Stents farmacolo gicos na o polime ricos e novas plataformas bioabsorvi veis: suma rio dos ensaios cli nicos

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1 Curso de Revisão SBHI São Paulo, 2011 Stents farmacolo gicos na o polime ricos e novas plataformas bioabsorvi veis: suma rio dos ensaios cli nicos J. Ribamar Costa Instituto Dante Pazzanese São Paulo Brazil

2 Stents farmacolo gicos na o polime ricos e novas plataformas bioabsorvi veis: suma rio dos ensaios cli nicos Declaro não possuir conflito de interesse em relação a esta apresentação J. Ribamar Costa Instituto Dante Pazzanese São Paulo Brazil

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

4 Melhor que qualquer tipo de polímero seria não haver poli mero

5 SF não-poliméricos Benefício essencialmente um SNF após período de eluição do fármaco (segurança máxima) Limitações dificuldades em prolongar o período de eluição do fármaco e possível perda de eficácia Exemplos Translumina (Yukon), Biosensors (BioFreedom), MIV (Vestasync)

6 Tecnologia de SF BioFreedom TM Hipótese: Fármaco liberado a partir de um stent com eluição porosa sem polímero pode reduzir os eventos tardios causados por cobertura polimérica Potenciais vantagens. Evitar efeitos adversos de longo prazo que poderiam ser atribuíveis ao polímero Otimizar a integridade da superfície já que não existe polímero para ser desintegrado ou arrancado das estruturas do stent Possível menor tempo necessário para terapia anti-plaquetária dupla Superfície com micro-estruturas seletivas contém o fármaco na face abluminal Biolimus A9 Lipofilicidade

7 Desenho do Estudo BIOFREEDOM BioFreedom Coorte 1 Total de 182 pacientes Coorte 2 Reestudo Angio. 4 Meses 75 pacientes Reestudo Angio. 12 Meses 107 pacientes Angio FU 92% Angio FU 92% BioFreedom Dose Padrão (BF-DP) BioFreedom Dose Baixa (BF-DB) TAXUS Liberador de Paclitaxel BioFreedom Dose Padrão (BF-DP) BioFreedom Dose Baixa (BF-DB) TAXUS Liberador de Paclitaxel Inclusão Completa Set/2008 Jan/2009 Inclusão Completa Jan/2009 Jun/2009

8 PLT no seguimento angiográfico de 4 meses (mm) PLT Intra-Stent aos 4 Meses (2 o ) P < 0,0001 P = 0,002. Valores apresentados como mediana e intervalo interquartil [25%-75%]

9 PLT no seguimento angiográfico de 12 meses (mm) PLT Intra-Stent aos 12 Meses (1 o ) P não-inferioridade P = 0,001 P = 0,21. Valores apresentados como mediana e intervalo interquartil [25%-75%]

10 Translumina Porous Surface Stent Pure Sirolimus

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

12 30 (%) 25,9 FIM-Trial: Dose-Dependent Effect of Restenosis Prevention Angiographic (In-Segment Analysis) 30 (%) TLR 20 P= ,5 18,9 17,2 14, ,4 P= , ,8 0 0 Bare Stent 0.5 % 1.0 % 2.0 % Hausleiter et al, Eur Heart J 2005

13 ISAR-TEST Equal Efficacy for Restenosis Prevention Angiographic Restenosis 14,2 15,5 TLR % all p=ns 10 9,3 9,3 5 0 non-polymer Sirolimus (225) Durable polymer Paclitaxel (225) J Mehilli et al., Circulation 2006

14 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: Secondary Endpoint: angiographic restenosis TLR R Byrne et al., Eur Heart J 2009

15 ISAR-TEST-2: Restenosis Analysis Angiographic Restenosis (1 ary EP) Clinical Restenosis (TLR) p=0.68 p=0.002 p=0.83 p= , % % 15 12,0 11, , ,2 6, Cypher Dual-DES Endeavor R Byrne et al., Eur Heart J 2009

16 VestaSync Sirolimus + Hidroxiapatita Superfície modificada com hidroxiapatita Superfície modificada recoberta com hidroxiapatita com a formulação de Sirolimus encapsulada 0,5um 0,6um Superfície do stent Superfície do stent 16

17 Vestasync : 3 componentes básicos Plataforma de Cromo-cobalto (605 L) de baixo perfil Superfície modificada com hidroxiapatita Formulação de Sirolimus livre de polímero 17

18 Curva de Liberação do Sirolimus Vestasync vs. Cypher

19 Resultados de ACQ e USIC 9 meses Variáveis N= 15 pts Resultados da ACQ Diâmetro luminal mínimo, mm 2,29 ± 0,38 Diâmetro de estenose, (%) 15,9 ± 8,20 Perda luminal tardia, mm 0,36 ± 0,23 Reestenose Binária, n(%) 0 Resultados USIC Volume de HNI, mm 3 6,1 ± 4,9 % obstrução do stent 3,8 ± 2,3 Costa Jr J. et al. J. Am. Coll. Cardiol. Intv., 2009

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

21 Desfecho Primário P = 0.03 Costa Jr J. et al. EuroPCR 2011

22 USIC P = ,4± 17,9 mm 3 P = ,4± 10,9 mm 3 Costa Jr J. et al. EuroPCR 2011

23 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.

24 Drug-release profile in comparison to other available DES

25 PAX A (PI: A Abizaid) First In-Man randomized n = 30 AMAZONIA Pax n = 15 Taxus Liberte n = 15 Primary Endpoint: Late Loss % obstruction OCT tissue coverage at 4 Months

26 Late lumen loss at 4-month FU (mm) PAX A: Late Lumen Loss Analysis In-stent Late Loss P = 0.20 AMAZONIA PAX TAXUS. Results are expressed as median values Costa Jr J. et al. EuroPCR 2011

27 . 50 IVUS Analysis % of Stent Obstruction (Median)* 40 P-value = % [12.% 24% ] 6% [ 2.0% 18% ] Amazonia Taxus 10 0 Amazonia Taxus Costa Jr J. et al. EuroPCR 2011

28 Bioresorbable Stents Igaki-Tamai BVS REVA BTI PLA PLLA Tyrosine- Policarbonate PAE-Salicylate Biotronik Magnesium

29 Bioresorbable Stents BVS (Abbott) PLLA

30 30 Everolimus-Eluting Bioresorbable Vascular Scaffold ML VISION Delivery System Bioresorbable Device Platform Bioresorbable Coating Everolimus Seven generations of MULTI-LINK success World-class deliverability Polylactide (PLLA) Naturally resorbed, fully metabolized Polylactide (PDLLA) coating Fully biodegradable Similar dose and release rate to XIENCE V All illustrations are artists renditions

31 Polylactide Degradation & Lactate Metabolism Strut Remnant C 3 H 6 O 3 Lactic Acid DIFFUSION Lactate Shuttle 1 Lactate serves as a carbohydrate fuel source for multiple metabolic pathways C 3 H 6 O 3 Lactic Acid CH 3 CH(OH)COO - + H + Lactate CH 3 CH(OH)COO - Lactate CH 3 COCOO - + H + Pyruvate CH 3 COSCoA Acetyl-CoA Oxaloacetate Citrate Intracellular Mitochondrion H 2 O CO 2 ATP Malate Fumarate Succinate TCA (Krebs) Cycle Isocitrate Ketogluterate Succinyl-CoA 1. Philp, A., et.al. J. Exp. Biol. 2005; 208:

32 Porcine Coronary Artery Safety Study: Representative Photomicrographs (2x) BVS Cohort A 1 month 6 months 1 year 2 years 3 years 4 years CYPHER 1 month 6 months 1 year 2 years 3 years 4 years Photos taken by and on file at Abbott Vascular.

33 ABSORB Cohort A (PI P. Serruys) Clinical Study Overall Population 30 patients n = 4 excluded in Per Treatment Population (3 received non-bvs stent, 1 device failure) 6-month follow-up Intent to treat 30 patients clinical n = 1 missed F/U visits* Per treatment 26 patients QCA n = 1 missed F/U visits* n = 1 non-cardiac death** n = 5 refused angiography 2 & 3-year follow-up 29 patients clinical 19 patients QCA/IVUS 2-year follow-up *One patient missed the 9, 12, 18 month and 2 year visits **Two patients died of non-cardiac causes at 706 and 888 days Serruys, PW., AHA 2009.

34 ABSORB Cohort A Temporal Lumen Dimensional Changes, Per Treatment Post-PCI 6 Mos. 24 Mos. n = 25 n = 25 n = 19 ABSORB Cohort A Scaffold Area MLA = 5.09mm mm mm % 17.2% Late Loss = 0.43 mm Late lumen loss at 6 months mainly due to reduction in scaffold area Very late lumen enlargement noted from 6 months to 2 years Serruys, PW, et al. Lancet 2009; 373:

35 BVS Device Optimization More uniform strut distribution More even support of arterial wall Cohort A Lower late scaffold area loss Maintain radial strength for at least 3-4 months Storage at room temperature Improved device retention Cohort B Unchanged: Material, coating and backbone Strut thickness Drug release profile Total degradation Time

36 ABSORB Cohort B N = 101; 12 sites (Europe, Australia, New Zealand) PIs: P. Serruys, J. Ormiston Clinical follow-up schedule: 30 days, 6 months, 12 months, annually to 5 years Imaging schedule: Group 1 (n = 45) QCA, IVUS, OCT, IVUS VH Group 2 (n = 56) Baseline Months Months Months

37 % Patients ABSORB Cohort B 6-Month QCA Intent to Treat (Group) Cumulative Incidence Curve for Late Loss 100% 90% 80% 70% Negative Loss 0.43 ± 0.37 mm 0.85 ± 0.36 mm 60% 50% 0.10 ± 0.23 mm 40% 0.19 ± 0.18 mm BVS Cohort A (N = BVS 26) 1.0 BVS Cohort B (N = 42) BVS 1.1 EES* (N = 23) EES BMS* (N = 27) BMS 30% 20% 10% 0% In-Stent Late-Loss (mm) *SPIRIT-First

38 Results of Cohort B2 Quantitative OCT Analysis 22 Paired OCT in 21 pts Post procedure 12 month % Difference P values Mean scaffold area, mm Minimal scaffold area, mm Mean prolapse area, mm na - - Mean strut core area, mm Mean Neointimal area, mm Mean flow area, mm <0.001 Minimal flow area, mm < Lumen area stenosis, % Uncovered struts, % na 3.11 ISA area, mm 2 (for patients with ISA) First signs of bioresorption 0.41 (n=18) 2.94 (n=4) - SE Rev. A Pipeline product. Currently in development at Abbott Vascular. Not available for sale.

39 Luminal area #4. Bioresorption and vessel wall integration are real phenomena. (Lancet 2009) Post-stenting Post-stenting Echogenicity 6-month 6-month Echogenicity Pre-stenting Post-stenting 6-month 24-month 3.9mm 2 7.1mm 2 6.9mm mm 2

40 #4. Bioresorption and vessel wall integration are real phenomena. (Lancet 2009) PRESERVED BOX, NON APPOSED OPEN BOX NON DISCERNIBLE PRESERVED BOX, NON APPOSED Dissolved bright box Corrugated Dissolved Smooth black box Baseline 6 months 2 years

41 3 Year Clinical Results Intent to Treat Hierarchical 6 Months 30 Patients 12 Months 29 Patients* 2 Years 29 Patients* 3 Years 29 Patients* Ischemia Driven MACE (%) 3.3% (1)* 3.4% (1)* 3.4% (1)* 3.4% (1)* Cardiac Death (%) 0.0% 0.0% 0.0% 0.0% MI (%) Q-Wave MI 0.0% 0.0% 0.0% 0.0% Non Q-Wave MI 3.3% (1)** 3.4% (1)** 3.4% (1)** 3.4% (1)** Ischemia Driven TLR (%) by PCI 0.0% 0.0% 0.0% 0.0% by CABG 0.0% 0.0% 0.0% 0.0% No stent thrombosis up to 3 years (only one patient on clopidogrel) No new MACE events between 6 months and 3 years Ormiston et al. 2008, Serruys et al. 2009

42 ABSORB EXTEND Non-Randomized, Single-Arm, Continued Access Trial 1000 subjects Up to 100 OUS sites Study Objective: Endpoints: Treatment: Device Sizes: Clinical follow-up MSCT follow-up OCT follow-up 30d 6mo 12 mo 24 mo 36 mo Continued Access trial. FPI: Jan 11, 2010 No hypothesis-testing, typical PCI clinical endpoints Up to 2 de novo lesions in different epicardial vessels Planned overlapping allowed in lesions >22 and 28 mm Scaffold diameters: 2.5, 3.0 mm Scaffold lengths: 18, 28 mm

43 ABSORB EXTEND (PI: A. Abizaid) 1000 pt ** clinical data Subgroup Analyses Diabetics Long lesions Dual vessel disease Jailed sidebranches Intermediate stenosis More complex patient/lesion subsets (MVD, bifurcations) ~ 100 pt MSCT subgroup ~ 50 pt OCT subgroup Subsets Health economics (Prospective study) QOL Restored vessel physiology (subset) ~ 100 pt AMI subgroup

44 Conclusão SFs não poliméricos podem ser uma alternativa àqueles com polímero duráveis. Os SFs totalmente biodegradáveis representam o início de uma nova era na cardiologia intervencionista. Estudos maiores com stents biodegradáveis estão em fase de inclusão e futuros estudos controlados serão necessário antes que adotemos este novo dispositivo na prática clínica.

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