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