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: 102g-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.