dr li shu kin frcp (lond, edin & glasg) facc fhkam cos … · ¾does not interfere with stent...
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Dr Li Shu KinFRCP (Lond, Edin & Glasg) FACC FHKAM
COS (Medicine)Pamela Youde Nethersole Eastern Hospital
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Des
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1st case in Sept1977Overtook CABG as the most popular form of coronary revascularizationCurrent rate: 2-3 million p.a.
Andreas Gruentzig1939-1985
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Acute Mechanism:◦ Dilatation of the
arterial wall◦ Plaque disruptionChronic Mechanism:◦ Arterial remodeling
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Acute closure◦ Usually due to severe dissection◦ Major adverse cardiac events (MACE)
e.g. AMI, death, emergency CABGRestenosis◦ Recurrent symptom: stable angina to ACS◦ Repeat revascularization: re-PCI or CABG
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Acute recoilNegative remodelingIntimal proliferation
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31% @ 6 months of 1st 169 patients of Andreas GruentzigMultiple trials of pharmacological agents◦ No successful storyMultiple trials of various devices
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POBA Stent PN 257 259Restenosis 32% 22% 0.02
BENESTENT
Event free 70% 80% 0.68N 203 207Restenosis 42% 32% 0.04
STRESS
Event free 76% 81% 0.16
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Acute: < 24 hoursSubacute: 1 to 30 days
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Eliminate early elastic recoilProvide mechanical scaffold that prevent negative remodeling
xPromotes the development of neointimal hyperplasia
In-Stent Restenosis (ISR): a new disease!
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Type 1 – Focal restenosis within the stent
Type 2 – Diffuse intra-stent restenosis
Type 3 – Proliferative restenosis in the stent and adjacent vessel
Type 4 – Diffuse total in-stent restenosis
19%
35%
50%
83%
TLR at 12 mth
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In-Stent Restenosis: a Problem ofExcessive Neointimal Hyperplasia
Exaggerated wound healing responseRole of◦ Smooth muscle cell◦ Endothelium
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Mechanism of Neointimal FormationMechanism of Neointimal FormationArterial InjuryArterial Injury
Growth factors & cytokines
Thrombus (platelets) Inflammation (macrophage)
Smoothmuscle
cellCellCycle
SignalTransduction
SMC ProliferationSMC Proliferation
MigrationMigration Matrix secretionMatrix secretion
Receptor activation
EndothelializationEndothelialization-ve
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Prevention of ISR Treatment of ISR
Drugs:◦ Systemic◦ Local deliveryDevices:
Prevention of further recurrenceDevicesDrugs
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Therapeutic Options to PreventNeointimal Hyperplasia
Energy
• Gamma• Beta
Radiation Pharmaceuticals
Delivery Systemic Local
CatheterStent
•Gene therapy?•Drugs?
• Sirolimus• Paclitaxel
• Catheter• Stent• Balloon
?
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Proven efficacy in oncologyProven effect in modifying wound healing and scar formation:◦ Keloid◦ Pterigium
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6-Month Angiographic Restenosis
SCRIPPS WRIST GAMMA-1
54%
17%
49%
14%
= - 68% = - 71% = - 43%
Placebo GroupIrradiated Group
1 Site, 55 Patients 1 Site, 100 Patients 12 Sites, 252 Patients
56%
32%
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As treatment for ISR ΧAs preventive measure
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Late thrombosisEdge effectFurther restenosis in ISR is still 20%Long term result?
StentInjuredIrradiatedAnalysed
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Rationale for Stent-Based Drug Therapy
Efficient method of preventing restenosisAddresses both remodeling and hyperplasiaCost effectiveRequires no additional safety measures
Targeted drug deliveryMaximizes drug effect where it is requiredMinimizes potential for systemic toxicityCreates options for controlled drug release
Broad utility Useful in de novo and restenotic lesions
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Growth Factors / Cytokines
RadiationActinomycin D
(target DNA)
FKBP
S
G2
M
cell cycleG0
SirolimusSirolimus
X
Cell Division
Smooth muscle cell
Receptor
TOR
p27, block Cyclins/Cdks
G1
Activation
Signal Transduction
Paclitaxel(targets
microtubules)
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A naturally occurring antibioticApproved by FDA as an immunosuppressive agent used in kidney transplantation. Approved in EU. (Rapamune® – Wyeth Ayerst Laboratories)Inhibits growth factor and cytokine-stimulated cell proliferationPrevents neointimal hyperplasia in various animal models Mechanism of action: cell-cycle inhibition
A potent and safe immunosuppressant
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CypherCypher™™ -- the Sirolimusthe Sirolimus--Eluting StentEluting Stent
SlowSlow--Release FormulationRelease FormulationTopcoat Topcoat
StentStent
Basecoat
•• Basecoat = polymer blend + Basecoat = polymer blend + sirolimussirolimus++
•• Topcoat = diffusion barrierTopcoat = diffusion barrier
Sirolimus is released in a controlled manner from aSirolimus is released in a controlled manner from apolymer matrix bound to the stentpolymer matrix bound to the stent
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• Nonrandomized study (Sao Paulo, Rotterdam)• 45 patients with de novo coronary artery lesions • Two month Plavix
Sirolimus Clinical Pilot Evaluation First in Man (FIM) Trial
PREPRE POSTPOST
4 m4 m 1 y1 y
0 % restenosis!0 % restenosis!
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• 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
RAVEL Trial
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@ 6 months@ 6 months
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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.
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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.
FDA approval
Aspirin + Plavix for 3 months
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Antineoplastic agent◦ naturally-occurring plant derivativeMechanism of action◦ Blocks mitosis by interfering with microtubule
functioninterferes with disassembly, resulting in formation of stable, but dysfunctional microtubulesinhibits activation of some protein kinases
Cytotoxic
X
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Stent Platform NiRx™ NiRx™ 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
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• 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 reducedfrom 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 to0.39 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
TAXUSTAXUS--IVIV
Objective
To evaluate the safety and effectiveness of the TAXUS ®Stent System with 1 μg/mm2 of paclitaxel incorporated into a slow-release formulation of a triblock copolymer carrier system for treatment of de novo coronary artery lesions
Stent PlatformExpress® 16, 24 and 32 mm lengths, 2.5, 3,0 and 3.5 mm diameters
Purpose Safety and Efficacy
Design Randomized
# Patients 662 TAXUS, 652 Control
Lesion de novo
Control Uncoated control
Release Kinetics Slow release
Primary Endpoint9-mo Ischemia-driven Target Vessel Revascularization, superiority to control arm
Principal Investigator G.W. Stone, and S. Ellis, USA
FDA approval
Aspirin + Plavix for 6 months
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Drug Drug carrier technology
DexamethasoneActinomycin DResten-NGTacrolimusEstrogenNitric OxideTrapidilBatimitastat……
Quanam stent
Non-drug mechanism• Monoclonal antibodies
to attract EPC
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Stent designDrug carrier-delivery mechanismDrug
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Optimized geometry for homogenous drug distributionConformability: circumferential stent-vessel wall contactSufficient radio-opacity for precise placement (in tandem stents)Maintain side-branch accessDeliverability
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Stent Coating for Drug DeliveryBio-compatible
Non-thrombogenic, non-inflammatoryPredictable drug elution kinetics (time & dose)Logistics:
Sterilizable, stability, shelf-lifeExpands without cracking or peelingDoes not interfere with stent scaffolding and delivery
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Specific mechanism of actionPharmacokinetics and pharmacodynamicsTherapeutic (toxic) marginSystemic toxicityStability: effect of sterilization, stability of drugs
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Device Restenosis Rates
0% 10% 20% 30% 40% 50% 60% 70%
Drug eluting Stents?
RT with Stent ?
RT
Stents
Atherectomy
PTCA Balloon Only
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Serruys, et al. Lancet. 2004;364: 1519–1521.
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Camenzind E, ESC 2006SES = Sirolimus Eluting StentPES = Paclitaxel Eluting Stent
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Lagerqvist: N Engl J Med, 2007;356:1009-1019
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Stone GW et al. NEJM 2007;356:998--1008
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Cardiac death MI
Stent thrombosis
Restenosis
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Washington, DC March 2006Dublin, Ireland July 2006
Academia, Industry and Regulatory
Industry FDA
US Investigators• Harvard Clinical Research Institute• Cardiovascular Research Foundation• Duke Clinical Research Institute
European Investigators• Cardialysis• Bern, Switzerland• Paris, France
Academic Research Consortium - ARC
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Definite/Confirmed◦ Acute coronary syndrome, AND◦ Angiographic confirmation of thrombus or
occlusion, OR◦ Pathologic confirmation of acute thrombosisProbable◦ Unexplained death within 30 days◦ Target vessel MI without angiographic
confirmation of thrombosis or other identified culprit lesion
Possible◦ Unexplained death after 30 days
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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 stentsThe 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
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Cause of some late events: MI/ deathsMechanism?◦ Delayed/ incomplete endothelialization?◦ Late catch up of disease?Need longer double anti-platelet therapy (DAPT )?
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Columbo A. ACC March 2007
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Based on consensus1 year of aspirin + thienopyridine (usually Plavix)Further prolongation of DAPT might need to balance the risk of bleeding
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Virmani et al. Circulation. 2007;115:1051-
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Virmani et al. Circulation. 2007;115:1051-1058
•Delayed/ poor healing response•Persistent inflammation•Hypersensitivity response to polymer?
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• 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)
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TLR for Cypher Vs BMS
Kirtane A, et al TCT 2007
TLR for Taxus Vs BMS
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Stettler C et al. Lancet 2007;370:937 -48
38 trials, 18,023 pts
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Tu JV et al. NEJM 2007;357:1393-402
All pts undergoing PCI in Ontario between 12/03 and 3/05, 7,502 propensity matched pts receiving DES or BMS
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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
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Kirtane A, et al Circulation 2009
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Kirtane A, et al Circulation 2009
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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
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Drug: Zotarolimus
Stent Delivery System
PC Technology
Driver Cobalt Alloy Stent
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XIENCE V
DRUG/DOSE
Everolimus881 μg
Everolimus881 μg
POLYMER
FluorinatedCopolymer
FluorinatedCopolymer
CobaltChromium
CobaltChromium
STENT MATERIAL
STENT DESIGN
MULTI-LINKVISION
MULTI-LINK82
DELIVERY SYSTEM
XIENCE PRIME SDS
ML VISION SDS
RBP: 16 atmTaper: 3-5 mm
RBP: 18 atmTaper: 1-2 mm
BALLOON
Consistency Across Key Components
XIENCE PRIME
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.
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BIOLIMUS A9™ DRUGBiosensors’ proprietary rapamycin derivativeHighest lypophilicity of the common limus drugs
BIODEGRADABLE PLAPLA biodegradation along with BA9™ elutionNo PLA /BA9™ coating on the stent after 6 to 9 months*
BioMatrix DES System
S-STENT™ PLATFORMHigh flexibility without compromising vessel supportUnmatched side branch access2
ABLUMINAL BIODEGRADABLE COATINGEarly BMS-like endothelial coverage1
More targeted tissue release Less systemic exposure
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Bioerodable polymer or no polymer
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Bio-aborbable stent
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1980s
1970s
1990s
2000s
POBA
Stents
DES
Devices
?
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Patient Need Innovation
Technology Assessment
Industry
Regulatory Body
Clinical Research