Dr Li Shu Kin FRCP (Lond, Edin & Glasg) FACC FHKAM COS … · ¾Does not interfere with stent scaffolding and delivery `Specific mechanism of action `Pharmacokinetics and pharmacodynamics

Dr Li Shu KinFRCP (Lond, Edin & Glasg) FACC FHKAM

COS (Medicine)Pamela Youde Nethersole Eastern Hospital

Des

1904-1979 1929

1st case in Sept1977Overtook CABG as the most popular form of coronary revascularizationCurrent rate: 2-3 million p.a.

Andreas Gruentzig1939-1985

Acute Mechanism:◦ Dilatation of the

arterial wall◦ Plaque disruptionChronic Mechanism:◦ Arterial remodeling

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

Acute recoilNegative remodelingIntimal proliferation

31% @ 6 months of 1st 169 patients of Andreas GruentzigMultiple trials of pharmacological agents◦ No successful storyMultiple trials of various devices

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

Acute: < 24 hoursSubacute: 1 to 30 days

Eliminate early elastic recoilProvide mechanical scaffold that prevent negative remodeling

xPromotes the development of neointimal hyperplasia

In-Stent Restenosis (ISR): a new disease!

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

In-Stent Restenosis: a Problem ofExcessive Neointimal Hyperplasia

Exaggerated wound healing responseRole of◦ Smooth muscle cell◦ Endothelium

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

Prevention of ISR Treatment of ISR

Drugs:◦ Systemic◦ Local deliveryDevices:

Prevention of further recurrenceDevicesDrugs

Therapeutic Options to PreventNeointimal Hyperplasia

Energy

• Gamma• Beta

Radiation Pharmaceuticals

Delivery Systemic Local

CatheterStent

•Gene therapy?•Drugs?

• Sirolimus• Paclitaxel

• Catheter• Stent• Balloon

?

Proven efficacy in oncologyProven effect in modifying wound healing and scar formation:◦ Keloid◦ Pterigium

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%

As treatment for ISR ΧAs preventive measure

Late thrombosisEdge effectFurther restenosis in ISR is still 20%Long term result?

StentInjuredIrradiatedAnalysed

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

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)

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

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

• 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!

• 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

@ 6 months@ 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

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

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

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

• 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

Drug Drug carrier technology

DexamethasoneActinomycin DResten-NGTacrolimusEstrogenNitric OxideTrapidilBatimitastat……

Quanam stent

Non-drug mechanism• Monoclonal antibodies

to attract EPC

Stent designDrug carrier-delivery mechanismDrug

Optimized geometry for homogenous drug distributionConformability: circumferential stent-vessel wall contactSufficient radio-opacity for precise placement (in tandem stents)Maintain side-branch accessDeliverability

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

Specific mechanism of actionPharmacokinetics and pharmacodynamicsTherapeutic (toxic) marginSystemic toxicityStability: effect of sterilization, stability of drugs

Device Restenosis Rates

0% 10% 20% 30% 40% 50% 60% 70%

Drug eluting Stents?

RT with Stent ?

RT

Stents

Atherectomy

PTCA Balloon Only

Just stent it!

Just DES!

Serruys, et al. Lancet. 2004;364: 1519–1521.

Camenzind E, ESC 2006SES = Sirolimus Eluting StentPES = Paclitaxel Eluting Stent

Lagerqvist: N Engl J Med, 2007;356:1009-1019

Stone GW et al. NEJM 2007;356:998--1008

Cardiac death MI

Stent thrombosis

Restenosis

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

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

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

Cause of some late events: MI/ deathsMechanism?◦ Delayed/ incomplete endothelialization?◦ Late catch up of disease?Need longer double anti-platelet therapy (DAPT )?

Columbo A. ACC March 2007

Based on consensus1 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-

Virmani et al. Circulation. 2007;115:1051-1058

•Delayed/ poor healing response•Persistent inflammation•Hypersensitivity response to polymer?

• 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

Kirtane A, et al TCT 2007

TLR for Taxus Vs BMS

Stettler C et al. Lancet 2007;370:937 -48

38 trials, 18,023 pts

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

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

Drug: Zotarolimus

Stent Delivery System

PC Technology

Driver Cobalt Alloy Stent

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.

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

Bioerodable polymer or no polymer

Bio-aborbable stent

1980s

1970s

1990s

2000s

POBA

Stents

DES

Devices

?

Patient Need Innovation

Technology Assessment

Industry

Regulatory Body

Clinical Research