Transcript Slide 1
Non-Polymeric and Bioabsorbable Polymers
Will Reign Supreme in Near Future
Alexandre Abizaid, MD, PhD, FACC
Instituto Dante Pazzanese de Cardiologia
Sao Paulo - Brazil
Columbia University
New York - USA
First Generation DES
- Drug-Eluting Stents (DES) dramatically reduced restenosis
as compared to bare-metal stents (BMS)
But the problem is…
- Late stent thrombosis (LST) has emerged as a major safety
concern
0.6% per year
Daemen J et al. Lancet 2007; 369: 667
DES – Late incomplete apposition and
Cypher ® stent thrombosis
Pre
6m
18 m
Post
DES – Late incomplete apposition and
Cypher ® stent thrombosis
40 m
Post PCI
DES – Late incomplete apposition and
Taxus® stent thrombosis
Pre
Post
8m
Post
DES – Late incomplete apposition and
Taxus® stent thrombosis
12 m
PCI
Post PCI
Current Problems with Polymers
Shortcomings often associated
with polymers during stent delivery
Non uniform
polymer coating
“Webbed” polymer
surface leading to
stent expansion
issues”
Polymer delamination
● Durable Coatings-Potential for:
- Continuing source of inflammation
- Poor healing/thrombosis risk
Delayed Healing - DES
Persistent fibrin deposition
Lack of neointimal growth
(uncovered Struts)
*
*
Rabbit 28 days
*Inflammation
Incomplete endothelialization
CYPHER
TAXUS
Fibrin deposition
with malapposition
Severe inflammation
Porcine 28 days
Vermani et al.
Polymer Evolution
Durable Polymers
Bioabsorbable Polymers
Non-Polymeric
Polymer Evolution
Durable Polymers
Bioabsorbable Polymers
Non-Polymeric
Bioabsorbable Polymer with Sirolimus in the porcine model (SurModics Inc.)
Neoinimal Area
(mm2)
BMS
Bioabsorbable polymer
(SynBiosys) + sirolimus
3
2
1
Sustained efficacy
0
30
DES
90
30
90
30
90
(day)
(bioabsorbable polymer)
BMS
Vermani et al.
Bioabsorbable Polymer (SynBiosys GACL-LA) with
Sirolimus in the porcine model (SurModics Inc.)
Grade of inflammation
4
BMS
Bioabsorbable polymer (SynBiosys) + sirolimus
Cypher (historical)
Taxus (historical)
3
2
1
0
30
30
(Day)
90
90
Bioabsorbable Polymer (SynBiosys GACL-LA) with Sirolimus
Bioabsorbable Polymer DES Systems
BioMatrix (Biosensors)
Nevo (Cordis)
JACTAX (Boston Scientific)
Supralimus (Sahajanand)
Sirolimus + EPC capture (Orbus)
Bioabsorbable Polymer DES Systems
BioMatrix (Biosensors)
Nevo (Cordis)
JACTAX (Boston Scientific)
Supralimus (Sahajanand)
Sirolimus + EPC capture (Orbus)
BioMatrix® III Stent Platform
BioFlex™ II
Biodegradable Drug/Carrier:
- Biolimus A9® / Poly (Lactic Acid)
50:50 mix
- abluminal surface only (contacts
vessel wall)
- 10 microns coating thickness
- degrades in 9 months releasing
CO2+ water
BioFlex I
LEADERS: Primary Endpoint
Cardiac Death, MI, or TVR @ 9 months
Cumulative Incidence (%)
15
Risk Difference -1.3%, Upper Limit 95% CI 1.1%
Pnon-inferiority = 0.003
Sirolimus Stent 10.5%
10
Biolimus Stent 9.2%
5
Rate Ratio = 0.88, 95% CI 0.64 - 1.19
0
No. at risk
BES
SES
0
1
2
857
850
806
791
798
786
3
4
5
6
Months of Follow-up
796
784
792
781
784
777
779
771
7
8
9
777
758
771
751
761
746
Definite Stent Thrombosis
Definite stent thrombosis
Cumulative Incidence (%)
3
Sirolimus Stent 2.0%
2
Biolimus Stent 1.9%
1
Rate Ratio = 0.93, 95% CI 0.47 - 1.85
0
Number at risk
BES
SES
0
1
2
857
850
833
822
826
818
3
4
5
6
Months of Follow-up
825
816
824
815
821
815
818
813
7
8
9
817
806
816
803
808
799
LEADERS Bifurcation Subanalysis
MACE*
*MI, cardiac death and clinically driven TVR
Bifurcation Group BES vs. SES
HR 0-2 days
: 1.62 [0.77-3.40] p=0.20
3-360 days : 0.46 [0.24-0.88] p=0.02
Sirolimus Bifurcation group
Biolimus Bifurcation group
Sirolimus Non-bifurcation group
Biolimus Non-bifurcation group
Covered
malapposed strut
Uncovered struts
Hyperplasia of neointima
Well
covered
struts
LA 2.36 mm², SA 3.39 mm ²
Lesions with Stent 1
Lesions with Stent 0
Distribution of Uncovered Struts
within Lesions
Cypher
Biomatrix
Bioabsorbable Polymer DES Systems
BioMatrix (Biosensors)
Nevo (Cordis)
JACTAX (Boston Scientific)
Supralimus (Sahajanand)
Sirolimus + EPC capture (Orbus)
The NEVO™ Polymer
• Fully bioresorbable PLGA polymer
(exclusively housed in reservoirs):
•Benefits
• Complete resorption in 3-4 months
• Fully metabolized
• Highly biocompatible and hemocompatible
• Future applications could use different comonomer
ratios to permit variable resorption times
(few weeks-many months)
8 DAY
30 DAY
60 DAY
90 DAY
Arterial Sirolimus Content (µg/mg artery)
NEVO™: Sirolimus Release &
Tissue
Content
Sirolimus Release from NEVO™ Stent
100
Sirolimus Release (%)
80
60
40
NEVO™ Prototype Stents
CYPHER® Stents
20
0
0 1
3
8
14
30
Implant Duration (Days)
NEVO’s™ sirolimus release kinetics
approximate CYPHER® stent’s
Sirolimus Content in Tissue
80
NEVO™ Prototype Stents
®
CYPHER Stents
60
40
20
0
1
3
8
14
30
Implant Duration (Days)
NEVO™ achieves similar sirolimus
arterial tissue levels to CYPHER® .
Normal porcine coronary arteries, 10-15% implant overstretch; NEVO Data from: AP-061
NEVO RES-I Study Overview
Single De Novo Native Coronary Artery Lesions
Reference Vessel Diameter: 2.5 - 3.5 mm
Lesion Length: ≤28 mm
40 sites worldwide
Europe, South America, Australia and New Zealand
394 subjects, stratified by diabetic status, and randomized 1:1
NEVO™
TAXUS® Liberté™
Sirolimus-eluting Stent
Paclitaxel-eluting Stent
(n=202)
(n=192)
Primary Endpoint: 6-month in-stent late loss
Sub-Study: IVUS subset (50 patients per arm)
Dual antiplatelet therapy for ≥6 months
Clinical/ MACE
30 Day
6Mo
1Yr
2Yr
3Yr
4Yr
Angiographic/ IVUS
87% Angiographic follow up*
95% 180 day clinical follow up*
* Follow-up as of April 16, 2009
5Yr
DRAFT Slides: Awaiting final quality control review: CONFIDENTIAL
Late Lumen Loss at 6-Months
Primary Endpoint
Late Loss (mm)
P<0.001
±0.46
P<0.001
±0.39
±0.31
±0.32
n=180
n=162
n=180
n=162
DRAFT Slides: Awaiting final quality control review: CONFIDENTIAL
6-Month MACE and Components
10
P=0.19
% of Patients
8
NEVO
7.5
Taxus Liberte
6
P=0.37
4.3
4.1
4
P=0.33
P=0.75
P=0.37
2
2.7
3.2
2.6
2.1
1.6
1.6
0.5
0
8/193 13/187
MACE
1/193 3/187
Death
•No reports of Emergent CABG
4/193 5/187
MI
5/193 8/187
Death or MI
3/193 6/187
TLR
Bioabsorbable Polymer DES Systems
BioMatrix (Biosensors)
Nevo (Cordis)
JACTAX (Boston Scientific)
Supralimus (Sahajanand)
Sirolimus + EPC capture (Orbus)
JACTAX Trial
PI: Eberhard Grube
Stent Platform
Liberté® Pre-mounted stent (BSC)
JA Coating
9.2 μg. of Paclitaxel and 9.2 μg. DLPLA (16 mm)
2700 microdots (16 mm)
Mass of polymer approx 3.4 ng. per microdot
< 1 micron thick, abluminal and low molecular
weight biodegradable polymer decreases
persistence time
JACTAX HD Results vs. ATLAS
Matched (9 months)
p=0.14
Binary Restenosis (%)
p=0.12
Labcoat
Liberté
Taxus
Liberté
Labcoat
Liberté
Taxus
Liberté
(n=96)
(n=223)
(n=96)
(n=223)
In-Stent
In-Segment
Bioabsorbable Polymer DES Systems
BioMatrix (Biosensors)
Nevo (Cordis)
JACTAX (Boston Scientific)
Supralimus (Sahajanand)
Sirolimus + EPC capture (Orbus)
Supralimus-Eluting Stents
Supralimus™
Biodegradable Polymer Based Sirolimus Eluting Stent
Platform
Millennium Matrix
‘Intermediate Cell
Geometry’, Slotted Tube
Design
0.0032” strut thickness
Drug: Sirolimus
Drug Dosage: 102g-16mm
Unique Biodegradable Polymeric
Blend
Single layer of coating with drug
free top coat
4-5 m coating thickness
Supralimus-Eluting Stents
SERIES I: Study Design
N = 100
Real world coronary
artery lesions
Diameter: 2.5 to 4.0mm
Length: 11 to 33mm
Supralimus™ Sirolimus Eluting
Stent
Primary endpoint: MACE at 30 days & in-stent binary restenosis at
6 months
Secondary endpoint: Stent thrombosis and MACE at 9 months
Supralimus-Eluting Stents
Supralimus vs. Others
TRIALS
SERIES I
TAXUS IV
SIRIUS
ESIRIUS
ENDEAVORII
BRANDS
SUPRALIMUS
TAXUS
CYPHER
CYPHER
ENDEAVOR
DRUG
Sirolimus
Paclitaxel
Sirolimus
Sirolimus
Zatrolimus
Patients
100
662
533
175
598
MACE (%)
6
8.5
7.1
8.1
7.4
TLR
4
3.0
4.1
4
4.6
AT,SAT,LT
0
0.6
0.4
1.1
0.5
LL (IL-mm)
0.02
0.23
0.24
0.19
0.36
LL (IS-mm)
0.09
0.39
0.17
0.20
0.62
RR(%)
1.7
7.9
8.9
5.9
13.3
CRC
e-series Registry:
Baseline Demographics
VARIABLE
N = 1,223
Age, years
63.3 ± 11.0
Female gender
30.6 %
Hypertension
78.6 %
Diabetes mellitus
38.1 %
Insulin dependent
Dyslipidemia
8.3 %
64.2 %
Current smoking
31 %
Family history of CAD
46 %
History of CHF
3.9 %
Previous MI (>30 days)
22.7 %
Previous CABG
14.6 %
Previous PCI
33.5 %
Previous CVA
2.3 %
Renal insufficiency (baseline serum creatinine ≥2.0 mg/dL)
4.7 %
CRC
e-SERIES:
Adverse Events at 6 Months FU*
% of patients
N = 718
*Out-of-hospital
events
CRC
e-SERIES:
Kaplan-Meier Survival from MACE
Bioabsorbable Polymer DES Systems
BioMatrix (Biosensors)
Nevo (Cordis)
JACTAX (Boston Scientific)
Supralimus (Sahajanand)
Sirolimus + EPC capture (Orbus)
Early Endothelialization
Scanning EM of a Genous stent at 48 hours following stenting shows
complete coverage of the stents by endothelium (left). The detail (right) shows
leucocyte adherence and incomplete cell-cell contact.
Better than any polymer is no polymer…
BioMatrix Freedom Stent
Micro-structured Surface
• Selectively micro-structured surface holds
drug in abluminal surface structures
BioFreedom
Biosensors Polymer-Free FIM Study (PI: E. Grube)
Randomized Trial, 3 Arms, 7 Sites in Germany
Symptomatic, Ischemic heart disease
Native Coronary artery ≥ 2.25 mm and ≤ 3.0 mm
Lesion length ≤ 14 mm
Lesion amenable to percutaneous treatment with DES
BioFreedom DES
Low Dose 7.8u µg/mm
n=100
Taxus Liberte DES
Standard Dose
n=100
BioFreedom DES
Standard Dose 15.6µg/mm
n=100
30 d
4 mo
12 mo
2yr
3yr
4yr
5yr
Angiographic and IVUS Follow-up
Primary Endpoint:
In stent Late Lumen Loss (LL) at 12 months (25 patients from
each cohort will receive angio/IVUS at 4 months, balance 12 months)
Secondary Endpoints:
MACE and stent thrombosis rate at 30 days, 6 and 12 months
In-stent/In-segment binary restenosis at 6 months
In-stent, prox and dist, LL at 6 months
Neointimal hyperplastic volume at 6 months measured by IVUS
Translumina Porous Surface Stent
Pure
Sirolimus
Bioabsorbable, Silica Sol-Gel Matrix (Cobra system)
•
Polymer-free, biocompatible coating:
– Non-thrombogenic
– Non-inflammatory
•
Fully bioabsorbable
– Hydrates & erodes through dissolution in body fluids
– DES becomes BMS within 6 months
•
Controlled release of drug
• Silica Sol-gel Process:
1.
2.
Simple molecular precursors are converted into nanometer-sized particles to form a
colloidal suspension, or sol.
The colloidal nanoparticles are then linked with one another to form a 3D Network
PLUS-One Study Design
de novo lesions in native coronary arteries
RVD: 3.0 mm - 3.75 mm
Lesion length: ≤20 mm
Stent diameters: 3.0 - 3.5 mm
Stent length: 12, 18, 24 mm
Dose A: 4 mcg/ 18mm stent (0.03 mcg per mm2); n = 30
Dose B: 8 mcg/ 18mm stent (0.06 mcg per mm2); n = 30
Clinical
Clinical Follow-up
Follow-up
1m
4m
1y
2y
3y
4y
5y
QCA/ IVUS Follow-up
Primary Endpoint
4-month MACE event rate, defined as cardiac death, MI (Q wave & non-Q wave), and ischemia-driven
TLR
Secondary Endpoints
Lesion, Device & Procedure Success with <30% residual stenosis
MACE at Hospital Discharge & 30 days, 1, 2, 3, 4 & 5 years
4-Month Diameter Stenosis (%), in-stent and in-segment angiographic late loss (mm) and binary
restenosis rate (%) by QCA and 4-month NIH volume by IVUS (mm3)
Polymer Free Paclitaxel
Abluminal coating – 5µ thickness applied on
crimped stent.
Consistent coating ensuring 98% of the drug
delivered to the site.
Polymer free Paclitaxel.
2.5µg/mm² dose.
Boost-release (60% in 2 days)
Profile release established in 30 days (98% of the drug)
Back to regular Chromium Cobalt after 45 days.
PAX A
(PI: A Abizaid)
First In-Man
randomized
n = 30
AMAZONIA Pax
n = 15
Taxus Liberte
n = 15
Sub-analysis:
•Endothelial function in 30 pts
Primary Endpoint:
Late Loss
% obstruction
OCT tissue
coverage
at 4 Months
PAX B
(PI: A Abizaid)
Multicenter
Registry
n = 100
AMAZONIA Pax
n = 100
Primary Endpoint:
Late Loss
And MACE
at 9 Months
Bi PAX (Bifurcation)
(PI: J Fajadet)
Multicenter
Registry
n = 100
Nile Croco
n = 100
Primary Endpoint:
Late Loss
And MACE
at 9 Months
3D MicroPorous Nanofilm HAp
QCA Results
Follow-up
4 months
(n=15)
Variable
In-Stent
9 months
(n=12)
In-Lesion
In-Stent
In-Lesion
MLD, mm
2.34 ± 0.33 2.05 ± 0.38
2.27 ±0.33
2.02 ± 0.29
% Diameter stenosis
13.8 ± 7.0
15.9 ± 8.20
23.6 ±9.50
Late lumen loss, mm
0.29 ± 0.25 0.16 ± 0.29 0.36 ± 0.24 0.20 ± 0.31
Restenosis*, % (n)
0
23.6 ± 8.8
0
0
0
Abizaid et al. ACC 2008.
IVUS Volumetric Analysis
Baseline / 4 month / 9 month follow-up
Baseline
4-month follow-up 9-month follow-up
IVUS variables
N= 14 P*
N= 14 P*
N= 14 P*
Vessel Volume (mm3)
294.2 ± 117.1
286.9 ± 87.4
296.8 ± 85.6
Stent Volume (mm3)
144.5 ± 48.2
140.5 ± 36.7
143.1 ± 41.4
Lumen Volume (mm3)
144.7 ± 48.4
136.3 ± 34.2
136.8 ± 38.2
N/A
4.3 ± 3.5
6.1 ± 4.9
0.34 ± 0.87
0.14 ± 0.34
0.13 ± 0.36
N/A
2.8 ± 2.2
3.8 ± 2.3
NIH Volume (mm3)
Mallapposition Volume (mm3)
% Stent Obstruction
* 1 pt refused to undergo invasive FU at 9 months and therefore were excluded from this sub
analysis.
POST
Lower LLL (-0.1
mm)
PRE
4 MONTH- FU
9 MONTH- FU
PRE
POST
FOLLOW-UP 4 MONTHS
VESTASYNC II
Polymer-Free Sirolimus-Eluting Stent
First In-Man
3:1 randomized
n = 90
Vestasync Eluting Stent
n = 60
Bare Metal Stent
n = 30
• IVUS subanalysis: 30 pts
• OCT sub-analysis : 30 pts
• Endothelial function: 20 pts
Primary Endpoint:
Late Loss at 6
Months
Conclusions
First Genaration Durable Polymers
with thick polymer loading are being
gradually replaced to more advanced
technology.
Bioabsorbable Polymers with
abluminal release and reservoir
technology are slowing replacing
the first gen DES.
Non-Polymeric DES
with surface
modification will dominate the
market.