patrick w. serruys, md, phdassets.escardio.org/assets/presentations/other2011/... · 1 3 6 24 mos...
TRANSCRIPT
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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
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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
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Poly -LL- Lactide (PLLA)Everolimus Eluting Scaffold (BVS)
Mass Loss
Lactic Acid
PLA
Krebs Cycle
Mass Transport
Molecular Weight
H2O
Hydrolysis
CO2 + H2O
MSCT
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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
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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
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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)
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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
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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
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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
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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.
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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
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Do bioresorbable scaffolds answer
the unmet needs of metallic stents?
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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 %
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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> <
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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
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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
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Baseline Follow-up
Quantitative OCT Assessment of BVS 1.1
Preclinical model: histomorphometry28 days after implantation
#3. Late recoil is no longer the issue.
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Baseline Follow-up
Strut area
Strut Core area Strut Core area
Preclinical model: histomorphometry28 days after implantation
#3. Late recoil is no longer the issue.
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Lumen AreaScaffold AreaStrut Core area
Baseline Follow-up
Quantitative OCT Assessment of BVS 1.1
Neointimal area =Scaffold area – Lumen area –Strut core area
Strut area
Strut Core area Strut Core area
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Baseline Follow-up
Quantitative OCT Assessment of BVS 1.1
Neointimal area =Scaffold area – Lumen area –Strut core area
Strut area
Strut Core area Strut Core area
Lumen AreaScaffold AreaStrut Core area
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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
#3. Late recoil is no longer the issue.
No late scaffold shrinkage
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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
#3. Late recoil is no longer the issue.
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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
#3. Late recoil is no longer the issue.
No premature sign of bioresorption
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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
#3. Late recoil is no longer the issue.
Well controlled inhibition of neointima
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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
#3. Late recoil is no longer the issue.
Minimal reduction in functional lumen area
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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
#3. Late recoil is no longer the issue.
Almost complete coverage of the struts with resolution of incomplete apposition
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A
B
C
DE
A B C D E
Post-procedure
Pre-procedure
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A’
B’C’
D’ E’
A’ B’ C’ D’ E’
6 months Fup
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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
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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
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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
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Baseline
NON APPOSED
2 years
STRUTS NON DISCERNIBLE
Smooth
#4. Bioresorption is a real phenomenon. (Serruys et al. Lancet 2009)
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OFDI 3D reconstruction provides us with an
exquisite endoluminal view of the process
Film No : 091354 side branch
proximal→distal
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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
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#4. Bioresorption of jailed side branch are real phenomenon. (Okamura et al. EHJ 2010)
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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)
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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.
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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
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Autophagy of macrophage inducedby everolimus with clearance ofatherosclerotic plaque
Autophagosome
JACC 2009
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-
-
-
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
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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.
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#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
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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
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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
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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
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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
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2015-2020,
Thank you for your attention