Future Developments in Coronary Stenting. Keith D Dawkins MD FRCP FACC Southampton University Hospital UK

Transcription

1 Future Developments in Coronary Stenting Keith D Dawkins MD FRCP FACC Southampton University Hospital UK

2 Conflicts of Interest Research Grant Support Boston Scientific Corporation Advisory Board/Consultant Abbott Vascular Boston Scientific Corporation Conor Medsystems Eli Lilly Medtronic Nycomed

3 1977 Balloon Angioplasty ( March 1977) Bare Metal Stent (1986) Angioscopy Doppler Flow Intravascular Ultrasound Optical Coherence Tomography Palpography Pressure Measurements Thermography Virtual Histology Brachytherapy Cutting Balloon Directional Atherectomy Extraction Atherectomy Laser Atherectomy Perfusion Balloon Rotational Atherectomy Drug Eluting Stent (1999) 2007

4 Balloon Stent

5 Bare Metal Stent Drug Eluting Stent

6 >3 Million Patients >4.5 Million DES Worldwide DES Penetration

7 the debate over the safety of drug-coated stents could signal turmoil in the booming industry.

8 Changes in Stock Price ( )

9 Drug Eluting Stent Use (%) Des Use (%) % 76.4% 50 Jan March May July Sept Nov 2006 Wessex Cardiac Unit

10 The Players

11 Drug Eluting Stents Deliver on Ideal Stent Platform Drug Selection Elution Mechanism SAFETY & EFFICACY

12 What are the Expectations of the available Stent Technology?

13 Expectations of Stent Technology Efficacy Deliverable Low TLR Low Restenosis Low Late Lumen Loss Cost-Effective Safety No Device Malfunction No Early MACE Q AMI Non-Q AMI No Stent Thrombosis

14 Real World Target Lesions Long Lesions 10% Small Vessels 13% Bifurcations 20% Long Lesions Small Vessels Simple Diabetics 24% Simple 33% Diabetics Bifurcations

15 Efficacy The Patient The Analyst

16 Efficacy The Patient

17 Efficacy The Analyst Late Loss (mm) Sirius Taxus II Endeavor II

18 Coronary Artery Stent Late Loss LL TLR Headroom Restenosis >50% (TLR)

19 Late Loss vs. Restenosis Example: 3.0mm Bare Metal Stent Mean Late Loss = 1.0 ± 0.5mm Angiographic Restenosis = Late Loss >1.5 mm (50% DS) Clinical Restenosis (TLR) = Late Loss >2.1 mm (70% DS) Patients without Restenosis Mean Late Loss Patients with Angiographic Restenosis Distribution Density Patients with Clinical Restenosis mm Don Baim 2006 (Modified)

20 ENDEAVOR I vs. RESOLUTE Late Loss (mm) QCA 4 months N=100 N=30 Endeavor I Resolute

21 SPIRIT II Late Loss (mm) QCA 6 months 0.36 p< N=73 Taxus N=202 Xience V

22 X SPIRIT II Late Loss (mm) QCA 6 months 0.36 p< N=73 Taxus N=202 Promus

23 Stent A Lower Late Loss Stent B Higher Late Loss ü Low Restenosis ü Small Vessels ü Diabetes? Low Thrombosis? Low Restenosis? Small Vessels? Diabetes ü Low Thrombosis

24 Paclitaxel Multi-functional activities with cell Dose dependent effects Anti-proliferative Anti-inflammatory Prevents SMC migration Promotes apoptosis at low doses Cytostatic within the therapeutic range Taxus Brevifolia Taxol

25 Sirolimus (Rapamycin) Streptomyces hygroscopicus Easter Island (Rapa Nui) Macrolide antibiotic Potent immunosuppressant and anti-proliferative agent Binds to the cytosolic protein FK-binding protein 12 (FKBP 12) Inhibits m-tor Blockade of cell cycle progression at the G1/S transition Relaxation of smooth muscle Sirolimus

26 Antigen Cytokine/Growth Factor TCR Receptor Tyrosine Kinase PIP 2 PLC InsP 3 + DAG Ca ++ Calcineurin?? Pimecrolimus PHAS-1 mtor Sirolimus Calmodulin Translation Pimecrolimus Calcineurin MAPKKS Removal of p21/p27 P NFAT NFAT NF K B AP-1 IL-2 Activation of CDKs Cell cycle progression RNA Nucleus NFAT NF K B AP-1 IL-2 Modified from Donners 2003

27 Spectrum of Limus Analogues Pimecrolimus Tacrolimus Everolimus Biolimus A9 Zotarolimus Sirolimus Anti-inflammatory Calcineurin Inhibition Anti-proliferative mtor Binding

28

29 Genous Stent (48 hour Balloon-injured Porcine Model) Bare Metal EPC Capture M Kutryk (unpublished)

30 Polymer based Drug Delivery Local, targeted, short-term, low-dose drug delivery Controlled release of drug from polymer Homogeneous drug coverage along stent Retention of drug on stent during handling Prevention of: Drug loss during implantation Overdose from non-uniform drug distribution and immediate burst release of total loaded dose

31 DES Release Profiles Cumulative Drug Release (%) Days ENDEAVOR CYPHER XIENCE TAXUS

32 Normal appearance of DES Polymer TAXUS CYPHER

33 Problems with polymers Polymer damaged by expansion in air at room temperature Redundant polymer Bare areas

34 59 Year Old Female with TAXUS Stent in the LAD for 130 Days LAD1 LAD 3 LAD 6 Giant cells Eosinophils Fibrin 80% surface endothelialized 34 Circ 2004;109:

35 Polymer Thickness Taxus, Cypher & Xience Coating Thickness (µm) Taxus Cypher Xience

36 New Polymers & Coatings Reduced Polymer Volume Bioabsorbable Polymers No Polymer Depot Technology Setagon Nano Technology Surface Modifications Nano-membranous Filters Photolithographic Etching Hydroxyappetite HA

37 Reservoir Technology (Conor Medsystems) The reservoir system provides the ability to load drug and control the delivery time and rate A bioresorbable polymer with minimal contact with the vessel wall; thus, reduced polymer tissue interaction and no long term residual drug or polymer GENESIS Trial assesses the combination of Pimecrolimus (an anti-inflammatory), and Paclitaxel (an anti-restenotic) GENESIS is the first dual-drug RCT

38 Polymer Degradation (Porcine Model) 7 DAY 30 DAY 120 DAY 189 DAY

39 Paclitaxel and Pimecrolimus Dual Drug Components Thrombosis Inflammation Proliferation Extra-Cellular Matrix Production This drug combination targets two separate aspects of the restenotic process Pimecrolimus Paclitaxel Adapted from Nikol, Atherosclerosis 1996;123:17-31

40 TAXUS Element Stent Platform Geometry designed for drug delivery Four stent models Consistent surface-to-artery ratios Apex balloon Bi-component balloon Multilayer Platinum Enriched Stainless Steel Radio-opaque Thin Struts High radial strength Vision Driver Express Liberté Element

41 TAXUS Odyssey Stent Program Asymmetric Polymer Coating Arterial Wall Optimized Drug Release Bioresorbable Polymer PERSS Strut Pro-healing Surface Asymmetric Polymer Pro-healing Surface

42 BMJ January 20 th 2007

43 Bifurcations Devax BSC (Petal) Medtronic YMed

44 Intra-coronary stents Anticoagulant & Antiplatelet therapy Urokinase Dextran Warfarin Heparin Aspirin Ticlopidine Abciximab Clopidogrel Bivalirudin Year ?

45 Thrombus Stent Thrombosis

46 The Platelet, the enemy of the interventionist

47 History of Stent Thrombosis 20 Stent Thrombosis (%) PS STRESS Colombo ISAR STARS Schatz et al. Circulation.1991;83: Fischman et al. N Engl J Med. 1994; Colombo et al. Circulation.1995;91: Schömig et al.circulation.1994,90: Leon et al. N Engl J Med. 1998;339: Joner et al. J Am Coll Cardiol. 2006;48:193

48 Pooled Analysis of the Safety and Efficacy of Sirolimus and Paclitaxel eluting Stents Stent Thrombosis (%) Cypher (n=878) Taxus (n=1753) days p= days 1 year 1 4 years N Engl J Med 2006;356:

49 Sirolimus Eluting Stent vs. Bare Metal Stent n n D BMS 24 months after deployment Cypher 16 months after deployment 49 Circulation 2003;107:

50 Delayed Endothelialization in DES compared with BMS Percentage Endothelialization (%) BMS (n=25) 60 DES (n=23) >40 Duration Post-Implant (months) JACC 2006:48:

51 Sirolimus Eluting Stent vs. Bare Metal Stent BMS Confluent endothelial cells longitudinally aligned Confluent endothelial cells with few adherent platelets Cypher Pavement-shaped endothelial cells Rare non-confluent endothelial cells 51 with minute platelet thrombus

52 Endothelial Dysfunction after Sirolimus-Eluting Stent Implantation Baseline angiogram 6/12 post SES implant (LAD) Post acetylcholine (IC) 0.14 µgm/min (2mins) Post GTN (IC) 250 µgm/min bolus Circulation 2006;113:e

53 Biodegradable Stents Company Stent Polymer/Drug Features Biodegradable polymer (PLLA) + Everolimus Self-expanding + balloon expanding designs FIM trial: 30 pts Igaki-Tamai PLLA + Tranilast Zig-Zag design. Deployed with heated balloon FIM trial: 50 pts BSC-Reva Tyrosine derived polycarbonate + Paclitaxel Slide and lock ratchet mechanism. Iodine for radio-opacity Biosensors Asymmetric biodegradable PLA + Biolimus A9 Self-expanding with retractable sheath Biotronik AMS Magnesium (93%) +Conor technology FIM Progress-AMS trial: 63 pts (complete) Abbott-BVS and many more

54 Clopidogrel Non-Responsiveness Number of Patients Distribution of Changes in ADP-induced Platelet Aggregation Hypo-responders 4.2% (23/544) 0-20 [-10, 0] [11,20] [31,40] [51,60] [71,80] [91,100] Delta 5µM ADP Hyper-responders 4.8% (26/544) J Am Coll Cardiol 2005:45;

55 Coronary Imaging Crush Crush Sequential Stents (Gap) Blooming

56 Drug Eluting Stents vs. Bare Metal Stents BENEFIT RISK Reduced Restenosis? Stent Thrombosis Death, AMI, TLR

57 Lancet 2006;368:

58 2.5%

59

60 Conclusions The importance of Late Loss in relation to DES thrombosis is yet to be defined Polymer based drug delivery is likely to be responsible for some MACE Bioerodable polymers may be associated with less complications Multiple drug delivery may allow pacification of the arterial response to stent implantation Developments in dedicated bifurcation stent technology offer some promise Bioerodable stents (the Holy Grail ) may be clinically relevant within five years Developments in coronary imaging (MR, CT) will impact stent design Anti-platelet responsiveness should be further investigated