First Generation TAXUS Stent

• Binds tubulinBinds tubulin

• Stabilizes microtubular Stabilizes microtubular deconstructiondeconstruction

• Multi-cellularMulti-cellular

• Multi-functionalMulti-functional

• Cytostatic at low doseCytostatic at low dose

DrugDrug PolymerPolymer StentStent

• Polyolefin derivativePolyolefin derivative• UniformUniform• BiocompatibleBiocompatible• ElastomericElastomeric• Provides controlled Provides controlled

releaserelease

• Tandem Tandem architecturearchitecture

• Maverick balloon Maverick balloon systemsystem

• FlexibleFlexible• DeliverableDeliverable

PaclitaxelPaclitaxel TransluteTransluteTMTM ExpressExpress22

Mean ± SDMean ± SD

0

10

20

30

40

50

60

70

80

0 20 40 60 80 100 120 140 160 180 200

Time (days)Time (days)

% P

Tx

rele

ased

% P

Tx

rele

ased

In vivoIn vivo PTx Release From Explanted Stents PTx Release From Explanted Stents

fast releasefast release

moderate releasemoderate release

slow releaseslow release

1 ug/mm1 ug/mm22

• Long history of bio-medical applications…Long history of bio-medical applications… generally biocompatiblegenerally biocompatible

• Favorable mechanical properties… Favorable mechanical properties… usually usually integrates well with stent and balloon delivery integrates well with stent and balloon delivery systemssystems

• Precise elution kineticsPrecise elution kineticsoptimal anti-restenosis efficacyoptimal anti-restenosis efficacycontrols drug toxicity controls drug toxicity

Sustained Polymer DESSustained Polymer DES

AdvantagesAdvantagesAdvantagesAdvantages

SIRIUSSIRIUS – TLR Events @ 5 Years – TLR Events @ 5 Years

Sirolimus betterSirolimus better

OverallOverall 9.49.4 24.324.3 6.76.7

MaleMale 10.110.1 24.924.9 6.76.7

FemaleFemale 7.57.5 22.822.8 6.56.5

DiabetesDiabetes 13.713.7 33.133.1 5.25.2

No DiabetesNo Diabetes 8.08.0 20.820.8 7.87.8

LADLAD 11.511.5 28.428.4 6.06.0

Non-LADNon-LAD 7.77.7 21.421.4 7.37.3

Small Vessel (<2.75)Small Vessel (<2.75) 13.313.3 26.026.0 7.97.9

Large VesselLarge Vessel 5.65.6 22.622.6 5.95.9

Short LesionShort Lesion 9.39.3 21.821.8 8.08.0

Long Lesion (>13.5)Long Lesion (>13.5) 9.79.7 26.826.8 5.95.9

OverlapOverlap 11.011.0 30.130.1 5.25.2

No OverlapNo Overlap 8.68.6 21.621.6 7.77.7

Odds Ratio 95% CIOdds Ratio 95% CI

# pts needed # pts needed to preventto prevent

1 restenosis1 restenosisSirolimusSirolimus ControlControl P-valueP-value

0.00.0 0.10.1 0.20.2 0.30.3 0.40.4 0.50.5 0.60.6 0.70.7 0.80.8 0.90.9 1.01.0 1.11.1 1.21.2 1.31.3

<0.001<0.001

<0.001<0.001

<0.001<0.001

<0.001<0.001

<0.001<0.001

<0.001<0.001

<0.001<0.001

<0.001<0.001

<0.001<0.001

<0.001<0.001

<0.001<0.001

<0.001<0.001

<0.001<0.001

HR [95% CI]HR [95% CI]

1.01.0 1.51.50.50.500

TLR up to 5 Years: Subgroup SummaryTLR up to 5 Years: Subgroup Summary TAXUS I, II-SR, IV & V Meta-analysis TAXUS I, II-SR, IV & V Meta-analysis

All All (n=2797)(n=2797)

RVD ≤2.5 RVD ≤2.5 (n=635)(n=635)

RVD 2.5-≤3.0 RVD 2.5-≤3.0 (n=1071)(n=1071)

RVD >3.0 RVD >3.0 (n=1030)(n=1030)

LL <18 LL <18 (n=1758)(n=1758)

LL 18-26 LL 18-26 (n=621)(n=621)

LL >26 LL >26 (n=357)(n=357)

Non-DM Non-DM (n=2082)(n=2082)

DM-Oral DM-Oral (n=494)(n=494)

DM-Insulin DM-Insulin (n=221)(n=221)

Sing. Stent Sing. Stent (n=2293)(n=2293)

Mult. Stents Mult. Stents (n=469)(n=469)

Male Male (n=2003)(n=2003)

Female Female (n=794)(n=794)

HRHR TAXUSTAXUS ControlControl P ValueP Value 0.510.51 12.1%12.1% 21.0%21.0% <0.001<0.001

0.540.54 19.5%19.5% 30.0%30.0% <0.001<0.001

0.490.49 12.5%12.5% 23.1%23.1% <0.001<0.001

0.520.52 8.3%8.3% 14.1%14.1% 0.0010.001

0.540.54 10.7%10.7% 18.3%18.3% <0.001<0.001

0.580.58 16.7%16.7% 24.5%24.5% 0.0040.004

0.380.38 14.2%14.2% 31.3%31.3% <0.001<0.001

0.520.52 11.3%11.3% 19.5%19.5% <0.001<0.001

0.490.49 14.6%14.6% 26.5%26.5% <0.001<0.001

0.510.51 16.0%16.0% 24.3%24.3% 0.0450.045

0.530.53 10.9%10.9% 18.5%18.5% <0.001<0.001

0.390.39 18.2%18.2% 35.7%35.7% <0.001<0.001

0.510.51 11.7%11.7% 20.4%20.4% <0.001<0.001

0.520.52 13.1%13.1% 22.6%22.6% <0.001<0.001

Network meta-analysis:Network meta-analysis: 38 trials, 18,023 pts 38 trials, 18,023 pts

Stettler C et al. Lancet 2007;370:937- 48Stettler C et al. Lancet 2007;370:937- 48

TLR FrequencyTLR Frequency

First GenerationFirst Generation

Stent design and delivery systemStent design and delivery system

Pharmacologic Pharmacologic agentagent

Drug carrier Drug carrier vehiclevehicle

Drug-Drug-Eluting Eluting StentStent

Drug-Drug-Eluting Eluting StentStent

Drug-Eluting StentsDrug-Eluting Stents

““Off the shelf” outdated Off the shelf” outdated stent and delivery systemstent and delivery system““Off the shelf” outdated Off the shelf” outdated

stent and delivery systemstent and delivery system

Available, FDA-approved Available, FDA-approved biostable polymersbiostable polymers

Available, FDA-approved Available, FDA-approved biostable polymersbiostable polymers

Known FDA-approved Known FDA-approved drugs with approximated drugs with approximated

release kineticsrelease kinetics

Known FDA-approved Known FDA-approved drugs with approximated drugs with approximated

release kineticsrelease kinetics

LaSTLaST – Late DES Stent Thrombosis – Late DES Stent Thrombosis After 3 YearsAfter 3 Years

After 2 DESAfter 2 DES

Late Stent ThrombosisLate Stent Thrombosisat 3.5 yrsat 3.5 yrsBaselineBaseline

Hype and Hysteria: Hype and Hysteria: “If it Bleeds it Leads”“If it Bleeds it Leads”

Stent Safety Concerns Stent Safety Concerns Near Boiling PointNear Boiling Point09.08.0609.08.06

Cardiologists Question the Risks Cardiologists Question the Risks

in Using Drug-Coated Stentsin Using Drug-Coated StentsSeptember 5, 2006September 5, 2006

Boston Scientific Boston Scientific Acknowledges Risks Acknowledges Risks Tied to StentTied to StentSeptember 7, 2006September 7, 2006

Studies linking drug-eluting stents to Studies linking drug-eluting stents to increased mortality/MI spark impassioned increased mortality/MI spark impassioned pleas for reason and calls for calm pleas for reason and calls for calm September 3, 2006 September 3, 2006

Time since PCI in yearsTime since PCI in years

Cu

mu

lati

ve I

nci

den

ce,

%C

um

ula

tive

In

cid

ence

, %

55

44

33

22

11

0000 11 22 33 44

Cumulative Incidence of ARC Def/Prob STCumulative Incidence of ARC Def/Prob STover 4 yrs after DES (CYPHER & TAXUS)over 4 yrs after DES (CYPHER & TAXUS)

2.1% (17)2.1% (17)— CYPHER Stent (n=878)— CYPHER Stent (n=878)

2.1% (26)2.1% (26)—TAXUS Stent (n=1401)—TAXUS Stent (n=1401)

Cypher & TaxusCypher & Taxus Pooled AnalysesPooled Analyses11

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

5.7% [95% CI]5.7% [95% CI]CYPHER & TAXUSCYPHER & TAXUS(n=8,146)(n=8,146)

Bern-RotterdamBern-Rotterdam22

22 Wenaweser et al; J Am Coll Cardiol 2008;52:1134-40 Wenaweser et al; J Am Coll Cardiol 2008;52:1134-40

1st Generation DES….the good, the bad, and the ugly!

1st Generation DES….the good, the bad, and the ugly!

48 months48 months

40 mos40 mos

BMS DES

IncompleteIncompleteappositionapposition

Late stentthrombosis

-20

-15

-10

-5

0

5

10

15

20

25

Prox. Ref. Prox. Stent Distal Distal Ref.

Abn VasomotionAbn Vasomotion

*P<0.001*P<0.001 vs. control vs. control

Sirolimus Sirolimus Control Control

** **

Delayed Healing!Delayed Healing!

AngioscopyAngioscopy

BMS

DESLate loss = 0

Eos

Giant cells

IVUSIVUS

InflammationInflammation

Procedure Procedure Procedure Procedure

ClinicalEvents

Post DilationPost DilationFull AppositionFull AppositionPost DilationPost Dilation

Full AppositionFull Apposition

PatientPatientPatientPatient

Higher RiskHigher RiskAP ComplianceAP Compliance

Higher RiskHigher RiskAP ComplianceAP Compliance

ProductProductProductProduct

PolymerPolymerDrugDrug

PolymerPolymerDrugDrug

Vascular Impact of DES: Vascular Impact of DES: Procedure, Product, PatientProcedure, Product, Patient

Polymer is permanent and may have an increase impact long term when drug is exhausted

Stent has shown minimal long term impact in BMS

Drug is exhausted by 6 months to 1 year

DES: Stent, Drug, PolymerDES: Stent, Drug, PolymerWhat can Impact the Vessel Long Term?What can Impact the Vessel Long Term?

0 6 months 1 year 2 years 3 years 4 years 5 years

Po

ten

tial

Ves

sel I

mp

act

Time

• Some durable polymers can cause Some durable polymers can cause inflammation (acute and chronic) and can inflammation (acute and chronic) and can induce hypersensitivity reactions…induce hypersensitivity reactions… delayed delayed healing, abnormal vasoreactivity causes healing, abnormal vasoreactivity causes very late stent thrombosis very late stent thrombosis

• Erratic mechanical properties… Erratic mechanical properties… flaking, flaking, peeling, webs/bonds, and inhomogeneous peeling, webs/bonds, and inhomogeneous drug distribution (reduced effectiveness + drug distribution (reduced effectiveness + reduced safety) reduced safety)

Sustained Polymer DESSustained Polymer DES

DisadvantagesDisadvantagesDisadvantagesDisadvantages

Polymer-related problems which canPolymer-related problems which canhave clinical consequences…have clinical consequences…

Non uniform Non uniform polymer coatingpolymer coating ““Webbing and Webbing and

Bonding” of the Bonding” of the polymer surfacepolymer surface

Polymer delaminationPolymer delamination

1st Generation DES Polymers1st Generation DES Polymers

Conclusions—Compared with bare metal stents, drug-eluting stents further delay arterial healing and promote inflammation

Circulation. 2005;112:270-278

BMS TaxusCypherBMS

Overlap Overlap

Conclusions:

• BMS showed far greater endothelialization than DES

• Lack of coverage highlighted in areas of overlap

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

Delayed EndothelializationDelayed Endothelialization Rabbit Model of Coverage at 28 daysRabbit Model of Coverage at 28 days

Conclusions:Conclusions:

• DES (solid line) consistently show less endothelialization DES (solid line) consistently show less endothelialization compared with BMS (dashed line) regardless of time point. compared with BMS (dashed line) regardless of time point.

• DES are not fully endothelialized even beyond 40 months DES are not fully endothelialized even beyond 40 months whereas BMS are completely covered by 6 to 7 monthswhereas BMS are completely covered by 6 to 7 months

Per

cen

tag

e E

nd

oth

elia

liza

tio

n

Duration in months1 2 3 4 5 6 7 8 9 11 15 16 17 20 >40

Taxus and CypherBMS

0

10

20

30

40

50

60

70

80

90

100

Joner, Virmani et al. Circulation. 2005;112:3210.

Percent Struts EndothelializedPercent Struts Endothelialized Human Analysis: DES vs BMS out to 3 yearsHuman Analysis: DES vs BMS out to 3 years

Hypothesis: Polymer InflammationHypothesis: Polymer InflammationPotential Impact on Long term Safety and EfficacyPotential Impact on Long term Safety and Efficacy

Polymer Inflammation

Dysfunctional Endothelium

VASO-CONSTRICTION

PRO- THROMBOGENI

C

DELAYED HEALING

INCREASED

INFLAMATION

EfficacyEfficacyTLRTLR

??

SafetySafetyVLSTVLST

??

Drug-eluting Stents 2008Drug-eluting Stents 2008E

nd

eavo

En

dea

vorr

PhosphorylcholinePhosphorylcholineZotarolimusZotarolimus DriverDriver

DrugDrug PolymerPolymer

Xie

nce

X

ien

ce

V*

V*

VDF + HFP copolymerVDF + HFP copolymerEverolimusEverolimus VisionVision

*AKA Promus

OOOO

OOOO

OOOO OOOO HOHOHOHO

OOOO

OOOO

OOOOOOOOHHHHOOOO

OOOOOOOO

NNNNOOOO

HHHHOOOO

StentStent

• The PC Technology hydrophilic polymer mimics The PC Technology hydrophilic polymer mimics the outside surface of a red blood cell the outside surface of a red blood cell

Hayward JA et al., Biomaterials, 1984;5:135–142

Inner membrane

Outer membrane

The PC The PC HeadgroupHeadgroup

• Highly biocompatible - originally Highly biocompatible - originally designed for ocular implantsdesigned for ocular implants

More than 16 years of clinical More than 16 years of clinical

experienceexperience

OP OO

ON

The PC The PC HeadgroupHeadgroup

Endeavor Polymer TechnologyEndeavor Polymer Technology

ENDEAVOR Technology ConsiderationsENDEAVOR Technology ConsiderationsDesign FeaturesDesign Features

HistopathologyHistopathology

Rapid drug elutionRapid drug elution

Stent design = reduced injury Stent design = reduced injury (rounded thin struts)(rounded thin struts)

0

25

50

75

100

0 5 10 15 20 25

% D

rug

Elu

ted

Time (Days)

65

8798 99

PC Basecoat PC Basecoat (≈ 1μm)(≈ 1μm)

Drug LayerDrug Layer90% Zotarolimus90% Zotarolimus10% PC10% PC (≈ 2-4μm) (≈ 2-4μm)

Stent Strut

Biocompatible PCBiocompatible PC

SafeSafeformulationformulation

OCTAngioscopy

EndothelialFunctionProximal Distal

ENDEAVOR Technology ConsiderationsENDEAVOR Technology ConsiderationsHuman ResultsHuman Results

IVUSIVUS

ZES (n=14) vs. SES (n=16) @ 8 mos FU

ZES improved neointimal coverage (P=0.0004) and fewer thrombi

Awata et al; J Am Coll Cardiol 2008;52;789-90

44 overlapped ZES in 17 pts@ 6 mos FU (24,076 struts analyzed)

ZES no malapposed or uncovered struts; no intraluminal thrombus

Guagliumi et al; ESC 2008

541 ZES pts @ 8 mos FU0.4% late incomplete apposition; no positive remodeling; homogeneous

neointimal distributionFitzgerald et al; Stanford IVUS core lab

ZES (n=20) vs. SES (n=20) vs. BMS (n=10); Ach infusions

@ 6 mos; ZES improved endothelial function cw SES (P<0.001) and similar to BMS

Kim et al; ACC 2008

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

0 360 720 1080 1440

AR

C (

Def

/Pro

b

Days

Endeavor 2068 2036 1650 1087

No. at Risk

Cypher 863 848 824 789

Taxus 1351 1300 1117 715

1 Year 2 Years 3 YearsPooled Data 4 Years

1. Mauri et al. TCT 2008. 2. Mauri L et al. N Engl J Med. 2007;356:1020-1029.3. Serruys PW et al. ACC 20083. Stone GW et al. PCR 2008.

DES In Perspective: VLSTDES In Perspective: VLSTARC Def/Prob ST Landmark AnalysisARC Def/Prob ST Landmark Analysis

Xience V /Promus 892 865 NA NAThere are very significant differences in There are very significant differences in stent thrombosis rates among 1stent thrombosis rates among 1stst

generation DES cw Endeavor beyond the generation DES cw Endeavor beyond the first year after stent implantationfirst year after stent implantation

Coating Integrity – XIENCE™ V Coating Integrity – XIENCE™ V Fluoropolymer (7.8 um thick)Fluoropolymer (7.8 um thick)

Dilated to 3.5 mmDilated to 3.5 mm

• Uniform, consistent coating integrity upon deploymentUniform, consistent coating integrity upon deployment

• Good adhesion to stent – no bonding, webbing, tearingGood adhesion to stent – no bonding, webbing, tearing

• Non-tacky drug matrix prevents “unwanted” adhesionsNon-tacky drug matrix prevents “unwanted” adhesions

Photos taken by and on file at Abbott VascularPhotos taken by and on file at Abbott Vascular

14 Day Endothelialization: 14 Day Endothelialization: Rabbit Iliac ModelRabbit Iliac Model

XIENCE™ VXIENCE™ V CYPHERCYPHER®® TAXUSTAXUS®® ENDEAVOR™ENDEAVOR™

Joner and Virmani, JACC 2008Joner and Virmani, JACC 2008

SPIRIT II + III Pooled Meta-analysisSPIRIT II + III Pooled Meta-analysis

Late LossLate Loss

mm

Diff [95%CI]-0.11 [-0.18,-0.05]

P=0.0004

Diff [95%CI]-0.19 [-0.25,-0.12]

P<0.0001

±0.48

±0.44

±0.36±0.37

SPIRIT II + III Pooled Meta-analysisSPIRIT II + III Pooled Meta-analysis

Binary RestenosisBinary Restenosis

1.9

4.14.9

7.8

0

2

4

6

8

10

In-stent In-segment

XIENCE V (n=581) TAXUS (n=244)%RR [95%CI]

0.53 [0.30,0.95] P=0.039

RR [95%CI]0.39 [0.17,0.86]

P=0.02

SPIRIT II + III: SPIRIT II + III: Ischemic TLRIschemic TLR1-year HR

0.53 [0.30, 0.92]p=0.02

5.8%

3.0%

Δ2.8%

2-year HR0.59 [0.36, 0.96]

p=0.03

6.8%

4.1%

Δ2.7%

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24

Isch

emic

TL

R (

%)

Months

PROMUSTAXUS

Number at riskNumber at risk

XIENCE VXIENCE V 892892 880880 869869 852852 840840 819819 816816 808808 801801

TAXUSTAXUS 409409 397397 392392 375375 366366 354354 349349 348348 346346

SPIRIT II + III: SPIRIT II + III: All Death or MIAll Death or MI2-year HR

0.61 [0.39, 0.95]p=0.03

8.3%

5.1%

Δ3.2%

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24

All

Dea

th o

r M

I (%

)

Months

XIENCE VTAXUS

Number at riskNumber at risk

XIENCE VXIENCE V 892892 876876 871871 859859 848848 826826 824824 814814 810810

TAXUSTAXUS 409409 390390 388388 381381 375375 361361 357357 355355 352352

1-year HR0.62 [0.35, 1.09]

p=0.09

4.4%

3.1%

Δ1.3%

Drug• Zotarolimus – cytostatic limus analog

• Powerful antiproliferative with broad therapeutic window

• Lipophilic limus drug that aims to minimize proliferation of restenotic cells while preserving healthy endothelial cells

Stent• Medtronic Driver BMS platform

• Cobalt Alloy stent with highly conformable design

Stent Delivery System • Advanced, highly trackable delivery system incorporating Sprinter

balloon technology

Increased deliverability for tortuous

anatomy

Polymer• Proprietary polymer to provide extended elution kinetics

• Hydrophobic characteristics for uniform drug release

• Hydrophilic characteristics to provide biocompatibility equivalent to Endeavor

Extended elution designed to

provide physicians with more options to treat patients

Endeavor RESOLUTE DESEndeavor RESOLUTE DES

Cell Membrane

Hydrophobic and hydrophilic groups

The BioLinx PolymerThe BioLinx PolymerBioLinx Polymer

Hydrophilic

HydrophobicZotarolimus

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

BioLinx Polymer in vivo Elution

Greater than 85% of the drug is eluted at 60 daysComplete drug content exhausted by 180 days

100

80

60

40

20

0

% Z

ota

roli

mu

s L

oad

ing

0 50 100 150 200Days

<2% (LOQ)

% Eluted

% Remaining

Endeavor RESOLUTEEndeavor RESOLUTE

Carter et al TCT 2006Carter et al TCT 2006

Requirements of Polymer SafetyRequirements of Polymer Safety

Healed Vessel

Biocompatibility

HydrophilicNon-inflammatory

Non-thrombogenic

Less Pro-thrombotic genes expressed

Fewer platelets sticking

Excellent Safety Profile

Rapid, complete, andfunctioning endothelial cells

θ1

Hydrophilic

θ2

Hydrophobic

Hydrophobic Polymer

Hydrophilic Polymer

Contact Angle

Hydrophilic vs HydrophobicHydrophilic vs Hydrophobic

PC PC (Endeavor)(Endeavor)

BioLinx BioLinx (Endeavor Resolute)(Endeavor Resolute)

83º83º

9494oo

PBMA PBMA (Cypher)(Cypher) 115º115º

SIBS SIBS (Taxus)(Taxus) 118º118º

Fluoro Polymer Fluoro Polymer (Xience V)(Xience V) 129º129º

Water-loving Water-resistant

• Angle formed when water drop applied to polymer surface

• Smaller angle = more hydrophilic

Contact Angles determine if a polymer is Contact Angles determine if a polymer is hydrophilic or hydrophobichydrophilic or hydrophobic

θ1 < θ2

PBMA: Polybutyl methacrylate [Cypher cap coat]SIBS: Styrene-Isobutylene-Styrene Triblock Copolymer [Taxus]Fluoro Polymer: [Xience polymer]

Monocytic Adhesion to Polymers Monocytic Adhesion to Polymers Correlates With HydrophobicityCorrelates With Hydrophobicity

12912911811811511594948383

Less Biocompatible

More Biocompatible

Less Biocompatible

More Biocompatible

Contact Angle

Re

lati

ve

% A

dh

es

ion

200200

160160

120120

8080

4040

00Fluoro

PolymerS-IB-SPBMAPC BioLinxNegative

controlPositivecontrol

Up-Regulation of Prothrombotic Up-Regulation of Prothrombotic Genes by PBMA and SIBSGenes by PBMA and SIBS

compared with BioLinx compared with BioLinx

12

10

8

6

4

2

0BioLinx PBMA SIBS

PAI-1

Fo

ld I

nd

uc

tio

n o

ve

r C

ali

bra

tor

18

16

14

12

10

8

6

4

2

0BioLinx PBMA SIBS

Tissue Factor

Fo

ld I

nd

uc

tio

n o

ve

r C

ali

bra

tor

Biocompatibility of theBiocompatibility of theBioLinx PolymerBioLinx Polymer

Polymer

Inflammation score 0.10 ± 0.21Inflammation score 0.10 ± 0.21

Bare Driver

Inflammation score 0.11 ± 0.38Inflammation score 0.11 ± 0.38

Porcine Coronary Artery Implants at 28 DaysPorcine Coronary Artery Implants at 28 Days

Both BioLinx coated and bare metalBoth BioLinx coated and bare metalDriver stents had low inflammation scoresDriver stents had low inflammation scores

Consistently low inflammations scores with Endeavor and Endeavor Resolute across all time points

Endeavor RESOLUTE and Endeavor PCEndeavor RESOLUTE and Endeavor PCvs. other DESvs. other DES

Comparison of Inflammation Scores

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

28 days 90 days 180 days 365 days

Time after stenting

Infl

am

ma

tio

n S

co

re

Endeavor*

Endeavor Resolute*

Xience**

Cypher**

* Data on File Medtronic CardioVascular** Data from Abbott XIENCEV US Physician presentation SE2924433D

Endeavor not tested at 365 days

Endeavor RESOLUTEEndeavor RESOLUTEPorcine coronary arteryPorcine coronary artery

CONTROLENDEAVOR RESOLUTE

ENDEAVORRESOLUTE

Significant inhibition of neointimal development Significant inhibition of neointimal development compared to Driver controlscompared to Driver controls

Significant inhibition of neointimal development at both 28* and 90 days^*p=0.0006 ^p=0.05

Extended Efficacy in Porcine Coronary Arteries

0

10

20

30

40

50

60

Day 28 Day 90

Endeavor Resolute

Driver

% S

ten

osi

s

Endeavor RESOLUTEEndeavor RESOLUTE

Requirements of Polymer SafetyRequirements of Polymer Safety

Healed Vessel

Rapid, complete, andfunctioning endothelial cells

Biocompatibility

HydrophilicNon-inflammatory

Non-thrombogenic

Less Pro-thrombotic genes Fewer platelets sticking

Endeavor Resolute Endeavor Resolute

Full endothelialization achieved by 28 days with no aneurysms, incomplete apposition, medial necrosis, late thrombosis or filling defects

Complete Endothelialization Present After 28 Days

7 days 28 days 90 days 180 days 365 days0

25

50

75

100

125

ENDEAVOR RESOLUTE

Bare Driver

% E

nd

oth

eli

al

He

ali

ng

Endeavor RESOLUTE Endothelial Healing: Endeavor RESOLUTE Endothelial Healing: SEM AnalysisSEM Analysis

28 day Small Vessel Safety Study (FS144)

180 day Safety Study (FS129)

0.67 ±1.52 1.89 ± 1.95Inflammation Scores

2.06 ± 0.58 0.27 ± 0.26Relative eNOS Expression

Endeavor Resolute Xience

Lum

en D

iam

eter

(m

m)

Endothelial Function:Endothelial Function: ACH Challenge ACH Challenge

28 Days After Stenting in Porcine Coronary Arteries

RESOLUTE Clinical ProgramRESOLUTE Clinical Program

Program Focus is on initial & expanded indications and pooled safety analyses

RESOLUTE Single Arm First-in-Human (n=139) 2yrSingle Arm First-in-Human (n=139) 2yr

RESOLUTE Intl Non-RCT Observational (R=2,200)Non-RCT Observational (R=2,200)

RESOLUTE AC

RESOLUTE US 2.25 – 3.5 Clinical Non-RCT vs. Hx Control (R=1,241)2.25 – 3.5 Clinical Non-RCT vs. Hx Control (R=1,241)

1:1 RCT vs. Xience® (R=1,150,X=1,150) 30d1:1 RCT vs. Xience® (R=1,150,X=1,150) 30d

2.25 – 3.5 Angio / IVUS Non-RCT vs. Hx Control (R=100)2.25 – 3.5 Angio / IVUS Non-RCT vs. Hx Control (R=100)

4.0 Angio Non-RCT vs. Hx Control (R = 58) 4.0 Angio Non-RCT vs. Hx Control (R = 58)

2.5 – 3.5 Non-RCT (R = 100) vs. Hx. Control2.5 – 3.5 Non-RCT (R = 100) vs. Hx. ControlRESOLUTE Japan

38 mm – Long Lesion Non-RCT (R = TBD)38 mm – Long Lesion Non-RCT (R = TBD)

Enrollment Complete in Follow Up

Activating Sites / Enrolling

• Bioabsorbable polymers…Bioabsorbable polymers… sounds nice – polymer gone, only BMS leftsounds nice – polymer gone, only BMS left bioabsorption can cause inflammationbioabsorption can cause inflammation difficult to control elution kinetics preciselydifficult to control elution kinetics precisely each uniquely different (? class effect)each uniquely different (? class effect)

• Polymer-free delivery systems…Polymer-free delivery systems… sounds even nicer – NO polymer (=BMS)sounds even nicer – NO polymer (=BMS) rapid drug elution is the rule (reduced anti-rapid drug elution is the rule (reduced anti-

restenosis efficacy) restenosis efficacy)each uniquely different (? class effect)each uniquely different (? class effect)

Sustained Polymer DESSustained Polymer DES

AlternativesAlternativesAlternativesAlternatives

There are no meaningful long-term clinicalThere are no meaningful long-term clinicaloutcomes data indicating a safety advantageoutcomes data indicating a safety advantage

associated with either bioabsorbable or associated with either bioabsorbable or polymer-free DES systems!!!polymer-free DES systems!!!

Bioabsorbable Polymers - Preclinical InsightsBioabsorbable Polymers - Preclinical InsightsMarked Inflammatory Sequelae to Implantation of Biodegradable and Nonbiodegradable Polymers in Porcine Coronary Arteries Willem J. van der Giessen, MD, PhD; A. Michael Lincoff, MD; Robert S. Schwartz, MD; Heleen M.M. van Beusekom, PhD; Patrick W. Serruys, MD, PhD; David R. Holmes, Jr, MD; Stephen G. Ellis, MD; Eric J. Topol, MD

Circulation. 1996;94:1690-1697.)

(1) All polymer implants were associated with a significant inflammatory and proliferative response

(2) Observed with both biodegradable and nonbiodegradable polymer implants

(3) In some groups, implants were complicated by acute thrombotic vessel occlusion, although with no more frequency than that experienced with stainless steel coronary stents.

• Durable polymer DES systems have defined Durable polymer DES systems have defined the genre for a decade with > 10 million the genre for a decade with > 10 million implants and significant long-term FU!implants and significant long-term FU!

• The major purpose of a DES polymer carrier The major purpose of a DES polymer carrier is to precisely control extended drug release.is to precisely control extended drug release.This function is best accomplished by a This function is best accomplished by a durable polymer system!durable polymer system!

• 11stst generation DES polymers were flawed… generation DES polymers were flawed…Too much inflammationToo much inflammationInconsistent mechanical integrityInconsistent mechanical integrityStent thrombosis complicationsStent thrombosis complications

Sustained Polymer DESSustained Polymer DES

Final ThoughtsFinal ThoughtsFinal ThoughtsFinal Thoughts

• 22ndnd generation DES polymers (Endeavor and generation DES polymers (Endeavor and Xience ) are clearly improved…Xience ) are clearly improved…More biocompatible (similar to BMS)More biocompatible (similar to BMS)Improved mechanical integrityImproved mechanical integrityFewer complications (incl. stent thrombosis)Fewer complications (incl. stent thrombosis)

• In the future, In the future, dedicated dedicated DES durable polymer DES durable polymer systems will continue to evolve (e.g. Resolute) systems will continue to evolve (e.g. Resolute) to achieve optimal safety-efficacy balance!to achieve optimal safety-efficacy balance!

• Alternatives (bioresorbables and polymer-free) Alternatives (bioresorbables and polymer-free) require far more intensive and long-term data require far more intensive and long-term data analysis to claim superior clinical outcomes.analysis to claim superior clinical outcomes.

Sustained Polymer DESSustained Polymer DES

Final ThoughtsFinal ThoughtsFinal ThoughtsFinal Thoughts