Stanford
What Makes Endeavor Different?
Alan C. Yeung, MDAlan C. Yeung, MDLi Ka Li Ka ShingShing Professor of Medicine (Cardiology)Professor of Medicine (Cardiology)
Director, Interventional CardiologyDirector, Interventional CardiologyChief, Division of Cardiovascular MedicineChief, Division of Cardiovascular Medicine
Stanford University Medical CenterStanford University Medical Center
Conflict of Interest
Scientific Advisory Board to- Abbott Vascular - Boston Scientific Corp- Cordis- Medtronic
* pre-clinical studies on file at MDT comparing PC coated stents to uncoated stents
** Most lipophilic limus drug as compared to sirolimus and everolimus and paclitaxel
Endeavor is different by designEndeavor is different by designComponents Components
Design components of Endeavor allow for rapid, complete and functional healing
Mimics red blood cell chemistryLess platelets stick to polymer*
Biocompat ib l e Polymer The most lipophilic limus drug that is rapidly absorbed by the arterial tissue**
Lipophi l i c Drug Modular stent with thin, round struts to help preserve endothelium during stent delivery
Stent Design
90% of phospholipids in the outer 90% of phospholipids in the outer membrane of a red blood cell contain membrane of a red blood cell contain the PC (the PC (PhosphorylcholinePhosphorylcholine) ) headgroupheadgroup
Inner MembraneInner Membrane
Outer MembraneOuter Membrane
The Phosphorylcholine(PC) Headgroup
O
P OO
ON
O
P OO
ON
O
P OO
ON
PCPC11 mimics the chemical mimics the chemical structure of the structure of the phospholipidphospholipid headgroupheadgroup
Endeavor DES SystemEndeavor DES SystemPC TechnologyPC Technology
Stanford
PC AdvantagePC Advantage
•• Hydrophilic interface with bloodHydrophilic interface with blood•• ThromboresistanceThromboresistance•• Minimal inflammationMinimal inflammation•• Mechanically stable at deliveryMechanically stable at delivery•• Early endothelial coverageEarly endothelial coverage•• Functional endotheliumFunctional endothelium•• Thin polymerThin polymer•• Medtronic PC coating: polymer dissolution in 14 days Medtronic PC coating: polymer dissolution in 14 days
Biocompatible and nonBiocompatible and non-- inflammatoryinflammatory
In over 16 years of clinical experience In over 16 years of clinical experience and >150,000 stent implants, PC and >150,000 stent implants, PC technology has been proven:technology has been proven:–– SafeSafe–– DurableDurable–– BenignBenign
Endeavor has the most hydrophilic Endeavor has the most hydrophilic coating reducing protein adhesioncoating reducing protein adhesion
00.10.20.30.40.50.60.70.80.91.0
1.0 1.5Time Point (Hours)
Plat
elet
s A
dher
ed ×
109
Uncoated stentPC-coated stent
Endeavor PC TechnologyEndeavor PC TechnologyMimics the outside surface of the red blood cellMimics the outside surface of the red blood cell
Relative Relative HydrophilicityHydrophilicity of DES Polymersof DES PolymersContact Angle Measurements Evaluate Surface Contact Angle Measurements Evaluate Surface HydrophilicityHydrophilicity
PBMA: Polybutyl methacrylate [Cypher cap coat]SIBS: Styrene-Isobutylene-Styrene Triblock Copolymer [Taxus]
θ2
Lipophilic Amphiphilic/Hydrophilic
θ1
Polymer Contact AngleC10 118o
C19 91o
C10+C19 84o
BioLinx 94o
PC 83o
PBMA 115o
SIBS 118o
Data on File Medtronic Vascular
Endeavor PC TechnologyEndeavor PC TechnologyHydrophilic and Highly BiocompatibleHydrophilic and Highly Biocompatible
0
20
40
60
80
100
120
NegativeControl
PositiveControl
PC BioLinx C10/C19 C19 C10 PBMA S-IB-S
Rel
ativ
e %
Adh
esio
nMonocyte Adhes ion
PBMA: Polybutyl methacrylate [Cypher cap coat]SIBS: Styrene-Isobutylene-Styrene Triblock Copolymer [Taxus]
Data on File Medtronic Vascular
Endeavor BiocompatibilityEndeavor BiocompatibilityInflammation scores are consistently low up to 180 daysInflammation scores are consistently low up to 180 days
Data on File Medtronic Vascular
Endeavor DES SystemEndeavor DES SystemPC TechnologyPC Technology
020
406080
100120
140160180
Depth Force of Removal
0
2.5
1.5
3.54.0
3.0
2.0
1.0
0.5
Pre-ImplantPost-Implant
Forc
e of
Rem
oval
(x 1
07N
/m2 )
Mechanically StableMechanically Stable
Driver Endeavor
% of Struts Endothelialized
0
10
20
30
40
50
60
70
80
90
100
Mean % Endothel
DriverEndeavor
Virmani et. al, PCR 2006
Strut Coverage and EndothelizationStrut Coverage and EndothelizationEndeavor vs DriverEndeavor vs Driver
Cypher Taxus Endeavor
0
25
50
75
100
Mean % Endothel
CypherTaxusEndeavor
% of Struts Endothelialized
Strut Coverage and EndothelizationStrut Coverage and EndothelizationEndeavor vs Cypher vs TaxusEndeavor vs Cypher vs Taxus
Virmani et. al, PCR 2006
•Cypher, Taxus, Endeavor and Driver stents were implanted in porcine coronary arteries
•Harvest tissues 28 and 90 days after stenting–28 days evaluate polymer with drug present–90 days evaluate polymer after drug depleted
•Evaluate endothelial function–Acetylcholine challenge just prior to euthanasia
•Evaluate inflammation and polymer biocompatibility–Real Time RT-PCR to evaluate local gene expression –Histological with immunohistochemistry for cytokines, NOS, etc.
Study design
eNOS
00.40.81.21.6
Endeavor Cypher Taxus
Stented Vessel
eNOS
00.20.40.60.8
Endeavor Cypher Taxus
Proximal Vessel
eNOS is the protein that produces NO and is marker of endothelial cell functionBoth proximal and stent vessels have significantly more eNOS present than either Taxus or Cypher
NO and Endothelial Cell FunctionNO and Endothelial Cell FunctionEndothelial Nitric Oxide Synthase (eNOS)Endothelial Nitric Oxide Synthase (eNOS)
Haraguchi et al, TCT 2006
GTP Cyclohydrolase (GTPCH) is important for eNOS activity
• GTPCH increases tetrahydrobiopterin (BH4) production• Absence of BH4 may lead to eNOS uncoupling and generation of
reactive oxygen species
Franscini N et al. Circulation 2004; 110: 186-192.Foerstermann U and Muenzel T. Circulation 2006; 113: 1708-1714
Expression of GTPCH mRNA
28 day 90day
0
0.5
1
1.5
2
2.5
3
Endeavor Cypher Taxus Driver
* *
0
0.5
1
1.5
2
2.5
3
3.5
4
Endeavor Cypher Taxus Driver
*
*P<0.05 vs. Endeavor
The expression of GTPCH mRNA was significantly higher in regionsproximal to Endeavor stents compared to Cypher and Taxus suggesting
functional eNOS and NO generation
Localization of eNOS by Immunohistochemistry
EndeavorEndeavor Taxus
Cypher
eNOS protein was localized on the luminal surface of vessels proximal to Endeavor and Driver stents
Driver
EC Function Was Assessed by ACH Challenge 28 Days After Stenting
Baseline Ach (10-6M)
Driver (n=15)
Baseline Ach (10-6M)
Endeavor (n=7)
Cypher (n=9)
Baseline Ach (10-6M)
Taxus (n=8)
Baseline Ach (10-6M)
1.50
2.00
2.50
3.00
3.50
4.00
4.50
1 2
1.50
2.00
2.50
3.00
3.50
4.00
4.50
1 2
1.50
2.00
2.50
3.00
3.50
4.00
4.50
1 21.50
2.00
2.50
3.00
3.50
4.00
4.50
1 2
Cypher and Taxus constrict in response to acetylcholine (ACH) suggesting EC dysfunctionEndeavor and Driver show normal vasodilation in response to ACH suggesting normal EC function
ACH Responses Compared to Baseline
-20
-10
0
10
20
30
40
Driver Endeavor Cypher Taxus
*P<0.05 vs. Endeavor
Endeavor: Rapid recovery of EC functionACH Challenge 28 Days After Stenting
% A
ch /
Bas
elin
e
Haraguchi et al, TCT 2006
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14Days
0%
20%
40%
60%
80%
100%
Perc
ent D
rug
Elut
ed
* pre-clinical studies on file at MDT
90/10 Zotarolimus/PC3-4 microns
Cross-linkedPC Basecoat1-2 microns
Stent strut crossStent strut cross--sectionsection
Arterial WallArterial Wall
LumenLumen
Endeavor Endeavor ZotarolimusZotarolimus--PC InteractionPC InteractionDrug Eluted by 14 days;Drug Eluted by 14 days;
Only PC Basecoat Left BehindOnly PC Basecoat Left Behind
Comparison of Polymer ThicknessDrug Eluted by 14 days only PC Basecoat Left Behind
PBMA
33% Sirolimus33% PBMA33% PEVA
Parylene
SIBS
PC Basecoat
90% Zotarolimus10% PC
0
2
4
6
8
10
12
14
16
18
Cypher Taxus Endeavor
micr
ons
Top Coat
Drug Layer
Base Coat
At 15 days there is only a .5 micron thick layer of PC basecoat on Endeavor
Stanford
PC DisadvantagePC Disadvantage
•• Medtronic PC coating: polymer dissolution in 14 Medtronic PC coating: polymer dissolution in 14 days days
•• Elution characteristics set by dissolutionElution characteristics set by dissolution•• Polymer to drug formulation is difficult to modifyPolymer to drug formulation is difficult to modify
Endeavor™
Comparison of Comparison of in vivo in vivo Elution RatesElution RatesRabbit iliac modelsRabbit iliac models
Cypher data from B. Chevalier, EuroPCR 2004Cypher data from B. Chevalier, EuroPCR 2004Endeavor data from G. Endeavor data from G. LaarmanLaarman, EuroPCR 2004, EuroPCR 2004
~75% elution in 2 days100% elution in 10 days
~75% elution in 10 days100% elution in 30 days
0
20
40
60
80
100
120
0 10 20 30Time (days)
% D
rug
elut
ed
Cypher™
0
20
40
60
80
100
120
0 10 20 30
Time (days)
% D
rug
elut
ed
Concentration of Zotarolimus in Tissue Surrounding the Stent (ng/mg)
0
10
20
30
40
0 5 10 15 20 25 30Time (days)
[AB
T 57
8] (n
g/m
g)
Zotarolimus is retained in the tissue for up to 28 days at effective concentrations to control human arterial SMC proliferation.
Zotarolimus Tissue ConcentrationZotarolimus Tissue ConcentrationPig Coronary ArteriesPig Coronary Arteries
Data on File Medtronic Vascular
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0.0440
0.0472
0.042
0.043
0.044
0.045
0.046
0.047
0.048
Endeavor Xience V
Prof
ile (i
n)
How does the crossing profile of Xience V/ Promus compare with Endeavor?
Ref:Test data on file at Medtronic, Inc. 3.5 x 18mm stents
• Lower crossing profile for better access to challenging lesions.
• Xience claims thinner struts, but still has a higher crossing profile.
Endeavor hasa 7% lower
crossing profilethan Xience V
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How does the Stent Recoil of Xience V/Promus compare?
Ref: Test data on file at Medtronic, Inc. 3.5 x 18mm stents
0.0043
0.0066
0.0000
0.0010
0.0020
0.0030
0.0040
0.0050
0.0060
0.0070
Endeavor Xience V
Rec
oil (
in)
• Endeavor’s cobalt alloy and modular design minimizes stent recoil.
Endeavor has35% less
stent recoilthan Xience
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Endeavor’s platform presents more Radial Strength in all pressure levels compared with Xience V/ Promus platform.
How does the Radial Strength of Xience V/Promus platform compare?
Ref: Independent study by John Ormiston presentation, Auckland New-Zealand
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Does the thickness of Xience/Promus strut mean better clinical results? A
The Vision of Xience / Promus show:
• Higher crossing profile!
• Higher stent recoil!
• Lower radial strength!
So how does Xience / So how does Xience / Promus claim minimal Promus claim minimal injury? Is this claim clinically injury? Is this claim clinically meaningful?meaningful?
What is the relationship between What is the relationship between polymer thickness and minimal polymer thickness and minimal damage?damage?
ABT Vascular presented:
Compared to the Driver of Endeavor
Buller, Tremblant, February 2007
Stanford
DES Safety Fire StormDES Safety Fire Storm
Stanford
EndeavorEndeavor’’s safety is well provens safety is well proven
Endeavor, Safe by any Analysis
0.93%
0.30%0.54%
1.18%1.35%
2.21%
0.59%
0.93%
1.46%
EI EI I EI I CA EI I I, , , Endeavor N Dr iver N( = 1316; = 596)
Endeavor & Dr iver
HCRI CEC Def in i t ion
ARCDef in i te Probable+
ARCDef in i te +Probable Poss ib le +
HCRI CEC & ARC ST HCRI CEC & ARC ST ––2 Year Kaplan Meier Estimates2 Year Kaplan Meier Estimates
