ZoMaxx: Abbott`s Drug Eluting Stent Programme

ZoMaxx: Abbott`s Drug Eluting Stent Programme

ZoMaxx: Abbott's Drug
Eluting Stent Programme
John Ormiston
Green Lane and Mercy Hospitals
Auckland, New Zealand
ZoMaxx Drug-Eluting Stent
TriMaxx
Stent
Platform
ZoMaxx™
DrugEluting
Stent
ABT-578
PharmaCoat
PharmaCoat
Polymer
Polymer
Coating
Coating
ZoMaxx Drug-Eluting Stent
TriMaxx
Stent
Platform
ZoMaxx™
DrugEluting
Stent
ABT-578
PharmaCoat
PharmaCoat
Polymer
Polymer
Coating
Coating
TriMaxx Stent Platform
8-10 cells/
perimeter
Off-set crown
connector
2 connectors/
circumference
Stent Scaffolding
(Mean interstrut diameter)
Scaffolding Diameter (mm)
1.2
1.0
0.8
0.6
0.4
0.2
0.0
Driver
TriMaxx
Express 2
Vision
Driver
Driver is
is a
a trademark
trademark of
of Medtronic;
Medtronic; Express
Express22 is
is a
a trademark
trademark of
of Boston
Boston Scientific;
Scientific;
Vision
Vision is
is a
a trademark
trademark of
of Guidant;
Guidant; Bx
Bx Sonic
Sonic is
is a
a trademark
trademark of
of Johnson
Johnson &
& Johnson
Johnson
Data on file at Abbott Vascular Devices
BX Sonic
Triplex stent material
3 layered composite
Tantalum
Strut thickness
0.0029”
Tantalum layer
0.0029”
Stainless
steel
Stainless
steel
‰ Tantalum provides strength and increased
radioopacity
‰ It allows struts to be thinner without sacrificing
strength or radioopacity
Triplex is a trademark of Uniform Tubing, Inc.
Currently in development at Abbott Vascular Devices, not to be distributed or reproduced without permission of Abbott Vascular Devices
Stent Material and
Strut Thickness
Labeled Thickness (inches)
0.0060
0.0050
0.0040
Stainless
Stainless Steel
Steel
0.0030
Cobalt
Cobalt Chrome
Chrome
0.0020
Triplex
Triplex™™
0.0010
0.0000
TriMaxx
Vision
Driver
Liberte
Express 2
BX Sonic
Driver
Driver is
is a
a trademark
trademark of
of Medtronic;
Medtronic; Express
Express22 &
& Liberté
Liberté are
are trademarks
trademarks of
of Boston
Boston Scientific;
Scientific;
Vision
Vision is
is a
a trademark
trademark of
of Guidant;
Guidant; Bx
Bx Sonic
Sonic is
is a
a trademark
trademark of
of Johnson
Johnson &
& Johnson;
Johnson; Triplex
Triplex is
is a
a trademark
trademark of
of Uniform
Uniform Tubing,
Tubing, Inc.
Inc.
Data on file at Abbott Vascular Devices
Radiopacity
Strut thickness is less without sacrifice of radio-opacity
300
Radiopacity
250
200
Tantalum
Tantalum
Cobalt
Cobalt Chrome
Chrome
Cobalt
Cobalt Alloy
Alloy
Stainless
Stainless Steel
Steel
Triplex
Triplex™™
Wiktor
150
Bx Sonic
TriMaxx
100
Driver
Liberté
Penta
Zeta
50
0
Vision
Express2
MultiLink
0.001”
0.002”
0.003”
0.004”
Strut Thickness (inches)
Driver
Driver is
is a
a trademark
trademark of
of Medtronic;
Medtronic; Express
Express22 is
is a
a trademark
trademark of
of Boston
Boston Scientific;
Scientific;
Vision
Vision is
is a
a trademark
trademark of
of Guidant;
Guidant; Bx
Bx Sonic
Sonic is
is a
a trademark
trademark of
of Johnson
Johnson &
& Johnson;
Johnson; Triplex
Triplex is
is a
a trademark
trademark of
of Uniform
Uniform Tubing,
Tubing, Inc.
Inc.
Data on file at Abbott Vascular Devices
0.005”
Independent Measurement of
Stent/Delivery System Profile
(Diameter)
‰Calibrated travelling
microscope
‰3 points along 3 examples of
each stent/delivery system
Ormiston CCVI 2000
Ormiston
Diameter (mm)
Stent Delivery System Crossing Profile
1.6
1.5
1.4
1.3
1.2
1.1
1
0.9
Multilink
Ave GFX
Wiktor I
Wallstent
Crossflex LC
Bard XT
Nir 7 Cell
S7
Express
BeStent2
S670d
BiodivYsio
Duet
Tristar
Penta
Nir Royal
Tetra
Express 2
Vision
Jo Stent flex
Bx Velocity
Zeta
Sonic
Duraflex
DISA S-Flex
Antares
Driver
Trimaxx
Liberte
Tsunami
Ormiston
Stiffness was measured using a 3 point
bend test
F
r
(Instron)
r
Ormiston Cathet Cardiov
Interv 2000
stiff
Force
The slope of the
Force/Displacement
curve is Stiffness
Less stiff
Displacement
Stiffness is the
reciprocal of
Flexibility
1
Flexibility =
stiffness
Ormiston
0
Nir Royal
Nir 7 Cell
Antares
Bx Velocity
BeStent2
DISA S-Flex
Jo Stent
BiodivYsio
Duraflex
S670d
Tetra
Wallstent
Penta
Zeta
Tristar
S7
Express II
Expanded
Express
Duet
Liberte
Vision
Multilink
AVE GFX
Tsunami
Driver
CrossFlex
Bard XT
Trimaxx
Wiktor
gms force/mm
Stiffness (reciprocal of flexibility)
160
140
Mounted
120
100
80
60
40
20
Ormiston
Stent Flexibility
In Vitro Bench Testing
10g
10g
Bx
OC
10g
Express2
10g
Vision
10g
10g
TriMaxx
Driver
Driver
Driver is
is aa trademark
trademark of
of Medtronic;
Medtronic; Express
Express22 is
is aa trademark
trademark of
of Boston
Boston Scientific;
Scientific;
Vision
Vision is
is aa trademark
trademark of
of Guidant;
Guidant; Bx
Bx Sonic
Sonic is
is aa trademark
trademark of
of Johnson
Johnson &
& Johnson
Johnson
Data on file at Abbott Vascular Devices
Stent radial strength is needed
especially in calcified, fibrotic,
or ostial lesions to:
‰Resist compressive forces
‰Maintain size
‰Maintain circular shape
Ormiston
PRESSURE
PRESSURECHAMBER
CHAMBER
IVUS
tecoflex
p
Stent
Water
Ormiston
% CROSS-SECTIONAL AREA
% AREA and EXTERNAL PRESSURE
(IVUS on benchtop)
110
Stent D
100
10%
Stent X
90
80
25%
70
0
0.5
1
1.5
2
2.5
3
PRESSURE (Atmos)
Ormiston
2.5
2.0
1.5
1.0
0.5
P re s s u r e (b a r )
Radial Strength:
External Pressure and Stent Cross-sectional Area Reduction
Ormiston
D u ra fle x
Te tra
Duet
E xp re ss
S7
L ib e rte
D rive r
V is io n
Tsu n a m i
P e n ta
C ro s sfle x
Trim a xx
B x V e lo city
B e S te n t 2
V -Fle x
C ro w n
N IR 9
M u ltilin k
Jo S te n t
B io d ivy sio
B e S te n t
0.0
Collapse
Mean 25%
Mean 10%
3.0
Is the Zomaxx Stent Platform
suitable for Bifurcation stenting
in the DES era?
• Stents were deployed in a phantom
using contemporary bifurcation
techniques
• Stents were photographed externally
and internally
Ormiston
“Crush” Technique with Zomaxx
Main br
Side br
“Crush” Technique with Zomaxx
Deploy
side-br
stent
“Crush” Technique with Zomaxx
Deploy main br
stent crushing
side-br stent in
main br
“Crush” Technique with Zomaxx
2 layers
3 layers
“Crush” Technique with Zomaxx
2 layers
3 layers
“Kissing” balloon
post-dilatation
Kissing balloon postdilatation releases the
side-branch from “jail”
after “Crush” Bifurcation
Stenting
Before “kiss”
Side-br jail
After “kiss”
No Side br jail
Ormiston
“Kissing” balloon post-dilatation after “crush” fully
expands the Zomaxx stent at the side-br ostium and
corrects any main br distortion
Well expanded
at side-br
ostium
No obstruction to main br
No Side br jail
Ormiston
The “Culotte” Technique-
Provisional side-br stenting in the DES era
Ormiston 04
Trimaxx Stent after “Culotte” Bifurcation
followed by “kissing” balloon post-dilatation
Main br
Side br
Ormiston
Trimaxx Stent after “Culotte” Bifurcation
followed by “kissing” balloon post-dilatation
Main br
Side br
Ormiston
Trimaxx Trial (BMS)
• 100 patients to receive Trimaxx (BMS)
• Single-vessel, de novo coronary lesions (Type AB), length > 10 mm and < 15 mm; RVD 3.0-3.75
mm
• Brazil, Germany
• PI: Alex Abizaid
• Primary Endpoint:
MACE at 30 days
• Secondary Endpoints:
MACE, TLR, TVR,
ABR, Late Loss at 6 months
ZoMaxx Drug-Eluting Stent
TriMaxx
Stent
Platform
ZoMaxx™
DrugEluting
Stent
ABT-578
PharmaCoat
PharmaCoat
Polymer
Polymer
Coating
Coating
Polymer- PC Technology™
• PC Technology™ mimics
body’s own chemistry
– Hema-PC: Mimics outer
membrane of
red blood cell for
biocompatibility
– Lauryl: Hydrophobic
for stability and adhesion to the
stent surface
– Hydroxypropyl Methacrylate
(HPM) & Trimethoxysilyl
Methacrylate (SMT): Crosslinking for durability
• Following drug
elution, PC coating
remains bio-inert
and noninflammatory
PC Technology is a trademark of Biocompatibles, Inc.
Presented by N. Chronos, TCT 2004, Washington, DC
(
)2 3
(
O
O
O
O
Hema-PC
)5
O
O
O
O
Si
O CH 3
H 3CO O CH
3
O
N
(
OH
O
P
)2 5
O
O
-
(
)4 7
+
Lauryl
HPM & SMT
Effect of PC coating on Inflammation
in Porcine Coronary arteries
InflammationSco
Sco
Inflammation
2.00
2.00
Bare
BareTriplex
Triplex(n=8)
(n=8)
1.50
1.50
P
PC
C-coated
-coatedTriplex
Triplex(n=8)
(n=8)
1.00
1.00
0.50
0.50
0.00
0.00
00
30
30
60
60
90
90
120
120
150
150
D
Days
ays after
after implantation
implantation
PC Technology is a trademark of Biocompatibles, Inc.
Data on file at Abbott Vascular Devices
180
180
Area Stenosis
Stenosis (%)
(%)
Area
Effect of PC coating on Neointimal
Hyperplasia in Porcine Coronary
Arteries
50%
50%
Bare
Bare Triplex
Triplex (n=8)
(n=8)
40%
40%
PC-coated
PC-coated Triplex
Triplex (n=8)
(n=8)
30%
30%
20%
20%
10%
10%
0%
0%
00
30
30
60
60
90
90
120
120
Days
Days after
after im
implantation
plantation
PC Technology is a trademark of Biocompatibles, Inc.
Data on file at Abbott Vascular Devices
150
150
180
180
The ZoMaxx Stent - PharmaCoat
PC topcoat
ABT-578
PC basecoat
Not approved for sale in or
outside the United States.
Presented by L. Schwartz, TCT 2004, Washington, DC
Comparison of in vivo Elution Rates
120
120
120
120
100
100
100
100
80
80
% Drug
Drug eluted
eluted
%
% Drug
Drug eluted
eluted
%
Rabbit iliac models
Endeavor™
No top coat
60
60
40
40
~75% elution in 2 days
100% elution in 10 days
20
20
ZoMaxx™
Cypher™
80
80
60
60
40
40
~75% elution in 10 days
100% elution in 30 days
20
20
00
00
00
10
10
20
20
Time
Time (days)
(days)
30
30
00
10
10
20
20
Time
Time (days)
(days)
Presented by A. Carter, ACC 2003, presented by B. Chevalier, PCR 2004, data on file at Abbott Vascular Devices
30
30
ZoMaxx Drug-Eluting Stent
TriMaxx
Stent
Platform
ZoMaxx™
DrugEluting
Stent
ABT-578
PharmaCoat
PharmaCoat
Polymer
Polymer
Coating
Coating
ABT 578 is different from rapamycin
due to Tetrazole group on C42
HO
42
O
O
O
O
O
N
R apam ycin
Rapamycin
Tetrazole ring at
C42
O
HO
N
HO
O
O
O
O
N N
N
42
O
O
O
O
ABT-578
ABT 578
N
O
HO
O
HO
O
O
O
O
FK BP Binding
D om ain
m TO R Effector
D om ain
The cell cycle
and action of
ABT 578
cell responds to
growth factor stimulation
G0
mitosis
M
G1
cytostatic agents
allow cells in
G0 to re-enter
the cell cycle
Checkpoint
G2
prepares for mitosis
S
ABT-578 is cytostatic:
blocks entry into S
phase as does
sirolimus
DNA synthesis
‰ Delivered locally, ABT-578 inhibits inflammation and the
proliferation of SMCs
‰ ABT-578 is cytostatic by halting the cell cycle in the late G1 phase
Effect of TriMaxx, ZoMaxx, Cypher, and Taxus Stents on
Swine Coronary Morphometry at 28 days (mean + SEM)
Neointimal Area (mm2)
3
*
**
mm2
2
**
9
18
18
18
TriMaxx
Taxus
Cypher
ZoMaxx
1
0
*p<0.05 vs. TriMaxx
**p<0.01 vs. TriMaxx
Lipophilicity of Some Clinical DES Agents
45000
40000
P<0.0001
ABT-578 is 2.2 times more
lipophilic than rapamycin
P (C octanol/C Water)
35000
Lipophilicity increases tissue
retention of the drug
30000
25000
20000
15000
10000
5000
n=16
0
n=16
n=9
n=10
n=10
1
ABT-578
Rapamycin
Estadiol
Determination of Partition Coefficients for ABT-578, Rapamycin, Paclitaxel,
Dexamethasone, and Estradiol at 22 deg C, Abbott Laboratories Report on File, 2004
Presented by L. Schwartz, TCT 2004, Washington, DC
Paclitaxel
Dexamethasone
Rabbit Study – Preliminary results
Comparison of Drug Levels in Arterial
Tissue for ZoMaxx Stent versus Cypher
Stent
160
Drug in Tissue ( ug / g )
140
ZoMaxx™
Cypher™
120
bc3
100
80
60
40
20
Mean ± SEM
n=4
0
0
5
10
15
20
25
Time (days)
Cypher
Cypher is
is aa trademark
trademark of
of Johnson
Johnson &
& Johnson
Johnson
Presented by L. Schwartz, TCT 2004, Washington, DC
Data on file at Abbott Vascular Devices
30
슬라이드 42
bc3
the ratio between abt and sirolimus uptake in the first 4 days is around 10:1, are we sure that is safe?
Bernard, 2004-05-12
Zomaxx I Trial
• 400 patients to be randomized to receive
either a Zomaxx stent or a Taxus stent
• Non-inferiority trial
• Primary end-point is late loss 9 month angio
• Single de novo lesions
• > 10 mm and < 30 mm, RVD 2.5-3.5 mm
• 35 sites New Zealand, Australia, Europe
• PI Bernard Chevalier
161 of 400 pts enrolled as of 15.4.05
Zomaxx II Trial
• 1670 patients will be randomized to
receive either a Zomaxx stent or a
Taxus stent
• Non-inferiority trial
• Primary end-point is TVR
• Single de novo lesions
• 75 sites USA and Canada
ZOMAXX I and II Core labs
Data Center
– Harvard Clinical Research Institute, Boston
QCA
– Brigham and Women’s, Boston
IVUS
– Stanford Interventional Cardiology, Palo Alto
ECG
– Harvard Clinical Research Institute, Boston
Presented by A. Yeung, TCT 2004, Washington, DC
Summary
• Zomaxx Stent
– Trimaxx stent has excellent mechanical and
physical properties
– PharmaCoat polymer safe
– ABT 578
– Drug release rate similar to Cypher
• Trials -Zomaxx I underway, Zomaxx
II planned
ZOMAXX I Trial
Randomized, Non-inferiority Trial vs Taxus
N=400
34 sites
Europe
Australia
New Zealand
Single, de novo coronary lesions (Type A-B)
with length > 10 mm and < 30 mm,
and RVD 2.5-3.5 mm.
Pre-dilatation required
Stent Diameters
ZoMaxx™ Stent
N=200
Stent Lengths
2.5 mm
8, 18, 23, 28 mm
3.0 mm
8, 18, 23, 33 mm
3.5 mm
8, 18, 23, 33 mm
TAXUS™ Stent
N=200
Clinical follow-up
30d
6mo
Radiographic follow-up
Primary endpoint:
Secondary endpoints:
Medications:
Stratification:
9mo
12mo
2yr
3yr
4yr
5yr
QCA/IVUS
9-mos. in-segment late loss with equivalency limit of 0.25 mm, σ=0.4 mm;
> 99% power; 1-sided α=0.05
MACE, TVF, TLR, TVR, binary restenosis, in-stent late loss, neointimal volume,
neointimal volume obstruction
Clopidogrel 75 mg QD for at least 6 months, ASA 100 mg QD ≥ 12 months
Site
Presented by A. Yeung, TCT 2004, Washington, DC
ZOMAXX II Trial
Randomized, Non-inferiority Trial, Clinical Endpoint
1670 subjects
~ 75 sites
USA and
Canada
Single, de novo coronary lesions (Type A-B)
with length > 10mm and < 28mm
and RVD 2.5-3.75mm
Pre-dilatation required
Stent Diameters
ZoMaxx™ Stent
N=835
Stent Lengths
2.5 mm
8, 13, 18, 23, 28 mm
3.0 mm
8, 13, 18, 23, 33 mm
3.5 mm
8, 13, 18, 23, 33 mm
TAXUS™ Stent
N=835
Clinical follow-up
30d
6mo
Radiographic follow-up
Primary endpoint:
Secondary endpoint:
Additional Analyses:
Medications:
9mo
12mo
2yr
3yr
4yr
5yr
QCA/IVUS
Non-inferiority to TAXUS using 9-mo ischemia driven target vessel revascularization
(TVR)
In-segment late loss at 9 mo. (QCA)
Binary restenosis, MACE, TLR, TVR, in-stent late loss, neointimal volume, clinical
outcomes by vessel diameter and lesion lengths
Clopidogrel 75 mg QD for 6 months, ASA 325 mg QD for at least 12 months
Presented by A. Yeung, TCT 2004, Washington, DC
TriMaxx Stent Pattern
8 or 10 cells around perimeter
2 connectors between rings
Offset
O.C.C.™ (Offset Crown Connector): connecting foot pulls
the rings closer together and offsets the apexes of the
crowns for improved scaffolding
Distal