bioabsorbable and polymer-free des: current and new … gen des.pdf · 2010-05-03 · in...
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Gregg W. Stone, MDGregg W. Stone, MDColumbia University Medical CenterColumbia University Medical Center
Cardiovascular Research FoundationCardiovascular Research FoundationNew York CityNew York City
Bioabsorbable and Bioabsorbable and PolymerPolymer--Free DES: Free DES: Current and New Current and New
TechnologiesTechnologies
LaSTLaST –– Late DES Stent Thrombosis Late DES Stent Thrombosis After 3 YearsAfter 3 Years
After 2 DESAfter 2 DES
Late Stent ThrombosisLate Stent Thrombosisat 3.5 yrsat 3.5 yrsBaselineBaseline
BernBern--Rotterdam ExperienceRotterdam Experience8146 pts. treated with SES (n=3823) or 8146 pts. treated with SES (n=3823) or PES (n=4323) at 2 academic centersPES (n=4323) at 2 academic centers
0 3 6 9 13 18 24 31 46 85 146 192 224 260 336 356 381 441 464 491
Num
ber o
f eve
nts
Num
ber o
f eve
nts
Cum
ulative events (%)
Cum
ulative events (%)
2020
1515
1010
55
2.02.0
1.51.5
1.01.0
0.50.5
00 00
Days after PCIDays after PCI551 568 606 670 762 822 925 1074
Early stent thrombosis Early stent thrombosis Late stent thrombosisLate stent thrombosis Cumulative events (%)Cumulative events (%)
Daemon J, et al, Lancet 2007;369:667–78
Drug-Eluting StentsThe good, the bad, and the ugly!
Drug-Eluting StentsThe good, the bad, and the ugly!
48 months48 months
40 mos40 mos
BMS DES
IncompleteIncompleteappositionapposition
Late stentthrombosis
-20-15-10
-505
10152025
Prox. Ref. Prox. Stent Distal Distal Ref.
Abn VasomotionAbn Vasomotion
*P<0.001*P<0.001 vs. controlvs. control
Sirolimus Sirolimus Control Control
** **
Delayed Healing!Delayed Healing!
AngioscopyAngioscopy
BMS
DESLate loss = 0
Eos
Giant cells
IVUSIVUS
InflammationInflammation
Future DESFuture DES
PlatformPlatform
PolymerPolymerDrugDrug
DESDES
BioabsorbableBioabsorbable PolymerPolymer--freefree
• Bioabsorbable Polymers¡ Benefit – reduced polymer burden and
bioabsorption should reduce chronic polymer effects ( safety)
¡ Issues – degradation rates, inflammatory by-products, more complex elution profiles
¡ Examples: Biosensors (BioMatrix), Translumina (Yukon), Cordis (Nevo), BSC (Jactax), Genous DES
New Drug Carrier Systems…1 New Drug Carrier Systems…1
Future DES Future DES
Biodegradable Drug Carrier:Biodegradable Drug Carrier:•• Biolimus Biolimus A9A9 / / Poly (Lactic Acid) Poly (Lactic Acid)
50:50 mix50:50 mix•• Abluminal Abluminal surface only (contacts surface only (contacts
vessel wall)vessel wall)•• 10 microns coating thickness10 microns coating thickness•• DDegrades egrades in 9 months releasing in 9 months releasing
COCO22+ + HH22OO
BioMatrixBioMatrix Stent PlatformStent PlatformBioabsorbable Polymer DESBioabsorbable Polymer DES
LEADERS LEADERS –– MACE (n=1,707)MACE (n=1,707)
MACE = Cardiac Death, MI, or ClinicallyMACE = Cardiac Death, MI, or Clinically--Indicated TVR Indicated TVR
%
Months
13.0%
15.4%
2-year HR0.84 [0.65 to 1.08]
P = 0.18
Δ 2.4%12.1%
10.7%
1-year HR0.88 [0.66 to 1.17]
P = 0.37
Δ 1.4%
0
5
10
15
20
0 3 6 9 12 15 18 21 24
BESSES
Klauss V et alTCT2009
Windecker S et al. Lancet 2008; 372: 1163Windecker S et al. Lancet 2008; 372: 1163––7373
Translumina: Unique Microporous Stent SurfaceTranslumina: Unique Microporous Stent SurfaceCoating Capacity & Relase KineticsCoating Capacity & Relase Kinetics
Stent Surface
Rap
amyc
in /
sten
t sur
face
are
a(µ
g/cm
²)
479
132
284
0
100
200
300
400
500
600
0.5% 1.0% 2.0%rapamycin concentration
Release Kinetics
days0 5 10 15 20 25 30
0
20
40
60
80
100
microporous stent
Cypher stent
fractional release [%]
Coating Capacity
J Hausleiter et al. Eur Heart J 2005
10 µm10 µm
C
Yukon stent
The ISAR-TEST ProgramN Control stent Test stent (YUKON) Primary
endpoint
ISAR-TEST 1 450 TAXUS Rapapolymer-free
In-stent LL 6-8 months
ISAR-TEST 2 1007 CYPHER and ENDEAVOR
Rapa + probucolpolymer-free
In-stent LL 6-8 months
ISAR-TEST 3 605 CYPHERRapa polymer-free, andRapa with bioabsorbable
polymer
BAR 6-8 months
ISAR-TEST 4 2603 CYPHER and XIENCE V
Rapawith bioabsorbable polymer
TLF1 year
ISAR-TEST 5 (ongoing) 3000 RESOLUTE Rapa + probucol
polymer-freeMACE 1 year
Rapamycin-eluting Yukon Stentwith Bioabsorbable Polymer
-- InIn--stent late loss at 6stent late loss at 6--8 months8 months--
0.23
0.17
0.280.23 0.24
0
0.1
0.2
0.3
Late
loss
(mea
n, m
m)
CypherCypher YukonYukonraparapa
CypherCypher XienceXienceVV
YukonYukonraparapa
N=202N=202 N=652N=652 N=1299
ISARISAR--TEST 3TEST 3 ISARISAR--TEST 4TEST 4J Mehilli et al. Eur Heart J 2008J Mehilli et al. Eur Heart J 2008 R Byrne et al. Eur Heart J 2009R Byrne et al. Eur Heart J 2009
P=NS
P=NS
NEVO™ Stent DesignNEVO™ Stent Design•• ChromiumChromium--Cobalt PlatformCobalt Platform
¡¡ Flexible, thin struts, open Flexible, thin struts, open cell designcell design
•• Novel Reservoir TechnologyNovel Reservoir Technology¡¡ Minimizes polymer Minimizes polymer -- vessel vessel
wall contact wall contact •• Biodegradable PolymerBiodegradable Polymer
¡¡ Achieves CypherAchieves Cypher--like like sirolimus tissue levelssirolimus tissue levels
¡¡ Rapid endotheliazationRapid endotheliazation
Bridge elements
Reservoirs
Ductile Hinges
Polymer Structure and DegradationPolymer Structure and Degradation
•• PLGAPLGA polymer polymer resorbsresorbs within 3within 3--4 months4 months
•• Begins 75% BMS and becomes 100% BMS Begins 75% BMS and becomes 100% BMS within 3within 3--4 4 mosmos
8 days 30 days 60 days 90 days
Late Lumen Loss at 6Late Lumen Loss at 6--Months (N=342/394)Months (N=342/394)
0.13
0.06
0.36
0.20
0
0.1
0.2
0.3
0.4
0.5
0.6
In-Stent In-Segment
NEVO
Taxus Liberte
P<0.001
P<0.001
Primary EndpointLa
te L
oss
(mm
)
±0.31
±0.46
±0.32
±0.39
n=180 n=162 n=180 n=162
Properties of the JAProperties of the JACTAX Stent CTAX Stent JAJAÒÒCoatingCoating•• 9.2 9.2 μμg of Paclitaxel and g of Paclitaxel and
9.2 9.2 μμg g DLPLADLPLA (16 mm)(16 mm)•• 2700 microdots (16 mm)2700 microdots (16 mm)•• Mass of polymer approx Mass of polymer approx
3.4 3.4 ngng per microdotper microdot•• > 1 micron thick, abluminal > 1 micron thick, abluminal
and and lmwlmw biodegradable biodegradable polymer decreases polymer decreases persistence timepersistence time
Stent platformStent platform•• LibertéLiberté ™pre™pre--mounted mounted
stent (Boston Scientific)stent (Boston Scientific)
Unexpanded
Expanded
Directional Sirolimus Biodegradable Abluminal Coating and Anti-CD34
Surface Modification
Abluminal Drug/Polymer Layer
Genous CD34 AbStent Strut
Genous-DES Technology:• Rapamycin (5 µg/mm) applied
in biodegradable SynBiosys polymer on the abluminal side
Genous Technology:• Anti-CD34 surface to promote
healing through rapid stent endothelialization
Genous
• Polymer-free Drug Delivery¡ Benefit – “essentially” BMS after drug
delivery (maximal safety) ¡ Issues – difficulties in prolonging drug
elution¡ Examples: Translumina (Yukon),
Biosensors (BioFreedom), MIV (Vestasync), Medtronic (drug-filled wire stent)
New Drug Carrier Systems…2 New Drug Carrier Systems…2
Future DES Future DES
Translumina: Unique Microporous Stent SurfaceTranslumina: Unique Microporous Stent SurfaceCoating Capacity & Relase KineticsCoating Capacity & Relase Kinetics
Stent Surface
Rap
amyc
in /
sten
t sur
face
are
a(µ
g/cm
²)
479
132
284
0
100
200
300
400
500
600
0.5% 1.0% 2.0%rapamycin concentration
Release Kinetics
days0 5 10 15 20 25 30
0
20
40
60
80
100
microporous stent
Cypher stent
fractional release [%]
Coating Capacity
J Hausleiter et al. Eur Heart J 2005
10 µm10 µm
C
Yukon stent
The ISAR-TEST ProgramN Control stent Test stent (YUKON) Primary
endpoint
ISAR-TEST 1 450 TAXUS Rapapolymer-free
In-stent LL 6-8 months
ISAR-TEST 2 1007 CYPHER and ENDEAVOR
Rapa + probucolpolymer-free
In-stent LL 6-8 months
ISAR-TEST 3 605 CYPHERRapa polymer-free, andRapa with bioabsorbable
polymer
BAR 6-8 months
ISAR-TEST 4 2603 CYPHER and XIENCE V
Rapawith bioabsorbable polymer
TLF1 year
ISAR-TEST 5 (ongoing) 3000 RESOLUTE Rapa + probucol
polymer-freeMACE 1 year
ISAR-STENT 3Bioabsorbable polymer vs. polymer-free
-- InIn--stent late loss at 6stent late loss at 6--8 months8 months--
0.230.17
0.47
0
0.1
0.2
0.3
0.4
0.5
Late
loss
(mea
n, m
m)
CypherCypher
P=NS
P<0.001
Yukon Yukon raparapaPolymerPolymer--freefree
Yukon Yukon raparapaBioabsorbableBioabsorbable
polymerpolymer
N=201N=202 N=202
Mehilli J et al. Eur Heart J 2008Mehilli J et al. Eur Heart J 2008
Rapamycin-eluting Yukon StentPolymer-free
-- InIn--stent late loss at 6stent late loss at 6--8 months8 months--
0.23
0.47 0.48 0.480.58
0.24 0.23
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Late
loss
(mea
n, m
m) P=NS
P<0.001
TaxusTaxus YukonYukonraparapa
N=225N=225
ISARISAR--TEST 1TEST 1Mehilli J et al.Mehilli J et al.
Circulation 2006Circulation 2006Mehilli J et al.Mehilli J et al.
Eur Heart J 2008Eur Heart J 2008
YukonYukonraparapa
CypherCypher
ISARISAR--TEST 3TEST 3
N=201N=202
P<0.001
N=335EndeavorEndeavor CypherCypher YukonYukon
rapa+probucolrapa+probucol
N=339 N=333
ISARISAR--TEST 2TEST 2Byrne RA et al.Byrne RA et al.
JACC 2010JACC 2010
Selectively microSelectively micro--structured surface holds structured surface holds drug in abluminal surface structuresdrug in abluminal surface structures
BioFreedom Stent (Biosensors)BioFreedom Stent (Biosensors)Hypothesis: PolymerHypothesis: Polymer--free drug free drug
release via porousrelease via porous--eluting eluting stents may reduce late events stents may reduce late events
caused by polymer stent caused by polymer stent coatingscoatings..
Potential Potential advantagesadvantages
•• Avoid long term late adverse Avoid long term late adverse effects that might be attributable effects that might be attributable to the polymerto the polymer
•• Improved surface integrity since Improved surface integrity since there is no polymer to be sheared there is no polymer to be sheared or pealed away from the stent or pealed away from the stent strutsstruts
•• Possible Shorter need of dual Possible Shorter need of dual antiplatelet therapyantiplatelet therapy
Biolimus A9 Biolimus A9 -- lipophiliclipophilic
MIVMIV: 3D : 3D MicroPorousMicroPorous NanofilmNanofilm HapHapPolymerPolymer--free free DES (DES (VestasyncVestasync))
Drug Filled Stent (Medtronic)Drug Filled Stent (Medtronic)Drug elution controlled by diffusion physicsDrug elution controlled by diffusion physics
Elution Holes
Exits through holesExits through holes
Drug fills hollow structureDrug fills hollow structure
No Polymer!No Polymer!No Polymer!No Polymer!
Drug Filled Stent (Medtronic)Drug Filled Stent (Medtronic)Drug elution controlled by diffusion physicsDrug elution controlled by diffusion physics
Preliminary testing suggests a variety of elution profiles possible.
Standard non-polymeric elution
DFS Prototype Elution Comparison70%
60%
50%
40%
30%
20%
10%
0%
% E
lute
d
Time
Design 1
Design 2
Design 3
Design 4
Design 5
Design 6
Resolute
• Future DES are focusing on drug carrier enhancements to reduce safety concerns
¡ Bioabsorbable polymer-based drug delivery – many versions, much promise, insufficient long-term clinical data to assess incremental value
¡ Polymer-free drug delivery – best chance for “BMS-like” safety profile, BUT more difficult to achieve prolonged drug elution profiles, and little clinical data thus far
¡ Metallic stents with either bioabsorbable polymers or polymer-free systems will have to compete with the excellent safety and efficacy profiles of today’s DES with nonerodable polymers, as well as with fully bioabsorbable stents and drug-eluting balloons
Summary Conclusions Summary Conclusions