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 Coating TechnologyTranslumina Coating TechnologyYukon® CC CoCr Stent

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