Insights on ELUVIA from the IMPERIAL-trial and beyond: When to … · 2020. 9. 8. · de Rennes (Alain CARDON) ; Clinique Pasteur (Antoine SAUGUET); CHU de Nantes (Yann GOUËFFIC)

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Prof. Yann GouëfficDepartment of vascular surgery and endovascular surgery

Goupe Hospitalier Paris Saint Joseph, France.

Insights on ELUVIA from the

IMPERIAL-trial and beyond: When

to prefer a stent-based approach?

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Y. Gouëffic reports:

- Research funding from Bard, Medtronic, Terumo, WL Gore

- Personal fees and grants from Abbott, Bard, Biotronik, Boston

Scientic, Medtronic, Terumo, Vygon, WL Gore (medical advisory

board, educational course, speaking)

Disclosures

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Femoropopliteal algorythm

PTA

Bare metal stent

Covered stent

Drug eluting stent

Drug eluting balloon

Vessel preparation

To define the lesion

Treatment

To define the approach

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Rational for DES

A drug to inhibit SMC

proliferation and migration

• The true lumen ( ) of the superficial femoral artery is still open at 12 cm distance

• Dissection of the arterial wall located between the internal elastic lamina and the atherosclerotic plaque ( )

• The newly formed route in the arterial wall was filled with thrombus at all levels

• Reobstruction began at the distal part of the artery

Scaffolding to prevent subintimal

recoil

Scholtes, Circ Cardiovasc Interv. 2012 Iida, O. et al. Cath and Cardiov Intv. 2011; 78:611–617.

Kimura T, et al. N Engl J Med 1996;334:561–567.

D0 D3 D7

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Zilver PTX vs POBA for TASC A/B femoropopliteal lesions

At 5 years, sustained clinical, morphological and

hemodynamic outcomes

Dake, Circ Cardiovasc Interv. 2011Dake, Circulation, 2016

Zilver® PTX® RCT

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First arm of randomizationPrimary end point

12-month rates of event-free survival andpatency in the primary DES and PTA groups

Second arm of randomization- Sub groups (BMS/DES; 59/61)

- Secondary endpoints

Dake, Circ Cardiovasc Interv. 2011

479 patients to include

Sample size calculation of Zilver® PTX® RCT

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BATTLE trial French multicentric randomized clinical trial comparing MISAGO® vs. ZILVER® PTX® for the treatment of intermediate

femoropopliteal lesions (from February 2014 to September 2018)

10 centers: Clinique d'Antony (Jean-

Marc PERNES); CHU de Besançon

(Simon RINCKENBACH); CHU de

Bordeaux (Eric DUCASSE) ; CHU de

Clermont Ferrand (Eugenio ROSSET) ;

AP-HP, Hôpital Henri Mondor (Pascal

DESGRANGES) ; CHU de Lyon

(Patrick FEUGIER) ; CH de Bourgouin

(Patrick LERMUSIAUX); Clinique

Ollioules (Philippe COMMEAU) ; CHU

de Rennes (Alain CARDON) ; Clinique

Pasteur (Antoine SAUGUET); CHU de

Nantes (Yann GOUËFFIC)

**

*

**

**

* *

*Nantes University Hospital

BATTLE ClinicalTrials.gov number, NCT02004951

*

Gouëffic, JACC Intrv, In press

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Freedom from in-stent restenosis* @ 12 months(primary endpoint) (Kaplan Meier estimates)

*Defined by restenosis of >50% and by a peak systolic velocity index >2.4 at the target

lesion. Assessment by an independent core laboratory (thromboses were excluded)

Gouëffic, JACC Intrv, 2020

@ 12 months:

MISAGO®: 85.7%

ZILVER® PTX®: 90.3%

P=0.36

@ 24 months:

MISAGO®: 80.9%

ZILVER® PTX®: 85.8%

P=0.64

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The plateform and/or the absence of polymer could explain the absence

of a difference between MISAGO® vs. ZILVER® PTX®

Gouëffic, JACC Intrv, 2020

Zilver PTX does not use a polymer to release

paclitaxel, delivering approximately 95% of the

total drug within 24 h

of deployment, with sustained paclitaxel levels in

the artery wall over 56 days

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BSC PI Drug-Eluting Stent Clinical Program

IMPERIALMulticenter, RCT 2:1(Eluvia : ZilverPTX)

N = 465 2Y follow up complete

MAJESTICMulticenter, single-arm(Eluvia)


EMINENTMulticenter, RCT 2:1(Eluvia : BMS)

N = 750 Enrolling

REGALMulticenter registry(Eluvia)

N = 500 Enrolling

SPORTS*Multicenter, RCT 1:1:1 (Eluvia:DCB:BMS)

N = 222 Enrolling

SAVALMulticenter, RCT 2:1(DES BTK : PTA) & single-arm

N = 201 & N = 100

Enrolling

*These investigator-sponsored studies are supported by grant funding from Boston Scientific. Boston Scientific is not responsible for the collection, analysis or reporting of these studies which remain the sole responsibility of the investigators. Information for the use in countries with applicable product registrations.SAVAL is an investigational device and not available for sale in the US.

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Primary Investigators

Global: William A. Gray, MD

European: Stefan Müller-Hülsbeck, MD

Study Design

RCT

(Eluvia DES vs Zilver PTX)

Long Lesion Sub-study

(Eluvia)

Pharmacokinetic

Sub-study (Eluvia)

• 2:1 randomized

• Single-blind

• Non-inferiority trial

• Single arm

• Lesion length 140 mm-190 mm

• Single-arm

Patients

N=465

Eluvia N=309 vs

Zilver PTX N=156

N=50 N=13

InvestigationalCenters

65 study centers: US, Canada, New Zealand, Belgium, Germany, Austria, Japan

IMPERIAL Clinical Study Overview

Gray WA, Lancet 2018.

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IMPERIAL Study Devices

Eluvia™ DES

Boston Scientific

Zilver® PTX®

Cook Medical

Stent Platform Innova Zilver Flex

Material Nitinol Nitinol

PolymerBiostable Fluorinated

Polymer Matrix (PROMUS polymer)

None

Drug

Dose DensityPaclitaxel

0.167µg/mm2Paclitaxel

3 µg/mm2

Deployment Self-expanding Self-expanding

SizesDiameter Length Diameter Length

6-7 mm 40-150 mm 6-8 mm 40-120 mm

BSC Data on file. Cook Medical (2014). Zilver PTX Drug-Eluting Peripheral Stent Instructions for Use.

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CAUTION: The law restricts these devices to sale by or on the order of a physician. Rx Only.

Spacing of interconnects

provides balanced stress

distribution for all deformation

modes

Stent Fracture rates in studies using the INNOVA Stent platform:

• IMPERIAL (Eluvia): 0.3% at 12M• MAJESTIC (Eluvia): 0.0% at 24M

• SuperNOVA (Innova): 2.2% at 24M

Width, Length and angles

optimized for maximum

strength

Radial Force and Flexibility

must be matched by

excellent Fracture

Resistance

EluviaTM drug-eluting stent: stent architecture

Balanced geometry designed for even stress distribution and optimal radial strength

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• Active Polymer Layer (PTx, PVDF-HFP)– Controls Release of Paclitaxel

o Diffusion-controlled low-dose elution over time

• 0.167µg PTx/mm2 stent surface area

• Primer Layer (PBMA)– Promotes Adhesion of Active Layer to Stent

• Conformal Coating for Both Layers

Eluvia Dual-Layer Coating Design

Boston Scientific Data on File.

Stent

PBMA Primer Layer

Paclitaxel/PVDF-HFP Active Layer

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Polymer Selection: PVDF-HFP on PBMA

Biocompatible

PROMUS polymer:

PBMA-PVDF

• 20k clinical patients studied

• Over 10M WW implants

Durable

Durable coating during

deployment/fatigue testing

Tunable

Time

Dru

g R

elea

se

Ability To Tune Drug Release

Dep

loy

Forc

eBPolymer A DC E

Deployable

BSC evaluated multiple biostable & biodegradable polymers

Boston Scientific Data on File.

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o >90% of drug is released at 1 year

• Drug release coincides with the restenotic cascade

Based on pre-clinical PK analysis. Data on file at Boston Scientific.

*Dake MD, et al. J Vasc Interv Radiol. 2011;22(5):603-610.

*

Sustained Drug Release

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aSimulated use in a tortuous vessel model under clinically relevant flow conditions.

Device sizes for particulates testing: 6mmx120mm stents, 6mmx80mm balloons. BSC Data on file.Data from ELUVIA, Zilver PTX, Lutonix, Stellarex and IN.PACT DFUs. Abbreviations: DCB, drug-coated balloon; DES, drug-eluting stent.

Paclitaxel-Eluting Paclitaxel-Coated

ELUVIA DESZilver PTX

Stent

DCB

IN.PACT Lutonix Stellarex

Biostable Polymer ✓

Excipient ✓ ✓ ✓

Amorphous Coating Morphology

✓ ✓

Paclitaxel Dose Density(µg/mm2)

0.167 3 3.5 2 2

Total Dose(6 mm x 120 mm)

409 µg 1103 µg 8448 µg 4500 µg 4721 µg

Diffusion-Controlled Elution ✓

Particulate Countsa

(≥10µm size)1381 11,928 567,432 210,320 193,968

Eluvia Differs from Peripheral Paclitaxel-Coated Technologies

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IMPERIALPharmacokinetics Sub-study (N=13)

• All patients treated with Eluvia

• Plasma paclitaxel measured at 10 min, 30 min, and 1, 2, 3, 4, 6, 12, 24, 48 hours post-implant.

• Plasma paclitaxel unquantifiable (

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Treatment Difference for Primary Patency

Primary patency defined as duplex ultrasound PSVR ≤2.4, in the absence of clinically-driven target

lesion revascularization or bypass of the target lesion, as assessed by the DUS core lab.

Superior primary patency forEluvia vs Zilver PTX

Effectiveness I Primary Patency at 12 Months

Eluvia

(N=309)

Zilver PTX

(N=156)

77.5%

(110/142)

Δ

(95% CI)p value

86.8%

(243/280)

9.3%

(1.4%, 17.3%)0.0144

Gray WA, Lancet 2018.

IMPERIAL Trial: A global randomized controlled multi-center trial with 2:1 randomization of the Eluvia™ Drug-

Eluting Stent against Cook Medical’s Zilver™ PTX™ Stent, single-blind, non-inferiority design; independent core

lab adjudication. Superiority determined in a post hoc analysis that was specified prior to unblinding. 12-Month

Primary Patency rate of 86.8% in the Eluvia arm vs. 77.5% in the Zilver PTX arm (p-value = 0.0144).

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Effectiveness I Primary Patency at 12 Months

Kaplan-Meier Analysis of Primary Patency

Primary patency defined as duplex ultrasound PSVR ≤2.4, in the absence of clinically-driven target

lesion revascularization or bypass of the target lesion, as assessed by the DUS core lab.Gray WA, LINC 2020.

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Significant reduction TLR with Eluvia DES at 2 years

Circulatory System Surgery Devices Panel June 20, 2019 Boston Scientific Presentation.BSC Data on File. As-treated ELUVIA and PTx Control data from IMPERIAL RCT. FDA PTA reference based on FDA Executive Summary (median of PTA arms). Abbreviations: DES, drug-eluting stent; TLR, target lesion

revascularization; PTx, paclitaxel.

IMPERIAL outcomes at 2 Years

No significant primary patency at 2 years

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Primary Patency at 24 Months (Eluvia Treatment Arm)

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IMPERIAL with a clinically relevant

comparator contributes level 1 evidence to

support the use of DES to treat LEAD

IMPERIAL supports the effectiveness of

the longer paclitaxel elution profile of the

Eluvia stent in preventing restenosis while

maintaining similar safety to a

contemporary comparator.

IMPERIAL conclusions

Gray W, Lancet, 2018

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IMPERIALMulticenter, RCT 2:1(Eluvia : ZilverTMPTXTM)





N = 750 Enrolling


N = 500 Enrolling


N = 222 Enrolling

SAVALMulticenter, RCT 2:1(SAVAL : PTA) & single-arm

N = 201 & N = 100

Enrolling


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Clinical Study Overview: EMINENT

Title A Randomized Trial Comparing the ELUVIA™ Drug-Eluting Stent versus Bare Metal Self-Expanding Nitinol Stents in the Treatment of Superficial Femoral and/or Proximal Popliteal Arteries

Coordinating Principal Investigators

Prof. Yann Goueffic, Nantes, France

Prof. Giovanni Torsello, Münster, Germany

Objective To confirm superior effectiveness of the ELUVIA Drug-Eluting Vascular Stent System (ELUVIA Stent) for treating Superficial Femoral Artery (SFA) and/or Proximal Popliteal Artery (PPA) lesions up to 140 mm in length when compared against bare metal stents, and collect additional data including health economics data.

Study Design Prospective, multi-centre, single-blind, superiority trial (RCT)Randomized 2:1 (Eluvia : Self Expanding BMS)*Powered for 10% Primary Patency superiority*

Subjects 750 subjects to receive treatment Total lesion length (or series of lesions) ≥ 30 mm and ≤140 mmRutherford 2-4Stenosis ≥70% by visual angiographic assessment

EMINENT Clinical Study

CAUTION: The law restricts these devices to sale by or on the order of a physician. Rx Only.

Enrollment Complete

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N = 750 Enrolling


N = 500 Enrolling


N = 222 Enrolling


N = 201 & N = 100

Enrolling


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Clinical Study Overview: REGAL

Title A Real World Evaluation of ELUVIA™ Drug-Eluting stent in All-Comers Superficial Femoral Artery and Proximal Popliteal Artery Disease

Primary Investigator Prof Carlo Setacci, Siena, Italy

Objective Collect additional data including health economics data to support the use of the ELUVIA Drug-Eluting Vascular Stent System for treating Superficial Femoral Artery (SFA) and/or Proximal Popliteal Artery (PPA) lesions

Study Design Prospective, multi-centre, single-arm, open-label registry

Subjects 500 subjects at up to 30 study centres in up to 10 EU countries• Stenotic, restenotic or (re)occluded lesion(s) in the femoro-popliteal arteries suitable for endovascular

treatment

Primary Effectiveness Endpoint

Primary patency • Freedom from more than 50% stenosis based on PSVR ≤ 2.4• Assessed by duplex ultrasound (DUS) at 12 months post-procedure

Primary Safety Endpoint Major Adverse Event (MAE) rate defined as:• All cause death through 1 month• Target limb major amputation through 12M• Target lesion revascularization (TLR) through 12M

Follow-Up Index, 1m, 6m, 1-year (primary endpoint), and 2-years (standard of care)

REGAL Clinical Study Enrolling

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N = 750 Enrolling


N = 500 Enrolling


N = 222 Enrolling


N = 201 & N = 100

Enrolling


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Clinical Study Overview: SPORTS

Title Sequent Please Drug Coated Balloons Versus Primary Stent Application in Long SFA Lesions

Primary Investigator / Sponsor

Gunnar Tepe, MD - RoMed Klinikum Rosenheim, Germany

InnoRa GmbH

ObjectiveCompare angiographic and clinical outcome of PTA with a paclitaxel coated balloon versus nitinol stent (paclitaxel-eluting or bare metal) with regard to restenosis development

Study Design Prospective, multicenter, RCT 1:1:1 (Eluvia DES: SeQuent Please PCB : Nitinol stent)

Subjects

Up to 222 patients

• Rutherford stage 2-4

• Occlusion or stenosis ≥70% of diameter and ≥13 cm length in the SFA and/ or PI-segment of popliteal artery

Investigational Centers Up to 11 centers in Germany

Primary EndpointPercent diameter stenosis at 1 year post intervention in successfully treated patients by quantitative angiography

These investigator-sponsored studies are supported by grant funding from Boston Scientific. Boston Scientific is not responsible for the collection, analysis or reporting of these studies which remain the sole responsibility of the investigators. Information for the use in countries with applicable product registrations. CAUTION: The law restricts these devices to sale by or on the order of a physician. Rx Only.

ClinicalTrials.gov Identifier: NCT03332264

SPORTS Enrolled

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Prof. Yann GouëfficDepartment of vascular surgery and endovascular surgery

Goupe Hospitalier Paris Saint Joseph, France.

Insights on ELUVIA from the

IMPERIAL-trial and beyond: When

to prefer a stent-based approach?

Documents

Insights on ELUVIA from the IMPERIAL-trial and beyond: When to … · 2020. 9. 8. · de Rennes (Alain CARDON) ; Clinique Pasteur (Antoine SAUGUET); CHU de Nantes (Yann GOUËFFIC)