Importance of Polymer Biocompatibility for
Drug Eluting Stent (DES) Outcomes
Josiah N. Wilcox, Ph.D.
Vice President, Resident Scholar
Science & Technology, Medtronic CardioVascular
Santa Rosa, CA
BioInterface Conference 2010
October 17-19
Conflict of Interest
• Josiah N. Wilcox is a full time employee of Medtronic
CardioVascular which makes the Endeavor and Resolute
stents
Number of Different DES Available
Cypher®
Sirolimus-eluting Coronary Stent
Endeavor®
Zotarolimus-eluting Coronary Stent System
TAXUS® Liberté®
Paclitaxel-eluting Coronary Stent System
XIENCE/PROMUS® EverolimusEluting Coronary Stent System
DES Pooled Programs in Perspective
ARC Def/Prob ST Landmark to 5 Years
No. At Risk
3.0%
Pooled Data
1 Year
Endeavor1
2
2.5%
Cypher
2
ARC (Def/Prob)
Taxus
3
Xience V/Promus
2.0%
2 Years
3 Years
4 Years
5 Years
2131
2043
1987
1681
1116
858
835
809
783
694
1351
1300
1117
715
228
892
865
840
NA
NA
1.5%
1.0%
95% CI UB
0.35%
0.5%
0.0%
0
360
720
1080
1440
1800
Results come from separate clinical trials. Data may differ in a head-to-head comparison.
Xience V: No Pooled Data Available Beyond 3 Years
Stent thrombosis is a low-frequency event that current drug-eluting stent (DES) clinical trials are not adequately powered to fully characterize.
The true rate of VLST is unknown, however pooled data exist from the various DES programs that are shown here.
1. Popma et al. PCR 2009.
2. Mauri L et al. N Engl J Med. 2007;356:1020-1029.
3. Lansky, A et al., Pooled Spirit II and III, CRT 10.
Endeavor IV – Three Year Results
Cumulative Incidence of
Definite/Probable Thrombosis (%)
Significant Risk Reduction in VLST
ARC Definite/Probable ST
12–36 Months (VLST)
2
Endeavor DES
Taxus DES
1.5%
93% RRR
1
p = 0.004
(1–
(1–3 years)
0
360
0.1%
450
540
630
720
810
900
990
1080
Time After Initial Procedure (days)
Endeavor
732
732
719
716
710
699
688
684
680
Taxus
734
734
721
718
714
701
690
681
674
p-Values were calculated by logrank test. p-Values for outcome differences are unadjusted for multiple comparisons.
ENDEAVOR IV was not specifically designed or powered to individually compare VLST.
RRR= Relative Risk Reduction
Leon TCT 2009
Pivotal Trials TLR: DES Arms
Rates of TLR Overtime
Sirius
Taxus IV
SPIRIT III
(n=525)
(n=650)
(n=669)
2
2
R = 0.9762
9.4
R = 0.9915
9.1
7.9
6.3
2
R = 0.9973
7.8
7.6
6.9
6.8
5.6
4.9
5.4
4.4
4.4
3.3
1 yr
2 yrs
3 yrs
4 yrs
5 yrs
1 yr
2 yrs
3 yrs
4 yrs
5 yrs
Results come from separate clinical trials. Data may differ in a head-to-head comparison.
5 Year Clinical Results of TAXUS IV, Stone, TCT 2009
5 year Outcomes in the Sirius Trial, Leon, TCT 2008
4 year Outcomes in SPIRIT III, TCT 2010
1 yr
2 yrs
3 yrs
4 yrs
5 yrs
Clinical Event Late Catch Up With DES
SIRTAX Late: 5-year TLR results
n=503
n=509
TCT 2009
Late Catch-Up Trend Different Than BMS
j-Cypher: 3-year results
Total Lesion Revascularization (TLR)
9% Increase
Target Lesion Revascularization (TLR)
15.5% 15.5%
16.0%
14.2%
75% Increase
12.0%
10.0%
8.1%
8.0%
5.7%
4.0%
0.0%
1 Yr
2 Yr
3 Yr
TLR Years 1-3:
4.5%
Cypher
Cypher
n = 17,050
Yoshihisa Nakagawa, “The Incidence and Predictors of Late (Beyond 1 Year) Target Lesion Revascularization After
Sirolimus-eluting Stent Implantation: From Three-year Follow-up of the j-Cypher Registry”, AHA 2009.
1 Yr
2 Yr
1.4%
BMS
BMS
n = 1,259
3 Yr
p = 0.0007
Endeavor Trials TLR
Rates of TLR Overtime
2
2
R = 0.9665
5.9
6.5
(n=773)
(n=323)
(n=598)
7.2
Endeavor IV
Endeavor III
Endeavor II
7.2
2
R = 0.9995
R = 0.9226
7.5
6.6
6.9
7.3
7.7
8.1
5.8
6.5
4.5
1 yr
2 yrs
3 yrs
4 yrs
5 yrs
1 yr
2 yrs
3 yrs
4 yrs
5 yrs
Results come from separate clinical trials. Data may differ in a head-to-head comparison.
1 yr
2 yrs
3 yrs
Cumulative Incidence of TLR (%)
Target Lesion Revascularization to 5 Years
Cumulative Incidence of TLR to 5 Years
20
Driver® BMS
Endeavor DES
p < 0.001
16.5%
15
10
7.0%
5
0
0
360
720
1080
1440
1800
Time After Initial Procedure (days)
Endeavor
2132
2130
1908
1842
1552
1100
CI (%)
0.09
5.43
6.23
6.75
6.83
7.00
Driver
596
595
489
474
456
445
CI (%)
0.17
13.16
14.23
14.78
15.91
16.49
p-Values are unadjusted for multiple comparisons.
p-Values were calculated by logrank test.
ENDEAVOR Pooled Analysis: E I 5-year, E II 5-year, E II CA 5-year, E III 5-year, E IV 3-year, E pK 3-year.
DES: Stent, Drug, Polymer
What can Impact the Vessel Long Term?
Drug is exhausted by 6 months to 1 year
Potential Vessel Impact
Bare metal stents have minimal long term impact on the vessel
Hypothesis
Polymers are permanent and may have continued
impact long term after the drug is exhausted
0
6 months
1 year
2 years
3 years
4 years
5 years
Time
Low level inflammation due to lack of complete polymer biocompatibility
may contritute to late TLR catch-up and very late stent thrombosis
DES Polymers Must be Designed with
Biocompatibility in Mind
“Once the drug is eluted from the stent the remaining
polymer if not biocompatible may stimulate inflammation
Carter, AJ et al. Cardiovas. Res. 63:617;2004
and late intimal development.”
Lafont, A. Cardiovas. Res. 63:575;2004
Control
Neointimal Area
30-day
90-day
Cell Proliferation
(PCNA)
180-day
A.J. Carter et al. / Cardiovascular Research 63 (2004) 617–624
SRL
Increased Inflammation Over Time
3-day
30-day
90-day
180-day
“ the vascular response to ongoing injury and inflammation induced by
the stent with residual polymer may simply overwhelm the biological
effects of the drug in this model and result in the late formation of
neointima.”
A.J. Carter et al. / Cardiovascular Research 63 (2004) 617–624
R. Virmani et al. Circulation 109 (2004) 701-705
Requirements for DES Coating Polymers
Inflammatory
Biocompatible
Biocompatibility
Solubility in Volatile Solvents
Biodegradation Kinetics /
Products
Durability
Hydrophobicity /
Hydrophilicity
Sterilizability
DES
Polymer
Thermal Properties
Stability
Drug Elution Rate
Molecular Weight and Distribution
In vitro Cumulative Release (%) of a Drug from Different Polymers
100
90
80
70
Polymer Blend Compatibility
60
50
40
30
20
Packaging Requirements
10
0
0
4
8
12
16
20
24
28
32
Parameters affecting polymer biocompatibility
1. Polymer Mass
Contact angle
2. Surface architecture
θ1
θ2
3. Hydrophilicity / hydrophobicity
•
Hydrophilic surfaces better
4. Net surface charges
•
Hydrophilic
Hydrophobic
θ1 < θ2
Certain blood coagulation factors are activated in the
presence of negatively charged surfaces
Ultimately these factors influence the nature of the
protein layer found at the tissue / material interface
Biomaterials Science: An Introduction to Materials in Medicine.
Authored by Buddy D. Ratner, Allan S. Hoffman, Frederick J. Schoen and Jack E. Lemons
Academic Press, 1996, 484 pages.
Endeavor Drug Elution
Drug Eluted by 14 days only PC Basecoat Left Behind
16
16
14
14
PBMA
12
12
SIBS
Taxol
m
m
10
i i 10
cc
rr 88
oo
nn 66
ss
44
33% Sirol
33% PBMA
33% PEVA
22
83%PVDF-HFP
17%EVEROL
90% ZOT
10% PC
Parylene
PBMA
PC
00
Cypher
Cypher
Taxus
Taxus
Endeavor
Endeavor
Xience
Xience
Hydrophilic vs Hydrophobic
Contact Angle
• Angle formed when water drop applied to polymer surface
• Smaller angle = more hydrophilic
Contact Angle
Hydrophilic
Polymer
θ2
θ1
Hydrophilic
PC (Endeavor)
BioLinx (Resolute)
Hydrophobic
Polymer
Hydrophobic
81º
94o
PBMA (Cypher)
112º
SIBS (Taxus)
118º
PVDF-HFP (Xience V)
129º
Water-loving
Caution: Resolute utilizing the BioLinx polymer is an investigational device, not approved for sale or commercial use in US or Japan
Water-hating
PC Technology
90% of phospholipids in the
outer membrane of a red blood
cell contain the PC
(Phosphorylcholine) headgroup
Outer Membrane
PC* mimics the chemical
structure of the
phospholipid headgroup
Inner Membrane
O
N
O P
O
O
Hydrophilic Phosphoycholine
(PC) Headgroup
*Hayward JA & Chapman D; Biomaterials 5, 135, 1984.
PC Technology is licensed under patents or patent applications owned by Biocompatibles.
BioLinx Polymer Shows Low Inflammation Scores
and Allows for Extended Drug Elution
Biocompatible Polymer
Lower is Better
Inflammation Score
Resolute BioLinx Polymer
4.0
3.0
2.0
1.0
0.0
28 90 180 365
Resolute DES1
28 90 180 365
Xience V DES2
% Zotarolimus Release
Extended Drug Elution of 180 days
100
80
> 85% of drug
eluted by 60
days
60
Complete
drug elution
by 180 days
40
20
% eluted
0
0
50
Preclinical results may not be indicative of clinical performance of DES
porcine data on file at Medtronic, Inc.
2Preclinical porcine data from Abbott Xience V US physician presentation SE2924433D. Carter et al, TCT 2006.
100
Days
1Preclinical
Caution: Resolute utilizing the BioLinx polymer is an investigational device, not approved for sale or commercial use in US or Japan
150
200
BioLinx Polymer System
Composed of Hydrophilic and Hydrophobic Polymers
•
C10
C10 Polymer (Hydrophobic)
CH3
Based primarily on hydrophobic butyl
methacrylate to provide adequate
hydrophobicity for zotarolimus
CH2
C
C
•
C19 polymer (Hydrophilic)
Manufactured from a mixture of hydrophobic
hexyl methacrylate and hydrophilic vinyl
pyrrolidinone and vinyl acetate monomers to
provide enhanced biocompatibility
•
PVP (Hydrophilic)
Hydrophilic polyvinyl pyrrolidinone polymer
increases initial drug burst and enhances
biocompatibility
Overall the BioLinx polymer blend
displays a very hydrophilic surface
(94o contact angle) to the body for
biocompatibility
CH2
a
CH
b
O
O
O
C
C4H9
CH3
O
C19
CH3
CH2
C
CH2
CH
x
C
N
O
CH2
y
CH
O
O
C
C6H13
CH3
PVP
CH2
Caution: Resolute utilizing the BioLinx polymer is an investigational device, not approved for sale or commercial use in US or Japan
CH
N
z
O
a
O
O
BioLinx Polymer System
Composed of Hydrophilic and Hydrophobic Polymers
C19
C10
Hydrophilic
Hydrophobic
CH3
CH3
CH2
C
a
C
CH2
O
b
O
O
C
C4H9
CH3
Zotarolimus
Hydrophobic
CH2
CH
C
CH2
x
C
CH
N
O
CH2
y
O
C
C6H13
CH3
CH2
z
O
O
O
CH
O
CH
N
a
PVP
O
Hydrophilic
Caution: Resolute utilizing the BioLinx polymer is an investigational device, not approved for sale or commercial use in US or Japan
BioLinx Polymer System
Composed of Hydrophilic and Hydrophobic Polymers
C10, C19, PVP and Zotarolimus are mixed together in a common solvent
Caution: Resolute utilizing the BioLinx polymer is an investigational device, not approved for sale or commercial use in US or Japan
BioLinx Polymer System
Composed of Hydrophilic and Hydrophobic Polymers
The mixture of C10, C19, PVP and zotarolimus are sprayed as a
uniform layer onto the stent (no specific orientation all three
components show a uniform distribution)
Caution: Resolute utilizing the BioLinx polymer is an investigational device, not approved for sale or commercial use in US or Japan
BioLinx Polymer System
Composed of Hydrophilic and Hydrophobic Polymers
In the presence of water the polymer blend self-orients such that
the hydrophilic PVP groups in C19 will be on the surface and the
long chain hydrocarbons will form a hidden hydrophobliic domain
where the drug will be sequestered
C19
C10
PVP
Zotarolimus
Caution: Resolute utilizing the BioLinx polymer is an investigational device, not approved for sale or commercial use in US or Japan
BioLinx Polymer System
Composed of Hydrophilic and Hydrophobic Polymers
θ1
θ2
θ1 < θ2
Hydrophilic
Polymer
Hydrophobic
Contact Angle
C10
C19
C10 + C19 (30:70)
BioLinx
1180
910
840
940
Overall the combined BioLinx polymer blend is hydrophilic
Caution: Resolute utilizing the BioLinx polymer is an investigational device, not approved for sale or commercial use in US or Japan
Surface Analysis of BioLinx Polymers
Hydrophilic C19 Predominates at the Surface of the Final Blend
Polymer
C19
C10
C10:C19
BioLinx
%N
1.6
0
1.4
1.3
%C
81.5
79.7
81.4
81.2
%O
16.9
20.3
17.2
17.5
CH3
CH3
CH2
C
CH2
x
C
O
CH
N
CH2
y
CH2
CH
O
O
O
C
C6H13
CH3
C
a
z
C
O
C19
C10
CH2
O
CH
b
O
O
C
C4H9
CH3
O
Surface characterization by X-ray Photoelectron Spectroscopy (XPS) suggests that the
Nitrogen-rich C19 predominates on the surface of Endeavor Resolute polymer blends
Caution: Resolute utilizing the BioLinx polymer is an investigational device, not approved for sale or commercial use in US or Japan
DES Polymer Technologies
PC and BioLinx Polymers Designed to Have Hydrophilic Surface Chemistry
PC Technology
BioLinx
Drug Elution 28 Days
Drug Elution 6 Months
Hydrophilic outer surface
Hydrophilic outer surface
[
O
N
O P
Hydrophobic layer
]
N
O
O
Phosphorylcholine
(PC) Headgroup
Vinyl pyrrolidinone
groups
Similar Inflammatory profiles and vascular biocompatibility
Caution: Resolute utilizing the BioLinx polymer is an investigational device, not approved for sale or commercial use in US or Japan
O
In vitro and in vivo analysis of inflammation
associated with DES polymers
Monocyte Adhesion
Correlates With Polymer Hydrophobicity
200
180
HYDROPHOBIC
Relative % Adhesion
160
140
120
100
80
60
HYDROPHILIC
40
20
0
Negative Positive
Control Control
Contact Angle:
C10
1180
SIBS
1180
PBMA PVDF-HFP
1120
1290
PC
810
Hezi-Yamit et al. JBMR 90A:133;2009
Caution: Resolute utilizing the BioLinx polymer is an investigational device, not approved for sale or commercial use in Japan
C19
910
C10/C19
840
BioLinx
940
Monocytic Adhesion to Commercial DES
Differential Monocytic Adhesion To Various DES In-Vitro
24 hr incubation with activated monocytes
Followed by PBS wash and calcein staining
*
S
SE
PE
ZE
EE
S
S
S
p= 0.01367
*
*
p= 0.03351
p= 0.00019
FACS analysis
Driver
162
Taxus DES washed
4577
ZES
EES
PES
SES
HYDROPHOBIC
Increased adhesion of monocytes to DES with hydrophobic polymeric coatings
Hezi-Yamit et al. TCT 2008
Relative Gene Expression
Hydrophobic polymers stimulate inflammatory and pro-coagulant genes
POLYMER
CONTACT ANGLE
+
1-5 fold
++ 6-10 fold
+++ >10 fold
EC
C19
BioLinx
Fluoro
C10
SIBS
PBMA
91ºC
94ºC
129ºC
118ºC
118ºC
115ºC
SMC
EC
SMC
EC
SMC
EC
SMC
EC
SMC
EC
SMC
TF
-
-
-
-
-
+
-
+
+
+
+++
+
PAR-2
-
-
-
-
+
+
-
+
+
+
+
-
PAI-1
-
-
-
-
-
+
+
+
+
-
+
+
IL-8
-
-
-
-
-
+
-
-
+
-
+++
-
MCP-1
-
-
-
-
-
+
-
+
-
+
-
+
TNF
-
-
-
-
-
+
-
+
-
+
-
+
Endothelin-1
-
+
-
-
-
+++
+
+
++
+
+++
+
TSP-1
-
-
-
-
-
-
+
-
-
-
+
-
CTGF
-
-
-
-
-
+
+
-
+
-
+
-
Total
0
1
0
0
1
10
4
6
7
5
14
5
Hezi-Yamit et al. Comb. Chem & High Throughput Screening 12;2009
Caution: Resolute utilizing the BioLinx polymer is an investigational device, not approved for US sale or commercial use
Tissue Factor and Thrombosis
Tissue factor is a key
regulator of the
coagulation cascade
Steffel, J. et al. Circulation 2006;113:722-731
•
•
•
TF is produced by macrophages, endothelial cells, and SMC
TF is over-expressed in atherosclerotic plaques
TF triggers thrombosis formation associated with plaque rupture in acute
coronary syndrome
Monocytic TF Activation by DES Polymers
Correlates with Relative Polymer Hydrophobicity
Negative Positive
Control Control
Contact Angle:
Fluoro
Polymer
SIBS
PBMA
BioLinx
1290
1180
Hydrophobic
1150
940
PC
830
Hydrophilic
Caution: Resolute utilizing the BioLinx polymer is an investigational device, not approved for sale or commercial use in US or Japan
Upregulation of TF by Hydrophobic Polymers
Implantation of polymer only stents in porcine coronary arteries
Tissue Factor (Day 7)
18
Relative Gene Expression
16
14
12
10
8
6.7
6
4
2
0
3.4
3.0
0.0
Unstented
Unstented
0.6
0.8
Driver
Driver
BioLinx
BioLinx
PC
PC
94°
83°
Contact
Angle
0.4
Cypher
Polymer
PBMA
115°
Taxus
Polymer
Xience
Fluoro
Polymer
Polymer
118°
129°
SIBS
Caution: Resolute utilizing the BioLinx polymer is an investigational device, not approved for sale or commercial use in US or Japan
Upregulation of TF Protein by SES/PES
SES
PES
90 days afterBMS
stenting inZES
porcine coronary
arteries
TF
GAPDH
Relative protein levels
Protein Levels
Driver
ZES
SES
PES
TF Protein Levels
Haraguchi et al. TCT. 2007
TF
mRNA
Expression
SES
TF ImmunoStaining
Inflammation scores
Porcine Coronary Artery Implants
Hydrophobic
Hydrophilic
Low inflammation scores seen with Endeavor and Resolute DES
Higher inflammation scores (>1) seen with Xience and Cypher DES
Caution: Resolute utilizing the BioLinx polymer is an investigational device, not approved for sale or commercial use in US or Japan
Study design for Atherosclerosis
Blood Collection for Cholesterol measurements
1
2
5 wks.
Balloon injury
after 1 week
New Zealand White
Rabbits, n=45
3
4
5
4 wks.
4 wks.
Study duration
0
5w
9w
13w
Groups:
Diver
Endeavor
Xience V
Cypher
1% Atherogenic
Diet
0.025%
Atherogenic diet
Euthanasia
Stent
Implantation
Pre-Clinical Evaluation
Healing in Atherosclerotic Rabbit Model
Representative healing at 28 days
Virmani et al. CRT 2008
Nakazawa et al PCR 2009
Pre-Clinical Evaluation
Healing in Atherosclerotic Rabbit Model
(mm2)
Neoin&mal
Area
(%)
2.0
1.5
1.0
%Stenosis
p=0.01
35
P<0.0001
30
*
*
*
0.5
25
20
*
*
*
15
P<0.0001
0.25
*
0.20
0.15
*
*
0.05
5
Nakazawa et al PCR 2009
0.30
0.10
10
Cypher
(mm)
Neoin&mal
Thickness
Xience
V Endeavor
Driver
*significant vs. Driver
Pre-Clinical Evaluation
Healing in Atherosclerotic Rabbit Model
(%)
%Struts
with
Giant
cell
60
50
40
P<0.0001
*
*
*
30
(%)
40
%Struts
with
Fibrin
*
P=0.0005
(%)
80
60
30
P<0.0001
*
Number
of
Luminal
Inflammatory
cell
P=0.0002
60
50
*
*
40
*
40
20
20
Uncovered
Struts
*
30
20
20
10
10
10
0
Cypher
Nakazawa et al PCR 2009
Xience
V Endeavor
Driver
*significant vs. Driver
s
s
e
rTissue Factor
pThrombosis/ Inflammation
x
E 5
2
e .0
n 01
e .5
G 17
.0
e 05
5
v .
02
i 0.
t 50
a 2.
l .0D
ri
e 0
R -
Tissue Factor - Day 28
*Increase- Undesirable
Resolute versus Xience p = 0.029
Endeavor versus Xience p = 0.029
ve
rE
n
r
eavo
d
ie
X
Hezi-Yamit et al. PCR 2010
Caution: Resolute utilizing the BioLinx polymer is an investigational device, not approved for sale or commercial use in US or Japan
ce
n
i
s
s
e
r
Inflammation/Late
p
x
E
Endothelin 1
e
n
e
G
e
v
i
t
a
l
e
R
proliferation catch-up
Endothelin 1 - Day 28
*Increase- Undesirable
0
2
Driver versus Xience p = 0.025
Resolute versus Xience p = 0.057
0
1
0
ri
D
r
e
v
ie
X
Stent type
Hezi-Yamit et al. PCR 2010
Caution: Resolute utilizing the BioLinx polymer is an investigational device, not approved for sale or commercial use in US or Japan
e
c
n
s
s
e
r
pPro-Healing
x
E
NADPH oxidase 3
e
n
e
G
e
v
i
t
a
l
e
R
(low is bad)
NADPH oxidase 3 (gp91-phox) - Day 28
5
3
0
3
5
2
0
2
5
1
0
1
*Decrease- Undesirable
Driver vs Xience p = 0.034
5
0
Hezi-Yamit et al. PCR 2010
Caution: Resolute utilizing the BioLinx polymer is an investigational device, not approved for sale or commercial use in US or Japan
s
s
e
r
Protection
p
x
E 5
HO1 – Day 28
e
n
e
G
e
v
i
t
a
l
e
R
from Inflammation and Oxidative stress
HO1 - Day 28
.
2
0
1
.
*Low - Undesirable
Driver versus Xience p = 0.004
Endeavor versus Xience p = 0.057
0
15
.
7
0
.
5
5
.
2
0
.
0
ltD
a
is
Hezi-Yamit et al. PCR 2010
Caution: Resolute utilizing the BioLinx polymer is an investigational device, not approved for sale or commercial use in US or Japan
e
c
n
i
X
Incomplete Healing of Cypher Stents
Angioscopy 3-6 months post-stenting
Kotani et al. JACC 2006;47:2008
Serial Angioscopy Cypher vs. BMS
Persistent Lack of Healing – Role of Polymers?
Cypher
BMS
Awata et al. Circulation 2007;116:910
Clinical Evaluation: Vessel Coverage
Coverage Grade: ZES vs SES at 8 months
P = 0.0004
80
ZES (n = 14)
SES (n = 16)
Grade 0: struts were
exposed similarly to
the time of
implantation
Percent
60
Grade 1: struts were
covered, but not
embedded
40
Grade 2: struts were
embedded by the
neointima, but no
translucency seen
20
00
Grade 0
Grade 1
Awata et al. JACC 2008;52:789
Grade 2
Grade 3
Grade 3: struts were
fully embedded and
invisible by
angioscopy
Representative Cases
Grade 1
SES 3.5x23mm
Awata et al. JACC 2008;52:789
Grade 3
ZES 3.5x23mm
OCT Studies Verify Endeavor Strut Coverage
P < 0.001
Uncovered Struts (%)
12.2%
Overlapped Stents
ACS Stenting
P < 0.001
6.0%
100% Struts
Covered
P < 0.001
1.6%
0.3%
ZES
(N=32)
SES
(N=36)
9-Months1
1 Kim et al., Heart, 2009: 95 1907-1912.
2 Guagliumi et al. TCT 2008.
3 Kim et al. JACC: Cardio Int, vol. 2, no. 12, 2000.
0.01%
0.0%
ZES
ZES
(N=31)
3-Months3
PES SES
(N=22) (N=22) (N=22)
6-Months2
Functional Endothelial Healing
Biological Functions of Nitric Oxide
eNOS (Endothelial Nitric Oxide Synthase) is the protein that helps produce
NO and is a marker of endothelial cell function
Clinical Data Indicate SES and PES are Associated
with EC Dysfunction Proximal and Distal to Stent
Both SES and TES implantation have been shown to have adverse
effects on local endothelium-dependent vasomotor responses in response
to ACH or exercise stress six months after implantation
Tongi et al. JACC 2005;46:231
Hofma et al. Eur Heart J 2006;27:166
Tongi et al. Int. J. Cardiol. 2007;120:212
Kim, J. W. et al. JACC Intv 2008;1:65-71
EC Dysfunction Associated with PES
Tongi et al. Int. J. Cardiol. 2007;120:212
EC Dysfunction Associated with PES
Baseline
Exercise
Tongi et al. Int. J. Cardiol. 2007;120:212
EC function after SES or ZES Implants
Clinical evaluation of ACH six-nine months post-stenting
N=12
N=11
“SES implantation may induce significant impairment of long-term
coronary endothelial function, while ZES implantation may not’
Shin et al. Int Heart J 49(639) 2008
EC function after SES or ZES Implants
Clinical evaluation of ACH six months post-stenting
N=19
N=19
N=9
Kim et al. JACC 53(1653) 2009
Comparison of EC function by Atrial Pacing
Percent change in vessel diameter from baseline at 9-12 months follow-up
N
Hamilos Circ Cardiovas Intervent 1(193)2008
PES
10
SES
17
BES
23
ZES
9
BMS
12
Acetylcholine challenge response
Proximal to stents implanted in porcine coronary arteries
Vasodilation
Vasoconstriction
HYDROPHILIC
HYDROPHOB IC
Endeavor and Resolute stents
show high eNOS levels,
suggesting good NO production
and a functional endothelium
Caution: Resolute utilizing the BioLinx polymer is an investigational device, not approved for sale or commercial use in US or Japan
EC Function Assessed by ACH Challenge
28 Days After Stenting in Porcine Coronary Arteries
2.06 ± 0.58
Relative eNOS Expression
0.27 ± 0.26
0.67 ±1.52
Inflammation Scores
1.89 ± 1.95
Caution: Resolute utilizing the BioLinx polymer is an investigational device, not approved for sale or commercial use in US or Japan
Inflammation only found in the stented region
Why is this associated with vasomotor changes proximally and distally?
Cytokines
ROS
Cytokines
ROS
Cytokines
ROS
Cytokines
ROS
Hypothesize that inflammation exerts paracrine actions by releasing
cytokines and ROS that affect the adjacent segments
Polymer Related Oxidative Stress
Human peripheral blood monocytes
250
200
uV
150
Baseline
100
50
0
Neg. CTL
BioLinx
(Resolute)
PVDF-HFP
(Xience)
PBMA
(Cypher)
Caution: Resolute utilizing the BioLinx polymer is an investigational device, not approved for sale or commercial use in US or Japan
SIBS
(Taxus)
Superoxide Production in Porcine Coronary Artery
Chemiluminiscence (RLU/s/mg of tissue)
Comparison of PES vs BMS by lucigenin assay
50
100
*
#
40
80
30
60
20
40
10
20
0
0
Naïve
BMS
*
#
PES
Naïve
* P<0.05 PES vs. BMS
# P<0.05 PES vs.
Naive
Keith Robinson, LDDR 2008
BMS
PES
Copyright © 2008 Saint Joseph's. All Rights Reserved.
Superoxide Production in Porcine Coronary Artery
Comparison of BMS, ZES and SES by lucigenin assay
BMS
SES
ZES
Nakamura PCR 2010
Copyright © 2008 Saint Joseph's. All Rights Reserved.
Contributors to Late Stent Thrombosis
Inflammation and Vasomotor Dysfunction may be Relevant
DES Exposure
Flow disturbance associated with EC dysfunction
• Chronic
inflammation,
• Hypersensitivity
to polymer
• Expression of
Prothrombotic
Genes
Endothelial
dysfunction
Vasospasm
(conduit ± resistance)
Normal Laminar Flow.
Reduced blood flow,
Stasis & turbulence
Proximal Vasoconstriction.
Leukocyte adherence
Leukocyte activation
Platelet recruitment
Late Stent Thrombosis
K. Robinson LDDR 2008
Potential to create areas of disturbed flow within the
stent segment leading to further EC injury and platelet
activation.
Personal communication Dr. Peter Davies
Late Loss Changes Over Time
Factors contributing to late loss changes
(% Response)
SMC proliferation and changes in extracellular matrix
Smooth Muscle Cell
Migration/Proliferation
Extracellular Matrix
Production
Extracellular Matrix
Reabsorption
Thrombosis
3
Inflammation
14
90
440
1000
Time after stenting (days)
Growth of neointima
Increased late loss
Luminal narrowing
Intimal remodeling
Reduced late loss
Increase in lumen diameter
Seen in BMS but not all DES
BMS Demonstrate LL Regression
Hypothesize associated reabsorption of ECM proteins
Instent LLL
0.70
0.60
0.50
0.40
0.30
0.20
0.10
0.00
6 months
Kimura et al. NEJM 1996;334:561
1 year
3 years
Cypher Late “Catch-up” vs. BMS
Decreased MLD/Increased Late Loss over 3yrs
Cypher (n=531)
2.75
2.60
2.44
MLD (mm)
2.50
2.25
BMS (n=703)
2.35
2.09
2.02
2.20
2.00
1.75
1.50
6 mo
1 yr
Follow-up
Shiode et. al. Late Progression After Sirolimus-Eluting Stent Implantation:
Comparison with Bare Metal Stent Implantation. ACC 2009 Abstract 2501523/523
3 yr
LL Progression and ABR Changes
Taxus and Cypher LL progressed between 6-8 months
and 2 years in a paired analysis of 1,331 patients
J Am Coll Cardiol Intv 2009;2:291–99
In-stent Late Loss in Spirit II
Serial 6 Month and 2 Year Angio FU
6 Months
100%
90%
90%
% of Lesions
80%
70%
60%
2 Years
100%
*
XIENCETM V
80%
XIENCETM V
TAXUS®
70%
+
60%
TAXUS®
XIENCE
V
50%
50%
40%
40%
30%
30%
20%
20%
10%
10%
0%
-0.75
0%
-0.5
-0.25
0
0.25
0.5
0.75
1
1.25
1.5
1.75
2
-0.75 -0.5 -0.25
0
0.25
0.5
0.75
1
1.25
1.5
1.75
In-stent Late Loss (mm)
In-stent Late Loss (mm)
XIENCETM V: 0.17 ± 0.32 (nL=97)
XIENCETM V: 0.33 ± 0.37 (nL=97)
TAXUS®: 0.33 ± 0.32 (nL=35)
TAXUS®: 0.34 ± 0.34 (nL=35)
P=0.0037
P=0.6026
In this serial analysis, for patients having TLR, values of loss and neo-intimal hyperplasia observed prior to 6 month or 2 year
FU were imputed at 6 months and 2 years respectively
SE2926406 REV A
2
Spirit II Paired Changes in In-Stent
Late Lumen Loss from 6 to 24 Months
TAXUS® (nL=35)
P<0.0001
1.50
1.50
1.00
1.00
Change in LL (mm)
Change in LL (mm)
Mean Δ
0.01 mm ± 0.24
Xience™ V (nL=97)
0.50
0.00
0.50
0.00
-0.50
-0.50
-1.00
-1.00
6 Months
2 Years
Mean Δ
0.16 mm± 0.32
6 Months
2 Years
ISAR Test 4 – EES vs SES
Xxxxxx TCT 2010
Serial angiographic follow-up after successful implantation
of sirolimus, paclitaxel and everolimus-eluting stent for
chronic total occlusions: multicenter registry in Asia
InStent Late Loss (mm)
SES
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
PES
EES
0.54
0.52
0.5
0.54
0.41
0.31
0.12
0.31
0.11
9
0.27
0.16
0.13
12
18
0.43
0.33
0.23
24
M onths
Nakamura et al., European Heart Journal ( 2010 ) 31 ( Abstract Supplement ), 986
36
Endeavor Late Loss Stability/Regression
Change in Late Lumen Loss between 6 and 36 months
Three Year Follow-up E Five
BASELINE
6
MONTHS
Courtesy of Dr. Fausto Feres
POST
3.5X18.0mm
3
YEARS
Endeavor
‐3
years
MLD
pre,
post,
6‐month
and
3
years
(17
matched
lesions)
MLD Pre PCI: 0.77 ± 0.29
MLD Post PCI: 2.69 ± 0.52
6-Month MLD: 2.11 ± 0.60
3-Year MLD: 2.16 ± 0.52
Minimal Luminal Diameter, mm
Endeavor- 3 years
Late loss at 6-months and 3 years (17 matched lesions)
6-month Late Loss: 0.58 ± 0.31
3-Year Late Loss: 0.53 ± 0.33
Luminal Late Loss, mm
Pivotal Trials TLR: DES Arms
Rates of TLR Overtime
2
R = 0.9762
Sirius
(n=525)
9.4
2
Taxus IV
(n=650)
9.1
7.9
6.3
R = 0.9973
2
SPIRIT III
(n=669)
7.8
7.6
6.9
6.8
5.6
4.9
R = 0.9915
5.4
4.4
4.4
3.3
1 yr
2 yrs
3 yrs
Endeavor II
4 yrs
5 yrs
2
R = 0.9665
(n=598)
5.9
6.5
7.2 7.2 7.5
1 yr
2 yrs
3 yrs
4 yrs
5 yrs
1 yr
2 yrs
3 yrs
2
Endeavor III
R = 0.9226
(n=773)
(n=323)
6.6
7.7
6.9 7.3
Endeavor IV
8.1
5.8
6.5
4.5
1 yr 2 yrs 3 yrs 4 yrs 5 yrs
1 yr 2 yrs 3 yrs 4 yrs 5 yrs
1 yr 2 yrs 3 yrs
Results come from separate clinical trials. Data may differ in a head-to-head comparison.
5 Year Clinical Results of TAXUS IV, Stone, TCT 2009
5 year Outcomes in the Sirius Trial, Leon, TCT 2008
4 year Outcomes in SPIRIT III, TCT 2010
4 yrs
5 yrs
R2 = 0.9995
Long-Term Results with RESOLUTE
Using the Hydrophilic BioLinx Polymer Blend
RESOLUTE 3-year data show very low rate of events at 3 years
TLR 1-3 Years
ST (ARC Def/Prob) 1-3 Years
RESOLUTE (n = 130)
RESOLUTE (n = 130)
2 events
1 event
1.5%
2 events
2 Years
0 events
12–24 months
1.6% *
0.8%
1 Year
ST (%)
0 events
2–3 Years
3 Years
0 events
24–36 months
0.0
0.0
0.0
12 Months
24 Months
36 Months
*n=129, missing data from one patient.
Three Year Follow-up with Zotarolimus-eluting Stent, Resolute DES, Ian Meredith, TCT 2009. RESOLUTE had
single de novo native coronary artery lesions. Lesion length: 14–27 mm. Stent diameters: 2.5, 3.0, 3.5 mm.
Stent lengths: 18, 24, 30 mm (8/9 mm bailout).
Caution: Resolute utilizing the BioLinx polymer is an investigational device, not approved for sale or commercial use in US or Japan
Hydrophilic vs Hydrophobic Polymers
DES polymers can either be hydrophilic or hydrophobic
We hypothesize that hydrophilic polymers are more
biocompatibile for DES applications
• Healthy Healing
• Less Inflammation
• Reduced cytokine and procoagulant production
• Restoration and maintenance of endothelial function
Hypothesize that polymer biocompatibility is important for long-term outcomes
Thanks to the team that
contributed to this work
Kishore Udipi
Ayala Hezi-Yamit
Mingfei Chen
Peiwen Cheng
David Shumaker
Carol Sullivan
Robert Melder
Go Haraguchi
Andrew Carter
Thank You!