Disclosure Eberhard Grube, M.D.

Transcription

1 Disclosure Eberhard Grube, M.D. I disclose the following financial relationships: Consultant Sadra Medical, Core Valve, Biosensors, Orbus Neich, Cordis Johnson & Johnson, Boston Scientific, Mitralign, Devax, Xtent.

2 ISET 2009 January 18-22, 2009 Are All Drug-eluting Stents the Same? Eberhard Grube MD FACC, FSCAI HELIOS Heart Center Siegburg, Germany Instituto Dante Pazzanese, São Paulo, Brazil Stanford University, Palo Alto, California, USA Siegburg / Stanford

3 Siegburg / Stanford

4 DES Are Designed Differently Stent & SDS Strut Thickness Scaffolding Conformability Balloon Tapers Trackability Drug Mechanism of Action Therapeutic Window Drug Load Stability Polymer Biocompatibility Mechanical Integrity Polymer Load Release Profile Different inputs can produce different outputs as demonstrated pre-clinically and clinically

5 Drug Eluting Stent System Design Mechanical Engineering Stent Coating integrity Matrix Polymer Chemistry Mechanical scaffolding Vascular biology Drug polymer compatibility Loading capacity Release kinetics Vascular Biology Tissue Vascular biology Tissue pharmacokinetics Preclinical models Drug Pharmacology

6 Siegburg / Stanford Strategies to Improve Outcome with DES Optimal Stent Design Drug Duration Optimal Stent Design Optimal Procedural Result Improved Outcome

7 Siegburg / Stanford Old vs. New DES SAFETY reducing stent thrombosis EFFICACY reducing restenosis OTHER cost-value deliverability durability

8 Siegburg / Stanford The Science of Safety Acute Long-Term Minimal Injury Complete Apposition Thromboresistant Materials Rapid re-endothelialization Functional endothelial layer No chronic inflammation No persistent fibrin

9 Problems with polymers Polymer damaged by expansion in air at room temperature Redundant polymer Bare areas Information contained herein for presentation outside the United States and Japan ONLY. EHQ /2008 Photos taken by and on file at Abbott Vascular 9

10 Coating Integrity Polymer webbing Touch points led to webbing and pulling of polymer Nominal expansion (3.0 mm) conditions Information contained herein for presentation outside the United States and Japan ONLY. EHQ /2008 Photos taken by and on file at Abbott Vascular 10

11 Coating Integrity Brittle polymer coating Poor polymer integrity upon expansion Nominal expansion conditions (3.0 mm) Information contained herein for presentation outside the United States and Japan ONLY. EHQ /2008 Photos taken by and on file at Abbott Vascular 11

12 DES Drug Release Profiles (in vivo) Percentage Released 100 Endeavor CYPHER 80 XIENCE V TAXUS Time (day) Source: Medtronic Vascular Data Presentation, TCTMD; TAXUS IV SR Presentation, TCTMD; Cypher Presentation, TCTMD; Data on file at Abbott Vascular. Information contained herein for presentation outside the United States and Japan ONLY. EHQ /2008 Photos taken by and on file at Abbott Vascular 12

13 Old vs. New DES Meaningful Changes? Thin strut stents with enhanced radiopacity Improved deliverability Biostable polymer refinements Reduced drug dosing and optimized kinetic release Bioabsorbable polymers and polymer-free systems Surface modifications (active and passive) New stent platforms Bioabsorbable drug-eluting stents Siegburg / Stanford

14 Advanced Approaches to Drug Release Bioabsorbable polymers Conor Bioabsorbable stents Controlled polymer application BVS Labcoat Reva Non polymer release ESI Setagon Siegburg / Stanford

15 XIENCE V DES Components MULTI-LINK VISION Stent MULTI-LINK VISION Stent Delivery System Everolimus Fluorinated Copolymer Information contained herein for presentation outside the United States and Japan ONLY. EHQ /2008 Photos taken by and on file at Abbott Vascular 15

16 Rapid Re-endothelialization 14-Day Rabbit Iliac Study XIENCE V CYPHER TAXUS ENDEAVOR Information contained herein for presentation outside the United States and Japan ONLY. EHQ /2008 Photos taken by and on file at Abbott Vascular 16

17 SPIRIT II & III Meta-Analysis MACE at One Year MACE, % HR = 0.51 [0.33, 0.78] P logrank = XIENCE V TAXUS 10.0% 5.2% Days Number at Risk XIENCE V TAXUS Information contained herein for presentation outside the United States and Japan ONLY. EHQ /2008 Photos taken by and on file at Abbott Vascular 17

18 Properties of the JACTAX Stent Unexpanded Expanded JA Coating 9.2 g. of Paclitaxel and 9.2 g. DLPLA (16 mm) 2700 microdots (16 mm) Mass of polymer approx 3.4 ng. per microdot < 1 micron thick, abluminal and low molecular weight biodegradable polymer decreases persistence time Stent platform Liberté pre-mounted stent (Boston Scientific) Siegburg / Stanford

19 Siegburg / Stanford Jactax Clinical Trial Design DESIGN: Prospective, non-randomized, single-arm, multi-center clinical evaluation of the Jactax TM DES System (patterned after ATLAS) OBJECTIVE: To evaluate the acute and long-term safety of the Jactax System PRINCIPAL INVESTIGATOR Eberhard Grube, MD Helios Heart Center, Siegburg, Germany PRIMAY ENDPOINT: MACE at 9 mo (Cardiac Death, QMI, nonqmi, TVR) 103 patients enrolled and implanted between July 07 and Jan 08 in 5 clinical sites in Europe Clinical follow-up at 9 mo in 73 pts Clinical follow-up at 12 mo in 19 pts 102 pts with 1 mo f/u 102 pts with 4 mo f/u Currently 1 pt missed visit 1 pt missed visit Angiographic f/u at 9 mo in 72 pts IVUS f/u at 9 mo in 59 pts

20 Siegburg / Stanford JACoating vs. Reservior - illustration JACoating is approx. 1 micron thick vs Reservior polymer approx. 75 micron thick

21 Jactax 9 Months Follow-up (IVUS and OCT) Siegburg / Stanford

22 9 Month Angiographic Outcome Pre Procedure N=72 patients RVD MLD % DS Post Procedure N=72 patients RVD MLD in-stent MLD in-segment % DS in-stent % DS in-segment month N=72 patients RVD MLD in-stent MLD in-segment % DS in-stent % DS in-segment Binary restenosis in stent (%) 4.2 Binary restenosis in segment (%) 5.6 Late Loss in-stent *Includes one pt with early TVR in branch vessel Siegburg / Stanford

23 Siegburg / Stanford OCT Sub study 9 mo f/u Analysis performed on: Reference Landmarks

24 Siegburg / Stanford Cumulative Strut Coverage > 96 % coverage at 20 micron resolution 2650 struts analyzed

25 Siegburg / Stanford Not available for sale in the United Sates. BioMatrix III Stent Platform BioFlex II Biodegradable Drug/Carrier: - Biolimus A9 / Poly (Lactic Acid) 50:50 mix - abluminal surface only (contacts vessel wall) - 10 microns coating thickness - degrades in 9 months releasing CO 2 + water Stent Platform: - stainless steel (112 microns) - corrugated ring, quadrature-link design - radius link enhances axial fatigue resistance BioFlex I

26 TAXUS versus Biomatrix Intraindividual Comparison Siegburg / Stanford TAXUS BioMatrix

27 TAXUS LAD IVUS 2004 and 2008 Siegburg / Stanford

28 BioMatrix LCx IVUS 2004 and 2008 Siegburg / Stanford

29 TAXUS (LAD) and Biomatrix (RCX) OCT 2008 Siegburg / Stanford TAXUS Biomatrix

30 Siegburg / Stanford LEADERS Trial Design Stable and ACS Patients Undergoing PCI Assessor-blind 1:1 Randomisation N=1700 Patients Biolimus Stent BioMatrix Flex N=850 Sirolimus Stent Cypher Select N=850 1:3 Randomisation Clinical F/U N=640 Angio F/U N=210 Clinical F/U N=640 Angio F/U N=210 1 o endpoint: CV death, MI, clinically-indicated TVR 2 o endpoints: Death, CV death, MI, TLR, TVR Stent Thrombosis according to ARC Angiographic study: In-stent % diameter stenosis Late loss, binary restenosis

31 Primary Endpoint Cardiac Death, MI, or 9 months 15 Risk Difference -1.3%, Upper Limit 95% CI 1.1% P non-inferiority = Cumulative Incidence (%) 10 5 Sirolimus Stent 10.5% Biolimus Stent 9.2% Rate Ratio = 0.88, 95% CI No. at risk Months of Follow-up BES SES Siegburg / Stanford

32 Efficacy 9 Months RR=0.87 ( ) P=0.52* RR=0.90 ( ) P=0.62* RR=0.79 ( ) P=0.29* RR=0.77 ( ) P=0.18* RR=0.76 ( ) P=0.15* % Clinically-Indicated TLR Any TLR Clinically Indicated- TVR Any TVR Any Repeat Revascularisation Biolimus Stent (N=857) Sirolimus Stent (N=850) * P values for superiority Siegburg / Stanford

33 Siegburg / Stanford SAFETY 12 MONTHS Biolimus Stent (N=857) 10 Sirolimus Stent (N=850) % P= P= P= P= P= P= Death Cardiac Death Myocardial Infarction NQWMI QWMI Cardiac Death or MI

34 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 Siegburg / Stanford

35 Biolimus A9 Release From Freedom Stent vs. BioMatrix II Siegburg / Stanford Biolimus A9 Elution from Stents 100% (MEDIUM: PBS ph 7.4/Tween, 37 C) 90% Cumulative Release (%) 80% 70% 60% 50% 40% 30% Polymerless Biomatrix 20% 10% 0% Time (Hrs)

36 BioMatrix Freedom Stent Biolimus A9 Drug Siegburg / Stanford First-in-man: Baseline, Oct 2006

37 Siegburg / Stanford BioMatrix Freedom Stent Biolimus A9 Drug First-in-man: 12 Months Follow-up, March 2008

38 Endothelial Progenitor Cell Capture Coating Technology - Orbus Neich Genesis Siegburg / Stanford CD34 Antibody Layer Intermediate Layer Captured EPC Cells on Surface Stent Adhering Bottom Layer Stent Surface

39 Siegburg / Stanford The Elixir Stent Stent Design Cobalt-Chromium alloy 8 crown design for optimal scaffolding strut thickness Controlled Release Technology Methacrylate polymer family Durable Biocompatible History of clinical use on vascular implants dose Reduce dose (85 µg) and polymer load (<3 microns)

40 Siegburg / Stanford RESULTS (4 months f/u) Quantitative Coronary Angiography Variables Lesions (n = 15) Pre procedure Reference vessel diameter, mm Lesion length, mm Minimum lumen diameter, mm Diameter stenosis, (%) Post procedure Minimum lumen diameter, mm Diameter stenosis, (%) Acute gain, mm 4 month follow up Minimum lumen diameter, mm Diameter stenosis, (%) Lumen loss, mm Binary restenosis, n(%)

41 MIV 3D MicroPorous Nanofilm HydroxyHepatide (HAp) Siegburg / Stanford

42 IVUS Volumetric Analysis Baseline / 4 month follow-up Siegburg / Stanford IVUS variables Baseline N= 15 P 4-month follow-up N= 15 P Vessel Volume (mm 3 ) Stent Volume (mm 3 ) Lumen Volume (mm 3 ) NIH Volume (mm 3 ) N/A Mallapposition Volume (mm 3 ) % Stent Obstruction N/A

43 Siegburg / Stanford PCI in the Future Evolving DES Platforms & Indications Safer DES without late stent thrombosis Expanded stent delivery platforms (selfexpanding, long-modular, micro-, and bifurcation stents) Bioabsorbable stents Validated indications for AMI, MVD, and LM disease

44 Siegburg / Stanford PCI in the Future Evolving DES Platforms New site-specific specific local drug delivery systems which are not stent-based (e.g. drug eluting balloons and drug carrying nano-particles) Systemic pharmacotherapies with «homing» features targeted to sites of vascular injury

45 Siegburg / Stanford There are several additional new stars which will play an important role in the future

46 Vielen Dank Siegburg / Stanford