preclinical evidence on des performance - pcronline · preclinical evidence on des performance...

Preclinical Evidence on DES Performance

Aloke Finn, MD.

CVPath Institute, Inc.

Gaithersburg, MD, USA.

Assoc. Professor

University of Maryland

Baltimore, MD

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-

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

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

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

Preclinical Models of Thromboresistance: Xience versus

Competitors

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

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

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

Representative images of

Scanning Electron Microscopy

Flu

oro

Po

lym

er

co

ate

dV

isio

n (

BM

S)

Otsuka F, et al. JACC Cardiovasc Interv, 2015;8:1248-1260

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

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

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


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


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



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




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


Number of CD14 positive cell

P<0.01

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.

Preclinical and Clinical Data on Endothelialization: Xience versus

Competitors

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

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)

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

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.

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.

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

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

Long-term durability of polymer

59 years old maleDuration 5 years



2x 40x Polarized

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

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]

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