preclinical evidence on des performance - pcronline · preclinical evidence on des performance...
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![Page 1: Preclinical evidence on DES performance - PCRonline · Preclinical Evidence on DES Performance Aloke Finn, MD. CVPath Institute, Inc. Gaithersburg, MD, USA. Assoc. Professor University](https://reader030.vdocuments.us/reader030/viewer/2022020215/5b59fc507f8b9a88698e2c63/html5/thumbnails/1.jpg)
Preclinical Evidence on DES Performance
Aloke Finn, MD.
CVPath Institute, Inc.
Gaithersburg, MD, USA.
Assoc. Professor
University of Maryland
Baltimore, MD
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History of Percutaneous Coronary Intervention
The first angioplasty(Dotter and Judkins)
The first balloon angioplasty(Grünzig)
Balloon Angioplasty BMS DES BVS
Success rate 70-85% >95% >95% >95%
Restenosis 40-45% 20-30% <10% <10%
Early Thrombosis (30 days) 3-5% 1-2% 1-2% 1-2%
Late Thrombosis (>30 days,
1y)NA <0.5% 1% >2%
Very Late Thrombosis (>1y) NA 0% 1-2% ?
1986The first stent implantation “Wallstent” (Sigwart)
1994DAPT reduces SAT (Schömig, et al. )
Efficacy of BMS vs. POBA (BENESTENT,STRESS trials)
The first human DES (SES) (Sousa)
Concerns about DES VLST (ESC2006)DCB effective for ISR
Safety and efficacy of 2nd-gen DES (ENDEAVOR I-IV, SPIRIT I-V, COMPARE)
20062002-1999Biodegradable polymer DES (LESDERS)BVS (ABSORB chohort A, B)
Late catch-up
1996
LST / VLST
Acute vessel closureSubacute thrombosis
In-stent restenosis
NeoatherosclerosisStent fracture
Efficacy of 1st-gen DES vs. BMS(RAVEL,SIRIUS,TAXUS I-VI)
2008-Igaki-Tamaistent,RESOR-ABLE Scaf
20003rd-gen DES RESOLUTE PLATINUM
POBABMS
Biodegradable Scaffold
2011-
DCB
1st-genBiodegradable polymerPolymer free
3rd-genDurable polymer
DES2nd-gen
Durable polymer
Raised Issues
2006-
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Contemporary DES Platforms
Strut and Coating Thickness In Perspective
Durable Polymer Coated Bioabsorbable Polymer Coated
Xience
CoCr-EESResolute Biomatrix COMBO SYNERGY BioMime Ultimaster Orsiro
Material/
Drug
Promus
PtCr-EESCoNi-ZES 316L-BES 316L-SES PtCr-EES CoCr-SES CoCr-SES
CoCr-
SES
Strut
thickness
81µm
0.0032”
89µm
0.0035”
120µm
0.0046”
100µm
0.0040”
74µm
0.0029”
65µm
0.0026”
80µm
0.0030”
61µm
0.0024”
Polymer PVDF BioLINX PLA Synbiosys PLGAPLLA +
PLGA
PDLLA +
PCL
PLLA
Probio*
Distribution
/ thickness
Conformal
7-8µm / side
Conformal
6µm / side
Abluminal
10µm
Abluminal
3-5µm
CD34 Ab
Abluminal
4µmConformal
2µ / 2µ
Abluminal
15µm
Conformal
3.5µm /
7.5µm
Synbiosys = Urethane-linked multi-block copolymers (MBCP) that comprise blocks of lactide, glycolide, epsilon-caprolactoneand/or poly(ethylene glycol) chain-extended with 1,4-butanediisocyanate. J Biomater Sci Polym Ed. 2010;21(4):529-52
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Fundamental Questions
• Are “polymers” the cause of poor DES outcomes?
• Are vascular responses to all polymers the same?
• Could some polymers be beneficial?
• Will returning a DES to a “BMS-like state” lead to better outcomes?
• Lets discuss the scientific evidence
Polymers Are Ubiquitous in Interventional Cardiology Today
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5
© 2010 Abbott
• Fluoropassivation
An observed blood contact phenomena of fluorinated surfaces eliciting decreased local thrombotic response and faster rate of endothelialization.1-4
• Mechanistic hypotheses behind fluoropassivation
A fluorinated polymer induces preferential adsorption and optimal conformation of proteins (specifically, albumin affinity over culprit blood proteins such as fibrinogen).5
Protein modulation subsequently minimizes platelet adhesion and activation and also leukocyte recruitment.6
The modulation of host-material interface by a fluorinated surface, combined with chemical stability of the fluorinated copolymer, elicits a cellular response conducive to healing (endothelialization)4 with minimal chronic inflammation.
Fluorinated Copolymer Biological Concept of Fluoropassivation
1. Paton et al. US Patent 5,356,668. 1994. 2. Garfinkle AM et al. Trans Am Soc Artif Int Organs. 1984;30:432-439 3. Kiaei D et al. J Biomater Sci Polym Ed. 1992;4:35-44. 4.
Chinn et al. J Biomed Mater Res. 1998;39:130-140 5. Horbett et al. Trans Annual Mtg Soc Biomater. 1984;v7: p361 6. Peterson et al. Trans Am Soc Artif Int Organs.
1975;21:242-248
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Preclinical Models of Thromboresistance: Xience versus
Competitors
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ALBUMIN ADSORPTION
2 hr adsorption
24 hr elution
Two-hour ALBUMIN adsorption from a pure Albumin solution (0.3 mg/mL)
Reference: “Blood compatibility assessment of polymers used in drug eluting stent coatings” Luisa Mayorga Szott, Colleen A. Irvin, Mikael Trollsas, Syed Hossainy, and Buddy D. Ratner Citation: Biointerphases 11, 029806 (2016).
MONOCYTE ADHESION
To SurfacesPre-Adsorbed with 1% Human Plasma
0
140
120
100
80
60
40
20
PVDF-HFP StainlessSteel
Ad
sorb
ed A
lbu
min
(n
g/cm
2)
PVDF-HFP StainlessSteel
0
16000
14000
12000
10000
8000
6000
4000
2000#
of
Ad
her
ent
Mo
no
cyte
s (c
ells
/cm
2)
XIENCE Fluoropolymer: Fluoropassivation Confirmed
XIENCE Fluoropolymer has higher albumin absorption/retention than bare metal
Preferential albumin adsorption of XIENCE Fluoropolymer offers the lower monocyte
adhesion than bare metal
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1. Porcine AV shunt: carotid-
jugular using customized sheath 2. Arterialized flow using Sylgard tube 3. Thrombus formation after 1 hour
Proximal DistalMiddle
Artery
Vein
Proximal DistalMiddle
Bisected longitudinally
Immunofluorescent
staining for platelet
(CD61/42b) and
assessed by CM
SEM
Fig
ure
1.
A
B
C
D
All shunts running for 60 minutes No anti-platelet treatment Target ACT 150-200 seconds
Ots
uka
F, e
t al
JA
CC
Car
dio
vasc
Inte
rv2
01
5;8
:12
48
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Confocal Microscopy of Shunt Model
for Platelets
CD42b/CD61 positive staining area
Flu
oro
Po
lym
er
co
ate
dV
isio
n (
BM
S)
p=0.03
Th
rom
bu
s (
%)
0
5
10
15
20
25
30
Fluoro Polymer Vision
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Representative images of
Scanning Electron Microscopy
Flu
oro
Po
lym
er
co
ate
dV
isio
n (
BM
S)
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Otsuka F, et al. JACC Cardiovasc Interv, 2015;8:1248-1260
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XIENCE
Xpedition™
BioMatrix
Flex™Nobori® OrsiroSynergy™
Durable Polymer Biodegradable Polymer-Coated DES
Platform MULTI-LINK 8 Juno Stent (SS) S- Stent (SS) Element PRO-Kinetic Energy
Material CoCr 316L stainless steel 316L stainless steel PtCr CoCr
Strut thickness 81 µm 120 µm 120 µm 74 µm 60 µm
Drug type Everolimus Biolimus A9 Biolimus A9 Everolimus Sirolimus
Drug dose 100 µg/cm2 15.6 µg/mm 15.6 µg/mm 100 µg/cm2 1.4 µg/mm2
Materials of the polymer
PBMA/PVDF-HFP PDLLA PDLLA, parylene C PLGA PLLA, silicon carbide
Coating type Circumferential AbluminalAbluminal (PDLLA)
Circumferential (parylene C)
Abluminal Circumferential
Coating thickness
7-8 µm / side 11 µm 20 µm 4 µm 4-7 µm / side
Stent size used
3.0 x 15 mm 3.0 x 14 mm 3.0 x 14 mm 3.0 x 16 mm 3.0 x 15 mm
Number of stents used
24 6 6 6 6
Otsuka et al., JACC Cardiovasc Interv. 2015 Aug 17;8(9):1248-60
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0
10
20
30
40
0
50
100
150
200
250
Percent fluorescent positive area for
CD61/42b (platelets) (/entire area)(%)
Biomatrix
(n=6)
Nobori
(n=6)
Orsiro
(n=6)
Synergy
(n=6)
Xience
(n=24)
Biomatrix Flex
Nobori
Synergy
Xience Xpedition
Orsiro
Significantly Reduced Platelet Aggregation in
Xience than Comparator DES by Confocal
Microscopy
(%)
Adjusted percent fluorescent positive area
for CD61/42b (platelets) (/stent surface area)
Biomatrix
(n=6)
Nobori
(n=6)
Orsiro
(n=6)
Synergy
(n=6)
Xience
(n=24)
PBMA/PVDF-HFP
Parylene C/PDLLA
PDLLA
PLGA
PLLA
Otsuka et al., JACC Cardiovasc Interv. 2015 Aug 17;8(9):1248-60
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Confocal Microscopy of Shunt Model (Platelet)
CD42b/CD61 positive staining area
p=0.003
Xie
nc
eU
ltim
as
ter
Vis
ion
Numbers of Clot Counting
Nu
mb
ers
of C
lot
p=0.07
DE
SB
MS
p=0.13
p=0.38
p=0.05
p<0.01
N=8 each
N=8 each
Th
rom
bu
s (
%)
Based on the relativesurface area
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Confocal Microscopy of Shunt Model
Inflammatory Cell AssessmentX
ien
ce
Ult
imaste
rV
isio
n
Green= CD14 (Monocytes)
Red= CD42b/CD61
Blue= DAPI
CD14 positive cells
0
50
100
150
200
250
300
350
400
450
Xience Alpine Ultimaster Vision
p=0.0004
CD
14
(n
um
be
r/m
m2)
DE
SB
MS
P<0.05
P<0.05
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Confocal Microscopy of Shunt Model
for PlateletsX
ien
ce
Bio
fre
ed
om
Vis
ion
DE
SB
MS
CD42b/CD61 positivestaining area
0
10
20
30
40
50
60
70
Xience Biofreedom Vision
P<0.01
P<0.01P<0.0001
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Confocal Microscopy of Shunt Model
Inflammatory Cell AssessmentX
ien
ce
Bio
fre
ed
om
Vis
ion
DE
SB
MS
Number of PM-1 positive cell
P<0.05
P<0.005P<0.0001
Green= PM-1 (Macrophage)
Red= CD42b/CD61
Blue= DAPI
0
200
400
600
800
1000
1200
1400
1600
1800
Xience Biofreedom Vision
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Confocal Microscopy of Shunt Model
Inflammatory Cell AssessmentX
ien
ce
Bio
fre
ed
om
Vis
ion
DE
SB
MS
Green= CD14 (Monocytes)
Red= CD42b/CD61
Blue= DAPI
0
100
200
300
400
500
600
700
800
900
Xience Biofreedom Vision
Number of CD14 positive cell
P<0.01
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SummaryEx Vivo Swine Shunt
The overall design of Xience confers acute
thromboresistance relative to contemporary DES with
biodegradable coatings
Fluoropolymer only stent had less platelet
accumulation versus bare metal stents (no polymer)
There was less platelet accumulation and
inflammation on Xience relative to BioMatrix Flex,
Synergy, Ultimaster, Orsiro and Biofreedom
Overall, these data lend support to reported clinical
findings of lower rates of early stent thrombosis with
Xience EES.
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Preclinical and Clinical Data on Endothelialization: Xience versus
Competitors
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Comparison of Xience (Permanent polymer) and Synergy (biodegradable polymer) Stent in
Iliofemoral Rabbit Model at 14 and 28 days
Synergy and Xience Implants.
Animals received bromodeoxyuridine (BrdU) thymidine
analog for cell proliferation just prior to termination.
Select stents were imaged by confocal microscopy following
labeling with the EC marker (VE cadherin), macrophage
marker (RAM11) and anti-BrdU
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0
100
200
300
400
500
14 days 28 days
Xience Alpine Synergy
Confocal Microscopy of rabbit stented iliac
arteries at 14 and 28 days
Xie
nce
Syn
erg
yX
ien
ce
Syn
erg
y
0
20
40
60
80
100
14 days 28 days
Xience Alpine SynergyGreen= VE-Cadherin
Red= BrdU (cell proliferation marker)14 days
28 days
VE-Cadherin (above struts)
BrdU (above struts)
P=n.s. P=n.s.
P= n.s P=n.s.
Co
ve
rage
(%
)B
rdU
Nu
cle
i (n
um
be
r/m
m2)
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Confocal Microscopy of rabbit stented iliac
arteries at 14 and 28 days
Xie
nce
Syn
erg
yX
ien
ce
Syn
erg
y
Green= VE-Cadherin
Red= Ram11 (Macrophage)14 days
28 days
RAM11 (Macrophage)
0.0
0.5
1.0
1.5
2.0
14 days 28 days
Xience Alpine Synergy
P=0.06 P=0.01
Ma
cro
ph
age s
co
reScore 0 < 10 cells/HPF
Score 1 <10 but ≥ 20 cells/HPF
Score 2 >20 cells/HPF
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Pathology of 2nd-gen CoCr-EES vs. 1st-gen SES/PES
DES for
Stable
CAD
DES for
ACS
CoCr-EES 6MSES 13M PES 11M
CoCr-EES 5M
NC
SES 18M
NC
Ca
Ca
NC
CaNCNC
PES 9M
NC
NC
0
5
10
15
20
25
30
SES(n=73)
CoCr-EES(n=46)
21%
4%
p=0.029
Prevalence of LST/VLST
(%)
Duration of implant: >30 days, 3 years
PES(n=85)
Cypher: 15/73 (21%)Taxus: 22/85 (26%)Xience V: 2/46 (4%)
26%
p=0.008
Otsuka F, et al. Circulation. 2014;129:211-223.
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0
20
40
60
80
100
120
0.0
0.2
0.4
0.6
0.8
Ma
xim
um
Ne
oin
tim
al T
hic
kn
ess (
mm
)
Pre
va
len
ce
of D
ES
with
>30
% U
nco
ve
red
Str
uts
(%
)
>1, 3
months
>3, 9
months
>9, 36
months
>1, 3
months
>3, 9
months
>9, 36
months
n=13n=16 n=5 n=44n=23 n=25 n=28n=34 n=16 n=13n=16 n=5 n=44n=23 n=25 n=28n=34 n=16
SES PES CoCr-EESSES PES CoCr-EES
p=0.42
Duration of Implant Duration of Implant
p=0.41
p=0.39
p=0.17
p=0.21
p=0.86
p=0.006
p=0.005
p=0.048
p=0.001
p=0.11
p=0.065
Neointimal Thickness and Prevalence of Uncovered Struts Stratified by Duration of Implant in CoCr-EES vs. SES/PESMaximum Neointimal Thickness (mm) Prevalence of >30% Uncovered Struts
Otsuka F, et al. Circulation. 2014;129:211-223.
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Morphometric Analysis: CoCr-EES vs. SES/PES
Uncovered struts
CoCr-EESSES
Mean neointimal thickness(mm) (mm)
Maximum neointimal thickness
Inflammation score Struts with fibrin(%)Maximum number of eosinophils per strut
0
20
40
60
80
100
120
0
0.2
0.4
0.6
0
0.2
0.4
0.6
0.8
0
1
2
3
4
5
0
10
20
30
40
50
0
20
40
60
80
100
120
Modified from Otsuka F, et al. Circulation. 2014;129:211-223.
PES CoCr-EESSES PES CoCr-EESSES PES
CoCr-EESSES PES CoCr-EESSES PES CoCr-EESSES PES
(%)
SES (n=72) PES (n=78) CoCr-EES (n=41)
p<0.0005p<0.0005
p=0.89p=0.32
p=0.93p=0.13
p<0.0005
p=0.006
p=0.009
p=0.59
p=0.001p<0.0005
All statistical analyses were corrected for duration of implant.
Duration of implant: >30 days, 3 years
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Summary
Although endothelialization was similar between Xience and
Synergy, inflammation was significantly less in Xience than
Synergy.
Drug-Eluting Stent (DES):
1st generation DES vs Xience
Compared to 1st gen DES, Xience demonstrates equivalent or
superior intimal suppression with significantly better strut
coverage/endothelialization and lower inflammation in human
DES autopsy specimens.
Endothelialization and inflammation:
Synergy vs Xience
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Long-term durability of polymer
59 years old maleDuration 5 years
73 years old maleDuration 7 years
60 years old maleDuration 5 years
2x 40x Polarized
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Xience-EES’s overall design is associated with acute
thromboresistance with respect to platelet aggregation
relative to contemporary DES with biodegradable polymer
coatings in a 1 hour ex vivo shunt model in swine and lends
support to reported clinical findings of lower early stent
thrombosis.
Overall endothelial coverage was similar between Xience
and Synergy at 14 and 28 days in a rabbit model.
Less Inflammation (macrophage) above struts was observed
in Xience compared to Synergy at 14 and 28 days.
Human autopsy specimens of Xience show significantly
enhanced endothelialization compared to 1st generation DES
and long-term stability of the polymer
Drug-Eluting Stent (DES) (Xience vs biodegradable polymer)
Summary
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Acknowledgments
Washington DC
CVPath Institute, Inc.
CVPath Institute
Hiroyoshi Mori, MD
Sho Torii, MD
Emanuel Harari, MD
Elena Ladich, MD
Robert Kutz, MS
Ed Acampado, DVM
Youhui Liang, MD
Abebe Atiso, HT
Jinky Beyer
Lila Adams, HT
Frank D Kolodgie, PhD
Liang Guo, PhD
Harry Davis, PhD
Renu Virmani, MD
My email: [email protected]