NEW GENERATION DES WITH NEW GENERATION POLYMERS Prof. Dr. Rainer Wessely, Duisburg, Germany
Sousa J et al., JACC Cardioasv Interv 2010 10 years DES
NEXT DES BMS + DAPT DES DES + DAPT S A F E T Y BMS E F FI C A C Y Wessely R. C&V Update 2011
DES: complex interplay between components Wessely R, Nat Rev Cardiol, 2010
First generation DES SES PES ZES EES [Cypher] [Taxus] [Endeavor] [Xience/Promus] Earlier Later
Polymer Problem: No model to reliably and reproducibly test short and long term safety of polymers ( biocompatibility )
Current shortcomings of DESs Limited effectivity: Dosage, drug selection? bifurcated lesions; (insulin dependent) diabetics; ostial lesions Safety: (Late) stent thrombosis (particularly after discontinuation of antiplatelet therapy?) Polymer? Late restenosis: Polymer? Might be apparent in a yet undefined percentage of patients, especially with complex lesions
Polymer related issues mechanical biological
Polymer associated problems: not the end of the world
Polymer related issues Possible solution Avoid long term presence of polymer Avoid surface coating with polymer
Evidence and polymers: still much to learn
Even modern imaging tools are not sensitive enough to allow anatomical assessment of endothelialization resolution [ m] 1000 angioscopy 100 IVUS 1st gen OCT OFDI 10 Nagano M et al., Circulation. 2010;122:A18936 0
Physical presence and functional integrity: a whole new ballgame!
Functional vs. anatomical recovery: a different story? Pendyala LK et al., JACC Interv 2010
THE POLYMER necessary evil?
WHY might there be a current need for polymers on DES? Protection Protection of of non non intentional intentional drug drug release release during during stent stent delivery delivery and and placement placement Modulation, retardation of drug release, prevention of boost release Minimization Minimization of of cytotoxicity cytotoxicity of of drugs drugs with with small small therapeutic therapeutic window window
Time cascade for major pathophysiological events in ISR no polymer polymer
WHY is there a current need for polymers on DES? 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0 CYPHER (n=202) Polymer-Free SES (n=201) 0,47 0,23 6-8 m In-Stent Late Loss (mm) ISAR-TEST 3: Polymer-free SES failed to meet non-inferiority vs CYPHER, despite >3-fold increase of drug dosage Mehilli J et al. Eur Heart J. 2008;29:1975-1982. Modulation of drug release is necessary to prevent boost release for optimized anti restenotic efficacy
Reducing adverse events precipitated by the polymer Limit presence of polymer to time necessary for drug delivery to counteract key events of restenosis (biodegradability) Avoid or limit polymer tissue contact Avoid mechanical disruption of polymeric coating Decrease amount and area coated by polymer relative to stent surface Anti inflammatory drug properties may counteract pro inflammatory (and therefore also pro thrombotic) polymer effects
Biodegradable polymers: application possible with any drug? Wessely R et al., Eur Heart J 2007
Biodegradable polymers: application possible with any drug? Paclitaxel Pimecrolimus 1,40 1,40 Late lumen loss [mm] 1,20 1,00 0,80 0,60 0,40 0,42 0,58 0,69 0,96 1,07 In-segment In-stent 0,20 0,00 PTX PTX+PMC PMC Verheye S et al., JACCI 2009
Parker T et al., Cur Pharmac Des 2010 Bioabsorbable polymer coatings for DES
Major DES platforms with biodegradable polymer DES System Platform Antiproliferative Agent Polymer BioMatrix (Biosensors Inc) S Stent (316 L) stainless steel stent with a strut thickness of 0.0054 inches (137 μm) Biolimus A9 ( 15.6 μg/mm of stent length) Polylactic acid (PLA) applied to the abluminal surface Cardiomind 0.014 inches Sparrow (CardioMind, Inc) CardioMind self expandable Nitinol stent platform with strut thickness of 0.0024 inches (61 μm) Sirolimus ( 5.2 μg/mm of stent length) Polylactic acid (PLA)/Polylactic co glycolic acid (PLGA) block copolymer matrix ELIXIR DES program (Elixir Medical Corp) Cobalt chromium (Co Cr) stent with strut thickness of 0.0032 inches (81 μm) Novolimus ( 5 μg/mm of stent length) Myolimus ( 2 3 μg/mm of stent length Polyester based or polylactide based JACTAX (Boston Scientific Corp) Liberté (316 L) stainless steel stent with a strut thickness of 0.0038 inches (96.5 μm) Paclitaxel ( 0.6 μg/mm of stent length) D lactic polylactic acid (DLPLA) applied to the abluminal surface on premounted stent (no postcoating crimping distortion) NEVO (Cordis Corporation, Johnson & Johnson) Cobalt chromium (Co Cr) stent with strut thickness of 0.0039 inches (99 μm) Sirolimus ( 7.4 μg/mm of stent length) Polylactic co glycolic acid (PLGA) exclusively housed in reservoirs Sirolimus+EPC capture (OrbusNeich Medical Inc) OrbusNeich R stent (316L) stainless steel stent with a strut thickness of 0.0040 inches (101 μm) Sirolimus ( 5 μg/mm of stent length) SynBiosys polymer (2 bioabsorbable urethanelinked poly(ether ester) multiblock copolymers composed of glycolide (GA), lactide (LA), ϵ caprolactone (CL), and polyethylene glycol (PEG) pre polymer blocks) Supralimus and Supralimus Core (Sahajanand Medical Technologies Pvt Ltd) Millennium Matrix (316L) stainless steel stent with a strut thickness of 0.0032 inches (81 μm) Coronnium (L605) cobalt chromium stent with a strut thickness of 0.0023 inches (60 μm) Sirolimus ( 4.7 μg/mm of stent length) Poly L Lactide, 50/50 Poly DL Lactide co Glycolide and Polyvinyl Pyrrolidone Abizaid A et al., Circ Cardiovasc Interv 2010
New DES platforms with biodegradable polymer Nobori (Terumo) Biomatrix (Biosensors) JACTAX HD (Boston Scientific) ISAR Stent System (Translumina) NEVO (Cordis)
New DES platforms with biodegradable polymer: Biolimus A9 [LEADERS] Windecker S et al., Lancet 2008 [NOBORI CORE] Endothelial function in humans Hamilos MI et al., J Am Coll Cardiol 2008
New DES platforms with biodegradable polymer: JACTAX Grube E et al., JACC Interv 2010
New DES platforms with biodegradable polymer: ISAR Wessely R et al., ATVB 2005 [ISAR-TEST 4] Byrne et al., Eur Heart J 2009 Mehilli J et al., Eur Heart J 2008
Reservoir Technologie (Nevo) Recesses drug-polymer matrix into reservoirs Minimizes polymer contact with vessel wall Eliminates polymer-related friction Allows directional drug delivery Allows multi-drug delivery 2nd drug Wessely R. Nat Rev Cardiol, 2010
Polymer characteristics for the new NEVO DES platform SRL highly suited for biodegradable polymer delivery No polymer contact to vessel wall Polymer Absolute amount of polymer used only a fraction of current FDA approved DES Biodegradable polymer (PLGA) Stent design minimizes risk of polymer webbing, chibbing, etc.
Different polymers in comparison: preclinical data Severe 30 days 90 days Inflammation Moderate Mild 0 Xience Endeavor CYPHER BMS BioMatrix NEVO Taxus Price S et al. TCT 2009; poster presentation.
Spaulding C, presentation at EuroPCR 2011
NEVO RES I Nevo effective across all subgroups Spaulding C et al., Circ Cardiovasc Interv 2010
Take home messages The first decade of DESs has enabled interventional cardiology to safely and efficiently treat the vast majority of coronary lesions. Unlike paclitaxel, mtor inhibitors such as sirolimus can efficiently and safely be delivered with the use of a biodegradable polymer. Use of a biodegradable polymers is likely to improve safety of DES platforms, yet this has to be shown in appropriately sized RCTs. The potential use of multiple drugs, directional drug delivery, protected biodegradable polymer in low amounts and improved deliverability makes the upcoming generation of drug eluting stent platforms with reservoir technology an exciting novelty in the DES arena.