Will the Future of DES be Non-Polymeric ? CRT 2011 Washington, DC Will the Future of DES be Non-Polymeric ? Alexandre Abizaid, MD, PhD, FACC Instituto Dante Pazzanese de Cardiologia Sao Paulo - Brazil Columbia University New York - USA

Alexandre Abizaid, MD, PhD Consulting Fees Abbott Laboratories Boston Scientific Corporation Cordis Corporation

Current Problems with Polymers Shortcomings often associated with polymers during stent delivery “Webbed” polymer surface leading to stent expansion issues” Non uniform polymer coating Polymer delamination ● Durable Coatings-Potential for: - Continuing source of inflammation - Poor healing/thrombosis risk

DES – Late incomplete apposition and DES stent thrombosis 40 m 6 m 18 m Post PCI

Better than any polymer is no polymer…

Non-Polymeric Systems: BioFreedom (Biosensors) Yukon (Translumina) Pax Technology (Minvasys) Vestasync (MIV) Cre8 Anphilimus (CID)

BioMatrix Freedom Stent Micro-structured Surface Selectively micro-structured surface holds drug in abluminal surface structures

BioFreedom FIM Design BioFreedom FIM 4 Months follow up 180 total patients First Cohort Second Cohort 4 Months follow up 75 patients 12 Months follow up 105 patients BioFreedom Standard dose Low dose TAXUS® Liberté BioFreedom Standard dose Low dose TAXUS® Liberté This study is a prospective, single blinded, randomized study to evaluate the safety and effectiveness of Bio-FreedomTM Biolimus A9® drug-eluting coronary stent delivery system carrying a standard dose of Biolimus A9® drug, or alternately a low dose of BA9 drug compared with a TaxusTM LiberteTM control arm at two time points 4M and 1 yr. The objectives of this study are to establish the long term safety, effectiveness and performance of the Biosensors Bio-FreedomTM DES, assessed at multiple time points through assessment of clinical and/or angio/IVUS data from the primary and secondary data sets obtained from the trial. There are 75 patients in the 4M study and 105 patients in the 1 yr study. There are two dose groups in the Bio-Freedom arm at each time point: standard dose and low dose. Enrollment Complete Sept 2008 – Jan 2009 Enrollment Complete Jan 2009 – Jun 2009

4 Month vs 12 Month Angiographic FU In- Stent Late Lumen Loss First Cohort 12 Month Second Cohort Median values

Non-Polymeric Systems: BioFreedom (Biosensors) Yukon (Translumina) Pax Technology (Minvasys) Vestasync (MIV) Cre8 Anphilimus (CID)

Translumina Porous Surface Stent Pure Sirolimus Examples of drug delivery from pure drug coated on a stent: Certain drugs can be deposited directly on the stent surface by solvent dipping or spraying methods. Here a stent with an irregular rough surface topology is employed to release sirolimus. This stent has been implanted in hundreds of patients in Europe with promising results (Kastrati,et al, Munich)

New-Generation Stents & Coating Device from Translumina Yukon® CHOICE 4 Yukon® CC CoCr Stent

FIM-Trial: Dose-Dependent Effect of Restenosis Prevention Angiographic (In-Segment Analysis) TLR P=.024 P=.006 Bare Stent 0.5 % 1.0 % 2.0 % Hausleiter et al, Eur Heart J 2005

ISAR-TEST Equal Efficacy for Restenosis Prevention Angiographic Restenosis TLR % all p=NS non-polymer Sirolimus (225) Durable polymer Paclitaxel (225) J Mehilli et al., Circulation 2006

ISAR-TEST 2: Testing Dual-Drug Sirolimus + Probucol 1007 pts with de-novo lesions randomized Cypher (n=333) Dual DES (n=335) Endeavor (n=339) Polymer-free, probucol + sirolimus-eluting stent Primary Endpoint: angiographic restenosis Secondary Endpoint: TLR R Byrne et al., Eur Heart J 2009

ISAR-TEST-2: Restenosis Analysis Angiographic Restenosis (1ary EP) Clinical Restenosis (TLR) p=0.83 p=0.001 p=0.68 p=0.002 % % The differences that we have already seen in angio restenosis, were also seen w clin restenosis Cypher Dual-DES Endeavor R Byrne et al., Eur Heart J 2009 16

(n=202) ISAR-TEST 3: Testing Different Sirolimus-Coating Strategies 605 pts with de-novo lesions randomized polymer-free (n=201) biodegradable polymer (n=202) durable polymer (Cypher) (n=202) Primary Endpoint: in-stent late lumen loss (non-inferiority trial) Secondary Endpoint: binary restenosis rate, clinical events at 1 yr. J Mehilli et al., Eur Heart J 2008

ISAR-TEST 3: Less Efficacy with Non-Polymer vs. Polymer-Based SES Primary EP: In-Stent Late Lumen Loss at FU mm polymer- free biodegradable polymer durable polymer (Cypher) Sirolimus-eluting stents J Mehilli et al., Eur Heart J 2008

ISAR-TEST 5 3002 patients with de novo lesions Intracoronary Stenting and Angiographic Results: Test Efficacy of Rapamycis/Probucol- and Zotarolimus-Eluting STents - 5 3002 patients with de novo lesions Probucol/Sirolimus-Eluting Dual-DES n=2002 Zotarolimus-Eluting Resolute ZES n=1000 6 to 8-month repeat angiogram 12-month clinical follow-up Mehilli et al. TCT LBCT 2010

ISAR-TEST 5: Primary Endpoint Cardiac Death/TV-related MI/TLR 50 % 40 30 P=0.83 RR 1.03 [0.80-1.31] 20 Resolute ZES 13.1% 10 Dual-DES 13.1% 1 2 3 4 5 6 7 8 9 10 11 12 Mehilli et al. TCT LBCT 2010

Angiographic Restenosis In-stent late lumen loss In-segment binary restenosis P=.62 P=.81 mm % Dual-DES ZES Mehilli et al. TCT LBCT 2010

Non-Polymeric Systems: BioFreedom (Biosensors) Yukon (Translumina) Pax Technology (Minvasys) Vestasync (MIV) Cre8 Anphilimus (CID)

Polymer Free Paclitaxel 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.

PAX A PAX B and Bi Pax First In-Man randomized n = 30 Multicenter (PI: A Abizaid) AMAZONIA Pax n = 15 Primary Endpoint: Late Loss % obstruction OCT tissue coverage at 4 Months First In-Man randomized n = 30 Taxus Liberte n = 15 PAX B and Bi Pax (PI: A Abizaid / Jean Fajadet) AMAZONIA Pax n = 100 Multicenter Registry n = 200 Primary Endpoint: Late Loss And MACE at 9 Months Bi Pax n = 100

PAX-A: Index Procedure Amazonia-PAX 3.5 x 24 mm A B C A B C

PAX A: 4-Month Follow-up

PAX-A Index Procedure Taxus Liberte 3.5 x 20 mm A B A B

PAX A: 4-Month Follow-up Late-acquired ISA in prox & distal edges A B B B

Non-Polymeric Systems: BioFreedom (Biosensors) Yukon (Translumina) Pax Technology (Minvasys) Vestasync (MIV) Cre8 Anphilimus (CID)

3D MicroPorous Nanofilm HAp

QCA Results Follow-up 4 months (n=15) 9 months (n=12) Variable In-Stent In-Lesion MLD, mm 2.34 ± 0.33 2.05 ± 0.38 2.27 ±0.33 2.02 ± 0.29 % Diameter stenosis 13.8 ± 7.0 23.6 ± 8.8 15.9 ± 8.20 23.6 ±9.50 Late lumen loss, mm 0.29 ± 0.25 0.16 ± 0.29 0.36 ± 0.24 0.20 ± 0.31 Restenosis*, % (n) Abizaid et al. ACC 2008.

IVUS Volumetric Analysis Baseline / 4 month / 9 month follow-up IVUS variables Baseline N= 14 P* 4-month follow-up 9-month follow-up Vessel Volume (mm3) 294.2 ± 117.1 286.9 ± 87.4 296.8 ± 85.6 Stent Volume (mm3) 144.5 ± 48.2 140.5 ± 36.7 143.1 ± 41.4 Lumen Volume (mm3) 144.7 ± 48.4 136.3 ± 34.2 136.8 ± 38.2 NIH Volume (mm3) N/A 4.3 ± 3.5 6.1 ± 4.9 Mallapposition Volume (mm3) 0.34 ± 0.87 0.14 ± 0.34 0.13 ± 0.36 % Stent Obstruction 2.8 ± 2.2 3.8 ± 2.3 * 1 pt refused to undergo invasive FU at 9 months and therefore were excluded from this sub analysis.

PRE POST Lower LLL (-0.1 mm) 4 MONTH- FU 9 MONTH- FU

PRE POST FOLLOW-UP 4 MONTHS

VESTASYNC II Polymer-Free Sirolimus-Eluting Stent Vestasync Eluting Stent n = 50 First In-Man 3:1 randomized n = 75 Primary Endpoint: Late Loss at 6 Months Bare Metal Stent n = 25 IVUS subanalysis: 30 pts OCT sub-analysis : 30 pts Endothelial function: 20 pts

VestaSync II trial Late Loss P = 0.0036 0.78± 0.45 mm 0.35± 0.38 mm Vestasync Vestacor

VestaSync II trial Preliminary IVUS Results 29,4± 17,9 mm3 P = 0.0016 P = 0.0036 15,4± 10,9 mm3

9-month Major Cardiac Events Site report (no adjudication) Vestasync N=50 VestaCor N=25 Death 0 1 (4%) MI 1 (2%) 0 TLR 1 (2%) 2 (8%) Non-TLR 1 (2%) 1 (4%) MACE 2 (4%) 2 (12%) No cases of stent thrombosis in either groups

Non-Polymeric Systems: BioFreedom (Biosensors) Yukon (Translumina) Pax Technology (Minvasys) Vestasync (MIV) Cre8 Anphilimus (CID)

CID Polymer-free Abluminal Reservoir DES Technology

The Bio-Inducer Surface (BIS) is made of pure carbon atoms Bio-Inducer Surface (2° gen coating ) applied to CID bare platform (AVANTGARDE) The Bio-Inducer Surface (BIS) is made of pure carbon atoms Bio/haemo-compatibility % % Graphite Diamond Improved Bio/Haemo-compatibility This 2nd generation coating (≤0.3 µm) brings the cristalline structure closer to the diamond with a further improvement of its bio/haemo compatibility

Drug Release Polymeric Drug System CID AmphilimusTM Formulation ACTIVE PRINCIPLE + AMPHIPHILIC CARRIER ACTIVE PRINCIPLE POLYMERIC MATRIX “Discrete” system “Homogeneous” system 43

Animal data*: Complete endothelialization @ 5d CID (Avantgarde) Competitor BMS Continuum endothelial layer: Clearly visible polygonal shape of the endothelial cells both original or covering stent struts. Non-Continuum endothelial layer: Wide areas non covered with endothelium; few adherent cells are present (RBCs, leukocytes…). * Stent implants in pig coronary arteries. University of Turin

The NEXT Study Clinical Angiographic/IVUS Patients with ischemic myocardial symptoms related to de novo lesions (max 2 in 2 different vessels) in native coronary arteries Cre8 – CID DES (n=150 pts)  3.0 – 3.5 mm L 12 -16 – 20 – 25 mm 11 European Sites Randomisation 1:1 100% angiographic f-up 20% IVUS f-up PI: Prof Carrié - Fr TAXUS LIBERTÉ (n=150 pts)  3.0 – 3.5 mm L 12 -16 – 20 – 25 mm Primary Endpoint: LLL in-stent at 6 months post-procedure Secondary Endpoints: QCA measurements in-stent and in-segment at 6 months IVUS measurements at 6 months (20%) Clinical composite occurrence of death, MI, any revascularization at 1 and 6 months, and yearly up to 5 years Thrombosis throughout the study duration, according to ARC definition Clinical Angiographic/IVUS 12 & 24 months 6 months 1 month 3, 4, 5 years

Drug fills hollow structure Drug Filled Stent (DFS) Concept (Medtronic) Drug elution controlled by diffusion physics Exits through holes Drug fills hollow structure Elution Holes No Polymer!

Conclusions First Genaration Durable Polymers with thick polymer loading are being gradually replaced to more advanced technology. Bioabsorbable Polymers with abluminal release and reservoir technology are slowing replacing the first gen DES. Non-Polymeric DES with surface modification will be an attractive alternative to improve safety

Delayed Healing - DES Severe inflammation Lack of neointimal growth (uncovered Struts) Persistent fibrin deposition * Rabbit 28 days * *Inflammation Incomplete endothelialization CYPHER TAXUS Fibrin deposition with malapposition Severe inflammation Porcine 28 days Virmani et al.

JEMRS – Curso Revisão SBHCI – nov08 Instituto Dante Pazzanese de Cardiologia: The Place of the First Drug Eluting Stent 14/09/2018 Dr. J>Eduardo Sousa