orsiro hybrid drug eluting stent insights into the ...summitmd.com/pdf/pdf/pm0115_lefevre.pdf ·...

Orsiro Hybrid Drug Eluting StentInsights into the Sirolimus-eluting DES withInsights into the Sirolimus-eluting DES withbioabsorbable polymer

April 24, 2013April 24, 2013

Thierry Lefèvre

Institut HospitalierJacques Cartier, Jacques Cartier, France

Pathological Healing Response to Implantation of Early Generation DES

Eosinophilic Infiltrates Delayed Healing

Generation DES

p

P<0 0001

Delayed Healing

P<0.0001P<0.0001

P=0.0003

Guagliumi et al. Circulation 2011Cook et al. Circulation 2009

Vessel Remodeling Neoatherosclerosis

Cook et al. Circulation 2007 Nakazawa JACC 2011

Comparison of Biolimus‐ and Sirolimus‐Eluting Stents Cardiac Death MI or indicated TVR @ 4 earsCardiac Death, MI, or indicated-TVR @ 4 years

Stefanini G et al. Lancet 2011

25

BES SES

23 1%

3-year RR0.80 (0.63 -1.01)

2-year RR0.83 (0.64 -1.07)

4-year RR0.81 (0.66 -1.00)

1-year RR0.88 (0.66 -1.17)

2015 5%

19.3%

23.1%

Δ 3 7

Δ 4.0

15

% 13%15.6%

19.1%12.1%

15.5%

Δ 2.5

Δ 3.7

5

10

10.7%

13%Δ 1.4

Pnon-inferiority < 0.0001

P = 0 050

0

5

0 6 12 18 24 30 36 42 48

Psuperiority = 0.050

0 6 12 18 24 30 36 42 48Months

Numbers at risk

SES 850 775 738 718 702 676 656 639 614

BES 857 781 749 733 723 710 697 677 659

Comparison of Biolimus‐ and Sirolimus‐Eluting Stents Definite Stent Thrombosis @ 4 yearsDefinite Stent Thrombosis @ 4 years


6BES SES

3-year RR0.78 (0.43 -1.432)

P=0 43*

2-year RR0.90 (0.483 -1.67)

P=0 73*

4-year RR0.62 (0.35 -1.08)

P=0 09*

1-year RR0.99 (0.51-1.95)

P=0 98*

4

54%

P=0.43 P=0.73 P=0.09P=0.98

2

3%

2 4%2%

2.5%2.9%

Δ 0.3Δ 0.7

Δ 1.6

1

2

2%2.2% 2.2%

2.4%

00 6 12 18 24 30 36 42 48

Months

Numbers at risk

SES 850 817 801 787 776 759 750 730 714SES 850 817 801 787 776 759 750 730 714

BES 857 821 804 792 787 780 774 757 746

* P values for superiority

Efficacy and Safety with Biodegradable Polymer DES versus Durable Polymer Sirolimus-Eluting y gStent During Long-Term Follow-up

TLR Definite ST

ISAR‐TEST 3 17/202 21/202 0∙81 (0∙44, 1∙49)

RR (95% CI)

ISAR‐TEST 3 1/202 2/202 0∙50 (0∙05, 5∙47)

BP‐DES DP‐SES RR (95% CI)BP‐DES DP‐SES

ISAR‐TEST 4 168/1299 95/652 0∙89 (0∙70, 1∙12) ISAR‐TEST 4 9/1299 9/652 0∙50 (0∙20, 1∙26)

( , )

Overall (I2 = 0∙0%, p=0∙79)

LEADERS 88/857 111/850

0∙84 (0∙71, 0∙99)

0∙79 (0∙60, 1∙02)

Overall (I2 = 0∙0% p=0∙92)

LEADERS 20/857 32/850

0∙58 (0∙37 0∙93)

0∙62 (0∙36, 1∙08)

Overall (I 0 0%, p 0 79) 0 84 (0 71, 0 99)

10∙1 0∙2 2 5 100∙5Risk ratio

Overall (I 0 0%, p 0 92) 0 58 (0 37, 0 93)

10∙1 0∙2 2 50∙5Risk ratio

Favoursbiodegradablepolymer DES

Favoursdurable

polymer SES

Favoursbiodegradablepolymer DES

Favoursdurable

polymer SES

5

130423_Orsiro TCTAP 2013_TL

p y p y


p y p y

Are absorbable polymers the future?

Biodegradable polymer DES represent the first newer Biodegradable polymer DES represent the first newer generation DES that improves efficacy and safety outcomes compared to the earlier generation gold-standard SES

Other newer generation durable polymer DES have not shown superiority over SES in randomized clinical trials to date

Further studies are needed to investigate whether biodegradable polymer technology improves clinical outcomes compared to newer generation durable polymer DEScompared to newer generation durable polymer DES

6


BIOTRONIK Orsiro Hybrid DES Hybrid coating contains active and passive layersHybrid coating contains active and passive layers

Passive coating

PROBIO silicon carbide barrier

Encapsulates the stent surface, reducing ion release

Active coating

BIOl t PLLA bi b b bl l BIOlute PLLA bioabsorbable polymer

Limus drug (1.4 μg/mm2)

Stent platform

PRO-Kinetic Energy Cobalt PRO Kinetic Energy, Cobalt Chromium, L-605

60 µm struts, double helix design

7


Passive Coating: PROBIOS i C d ti Sili C bid C tiSemi-Conductive Silicon Carbide Coating

PROBIO reduces the interaction between tissue/blood with the metallic stent

I it t di h t 96% d ti f t l i In vitro studies show up to a 96% reduction of metal ions

25 000

20 000

on in n

g/l Cobalt nickel

alloy

15 000

10 000

centr

atio Cobalt

chromium alloy

Ch i ll 5 000

0

Con Chromium alloy

with PROBIO

Cobalt Nickel Tungsten Chromium

8


Source: Data on file, BIOTRONIK AG.

Active Coating: BIOluteBi b b bl PLLA d A ti DBioabsorbable PLLA and Active Drug

PLLA was chosen for its biocompatible and

on

sco

re

2.0

3.0 28 days

90 days

controlled drug release

Metabolizes into CO2 and H O fl

am

mati

o

1.0

0.3 0.330 12

0.310.49

0 16 0 17

0.51 0.50

180 days

H2O Inf

0.0

Stent+ PROBIO

Stent + PROBIO & PLLA only

Orsiro

0.12 0.16 0.17

Drug dose 1.4 μg/mm2

with complete elution in about 100 days

80

100

ease

(%

)about 100 days

Elution curve is in-line with other Limus-based 40

60

dru

g r

ele

stents

0

20

In v

ivo

9


0

Time (days)

0 10 20 30 40 50 60 70 80 90 100

Source: Koppara, T., et al.Thrombosis and Haemostasis 107. (2012): 1009–1194.

Stent Strut ThicknessN G ti DESNew Generation DES

OrsiroXience PrimeEndeavor

R l tBioMatrix Flex OrsiroXience PrimeResoluteBioMatrix Flex

112 μm 91 μm 81 μm 60 μm

10


Orsiro Cell Size

Two different platform designs

Small (ø2.25-3.0mm)

Medium (ø3.5, 4.0mm)

DesignLength of cell edge

Corresponding Circle

Di t g g

(mm)Diameter

(mm)

Small 11.28 3.5911.28 3.59

Medium 13.90 4.42

11


Entire length of cell edge

Corresponding circumference after maximum expansion of cell

Biodegradable Polymersg y

P-L-LA P-D-LA or P-DL-LA P-L-GA

Poly-L-Lactid Acid Poly-D-Lactid Acid; PDLA or Poly-D-L-

Poly-lactid co -glycolic acid

L- and D- isomer of polylactides

PDLA or Poly D LLactid acid

glycolic acid

Contains only the L isomer

Contains a mix of the L and D isomer

Combination of lactid acid monomers and

L-Lactid

L-isomer L and D-isomer acid monomers and glycolic acid monomers

Naturally occurring Synthetically producedNaturally occurring Synthetically produced

Orsiro, ABSORB BioMatrix, Nobori Nevo, CoStar, Synergy

D-Lactid

y gy

Absorbs slower than PDLLA, but is more

In medical device industry the PDLLA is often called PDLA

Has less mechanical strength and release control than PLA type

biocompatibleyp

polymers. Absorbs quickly.

Less than 2 years About 9mo - 1 year About 3-9 months

12


y y

Differences among bioabsorbable and permanent polymer DESpermanent polymer DES

Pre-clinical histology, mean values at 28 day

3.0

Pre clinical histology, mean values at 28 day

Intimal area (mm) Injury score Fibrin score

PEVA/PBMA SES PUR SESOrsiro 2.0

/Orsiro formulation

1.0

PLLA SES PLGA SES

0.0BMS PEVA/PBMA SES PUR SES PLLA SES PLGA SES

13


BMS

Pre-clinical histology shows benign affects with overlapped Orsiro deviceswith overlapped Orsiro devices

Pre-clinical histology

3.0

fl

Pre clinical histologyMean values at 28 day

Injury score

Inflammation score

Fibrin score

No stent Stent overlap

2.0

1.0

No overlap Stent overlap

0.0Single stent Overlap

14


Orsiro Clinical Program

Study Study design n 1° endpoint Status

g

Study Study design n 1 endpoint Status

FIM 30 9 mo LLL Published

International, RCT vs. Xi P i

440 9 mo LLL Enrollment completed Xience Prime

0 9 o o o p d

International registry 1,000 12 mo TLF Enrollment completed

Satellite registries 3,000+ 12 mo TLF Enrollment ongoingIOTR

ON

IK

init

iate

d

g g g

Indian single-armed trial 120 9 mo LLL Enrollment completed

RCT vs. Pantera Lux in ISR 2106 mo LLL 12 mo TLF

Enrolling

BI

12 mo TLF

Swiss RCT vs. Xience Prime 2,100 12 mo TLF Enrolling

HAT-TRICK-OCTFinnish RCT vs. Endeavor Resolute

403 mo strut coverage

Enrollment completedResolute coverage

p

PRISON-IVRCT vs. Xience Prime in CTO

330 9 mo LLL Enrolling

Dutch RCT vs Xience nvest

igato

r in

itia

ted

BIO-RESORTDutch, RCT vs. Xience Prime

3,500 12 mo TVF Enrolling

ISAR-ORSIROGerman, RCT vs. Xience Prime

606 & 24 mo Strut coverage

Enrolling

In

15


g

Total 10,830+

BIOFLOW-I (FIM)( )

DESIGN: Prospective, multi-centre, non-randomized, first in man trial 30 patients enrolled July 2009

i 2 li i l it i R i OBJECTIVE: To assess the safety

and clinical performance of the ORSIRO in coronary de-novo Clinical follow up at 1 month

in 2 clinical sites in Rumania

ORSIRO in coronary de-novo coronary artery lesions

PRIMARY ENDPOINT: LLL at 9 Clinical & angiographic

Clinical follow-up at 1 month

PRIMARY ENDPOINT: LLL at 9 months

Clinical coordinate investigator:

Clinical & angiographicfollow-up at 4 months

gProf. Martial Hamon, University Hospital of Caen, France

O

Clinical & angiographicfollow-up at 9 months

PRINCIPAL INVESTIGATORS:Dr. Rodica Niculescu, MD, PhD, FESC, Dr. Dan Deleanu, MD, FESC

Clinical follow-up at 12, 24 & 36 months

16


Source: Hamon M., et al. EuroIntervention 2013;8:1006-1011.

Baseline clinical characteristicsBaseline clinical characteristics

N 30N=30

Age, years 58.10 yrs ± 9.80

Male sex 60 0% 18/30Male sex 60.0% 18/30

Hyperlipidemia 93.3% 28/30

History of MI 73 3% 22/30History of MI 73.3% 22/30

Hypertension 66.6% 20/30

Smoker 53.3% 16/30Smoker 53.3% 16/30

Diabetes 23.3% 7/30

CHF 20.0% 6/30

17


Baseline lesion characteristics

A, 27%

C, 7%Pre-Procedure N=30

RVD (mm) 2.75 ± 0.34B2,

27%

27%MLD (mm) 0.95 ± 0.29

% Diameter stenosis 65.52 ± 9.47

Mean Lesion length (mm) 11 71 ± 4 40B1,

40%

Mean Lesion length (mm) 11.71 ± 4.40

Procedural N=30Procedural N=30

Stent length per lesion (mm) 19.93 ± 5.33

Stent diameter per lesion (mm) 3.08 ± 0.37

LAD,

LCX, 17%

p ( )

Direct stenting 20.0%

Device success* 100.0%LAD, 53%

RCA, 30%

* Defined as In-Stent < 30% residual stenosis by offline QCA

18


Angiographic follow-up results

4-month 9-month

RVD (mm) 2.81 ± 0.28 2.81 ± 0.30

Mi i l L Di t

Primary EndpointLate Lumen Loss

Minimal Lumen Diameter

In-stent (mm) 2.50 ± 0.36 2.56 ± 0.38

In-segment (mm) 2.20 ± 0.35 2.21 ± 0.310.2

@ 9 Months

g ( )

Diameter Stenosis

In-stent (%) 15.19 ± 4.55 13.60 ± 4.27

In-segment (%) 23.66 ± 9.80 23.55 ± 8.06

Late Loss

In-stent (mm) 0 12 ± 0 19 0 05 ± 0 22

0.1

In stent (mm) 0.12 ± 0.19 0.05 ± 0.22

In-segment (mm) 0.06 ± 0.23 0.05 ± 0.26

Binary Restenosis

0.05±0.22 0.05±0.26

In-stent (mm) 0% 0%

In-segment (mm) 0% 0%

0

In‐stent In‐segment

19



Clinical outcomes at 9 months

9-month clinical results N %

MACE 2 6.7

Cardiac Death 0 0.0

MI 0 0.0

Stent thrombosis 0 0.0Stent thrombosis 0 0.0

TLR (clinically driven) 2 6.7

MACE defined as:Composite of cardiac death, MI attributed to the target vessel, stent thrombosis and clinically driven target lesion revascularization

20



The Orsiro FIM BIOFLOW-I showed promising resultspromising results

90

100(%

)

9 th i d i t n=30

70

80

quen

cy ( 9-month primary endpoint

In-stent LLL 0.05 ± 0.22 mm

n=30

50

60

ativ

e fr

eq

9-month clinical results n %

Death 0 0.0

30

40

Cum

ula

Stent thrombosis 0 0.0

MI 0 0.0

0

10

20 TLR (clinically driven) 2 6.7

MACE 2 6.7

0

‐0.6 ‐0.4 ‐0.2 0 0.2 0.4 0.6 0.8 1

Late Lumen Loss (mm)

21



Late Lumen Loss (mm)

BIOFLOW-II

440 patients Enrollment finished

March 2012 DESIGN: A prospective, multicenter,

international, non-inferiority, randomized controlled study

Orsiro Xience Prime2:1randomized controlled study

OBJECTIVE: To compare the Orsiro to Xience Prime in de novo coronary

Clinical follow-up at 1 and 6- monthlesions

PRIMARY ENDPOINT:In stent late lumen loss at 9 months Clinical, angiographic,

IVUS* and OCT* follow-up at 9 months

In-stent late lumen loss at 9 months

Co-PIs:Prof. Stephan Windecker

Clinical follow up at 12 months

* Pre specified sub groups with 60 patients in each

University Hospital Bern, SwitzerlandDr. Thierry LefevreHospital Jacques Cartier, Massy,

Clinical follow-up at 12 months

Clinical follow-up annually out to 5 years

France

22


Source: ClinicalTrials.gov Identifier: NCT01356888 out to 5 years

BIOFLOW-III

DESIGN: International, prospective, non-randomized, multicenter, open-l b l li i l l ti

1,000+ patients enrolled August 2011 - April 2012 in 42 label clinical evaluation

OBJECTIVE: To assess the clinical performance of the ORSIRO in Clinical follow up at 6 month

August 2011 April 2012 in 42 clinical sites in Europe

pcoronary arteries in an “all comers” population

Clinical follow-up at 6 month

PRIMARY ENDPOINT:TLF at 12 months

COORDINATING INVESTIGATOR :Clinical follow-up at 12 months

COORDINATING INVESTIGATOR :Johannes WaltenbergerUniversity Hospital Muenster, GermanyGermany

Clinical follow-up at 18 months

23


Source: ClinicalTrials.gov Identifier: NCT01553526

BIOSCIENCE

2100 patients Enrollment started February 2012 DESIGN: Prospective, multi-center,

randomized, non-inferiority trial

O i Xi P i

1:1

, y

OBJECTIVE: To compare the safety and efficacy of SES with a

Cli i l f ll t 1 6 d 9 th

Orsiro Xience Primebiodegradable polymer with an EES with a durable polymer

PRIMARY INVESTIGATOR Clinical follow-up at 1, 6 and 9- month

Clinical follow-up at 1 year

PRIMARY INVESTIGATOR:Prof. Stephan WindeckerUniversity Hospital Bern, S it l d

Clinical follow-up at 2 years

Clinical follow up at 1 yearSwitzerland

PRIMARY ENDPOINT:TLF at 12 month Clinical follow up at 2 years

Clinical follow-up at 5 years

TLF at 12-month.

24


Clinical follow-up at 5 yearsSource: ClinicalTrials.gov Identifier: NCT01443104

Conclusions

Biodegradable polymer technology has shown to improve Biodegradable polymer technology has shown to improve outcomes compared with the previous gold-standard of durable polymer SES

Orsiro Hybrid DES applies biodegradable polymer based drug elution with an attractive platform, and has shown promising results in a FIM studyresults in a FIM study

Further BIOFLOW studies will provide further data on this novel device by directly comparing angiographic outcomes with durable y y p g g g ppolymer EES (Xience Prime) and in broader populations

25


orsiro hybrid drug eluting stent insights into the ...summitmd.com/pdf/pdf/pm0115_lefevre.pdf ·...

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