Patrick W. Serruys, MD, PhDassets.escardio.org/assets/Presentations/OTHER2011/... · 1 3 6 24 Mos...

The 4th revolution in percutaneous coronary revascularization:

Biodegradable drug eluting scaffold

Patrick W. Serruys, MD, PhD

Thoraxcenter, Erasmus MC, Rotterdam, The Netherlands

Cardiology Update 2011

POBA Bare-metal

stent Drug-eluting metallic stent

Bioresorbable scaffold therapy

Acute Occlusion - + + +

Acute ST na - + +

Subacute ST na - - +

Acute recoil - + + +

Constrictive remodeling - + + +

Neointimal hyperplasia - -- + +

Expansive remodeling + - - +

Late Luminal Enlargement

+ - - +

Late ST na - - +

Post angioplasty

4 months later

Dissection and

intraparietal

hemorrhage

Dissection

Scaffolded by stent

The four revolutions

Poly -LL- Lactide (PLLA)Everolimus Eluting Scaffold (BVS)

Mass Loss

Lactic Acid

PLA

Krebs Cycle

Mass Transport

Molecular Weight

H2O

Hydrolysis

CO2 + H2O

MSCT

Poly-lactic Acid ( PLA ) Polymer

PLLA scaffold Backbone

Provides scaffold integrity

Higher crystallinity

Processed for increased radial strength

Thin coating of amorphous PDLA containing Everolimus at a ratio of 1:1Lower crystallinityControlled drug release

Bioabsorbable Drug Everolimus Eluting scaffold (BVS 1.0)

BACKBONE

OF

SCAFFOLD

Coating

Vessel wall

Crystalline

Amorphous

Uncoated

Coated

1 3 6 24 Mos

Support

Mass Loss

Tie chains

Molecular

Weight

12 18

Polylactide Degradation versus Radial Support

Bioabsorbable Drug Everolimus Eluting Stent (BVS)

Amorphous Tie chains

Crystal lamella

44 pigs implanted with BVS fully bioresorbable scaffold (BVS)

•2 Yucatan minipigs underwent OCT and GPC (5 BVS): OCT+GPC •1 Yucatan minipig was sacrificed after OCT (2 BVS): OCT+ Histology•4 Yucatan minipig was sacrificed (7 BVS): Histology*

•5 Yucatan minipigs were sacrificed after OCT at 3 years (8 BVS): OCT + Histology•3 Yucatan minipigs underwent GPC (5 BVS)

2 Yorkshire landrace pigs were sacrificed after OCT immediately after procedure (4 BVS)OCT + Histology

•5 Yucatan minipigs were sacrificed after OCT at 4 years (12 BVS): OCT + Histology•2 Yucatan minipigs underwent histology at 4 years (3 BVS)*

•2 Yorkshire landrace pigs were sacrificed after OCT at one month after procedure (4 BVS): OCT + Histology•7 Yucatan minipigs underwent histology only at one month (14 BVS): Histology*

7 Yucatan minipigs underwent histology only at 6 months (12 BVS): Histology*

Acute

1 month

6 months

24 months

36 months

48 months

One pig died before 48 months

12 months

18 months

1 Yucatan minipig underwent Gel Permeate Chromatography (GPC, 3BVS)

2 Yucatan minipigs underwent GPC (6BVS)

E F G H

OCT and Histology: 2 years after Procedure

A, B: OCT: the “preserved box” appearance of strutsC, D: Locations of bioresorbed struts readily visible in histological sections stained with HEE: Alcian blue fills in the regions previously occupied by the struts (proteoglycan). F, G: Neither collagen (red in Trichrome staining) nor smooth muscle (brown in smooth muscle actin immunohistochemical staining) were detected in the strut footprint .H: A small rim of calcification in von Kossa staining, corresponding to the location of the PDLLA coating (black arrows, H).

G H

2 years

3 years

1.5 years

1 years

In-vitro

C

FE G

A D

H

OCT, Histology and TEM: 3 years after Procedure

A: OCT: “Preserved box” subcategory visible only at 8 and 9 o’clock.

B, C: HE staining: Strut footprints now coalesced with the surrounding tissue.

D: Trichrome staining: the connective tissue filled in the strut footprint

E: Alcian Blue: proteoglycan matrix in the strut footprint (blue)

F: von Kossa: minimal calcification outlining the sites.

G: SMA staining: Only a minority of cells positive with SMA in the strut footprints indicating that these cells are

likely of alternate cellular origin (e.g. fibroblasts)

H: Transmission electron microscopy: the strut footprints are composed of condensed, non-fibrillar glycoprotein.

Transmission electron microscopyNon –fibrillar

Glycoprotein

Non –fibrillar

Glycoprotein

2 years

3 years

4 years

By chromatography,

polymeric struts

were no longer

detectable

Strut voids were

filled with young

connective tissue

and coalesced

with vessel wall.

Strut voids are

minimally

discernible in

histology, with

localized low

density of smooth

muscle cells at the

presumed site of

polymeric struts.

HE staining

Alcian Blue

Movat

Alcian Blue

Maturation of endothelial cell junctions

48 month BVS

Overlaying

endothelial cells,

dense continuous

junctions

“weak”

single junction

1 month BVS

AP2932133 Rev. A 15Information contained herein for presentation at EuroPCR 2010 only.

Tests performed by and data on file at Abbott Vascular.

MediaNeointima

Transmission Electron Microscopy of Neointima and Media at

1 and 36 months Following Placement of BVS Stents

a b

c

d

1 Month

36 Month

2μm

2μm 2μm

2μm

AP2932133 Rev. A 14Information contained herein for presentation at EuroPCR 2010 only.

Tests performed by and data on file at Abbott Vascular.

More Intracellular

organelles

Do bioresorbable scaffolds answer

the unmet needs of metallic stents?

2011/3/25

0

10

20

30

40

50

60

70

80

90

100

-15 -10 -5 0 5 10 15 20 25

Cumulative frequency distribution curve of Relative Recoil of bioresorbable scaffolds (BVS) and metallic

Everolimus-eluting stents (EES,Xience V)

%

%Acute Recoil

EES : 4.3 ± 7.1%

#1. We do not have to worry about acute recoil

Onuma et al. CCI 2010

BVS 1.1: 6.7±6.4 %

91° 88°128°

Conformability in BVS 1.1 (N=89)

#2. Exceptional conformability of the BVS has already been clinically observed.

Gomez et al. JACC int 2010

Pre-scaffold

Balloon Post-scaffold

P* P

Angulation, ° 28.7 10.4 26.9 0.06 <0.001> <

Δ Vessel Area = +0.3%

Δ scaffold Area = -11.8%

Δ Lumen Area = -16.8%

% Scaffold Obstruction = 5.3%

Late Loss = 0.43mm

The first generation of everolimus-eluting bioresorbable scaffold (BVS1.0) showed signs of shrinkage at 6 months (dubbed “late recoil”) that contributed to the late luminal loss.

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

-0.5 0 0.5 1 1.5 2

BMS**: 0.85 mm (N=27)

BVS1.0: 0.43mm (N=26)

EES*: 0.10 mm (N=23)

Deficiency of the BVS 1.0 in the ABSORB Cohort A

LATE LOSS

angiographic

IVUS measurement

Angiographic measurement

Revision 1.1 has

• More radial strength

• More uniform support and drug

application

• Longer duration of support

• Profile less than Cypher

• Track test better than ML Vision

• No change in strut thickness

Larger Maximum Circular Unsupported scaffold area (MCUSA)

The second generation (BVS1.1) has a modified platform design and a different manufacturing process of the polymer.

BVS 1.0: Circumferential out-of-phase zigzag

hoops linked together by three longitudinal

struts between each hoop

BVS 1.1: in-phase zigzag hoops

linked by bridgesdistal

proximal

Side branch

tissue prolapse

Deficiency of the BVS 1.0 in the ABSORB Cohort A

Baseline Follow-up

Quantitative OCT Assessment of BVS 1.1

Preclinical model: histomorphometry28 days after implantation

#3. Late recoil is no longer the issue.

Baseline Follow-up

Strut area

Strut Core area Strut Core area

Preclinical model: histomorphometry28 days after implantation


Lumen AreaScaffold AreaStrut Core area

Baseline Follow-up


Neointimal area =Scaffold area – Lumen area –Strut core area

Strut area


Baseline Follow-up


Neointimal area =Scaffold area – Lumen area –Strut core area

Strut area


Lumen AreaScaffold AreaStrut Core area

Intent-to-treat (n=25)

Post PCI 180 days % difference P value

Mean Scaffold area, mm2 7.53 7.74 +2.67% 0.1

Minimum scaffold area, mm2 6.31 6.20 -1.99% 0.63

Mean Prolapse area, mm2 0.26 na

Mean strut area, mm2 0.46 na

Mean strut core area, mm2 0.21 0.20 -1.37% ns

Mean Neointimal Area, mm2 na 1.25

Mean Flow area, mm2 6.86 6.14 -11% <0.001

Minimal flow area, mm2 5.56 4.73 -15% <0.001

% area stenosis 19% 24% 0.03

% Uncovered struts - 3.23%

ISA area, mm2 0.19 (n=12) 0.31 (n=3)

Results of Quantitative OCT Analysis


No late scaffold shrinkage









Mean Flow area, mm2 6.86 6.14 -11% <0.001




ISA area, mm2 0.19 (n=12) 0.31 (n=3)











Mean Flow area, mm2 6.86 6.14 -11% <0.001




ISA area, mm2 0.19 (n=12) 0.31 (n=3)



No premature sign of bioresorption









Mean Flow area, mm2 6.86 6.14 -11% <0.001




ISA area, mm2 0.19 (n=12) 0.31 (n=3)



Well controlled inhibition of neointima









Mean Flow area, mm2 6.86 6.14 -11% <0.001




ISA area, mm2 0.19 (n=12) 0.31 (n=3)



Minimal reduction in functional lumen area









Mean Flow area, mm2 6.86 6.14 -11% <0.001




ISA area, mm2 0.19 (n=12) 0.31 (n=3)



Almost complete coverage of the struts with resolution of incomplete apposition

A

B

C

DE

A B C D E

Post-procedure

Pre-procedure

A’

B’C’

D’ E’

A’ B’ C’ D’ E’

6 months Fup

QCA, IVUS, OCT, IVUS VH MSCT

Group B1 (n = 45)

Baseline 6 12 24

MonthsMonthsMonths

Group B2 (n = 56)

18

Months

MSCT

36

Months

What did we learn from ABSORB B1,B2 (2009-2012)?

MSCT

Circulation

0

10

20

30

40

50

60

70

80

90

100

-0,5 0,5 1,5

0

10

20

30

40

50

60

70

80

90

100

-0,5 0,5 1,5

EES: 0.10±0.23 mm (N=22)

Cohort B: 0.25 ± 0.23 mm (N=54)

EES: 0.23 ± 0.29 mm (N=22)

Cumulative frequency distribution curves of Late loss: BVS 1.1 (Cohort B) vs. Xience V (Spirit I)

6 Months (SPIRIT I vs. B1) 12 Months (SPIRIT I vs. B2)

Cohort B: 0.19±0.18 mm (N=42)

Circulation ACC,april

What did we learn from ABSORB

cohort A (2006-2011)?

QCA, IVUS, OCT, IVUS VH

Baseline 6 12 2

YearsMonthsMonthsMSCT

18

Months

3

Years

4

Years

5

Years

MSCT

Group A (n = 30)

MSCT

Baseline

NON APPOSED

2 years

STRUTS NON DISCERNIBLE

Smooth

#4. Bioresorption is a real phenomenon. (Serruys et al. Lancet 2009)

OFDI 3D reconstruction provides us with an

exquisite endoluminal view of the process

Film No : 091354 side branch

proximal→distal

1 2

1

2

3

1

2

34

V type

T type

H type

1b

Non-jailed

Classification of

Jailed sidebranch

ostium according

to number of

compartment

created by the

overhanging struts

with different

configuration (e.g.

V, T and H type)

40%

25%

25%

10%

Today, with 3-D OFDI we can further evaluate the

bioresorption process.

Absorb Cohort B (n=17)

V type

#4. Bioresorption of jailed side branch are real phenomenon. (Okamura et al. EHJ 2010)

3.9mm2 7.1mm2

6.9mm210.1mm2

Pre-stenting Post-stenting 6-month 24-month

#4. Bioresorption and vessel wall integration are real phenomena. (Lancet 2009)

2-Year IVUS Unpaired (BVS1.0)

Post-

PCI

6-month

F/U

2-year

FU

% Diff

(6M to 2Y)

p-

value

n=25 n=25 n=18

Vessel (EEM) area

(mm2)13.49* 13.79 12.68 -3.91 0.08

Lumen area (mm2) 6.04 5.19 5.46 +10.85 0.03

Minimal Lumen

area (mm2)5.09 3.92 4.35 +17.24 0.005

Plaque area (mm2) 7.44* 8.60 7.22 -12.74 <0.001

*n=24P-values per Wilcoxon’s signed rank test

% Diff based on paired values

#5. Late plaque reduction and lumen enlargement have been documented.

Bioresorbable Scaffold – A new treatment Paradigm for Atherosclerotic Plaque

-

-

-

Lum

en R

educt

ion

+PIT FAIT

Lumen Reduction

Compensatory Expansive Remodeling of EEM

Struts

Lumen Enlargement By Bioresorbable

Scaffolding

Scaffolding

Lumen Enlargement by Plaque

Regression

Autophagy of macrophage inducedby everolimus with clearance ofatherosclerotic plaque

Autophagosome

JACC 2009

-

-

-

Lum

en R

educt

ion

+PIT FAIT

Compensatory Expansive Remodeling of EEM

Struts

Lumen Reduction by Intrastent Growth

of tissue

Metallic Struts

Metallic stent is the cage

Metallic Stent – A classical treatment Paradigm for Atherosclerotic Plaque

Metallic Stent – A caged lumen doomed to get reduced

18M FU

3.0

4.0

5.0

6.0 In-stent

Lum

en A

rea (

mm

2)

3.1

5.2

40%

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

9.0

10.0

Lum

en

Are

a (

mm

2)

ReferenceArea

MeanArea

MinimalArea

5.2 ±1.3 5.5 ±1.0

3.6 ±0.919 ± 9%

Mean

Diameter

Stenosis

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

#6. Non-invasive imaging for early and late follow-up is now feasible.

#7 Endothelium-dependent vasomotion is restored (Lancet 2009)

1

1.5

2

2.5

3

3.5

Pre-Ach

Ach

Nitro

Me

an

lu

me

n d

iam

ete

r, m

m P=0.3 P=0.4

P=0.03

1.81 1.86 1.93

Ach

te

st

(n

=9

)

Scaffolded segment

Pre-Ach

Post- Ach

Hierarchical6 Months

30 Patients

12 Months

29 Patients*

3 Years

29 Patients*

4 Years

29 Patients*

Ischemia Driven MACE, %(n) 3.3% (1)* 3.4% (1)* 3.4% (1)* 3.4% (1)*

Cardiac Death, % 0.0% 0.0% 0.0% 0.0%

MI, %(n)

Q-Wave MI 0.0% 0.0% 0.0% 0.0%

Non Q-Wave MI 3.3% (1)** 3.4% (1)** 3.4% (1)** 3.4% (1)**

Ischemia Driven TLR , %

by PCI 0.0% 0.0% 0.0% 0.0%

by CABG 0.0% 0.0% 0.0% 0.0%

No new MACE events between 6 months and 4 years

No stent thrombosis up to 4 years (All patients off clopidogrel)

Ormiston et al. 2008, Serruys et al. 2009, Onuma et al. 2010

*One patient withdrew consent after 6 months but the vital status of the patients and absence of cardiac event is known through

the referring physician.

**This patient also underwent a TLR, not qualified as ID-TLR (DS = 42%) followed by post-procedural troponin qualified as non-

Q MI and died from his Hodgkin’s disease at 888 days post-procedure.

#8 No acute/Subacute/Late stent thrombosis up to 4 years

4 Year Clinical Results – Intent to Treat

6.0%

7.5%

=1.5%

393-day HR0.85 [0.35,2.05]

p=0.7149

BVS(A+B1+B2)

XV(SPI+SPII+SPIII RCT)

MA

CE

(C

-De

ath

, M

I, I

D-T

LR

)

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

Time Post Index Procedure (Months)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

6.0%

7.5%

=1.5%

393-day HR0.85 [0.35,2.05]

p=0.7149

BVS(A+B1+B2)

XV(SPI+SPII+SPIII RCT)

MA

CE

(C

-De

ath

, M

I, I

D-T

LR

)

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

Time Post Index Procedure (Months)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

XV Includes only patients with single 3.0 x 18mm stent

BVS Includes all patients with single lesion

KM estimate of MACE rate in patients treated with BVS (Cohort A and B Absorb, n=130) vs. patients treated

with a single 3x 18 mm metallic EES (Spirit I+II+III, n=227)

#8 Clinical performance comparable to Everolimus eluting metalic stent

A

B

C

2009 Thorax center

C

B

A

D

D

E

E

Arrow indicates a metallic marker

#10 the safety of this technology remains up to 10 years.

1999 Thorax center

Past, Present and Future…

* Timelines based on patient follow-up dates, not data availability

Lancet 2008 & 2009, Eurointervention 2010

Circ 2010

EH 2010

Follow-up Enrolled To be Enrolled

Just CE marked!

N=30

N=45

N=56

N=171

Grand total:302

2015-2020,

Thank you for your attention

Patrick W. Serruys, MD, PhDassets.escardio.org/assets/Presentations/OTHER2011/... · 1 3 6 24 Mos...

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