non-polymeric and bioabsorbable polymers will reign supreme in near future instituto dante pazzanese...

Non-Polymeric and Bioabsorbable Polymers Non-Polymeric and Bioabsorbable Polymers Will Reign Supreme in Near FutureWill Reign Supreme in Near Future

Instituto Dante Pazzanese de Cardiologia Instituto Dante Pazzanese de Cardiologia Sao Paulo - BrazilSao Paulo - Brazil

Alexandre Abizaid, MD, PhD, FACCAlexandre Abizaid, MD, PhD, FACC

Columbia University Columbia University New York - USANew 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

Daemen J et al. Lancet 2007; 369: 667

0.6% per year

DES – Late incomplete apposition and DES – Late incomplete apposition and Cypher Cypher ®® stent thrombosis stent thrombosis

6 m

18 m

PostPre

DES – Late incomplete apposition and DES – Late incomplete apposition and Cypher Cypher ®® stent thrombosis stent thrombosis

40 m

Post PCI

DES – Late incomplete apposition and DES – Late incomplete apposition and TaxusTaxus®® stent thrombosis stent thrombosis

Pre Post

8 m

Post

DES – Late incomplete apposition and DES – Late incomplete apposition and TaxusTaxus®® stent thrombosis stent thrombosis

12 m

Post PCI

PCI

Shortcomings often associated Shortcomings often associated with polymers during stent deliverywith polymers during stent delivery

Non uniform Non uniform polymer coatingpolymer coating

““Webbed” polymer Webbed” polymer surface leading to surface leading to stent expansion stent expansion

issues”issues”

Polymer delaminationPolymer delamination

Current Problems with PolymersCurrent Problems with Polymers

● ● Durable Coatings-Potential for:Durable Coatings-Potential for: - Continuing source of inflammation- Continuing source of inflammation - Poor healing/thrombosis risk- Poor healing/thrombosis risk

Delayed Healing - DES

Rabbit 28 days

Lack of neointimal growth (uncovered Struts)

* *

*Inflammation

Persistent fibrin deposition

Incomplete endothelialization

Porcine 28 days

Severe inflammation

Fibrin deposition with malapposition

CYPHER TAXUS

Vermani et al.

Polymer EvolutionPolymer Evolution

Durable PolymersDurable Polymers

Non-PolymericNon-Polymeric

Bioabsorbable PolymersBioabsorbable Polymers

(mm2)

3

2

0

1

Bioabsorbable Polymer with Sirolimus in the porcine model (SurModics Inc.)

Neoinimal Area

30 90 (day)

Sustained efficacy

DES (bioabsorbable polymer)

BMS

30

30 90

90

Bioabsorbable polymer (SynBiosys) + sirolimus

BMS

Vermani et al.

(Day)

Grade of inflammation

3090

30 90

3

2

1

0

4Bioabsorbable polymer (SynBiosys) + sirolimusBMS

Cypher (historical)Taxus (historical)

Bioabsorbable Polymer (SynBiosys GACL-LA) with Sirolimus in the porcine model (SurModics Inc.)

Bioabsorbable Polymer (SynBiosys GACL-LA) with Sirolimus

Bioabsorbable Polymer DES SystemsBioabsorbable Polymer DES Systems

BioMatrix (Biosensors)BioMatrix (Biosensors)

JACTAX (Boston Scientific)JACTAX (Boston Scientific)

Nevo (Cordis)Nevo (Cordis)

Supralimus (Sahajanand)Supralimus (Sahajanand)

Sirolimus + EPC capture (Orbus)Sirolimus + EPC capture (Orbus)

Biodegradable Drug/Carrier:Biodegradable Drug/Carrier:- Biolimus A9- Biolimus A9® ® / / Poly (Lactic Acid) Poly (Lactic Acid)

50:50 mix50:50 mix- abluminal surface only (contacts - abluminal surface only (contacts

vessel wall)vessel wall)- 10 microns coating thickness- 10 microns coating thickness- degrades in 9 months releasing - degrades in 9 months releasing

COCO22+ water+ water

BioFlex IBioFlex I

BioFlexBioFlex™™ II II

BioMatrixBioMatrix®® III Stent Platform III Stent Platform

LEADERS: Primary EndpointCardiac Death, MI, or TVR @ 9 months

00

55

1010

1515

850850 791791 786786 784784 781781 777777 771771 758758 751751 746746857857 806806 798798 796796 792792 784784 779779 777777 771771 761761

No. at riskNo. at risk

00 11 22 33 44 55 66 77 88 99Months of Follow-upMonths of Follow-up

SESSESBESBES

Cum

ulat

ive

Inci

denc

e (%

)C

umul

ativ

e In

cide

nce

(%)

Sirolimus Stent 10.5%

Biolimus Stent 9.2%

Risk Difference -1.3%, Upper Limit 95% CI 1.1%Pnon-inferiority = 0.003

Rate Ratio = 0.88, 95% CI 0.64 - 1.19

Definite Stent Thrombosis

Sirolimus Stent 2.0%

Biolimus Stent 1.9%

Rate Ratio = 0.93, 95% CI 0.47 - 1.85

0

1

2

3C

umul

ativ

e In

cide

nce

(%

)

850 822 818 816 815 815 813 806 803 799857 833 826 825 824 821 818 817 816 808

0 1 2 3 4 5 6 7 8 9Months of Follow-up

Definite stent thrombosis

Number at riskBESSES

LEADERS Bifurcation Subanalysis MACE*

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 groupBiolimus Bifurcation groupSirolimus Non-bifurcation groupBiolimus Non-bifurcation group

*MI, cardiac death and clinically driven TVR

Uncovered strutsUncovered struts

Hyperplasia of neointimaHyperplasia of neointima

LA 2.36 mm², SA 3.39 mm ²LA 2.36 mm², SA 3.39 mm ²

Covered malapposed strut

Covered malapposed strut

Well covered struts

Well covered struts

Distribution of Uncovered Struts within Lesions

Lesio

ns w

ith

Sten

t 0

Lesio

ns w

ith

Sten

t 1

Cypher Biomatrix

• 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 co-monomer ratios to permit variable resorption times (few weeks-many months)

The NEVO™ Polymer

8 DAY8 DAY

30 DAY30 DAY

60 DAY60 DAY

90 DAY90 DAY

NEVO’s™ sirolimus release kinetics approximate CYPHER® stent’s

NEVO™ achieves similar sirolimus arterial tissue levels to CYPHER® .

Implant Duration (Days)

0 1 3 8 14 30

Sir

oli

mu

s R

ele

as

e (

%)

0

20

40

60

80

100

NEVO™ Prototype Stents

CYPHER® Stents

Sirolimus Release from NEVO™ Stent Sirolimus Content in Tissue

NEVO™: Sirolimus Release &Tissue Content

Normal porcine coronary arteries, 10-15% implant overstretch; NEVO Data from: AP-061

Implant Duration (Days)

1 3 8 14 30

Art

eria

l Sir

olim

us

Co

nte

nt

(µg

/mg

art

ery)

0

20

40

60

80 NEVO™ Prototype StentsCYPHER

® Stents

NEVO RES-I Study Overview

40 sites worldwideEurope, South America, Australia and New Zealand

394 subjects, stratified by diabetic status, and randomized 1:1

Single De Novo Native Coronary Artery LesionsReference Vessel Diameter: 2.5 - 3.5 mm

Lesion Length: ≤28 mm

Primary Endpoint: 6-month in-stent late lossSub-Study: IVUS subset (50 patients per arm)

Dual antiplatelet therapy for ≥6 months

NEVO™ Sirolimus-eluting Stent

(n=202)

TAXUS® Liberté™ Paclitaxel-eluting Stent

(n=192)

30 Day 6Mo 1Yr 2Yr 3Yr 4Yr

Angiographic/ IVUS

5Yr

Clinical/ MACE

87% Angiographic follow up*95% 180 day clinical follow up*

* Follow-up as of April 16, 2009

DRAFT Slides: Awaiting final quality control review: CONFIDENTIAL Late Lumen Loss at 6-Months

P<0.001

P<0.001

Primary Endpoint

Late

Los

s (m

m)

±0.31

±0.46

±0.32

±0.39

n=180 n=162 n=180 n=162

DRAFT Slides: Awaiting final quality control review: CONFIDENTIAL 6-Month MACE and Components

4.1

0.5

2.12.6

1.6

7.5

1.6

2.7

4.3

3.2

0

2

4

6

8

10

MACE Death MI Death or MI TLR

P=0.19

P=0.37

P=0.75

•No reports of Emergent CABG

% o

f P

ati

en

ts

8/193 13/187 1/193 3/187 4/193 5/187 5/193 8/187 3/193 6/187

P=0.37

P=0.33

Taxus LiberteNEVO

JACTAX TrialPI: 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)

TaxusTaxusLibertéLiberté(n=223)(n=223)

TaxusTaxusLibertéLiberté(n=223)(n=223)

LabcoatLabcoatLibertéLiberté(n=96)(n=96)

LabcoatLabcoatLibertéLiberté(n=96)(n=96)

Bin

ary

Res

teno

sis

(%)

In-Stent In-Segment

p=0.14 p=0.12

SupralimusSupralimus™™ Biodegradable Polymer Based Sirolimus Eluting StentBiodegradable Polymer Based Sirolimus Eluting Stent

Supralimus-Eluting Stents

Platform Platform Millennium Matrix Millennium Matrix ‘‘Intermediate Cell Intermediate Cell

Geometry’, Slotted Tube Geometry’, Slotted Tube DesignDesign

0.0032” strut thickness0.0032” strut thickness

Drug: SirolimusDrug: Sirolimus Drug Dosage: 102Drug Dosage: 102g-16mmg-16mm Unique Biodegradable Polymeric Unique Biodegradable Polymeric

Blend Blend Single layer of coating with drug Single layer of coating with drug

free top coatfree top coat 4-5 4-5 m coating thicknessm coating thickness

SERIES I: Study Design

Real world coronary artery lesions

Diameter: 2.5 to 4.0mmLength: 11 to 33mm

Real world coronary artery lesions

Diameter: 2.5 to 4.0mmLength: 11 to 33mm

Supralimus™ Sirolimus Eluting Stent

Supralimus™ Sirolimus Eluting Stent

N = 100

Primary endpoint: MACE at 30 days & in-stent binary restenosis at 6 months

Secondary endpoint: Stent thrombosis and MACE at 9 months

Primary endpoint: MACE at 30 days & in-stent binary restenosis at 6 months

Secondary endpoint: Stent thrombosis and MACE at 9 months

Supralimus-Eluting StentsSupralimus-Eluting Stents

Supralimus-Eluting Stents

TRIALSTRIALS SERIES ISERIES I TAXUS IVTAXUS IV SIRIUSSIRIUS ESIRIUSESIRIUS ENDEAVORIIENDEAVORII

BRANDSBRANDS SUPRALIMUSSUPRALIMUS TAXUSTAXUS CYPHERCYPHER CYPHERCYPHER ENDEAVORENDEAVOR

DRUGDRUG SirolimusSirolimus PaclitaxelPaclitaxel SirolimusSirolimus SirolimusSirolimus ZatrolimusZatrolimus

PatientsPatients 100100 662662 533533 175175 598598

MACE (%)MACE (%) 66 8.58.5 7.17.1 8.18.1 7.47.4

TLRTLR 44 3.03.0 4.14.1 44 4.64.6

AT,SAT,LTAT,SAT,LT 00 0.60.6 0.40.4 1.11.1 0.50.5

LL (IL-mm)LL (IL-mm) 0.020.02 0.230.23 0.240.24 0.190.19 0.360.36

LL (IS-mm)LL (IS-mm) 0.090.09 0.390.39 0.170.17 0.200.20 0.620.62

RR(%)RR(%) 1.71.7 7.97.9 8.98.9 5.95.9 13.313.3

Supralimus vs. Others

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 8.3 %

Dyslipidemia 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*CRC

% o

f p

ati

en

ts

N = 718

*Out-of-hospital events

e-SERIES:Kaplan-Meier Survival from MACECRC

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…Better than any polymer is no polymer…

• Selectively micro-structured surface holds Selectively micro-structured surface holds drug in abluminal surface structuresdrug in abluminal surface structures

BioMatrix Freedom StentBioMatrix Freedom StentMicro-structured SurfaceMicro-structured Surface

BioFreedomBiosensors Polymer-Free FIM Study (PI: E. Grube)

Symptomatic, Ischemic heart diseaseSymptomatic, Ischemic heart diseaseNative Coronary artery ≥ 2.25 mm and ≤ 3.0 mmNative Coronary artery ≥ 2.25 mm and ≤ 3.0 mmLesion length ≤ 14 mmLesion length ≤ 14 mmLesion amenable to percutaneous treatment with DESLesion amenable to percutaneous treatment with DES

30 d30 d 4 mo 4 mo 12 mo 12 mo 2yr 3yr 4yr 5yr 2yr 3yr 4yr 5yr

Primary Endpoint: In stent Late Lumen Loss (LL) at 12 months (25 patients fromeach 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 monthsIn-stent, prox and dist, LL at 6 monthsNeointimal hyperplastic volume at 6 months measured by IVUS

BioFreedom DESStandard Dose 15.6µg/mmn=100

7 Sites in GermanyRandomized Trial, 3 Arms,

Angiographic and IVUS Follow-up

BioFreedom DES Low Dose 7.8u µg/mm n=100

Taxus Liberte DESStandard Dose n=100

Translumina Porous Surface Stent

PurePureSirolimusSirolimus

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. Simple molecular precursors are converted into nanometer-sized particles to form a

colloidal suspension, or sol. 2. The colloidal nanoparticles are then linked with one another to form a 3D Network

PLUS-One Study Design

Clinical Follow-up

1 m 4 m 1 y 2 y 3 y 4 y 5 y

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

Primary Endpoint4-month MACE event rate, defined as cardiac death, MI (Q wave & non-Q wave), and ischemia-driven TLRSecondary EndpointsLesion, Device & Procedure Success with <30% residual stenosisMACE at Hospital Discharge & 30 days, 1, 2, 3, 4 & 5 years4-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)

QCA/ IVUS Follow-up

Clinical Follow-up

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.

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.

Polymer Free PaclitaxelPolymer Free Paclitaxel

PAX A PAX A (PI: A Abizaid)(PI: A Abizaid)

First In-Man First In-Man randomizedrandomized

n = 30n = 30Taxus LiberteTaxus Liberte

n = 15n = 15

AMAZONIA PaxAMAZONIA Paxn = 15n = 15

Primary Endpoint: Primary Endpoint: Late Loss Late Loss

% obstruction% obstructionOCT tissue OCT tissue coverage coverage

at 4 Monthsat 4 Months

Sub-analysis:Sub-analysis:Sub-analysis:Sub-analysis:•Endothelial function in 30 ptsEndothelial function in 30 pts•Endothelial function in 30 ptsEndothelial function in 30 pts

PAX B PAX B (PI: A Abizaid)(PI: A Abizaid)

MulticenterMulticenterRegistryRegistryn = 100n = 100

AMAZONIA PaxAMAZONIA Paxn = 100n = 100

Primary Endpoint: Primary Endpoint: Late Loss Late Loss And MACEAnd MACEat 9 Monthsat 9 Months

Bi PAX (Bifurcation)Bi PAX (Bifurcation)(PI: J Fajadet)(PI: J Fajadet)

MulticenterMulticenterRegistryRegistryn = 100n = 100

Nile CrocoNile Crocon = 100n = 100

Primary Endpoint: Primary Endpoint: Late Loss Late Loss And MACEAnd MACEat 9 Monthsat 9 Months

3D MicroPorous Nanofilm HAp3D MicroPorous Nanofilm HAp

4 months4 months

(n=15)(n=15)

9 months9 months

(n=12)(n=12)

VariableVariable In-StentIn-Stent In-LesionIn-Lesion In-StentIn-Stent In-LesionIn-Lesion

MLD, mmMLD, mm 2.34 2.34 ± 0.33± 0.33 2.05 2.05 ± 0.38 ± 0.38 2.27 ±0.332.27 ±0.33 2.02 ± 0.292.02 ± 0.29

% Diameter stenosis% Diameter stenosis 13.8 13.8 ± 7.0 ± 7.0 23.6 23.6 ± 8.8± 8.8 15.9 ± 8.2015.9 ± 8.20 23.6 ±9.5023.6 ±9.50

Late lumen loss, mmLate lumen loss, mm 0.29 0.29 ± 0.25± 0.25 0.16 0.16 ±± 0.29 0.29

0.36 ± 0.240.36 ± 0.24 0.20 ± 0.310.20 ± 0.31

RestenosisRestenosis**, % (n), % (n) 00 00 00 00

Abizaid et al. ACC 2008.Abizaid et al. ACC 2008.

QCA ResultsQCA Results Follow-up Follow-up

IVUS Volumetric AnalysisIVUS Volumetric AnalysisBaseline / 4 month / 9 month follow-upBaseline / 4 month / 9 month follow-up

IVUS variablesIVUS variablesBaselineBaseline

N= 14 P*N= 14 P*

4-month follow-up4-month follow-up

N= 14 P*N= 14 P*

9-month follow-up9-month follow-up

N= 14 P*N= 14 P*

Vessel Volume (mmVessel Volume (mm33)) 294.2 294.2 ± ± 117.1117.1 286.9 ± 87.4286.9 ± 87.4 296.8 ± 85.6296.8 ± 85.6

Stent Volume (mmStent Volume (mm33)) 144.5 144.5 ± 48.2± 48.2 140.5 ± 36.7140.5 ± 36.7 143.1 ± 41.4143.1 ± 41.4

Lumen Volume (mmLumen Volume (mm33)) 144.7 144.7 ± 48.4± 48.4 136.3 ± 34.2136.3 ± 34.2 136.8 ± 38.2136.8 ± 38.2

NIH Volume (mmNIH Volume (mm33)) N/AN/A 4.3 ± 3.54.3 ± 3.5 6.1 ± 4.96.1 ± 4.9

Mallapposition Volume (mmMallapposition Volume (mm33)) 0.34 0.34 ± 0.87± 0.87 0.14 ± 0.340.14 ± 0.34 0.13 ± 0.360.13 ± 0.36

% Stent Obstruction % Stent Obstruction N/AN/A 2.8 ± 2.22.8 ± 2.2 3.8 ± 2.33.8 ± 2.3

* 1 pt refused to undergo invasive FU at 9 months and therefore were excluded from this sub * 1 pt refused to undergo invasive FU at 9 months and therefore were excluded from this sub analysis.analysis.

PREPRE POSTPOST

4 MONTH- FU4 MONTH- FU 9 MONTH- FU9 MONTH- FU

Lo

we

r L

LL

(-0

.1

Lo

we

r L

LL

(-0

.1

mm

)m

m)

PRE POST

FOLLOW-UP 4 MONTHS

VESTASYNC II VESTASYNC II Polymer-Free Sirolimus-Eluting Stent

First In-Man First In-Man 3:1 randomized3:1 randomized

n = 90n = 90Bare Metal StentBare Metal Stent

n = 30n = 30

Vestasync Eluting StentVestasync Eluting Stentn = 60n = 60

Primary Endpoint: Primary Endpoint: Late Loss at 6 Late Loss at 6

MonthsMonths

• IVUS subanalysis: 30 pts• OCT sub-analysis : 30 pts• Endothelial function: 20 pts

ConclusionsConclusions

First Genaration Durable Polymers First Genaration Durable Polymers with thick polymer loading are being with thick polymer loading are being gradually replaced to more advanced gradually replaced to more advanced technology.technology.

Non-Polymeric DES with surface Non-Polymeric DES with surface modification will dominate the modification will dominate the market.market.

Bioabsorbable Polymers with Bioabsorbable Polymers with abluminal release and reservoir abluminal release and reservoir technology are slowing replacing technology are slowing replacing the first gen DES.the first gen DES.

non-polymeric and bioabsorbable polymers will reign supreme in near future instituto dante pazzanese...

Documents

sirolimus slide

post slide

stent platform slide

postpre slide

year slide

post pci slide

cypher stent thrombosis

biolimus stent