Dr Li Shu Kin FRCP (Lond, Edin & Glasg) FACC FHKAM COS (Medicine) Pamela Youde Nethersole Eastern Hospital
Des
1904-1979 1929
Andreas Gruentzig 1939-1985 1 st case in Sept1977 Overtook CABG as the most popular form of coronary revascularization Current rate: 2-3 million p.a.
Acute Mechanism: Dilatation of the arterial wall Plaque disruption Chronic Mechanism: Arterial remodeling
Acute closure Usually due to severe dissection Major adverse cardiac events (MACE) e.g. AMI, death, emergency CABG Restenosis Recurrent symptom: stable angina to ACS Repeat revascularization: re-pci or CABG
Acute recoil Negative remodeling Intimal proliferation
31% @ 6 months of 1 st 169 patients of Andreas Gruentzig Multiple trials of pharmacological agents No successful story Multiple trials of various devices
BENESTENT STRESS POBA Stent P N 257 259 Restenosis 32% 22% 0.02 Event free 70% 80% 0.68 N 203 207 Restenosis 42% 32% 0.04 Event free 76% 81% 0.16
Acute: < 24 hours Subacute: 1 to 30 days
Eliminate early elastic recoil Provide mechanical scaffold that prevent negative remodeling x Promotes the development of neointimal hyperplasia In-Stent Restenosis (ISR): a new disease!
Type 1 Focal restenosis within the stent TLR at 12 mth 19% Type 2 Diffuse intrastent restenosis 35% Type 3 Proliferative restenosis in the stent and adjacent vessel Type 4 Diffuse total instent restenosis 50% 83%
In-Stent Restenosis: a Problem of Excessive Neointimal Hyperplasia Exaggerated wound healing response Role of Smooth muscle cell Endothelium
Mechanism of Neointimal Formation Thrombus (platelets) Arterial Injury Growth factors & cytokines Inflammation (macrophage) Smooth muscle cell Migration Receptor activation Cell Cycle Signal SMC Proliferation Transduction Endothelialization -ve Matrix secretion
Prevention of ISR Drugs: Systemic Local delivery Devices: Treatment of ISR Prevention of further recurrence Devices Drugs
Therapeutic Options to Prevent Neointimal Hyperplasia Radiation Pharmaceuticals Energy Delivery Systemic Local Gamma Beta Catheter Stent Balloon? Stent Catheter Sirolimus Paclitaxel Gene therapy? Drugs?
Proven efficacy in oncology Proven effect in modifying wound healing and scar formation: Keloid Pterigium
6-Month Angiographic Restenosis SCRIPPS WRIST GAMMA-1 1 Site, 55 Patients 1 Site, 100 Patients 12 Sites, 252 Patients 54% 49% 56% 32% 17% 14% = - 68% = - 71% = - 43% Placebo Group Irradiated Group
As treatment for ISR Χ As preventive measure
Stent Injured Irradiated Analysed Late thrombosis Edge effect Further restenosis in ISR is still 20% Long term result?
Rationale for Stent-Based Drug Therapy Efficient method of preventing restenosis Addresses both remodeling and hyperplasia Cost effective Requires no additional safety measures Targeted drug delivery Maximizes drug effect where it is required Minimizes potential for systemic toxicity Creates options for controlled drug release Broad utility Useful in de novo and restenotic lesions
Growth Factors / Cytokines Smooth muscle cell Activation Receptor FKBP Signal Transduction TOR Sirolimus G 0 p27, block Cyclins/Cdks S G 1 X cell cycle M Cell Division G 2 Radiation Actinomycin D (target DNA) Paclitaxel (targets microtubules)
A potent and safe immunosuppressant A naturally occurring antibiotic Approved by FDA as an immunosuppressive agent used in kidney transplantation. Approved in EU. (Rapamune Wyeth Ayerst Laboratories) Inhibits growth factor and cytokinestimulated cell proliferation Prevents neointimal hyperplasia in various animal models Mechanism of action: cell-cycle inhibition
Cypher - the Sirolimus-Eluting Stent Slow-Release Formulation Topcoat Sirolimus is released in a controlled manner from a polymer matrix bound to the stent Stent Basecoat Basecoat = polymer blend + sirolimus + Topcoat = diffusion barrier
Sirolimus Clinical Pilot Evaluation First in Man (FIM) Trial Nonrandomized study (Sao Paulo, Rotterdam) 45 patients with de novo coronary artery lesions Two month Plavix PRE POST 0 % restenosis! 4 m 1 y
RAVEL Trial Multicenter trial (21 sites) International (Europe - 17 sites and LA - 4 sites) Randomized & Double Blind Uncoated Bx Velocity vs Sirolimus-coated Bx Velocity (SR) Single de novo lesions Lesions < 18mm and > 2.5 and < 3.5mm diameter 220 patients (110 pts/study arm) 6 months angiographic follow up & IVUS (subset 120 pts) 1, 6, 12 month, 2, 3, 4 and 5 years clinical follow up
@ 6 months
SIRIUS Trial - Pivotal Study DESIGN: Multicenter, randomized, pivotal trial Two treatments: uncoated vs slow-release Bx Velocity 1,100 patients (550 patients/arm), 55 clinical sites De novo native coronary lesions Single vessel,15 mm-30 mm long, 2.5-3.5mm diameter ENDPOINTS: Primary: Target vessel failure at 9 months Secondary endpoints: QCA @ 8months in 850 pts. Composite MACE @ 30d, 6m, 9m, 12m, 5yr.
SIRIUS Trial - Pivotal Study DESIGN: Multicenter, randomized, pivotal trial Two treatments: uncoated vs slow-release Bx Velocity 1,100 patients (550 patients/arm), 55 clinical sites De novo native coronary lesions Single vessel,15 mm-30 mm long, 2.5-3.5mm diameter FDA approval ENDPOINTS: Primary: Target vessel failure at 9 months Secondary endpoints: QCA @ 8months in 850 pts. Composite Aspirin MACE @ 30d, + Plavix 6m, 9m, for 12m, 3 months 5yr.
Antineoplastic agent naturally-occurring plant derivative Mechanism of action Blocks mitosis by interfering with microtubule function interferes with disassembly, resulting in formation of stable, but dysfunctional microtubules inhibits activation of some protein kinases Cytotoxic X
Stent Platform NiR x NiR x Express Express Study Objective Safety & Feasibility Efficacy, dose-response Pivotal Indication Expansion N = ITT Patients 61 266 1,314 1,156 1 Endpoint Safety & Procedural Success % Net Volume Obstruction (IVUS) TVR TVR Long-Term FU Available 5 Years 4 Years 4 Years 2 Years RVD* (mm) 3.0 3.5 3.0 3.5 2.5 3.75 2.25 4.0 Lesion Single Single Single Multiple Overlapping Stents Lesion Length* (mm) 12 10-12 10-28 10 46 Max. # Planned Study Stents per Lesion/Patient 1 1 1 2
Objective Stent Platform Purpose Design TAXUS-IV To evaluate the safety and effectiveness of the TAXUS Stent System with 1 μg/mm2 of paclitaxel incorporated into a slowrelease formulation of a triblock copolymer carrier system for treatment of de novo coronary artery lesions Express 16, 24 and 32 mm lengths, 2.5, 3,0 and 3.5 mm diameters Safety and Efficacy Randomized # Patients 662 TAXUS, 652 Control Lesion Control Release Kinetics Primary Endpoint Principal Investigator de novo Uncoated control Slow release 9-mo Ischemia-driven Target Vessel Revascularization, superiority to control arm G.W. Stone, and S. Ellis, USA 9-Month Highlights Clinical Summary TVR reduction attributable to lower TLR rate in the TAXUS Express Paclitaxel-Eluting Stent group (3.0%) compared with the control group (11.3%) 9-month MACE was reduced from 15.0% in the control group to 8.5% in the TAXUS Express group No significant differences in stent thrombosis between groups QCA and IVUS Summary 9-month binary restenosis rate in the analysis segment was reduced from 26.6% in the control group to 7.9% in the TAXUS Express Group In-stent late loss was reduced from 0.92 mm in the control group to 0.39 mm in the TAXUS Express group 24-Month Highlights Sustained benefits over time with a statistically significant difference in MACE, TVR and TLR maintained at 2 years. New TLR events between 1 and 2 years were 22 or 3.5% for control group and 10 or 1.6% for Taxus Express group. BSC Message Lowest TLR ever reported in a randomized, pivotal DES Trial Consistent benefits across subgroups e.g. SV, Long, DB Safety and efficacy of the TAXUS Express Paclitaxel-Eluting Stent are sustained to 3 years FDA approval Aspirin + Plavix for 6 months
Drug Dexamethasone Actinomycin D Resten-NG Tacrolimus Estrogen Nitric Oxide Trapidil Batimitastat Drug carrier technology Quanam stent Non-drug mechanism Monoclonal antibodies to attract EPC
Stent design Drug carrier-delivery mechanism Drug
Optimized geometry for homogenous drug distribution Conformability: circumferential stent-vessel wall contact Sufficient radio-opacity for precise placement (in tandem stents) Maintain side-branch access Deliverability
Stent Coating for Drug Delivery Bio-compatible Non-thrombogenic, non-inflammatory Predictable drug elution kinetics (time & dose) Logistics: Sterilizable, stability, shelf-life Expands without cracking or peeling Does not interfere with stent scaffolding and delivery
Specific mechanism of action Pharmacokinetics and pharmacodynamics Therapeutic (toxic) margin Systemic toxicity Stability: effect of sterilization, stability of drugs
Device Restenosis Rates PTCA Balloon Only Atherectomy Stents RT RT with Stent? Drug eluting Stents? 0% 10% 20% 30% 40% 50% 60% 70%
Just stent it! Just DES!
Serruys, et al. Lancet. 2004;364: 1519 1521.
SES = Sirolimus Eluting Stent PES = Paclitaxel Eluting Stent Camenzind E, ESC 2006
Lagerqvist: N Engl J Med, 2007;356:1009-1019
Stone GW et al. NEJM 2007;356:998--1008
Cardiac death MI Stent thrombosis Restenosis
Academia, Industry and Regulatory Academic Research Consortium - ARC US Investigators Harvard Clinical Research Institute Cardiovascular Research Foundation Duke Clinical Research Institute European Investigators Cardialysis Bern, Switzerland Paris, France Industry FDA Washington, DC March 2006 Dublin, Ireland July 2006
Definite/Confirmed Acute coronary syndrome, AND Angiographic confirmation of thrombus or occlusion, OR Pathologic confirmation of acute thrombosis Probable Unexplained death within 30 days Target vessel MI without angiographic confirmation of thrombosis or other identified culprit lesion Possible Unexplained death after 30 days
Both approved DES are associated with a small increase in stent thrombosis compared to BMS that emerges 1 year post--stent implantation However, based on the data available, this increased risk of stent thrombosis was not associated with an increased risk of death or MI compared to bare metal stents The concerns about thrombosis do not outweigh the benefits of DES compared to BMS when DES are implanted within the limits of their approved indications for use
Cause of some late events: MI/ deaths Mechanism? Delayed/ incomplete endothelialization? Late catch up of disease? Need longer double anti-platelet therapy (DAPT )?
Columbo A. ACC March 2007
Based on consensus 1 year of aspirin + thienopyridine (usually Plavix) Further prolongation of DAPT might need to balance the risk of bleeding
Virmani et al. Circulation. 2007;115:1051-
Delayed/ poor healing response Persistent inflammation Hypersensitivity response to polymer? Virmani et al. Circulation. 2007;115:1051-1058
The polymer (hypersensitivity reactions, inflammatory and thrombogenic) The drug (delayed healing and incomplete late stent apposition) The procedure (suboptimal stent deployment and inflow/outflow problems) The patient (anti-platelet resistance, intrinsic thrombogenicity and more complex lesions)
TLR for Cypher Vs BMS TLR for Taxus Vs BMS Kirtane A, et al TCT 2007
38 trials, 18,023 pts Stettler C et al. Lancet 2007;370:937-48
All pts undergoing PCI in Ontario between 12/03 and 3/05, 7,502 propensity matched pts receiving DES or BMS Tu JV et al. NEJM 2007;357:1393-402
Mortality in all stented pts 1/02 6/05; N=12,395 pts with 17,152 lesions from 3 high volume centers Jensen LO et al. JACC 2007
Kirtane A, et al Circulation 2009
Kirtane A, et al Circulation 2009
DES Stent Drug Polymer Endeavor Driver (Co-Cr) Zotarolimus Phosphorycholine Endeavor Resolute Driver (Co-Cr) Zotarolimus Biolinx Xience V Vision (Co-Cr) Everolimus Fluorinated Copolymer Xience Prime Multilink 8 (Co-Cr) Everolimus Fluorinated Copolymer Biomatrix S-stent Biolimus A9 Polylactic acid Nobori S-stent Biolimus A9 Polylactic acid Promus Element Element (Pt-Cr) Everolimus Fluorinated Copolymer Taxus Element Element (Pt-Cr) Paclitaxel Transulute
Driver Cobalt Alloy Stent Stent Delivery System PC Technology Drug: Zotarolimus
DRUG/ DOSE POLYMER STENT MATERIAL STENT DESIGN DELIVERY SYSTEM BALLOON XIENCE V Everolimus 88 1 μg Fluorinated Copolymer Cobalt Chromium MULTI-LINK VISION ML VISION SDS RBP: 16 atm Taper: 3-5 mm XIENCE PRIME Everolimus 88 1 μg Fluorinated Copolymer Cobalt Chromium MULTI-LINK 8 2 XIENCE PRIME SDS RBP: 18 atm Taper: 1-2 mm Consistency Across Key Components 1. Dosing information for 3.0 x 18 mm stent. 2. MULTI-LINK 8 is the bare metal platform for XIENCE PRIME. Not available for sale and pending CE marking. Data on file at Abbott Vascular.
BioMatrix DES System ABLUMINAL BIODEGRADABLE COATING Early BMS-like endothelial coverage 1 More targeted tissue release Less systemic exposure BIOLIMUS A9 DRUG Biosensors proprietary rapamycin derivative Highest lypophilicity of the common limus drugs BIODEGRADABLE PLA PLA biodegradation along with BA9 elution No PLA /BA9 coating on the stent after 6 to 9 months * S-STENT PLATFORM High flexibility without compromising vessel support Unmatched side branch access 2
Bioerodable polymer or no polymer
Bio-aborbable stent
1970s POBA 1980s Devices 1990s Stents 2000s DES?
Patient Need Innovation Technology Assessment Industry Regulatory Body Clinical Research