Next Generations Drug Eluting Stentswill safety be addressed?

Ron Waksman MD FACC FSCAIProfessor of Medicine, Georgetown University,

Associate Chief of Cardiology, Washington Hospital Center, Washington DC

Any use of trade names is for reference only; no promotion of particular devices

or products should be inferred.

Next GenerationStent design and delivery system

Pharmacologic agent

Drug carrier vehicle

Drug-Eluting Stent

Drug-Eluting Stent

Drug-Eluting Stents

New Designs to address New Designs to address small vessels bifurcationssmall vessels bifurcationsNew Designs to address New Designs to address

small vessels bifurcationssmall vessels bifurcations

Bioresorbable polymers Bioresorbable polymers no polymersno polymers

Bioresorbable polymers Bioresorbable polymers no polymersno polymers

Pro healing, New Drugs, Pro healing, New Drugs, combination of drugs, combination of drugs,

change in release kineticschange in release kinetics

Pro healing, New Drugs, Pro healing, New Drugs, combination of drugs, combination of drugs,

change in release kineticschange in release kinetics

Complete Resorbable Stents

New Solutions for the Next Generation of Drug-eluting Stents1. New coating (absorbable coating, no coating) 2. New Biological target: (Endothelium, thrombosis,

inflammation) 3. New drug (less cytostatic or cytotoxic) 4. New technique of elution (reservoir, dual elution)

5. Pro Healing approach (EPC capture)

6. Pro Healing approach + Sirolimus or Paclitaxel 7. Complete Absorbable metallic or polymeric platform8. New Stent Design for challenging targets bifurcations

New DES Programs NO Donors Blue Medical Biolimus A9 Biosensors, Terumo, Devax

Zotarolimus Zomax, Endeavor CR Pimecrolimus Biotronik, Conor, Avantac Melatonin Blue Medical Gleevec Novartis Everolimus Guidant Tacrolimus Sorin EPC Progenitors Orbus Restin-NG AVI Biopharma Genistein Sahajanand Paclitaxel Balloon B- Braun Bioabsorbable Guidant, Biotronik, Reva

More More More !!!!!

Shortcomings often associated with polymers during stent delivery

Non uniform polymer coating

“Webbed” polymer surface leading to stent expansion

issues”

Polymer delamination

Current Problems with Polymers

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

New Polymers and CoatingBioabsrobable PolymersPLLAPLAPLGPLGANo PolymersTextured SurfaceDepot TechnologySetagon Nano TechnologySurface ModificationsNano membranous FiltersPhotolithographic EtchingHydroxyappetite HA

Advanced Approaches to Drug Release

Bioabsorbable polymers

Controlled polymer application

Non polymer release (porous surface)

Bioabsorbable stents

BioFlex I Biosensors

A Completely Polymer-Free StrategyTranslumina YUKON® ChoiceDES

Polymer-free coating

Unique roughened surface

Adjustable dosage for individualized treatment

Free choice of drugs

Directional Drug Delivery(ablumenal preference)Selective coating on the

outside surface of the stent– Reduced drug/polymer– Lumenal surface BMS– Drug only where needed

Labcoat JA™Coating Technology

Biodegradable Drug/Carrier:• Biolimus A9® / Poly (Lactic Acid) 50:50 mix• abluminal surface only (contacts vessel wall)• 15 µmeter coating thickness• degrades in 9 months releasing CO2+ water

Stent Platform: • stainless steel (112 m) • corrugated ring,

quadrature-link™ design• radius link enhances

axial fatigue life

Parylene Durable Primer Coating:• 5 µmeter thick, encapsulates stent• prevents surface metal ion migration• biostable + athrombogenic*

BioMatrix® II Stent Platform Design

BIOFLEX™ I

BioFlex I

stent

* Data per NHLBI sponsored study, available from BSI

2 Drugs with 2 Different Targets: Pimecrolimus-PaclitaxelIsoflavone-SirolimusDexamethazone-Zotarolimus

TacrolimusPimecrolim

us

Sirolimus, Biolimus A9 Everolimus, Zotarolimus

Isoflavone Inhibitor

Paclitaxel

Conor Drug Release Technology

Drug Reservoir

LuminalBarrier Layer

Simple Drug ReservoirUniform Release

SingleDrugStructure

MultipleDrugStructures

Drug A releasedto arterial wall

Barrier layer

Drug B releasedinto bloodstream

Two Drugs, One WellTwo Drugs, Two WellsTwo Directions

Luminal Barrier

Mural Barrier

Mural Side

Five Layers of Genistein-Sirolimus

Total Drug Dose: 2.51 g/mm2 (112 g Genistein and 76 g Sirolimus content on 16 mm stent)

Unique Biodegradable Heparinized Polymers Blend includes-Poly L-Lactide, 50/50 Poly DL-Lactide-co-Glycolide and Polyvinyl Pyrrolidone

Dual Elution Genistein and Sirolimus

No Drug- Top layer (Protective layer E)

Genistein (Top layer D)

Genistein + Sirolimus (Middle layer C)

Genistein + Sirolimus (Middle layer B)

Genistein (Base layer A)

Future Safe DES PlatformsThe Key is the Endothelium!

active support of endothelial cell proliferation and migration after stent implantation

accelerated endothelial cell strut coverage

decreased smooth muscle activation & reduced collagen secretion

optimal healingresponse =

accelerated functional

endothelium

Strut Coverage and EndothelizationCypher Taxus Endeavor

0

25

50

75

100

Mean % Endothel

Cypher

Taxus

Endeavor

% of Struts Endothelialized

Virmani et. al; PCR 2006

Virmani et. al. PCR. 2006.

Endeavor DES SystemKey Components

PC Technology Drug: Zotarolimus

Stent Delivery SystemDriver Cobalt Alloy Stent

Endeavor DES SystemPC Technology

90% of phospholipids in theouter membrane of a red bloodcell contain the PC(Phosphorylcholine) headgroup

Inner Membrane

Outer Membrane

The The PhosphoycholinePhosphoycholine(PC) Headgroup(PC) Headgroup

The The PhosphoycholinePhosphoycholine(PC) Headgroup(PC) Headgroup

PC1 mimics the chemicalstructure of thephospholipid headgroup

O

P OO

ON

ENDEAVORHCRI CEC Definition of Stent Thrombosis:

EIn=100

1 2 3 12 13 14Days Post Procedure

30 100 150 270 360 720

EIIn=598

EII CAn=296

EIIIn=323

= 1%

= 0.5%

= 0.0%

= 0.0%

Overall Thrombosis = 0.3%

ENDEAVOR I-III Plavix Rx for ≥ 3 months

1080

No Late Stent Thrombosis in Over 1,300 PatientsNo Late Stent Thrombosis in 994 Patients > 2 yr f/u

Surfaces to Encourage Cell GrowthBioactive surfaces to accelerate functional endothelialization

Orbus – EPC Capture cell

drugpeptide

protein

device surface

Peptide linkers

Cell specific peptide linkers (Affinergy)

Nanotextured Surfaces

Example of IrOx

Bioresorbable: The Future of Stenting?

Past… Present… …Future

Bare Metal StentBare Metal StentMore efficacious than POBAMore efficacious than POBA

Metal DESMetal DESMore efficacious than BMSMore efficacious than BMS

BVS

REVA

Cordis

Biotronik

no drug drug

Conclusions New DES Solutions The new generations of DES will focus more on safety

while preserving the efficacy. New designed DES will emerge and become available. These will address challenging anatomic subsets

(bifurcation, small vessels etc). Focus is on Prohealing and fast reendothelailization rather

antiproliferation solving late thrombosis, hypersensitivity, abnormal vasomotion, etc).

Thinner biostable polymers, Bioabsorbable, no polymers and surface modification will be the future carrier

Gentle Drugs and Dual drug will lower cytotoxic doses. Complete biodegradable stents with and without drugs

are on the horizon