Do Biodegradable Polymers Have an Advantage Michael Joner

Do Biodegradable Polymers Have an Advantage? Michael Joner, MD CVPath Institute Gaithersburg, USA

Michael Joner, MD Institutional grant/research support: • 480 Biomedical, Abbott Vascular, Atrium, Bio. Sensors International, Biotronik, Boston Scientific, Cordis J&J, GSK, Kona, Celo. Nova, Medtronic, Micro. Port Medical, Stentys, Orbus. Neich Medical, Re. Core, SINO Medical Technology, Terumo Corporation, and W. L. Gore. Consultant: Biotronik

Preclinical and Autopsy Perspective

Histologic Comparison: BMS vs. Durable vs. Biodegradable polymercoated DES in porcine coronary model (28 -days) Neointimal Area p = n. s. 4 3 2 1 0 BMS PEVA/PBMA SES PUR SES PLLA SES PLGA SES Inflammation Score p = 0. 01 3 2 1 0 -1 BMS PEVA/PBMA SES PUR SES PLLA SES PLGA SES Fibrin Score p = 0. 01 3 Koppara T, Thromb Haemost. 2012; 107: 1161 -71 2 1 0 poly(n-butyl methacrylate) (PBMA)/ poly(ethylene vinyl acetate) (PEVA), polyurethane (PUR), poly (L-lactide) (PLLA), poly(lactide-co-glyco- lide) (PLGA) -1 -2 BMS PEVA/PBMA SES PUR SES

Biodegradable PLLA-coated Orsiro vs. Cypher DES in porcine coronary model Neointimal Area 28 -days * 90 -days 180 -days * Orsiro 5 0 Orsiro 3 2 1 0 -1 3 2 Koppara T, Thromb Haemost. 2012; 107: 1161 -71 PLLA SES Cypher Inflammation Score * * PLLA SES Orsiro * Cypher Fibrin Score 1 0 -1 * sig. different from Cypher PLLA SES Orsiro Cypher

Inflammation in Biodegradable vs. Permanent Polymers in the Absence of Drugs Porcine Model at 28 Days Koppara et al. , Euro. Intervention. 2014 Oct 16. pii: 20131118 -01

Granulomatous Reaction and Inflammation Following Comparator DES Implantation in Pig Coronary Arteries Struts with Granulomas (%) 120 Permanent Polymers 100 Bioerodable Polymers 100 80 80 60 60 40 40 20 20 0 30 90 180 30 90 180 Cypher Taxus Resolute Xience V Biomatrix 0 30 90 180 Nevo (Days) 90 180 3030 90 Synergy Inflammation Score 6 4 Bioerodable Polymers Permanent Polymers Max; Score 4 5 4 3 2 Max; score 3 2 0 -2 6 1 0 30 90 180 30 90 180 Cypher Taxus Resolute Xience V Biomatrix Nevo (Days) 30 90 180 Synergy Wilson GJ, et al. Euro. Intervention. 2012; 8: 250 -7

Contemporary DES Platforms Strut and Coating Thickness In Perspective Durable Polymer Coated Bioabsorbable Polymer Coated Xience Resolut Biomatr Co. Cr. Nobori e ix EES Promus Pt. Cr. EES Co. Ni. ZES 316 LBES SYNER Bio. Mim Mi. Stent GY e Pt. Cr. EES Co. Cr. SES Orsiro Co. Cr. SES Strut 81µm 89µm 120µm 125µm 74µm 65µm 64µm 61µm thickne 0. 0032” 0. 0035” 0. 0046” 0. 0047” 0. 0029” 0. 0026” 0. 0025” 0. 0024” ss Polymer PVDF Bio. LINX PLA PLGA PLLA + PLGA Conforma Distributi Conformal Abluminal 7 -8µm / on / l 6µm / side 10µm 20µm 4µm side thickness 2µ / 2µ PLGA PLLA Probio* Conforma l l 5µm / 3. 5µm / *silicon carbide

Synergy Absorb Pt. Cr PLGA 74 μm Bio. Matrix PLLA PDLA 150 μm 316 L PLA 120 μm Omega Pt. Cr 74 μm Platelet Deposition in one half of stent following immunofluoroscent staining (CD 61/CD 42 b) viewed by Confocal Microscopy in Porcine ex-vivo Arterio-Venous Shunt Model. Endothelialization Platelets Fibrinogen ADP TF v. WF Prothrombin Coagulation Cascade Activation X Nonstreamline strut X Xa Activated platelets Atherosclerotic lesion Coagulation Cascade inhibition Fibrinogen Platelets ADP TF v. WF Prothrombin PGI 2 NO TFPI t. PA TM Heparan Streamline strut “Healed” atherosclerotic lesion

Vascular Response following Implantation of Sirolimus-eluting stents (Cypher) in Human A 58 -year-old man who had received 2 SES (for 3 years) and 1 Co. Cr-EES (for 7 months) died suddenly 1 day after nasal polyp surgery. DAPT was discontinued 5 days before the surgery. X-ray Luna (Eosinophils) H&E Movat CD 45 RO (T-cells) CD 20 (B-cells) SES CD 45 RO Luna 4 (mm) Inflammation score 0. 4 0. 3 0. 2 0. 1 0 -0. 1 -0. 2 -0. 3 -0. 4 -0. 5 -0. 6 -0. 7 -0. 8 -0. 9 -1 P=0. 15 3 2 1 0 N=30 N=21 N=18 ≥ 1 to <9 ≥ 9 to <18 ≥ 18 months CD 20 Neointimal thickness P=0. 28 ≥ 1 to <9 ≥ 9 to <18 ≥ 18 N=29 N=21 N=17 months Figures; Otsuka F, et al. Circulation. 2014; 129: 211 -223.

A 55 -year old male who presented with unstable angina secondary to diffuse disease in the LAD; four stents were implanted (3 Resolute zotarolimus-eluting stents (R-ZES) and a single cobalt-chromium everolimus-eluting stent (Co. Cr-EES). At 238 -days following implantation of the 4 stents the patient died suddenly. A LCX Radiograph RI LM RI -1 LM LAD RI -2 Co. Cr-EES B LCX RI Co. Cr. EES R-ZES LAD R-ZES LD LAD -4 Co. Cr-EES LD LAD -4 R-ZES LAD -3 LD Luna OCT LAD -3 R-ZES H&E LAD -2 R-ZES LAD -1 LAD -2 RI -1 LAD -1 OCT LD CD 68 CD 45 RO CD 20 Circulation 2015, In press Coronary angiograph Overlapped R-ZES/Co. Cr-EES Hypersensitivity Reaction in 2 nd Generation DES

Clinical Perspective

LEADERS 1707 pts Bio. Matrix (BP Biolimus) Cypher (PP Sirolimus) Cardiac death, MI, Reintervention 10. 5% 9. 2% Months Windecker et al. , Lancet 2008

SORT OUT V 2468 pts Nobori (BP Biolimus) Cypher (PP Sirolimus) Cardiac death, MI, ST, Reintervention 5. 4% Pnoninferiority=0. 06 4. 4% Months Christiansen et al. , Lancet 2013

COMPARE II 2707 pts Nobori (BP Biolimus) Xience (PP Everolimus) Cardiac death, MI, Reintervention 5. 2% 4. 8% Days Smits et al. , Lancet 2013

NEXT 3241 pts Nobori (BP Biolimus) Xience (PP Everolimus) TLR 4. 2% Natsuaki et al. , JACC 2013

EVOLVE II Primary Endpoint: 12 -month TLF (ITT) Synergy (BP Everolimus) 1684 pts Promus (PP Everolimus) Synegy Stent Kereiakes, ACC 2014

Century II 1120 pts Ultimaster (BP Sirolimus) Xience (PP Everolimus) TLF Xience 5. 27% [3. 69% ; 7. 50%] Ultimaster 4. 36% [2. 94% ; 6. 43%] Data up to 300 days W. Wijns, Euro PCR 2014

Summary § Preclinical and autopsy studies point to a benefit of biodegradable polymer DES with respect to chronic inflammatory reactions § However, not all DES (permanent and biodegradable polymer) are created equal and stent geometry, strut thickness, abluminal vs. circumferential coating all play an important role § From a clinical point of view, biodegradable polymer DES seem to be non-inferior to current generation DES and longer-term studies are needed to rule out their relative merits