Eberhard Grube MD FSCAI, FACC

Transcription

1 SCAI 30 th Annual Scientific Sessions Orlando/Fla BMS and DES Thrombosis Differences among DES Eberhard Grube MD FSCAI, FACC HELIOS Heart Center Siegburg, Siegburg, Germany Stanford University, School of Medicine, CA, USA Hospital Israelita Albert Einstein, São Paulo, Brazil

2 BMS and DES Thrombosis Differences in DES Eberhard Grube MD, FSCAI The following relationships exist related to this presentation: Grant support (GS), consultant (C), speakers bureau (SB), stock options (SO), equity interest (EI): Boston Scientific: GS, C, SB Cordis: C, SB Biosenors: GS, C, SB, EI Abbott: C, SB, Medtronic: C, SB Off label use of products will be discussed in this presentation.

3 Contributing Factors Honda Y et al., Circulation, 2003, 8;108(1):2-5 Stent factors Design/Length Polymer Surface Drugs Lesion factors Vessel size Thrombus Plaque characteristics Antiplatelet Treatment Resistance Drug-drug interaction Duration of therapy STENT THROMBOSIS Procedural factors Residual dissection Incomplete stent apposition Antithrombotic/anticoagulation therapy Patient factors Gene polymorphism LV function ACS Blood factors Coagulation activity Platelet inhibition

4 Contributing Factors Honda Y et al., Circulation, 2003, 8;108(1):2-5 Stent factors Design/Length Polymer Surface Drugs Lesion factors Vessel size Thrombus Plaque characteristics Antiplatelet Treatment Resistance Drug-drug interaction Duration of therapy STENT THROMBOSIS Procedural factors Residual dissection Incomplete stent apposition Antithrombotic/anticoagulation therapy Patient factors Gene polymorphism LV function ACS Blood factors Coagulation activity Platelet inhibition

5 Drug Polymer Stent TAXUS Paclitaxel Polyolefin derivative Express 2 CYPHER Sirolimus PEVA + PBMA blend BX Velocity

6 Localized Hypersensitivity Related to Sirolimus Eluting Stent Marked Chronic Inflammation and Medial Destruction

7 Inflammation in DES Overlapping SES vs PES Conclusions: DES delays arterial healing and promotes inflammation Compared to SES, PES induce greater: Fibrin deposition Medial cell loss WBC Infiltration Late Neointimal Hyperplasia Finn, A. V. et al. Circulation 2005;112:

8 DES Delayed Endothelialization BMS Overlapping SES vs PES SES BMS PES Overlap Overlap Conclusions: BMS showed far greater endothelialization than DES Lack of coverage highlighted in areas of overlap Less surface coverage by endothelial cells in PES than Siegburg SES / Stanford

9 REALITY % of Patients 2,5 2,0 1,5 1,0 0,5 0,0 Stent Thrombosis (Acute + Subacute) 0,6 CYPHER 1,6 0,4 1,7 TAXUS P= P= P= , ,8 Intention-to-Treat Per-Protocol Actually-Treated* Per protocol analysis: CYPHER 0.4, TAXUS 1.7: P=0.033 * 1 patient randomized to CYPHER actually treated with a TAXUS stent

10 Stent Thrombosis: DES vs. BMS Per Protocol Analysis Mauri L et al. N Engl J Med 2007;356: TAXUS I, II, IV, V Events to 4 Years (N=2,797) RAVEL, SIRIUS, E-SIRIUS, C-SIRIUS Events to 4 Years (N=1,748) 2 P= P= % Overall ST Early ST Late ST Very Late ST % Overall ST Early ST Late ST Very Late ST PES (N=1,400) BMS (N=1,397) SES (N=878) BMS (N=870)

11 FDA Requested Analysis (Commercial TAXUS Stent SR Only) Freedom From (Protocol) Stent Thrombosis 100 RAVEL, SIRIUS, E-SIRIUS, E and C-SIRIUS C (N=1,748) % 100 TAXUS I, II, IV, V-SRV (N=2,797) +0.48% % (5) 98.8% (10) P= % (10) 98.7% (16) p= After 1 year 5 vs. 0, p=0.025 log-rank 97 After 1 year 6 vs. 1, p=0.057 log-rank Bare Metal Stent (N=878) CYPHER Stent (N=870) Bare Metal Stent (N=1,397) TAXUS Stent (N=1,400) Time after Initial Procedure (years) Time after Initial Procedure (years) CRF analysis presented by Dr. Gregg Stone and Dr. Martin Leon, TCT TAXUS Stent data presented by Dr. Don Baim, December 7, TAXUS 4-year meta-analysis includes TAXUS I (5 yr), II-SR cohort I (4 yr), IV (4 yr), V (2 yr) (N=2,797). The safety and effectiveness of the TAXUS Stent have not been established in patients for longer than 12 months.

12 Different Definitions of Stent Thrombosis TAXUS Trials (TAXUS I, II-SR, IV, V*) (to 3 years) Cypher Trials (RAVEL, SIRIUS, E&C-SIRIUS*) (to 4 years) SAT (1-30 days) Late ST (>30 days) Confirmed (Angiographically) Presumed (Sudden death within 30 days or MI without angiographic confirmation) Total Reported Thrombosis 0.19% (7/1401) 0.45% (6/1401) 0.08% 1/1401 Included per Protocol 1.00% (10/1401) 0.46% (4/878) 0.57% (5/878)?% Protocol does not include Presumed?% 1.03% (9/878) *TAXUS I 3-year data presented at TCT 2004 by Dr. Eberhard Grube. TAXUS II 2-year data presented at TCT 2004 by Dr. Antonio Colombo. TAXUS IV 2-year data presented at TCT 2004 by Dr. Gregg W. Stone. TAXUS V 9-month data presented at ACC 2005 by Dr. Gregg W. Stone. RAVEL 4-year data presented at PCR 2005 by Dr. J. Eduardo Sousa. SIRIUS 3- year data presented at ACC 2005 by Dr. Martin B. Leon. E-Sirius 3-year data presented at ESC 2005 by Dr. Vieter Legrand. C-SIRIUS presented at ACC 2003 by Dr. Erick Schampaert.

13 Pooled Meta-Analysis Mauri et al. N Engl J Med 2007;356:

14 Stent Thrombosis after DES 2229 patients after successful DES implantation SES 1062 pts 2272 stents PES 1167 pts 2223 stents SAT 4 (0.4%) LST 5 (0.5%) P=0.5 P=0.3 SAT 10 (0.9%) LST 10 (0.9%) 10.2 ± 4.4 m 9.3 ± 5.6 months 7.9 ± 3.6 m Total SES Total DES 29/2229 (1.3%) Total PES 9 (0.9%) P= (1.7%) Iakovou et al, JAMA 2006

15 Solutions to Avoid Stent Thrombosis Optimal Stent Design Drug Duration Optimal Procedural Result Improved SAFETY

16 DES on the US Market Forecast BSC TAXUS Liberté PROMUS JNJ Cypher \ CoStar MDT Endeavor ABT Xience V As of January, TAXUS, Liberté and PROMUS are trademarks of Boston Scientific Corporation or its affiliates. PROMUS Stent is a private-labeled XIENCE V Everolimus Eluting Coronary Stent System manufactured by Abbott and distributed by Boston Scientific Corporation. XIENCE is a trademark of Abbott Laboratories group of companies. Cypher, Cypher-Mini and Cypher-Max are trademarks of Cordis Corporation. CoStar is a registered trademark of Conor Medsystems Inc. Endeavor is a trademark of Medtronic Vascular, Inc. Caution- TAXUS Liberté, TAXUS Atom, TAXUS 4.0mm, PROMUS, Xience V, Endeavor, CoStar, Cypher Mini and Max are investigational devices. Not currently available for sale in the US.

17 Generation of Evidence after Device Introduction Early Safety Efficacy Safety FIM Pivotal Post approval studies Device Introduction To assess stent thrombosis differences one needs large patient populations as well as long-term follow-up

18 Currently Available Drug-Eluting Stent Pivotal Clinical Trial Data TAXUS I (n=61) TAXUS II (n=536) TAXUS IV (n=1314) TAXUS V (n=1156) TAXUS VI (n=448) RAVEL (n=238) SIRIUS (n=1058) E-SIRIUS (n=352) C-SIRIUS (n=100) ENDEAVOR I (n=100) ENDEAVOR II (n=1197) ENDEAVOR III (n=436) SPIRIT I (n=54) SPIRIT II (n=300) SPIRIT III (n=980) 1 yr 2 yrs 3 yrs 4 yrs 5 yrs ~ 1334 patients ~1,700 patients ~3,500 patients ~1,800 patients Colombo et al. Circulation. 2003;108:788; Stone et al. N Engl Med. 2004;350:221; Stone et al. JAMA. 2005;294:1215; Dawkins et al. Circulation. 2005;112:3306; Morice et al. N Engl J Med. 2002;346:1773; Moses et al. N Engl J Med. 2003;349:1315; Schofer et al. Lancet. 2003;3362:1093; Schampaert et al. JACC. 43:1110; Dr. Meredith, EuroPCR 2006; Dr. Kandzari, ACC 2006; Dr. Serruys, ESC Dr. Stone, ACC 2007

19 Endeavor Shows More Complete Endothelization than Cypher and Taxus Cypher Taxus Endeavor % of Struts Endothelialized Cypher Taxus Endeavor Mean % Endothel Rabbit model at 21 days Virmani et. al; PCR 2006

20 Endeavor Clinical Program Rate of Protocol Defined Stent Thrombosis by Study ENDEAVOR I-III I III Clopidogrel Therapy for 3 months Days Post Procedure year 2 years 3 years EI n=100 EII n=598 EII CA n=296 EIII n=323 = 1% = 0.5% = 0.0% = 0.0% Overall Thrombosis = 0.3% Defined as angiographic thrombus or subacute closure within the stented vessel at the time of the clinically driven angiographic restudy for documented ischaemia (chest pain and ECG changes). Any death not attributed to a non-cardiac cause within the first 30 days is considered a surrogate for stent thrombosis in the absence of documented angiographic stent patency.

21 Different Definitions of Stent Thrombosis TAXUS Trials Cypher Trials (TAXUS I, II-SR, IV, V*) (RAVEL, SIRIUS, E&C-SIRIUS*) (to 3 years) (to 4 years) ENDEAVOR Trials (ENDEAVOR I & II*) (2 years) 0.46% 0.6% SAT (1-30 days) 0.19% (7/1401) (4/878) (4/691) Late ST (>30 days) 0.45% 0.57% Confirmed (Angiographically) (6/1401) (5/878) 0 Presumed (Sudden death within 30 days or MI without angiographic confirmation) 0.08% 1/1401 Included per Protocol?%?% Protocol does not include Presumed?%?% Total Reported Thrombosis 1.00% (10/1401) 1.03% (9/878) 0.6% (4/691) *TAXUS I 3-year data presented at TCT 2004 by Dr. Eberhard Grube. TAXUS II 2-year data presented at TCT 2004 by Dr. Antonio Colombo. TAXUS IV 2-year data presented at TCT 2004 by Dr. Gregg W. Stone. TAXUS V 9-month data presented at ACC 2005 by Dr. Gregg W. Stone. RAVEL 4-year data presented at PCR 2005 by Dr. J. Eduardo Sousa. SIRIUS 3- year data presented at ACC 2005 by Dr. Martin B. Leon. E-Sirius 3-year data presented at ESC 2005 by Dr. Vieter Legrand. C-SIRIUS presented at ACC 2003 by Dr. Erick Schampaert. ENDEAVOR I data presented at ESC 2005 by Dr. Wijns. ENDEAVOR II data presented at PCR 2005 by Dr.J. Fajadet. Data from trials that are not head-to-head are not intended to be comparative. Cypher is registered trademarks of Cordis Corporation, Endeavor is trademarks of Medtronic Corporation, NIR is a registered trademark of Medinol Ltd. - Jerusalem

22 Examples of Next Generation Stents 2. Generation DES Xience V: Everolimus Durable Polymer BioMatrix: Biolimus Absorbable Polymer Conor: Paclitaxel Absorbable Polymer?? ZoMaxx: Zotarolimus Durable Polymer Drug Combo and many more Lesion Dedicated DES Devax Bifurcations Xtent Multi-lesion Absorbable DES

23 Everolimus Durable Polymer Xience V (SPIRIT Trials) XIENCE V DES Everolimus Eluting Coronary Stent System Everolimus Durable Polymer ML VISION Platform ML VISION Stent Delivery System

24 XIENCE V Stent Thrombosis SPIRIT II Early stent thrombosis (%)(<30days) Late stent thrombosis (%)(>30days) XIENCE V 223 patients TAXUS 77 patients SPIRIT III Early stent thrombosis (%)(<30days) XIENCE V 658 patients 0.3 TAXUS 322 patients 0.0 Late stent thrombosis (%)(>30days)

25 Biolimus Absorbable Polymer BioMatrix Stent (STEALTH Trial) S-Stent (stainless steel) Biolimus A9 (rapamycin derivative) BioMatrix Stent PLA Polymer Asymmetrical bioresorbable coating

26 In-Segment Late Loss Across Multiple Randomized Clinical Trials 0.4 ENDEAVOR Stent TAXUS Stent CYPHER Stent Late Loss (mm) XIENCE V Stent (PROMUS Stent) BioMATRIX Stent TAXUS IV REALITY SPIRIT II SPIRIT III SPIRIT I SPIRIT II 8 mos. 9 mos. 8 mos. 6 mos. 8 mos. 6 mos. 6 mos. 8 mos. 8 mos. 8 mos. 8 mos. SIRIUS REALITY ENDEAVOR III ENDEAVOR III Data from trials that are not head-to-head are not intended to be comparative. SPIRIT is sponsored by Abbott. PROMUS Stent is a private-labeled XIENCE V Everolimus Eluting Coronary Stent System manufactured by Abbott and distributed by Boston Scientific Corporation. XIENCE is a trademark of Abbott Laboratories group of companies. PROMUS, PSST 4128 TAXUS and Express 2 are trademarks of Boston Scientific Corporation or its affiliates. Cypher is a trademark of Cordis Corp. Endeavor is a trademark of Medtronic Vascular, Inc. For products, sponsors, and publications, refer to the Clinical Trial Glossary. SPIRIT III STEALTH

27 STEALTH I Cumulative Hierarchical MACE MACE RESULTS 6 Months S-Stent BioMatrix 2.5% 3.8% 24 Months S-Stent BioMatrix 5.0% 5.1% Death* 0.0% 0.0% 2.5% 1.3% Q Wave MI 0.0% 1.3% 0.0% 1.3% Non-Q Wave MI 2.5% 1.3% 2.5% 1.3% TLR-CABG 0.0% 0.0% 0.0% 0.0% TLR-PTCA 0.0% 1.3% 0.0% 1.3% Stent thrombosis 0.0% 0.0% 0.0% 0.0% *Death events were noncardiac: 1 diabetic foot syndrome (S-Stent) and 1 acute leukemia (BioMatrix)

28 Conor/JnJ (CoStar) 10 µg Paclitaxel With Controlled Mural Release

29 Discrete MicroDrop Structures (Labcoat)

30 BioMatrix Freedom Stent Biolimus A9 Drug Abluminal drug coating targets blood vessel walls Small amounts are released into circulation Pure Biolimus A9 impregnated in metal stent surface Bloodstream

31 28-DAY Porcine Histology Results BARE Control BA9/PLA POLYMER BA9 MicroStruct. Drug 225µg/Poly 225µg 225µg drug

32 BioMatrix Freedom Stent Biolimus A9 Drug First-in-man: Baseline, Oct 2006

33 BioMatrix Freedom Stent Biolimus A9 Drug First-in-man: 6 Months Follow-up, March 2007

34 The STENT Thrombosis Study 10,000 consecutive pts receiving DES at up to 12 sites Aspirin and Clopidogrel responsiveness evaluated (Accumetrics VerifyNow system) Clinical FU for years Angiographic core lab assessment of all stent thromboses and 1:3 matching controls PIs: Gregg W. Stone and Chuck Simonton Sponsors: CRF and the Dickinson Inst. Principal study group: STENT Registry investigators Funded by grants from Boston Scientific (lead supporter), Accumetrics, Abbott Vascular, Cordis, and Medtronic

35 The PROTECT Randomized Trial Global randomized trial 8,000 patients Endeavor vs. Cypher stent Primary endpoint = stent thrombosis PI: W. Wijns Sponsor: Medtronic Corp.

36 Thank you