Two Year Safety And Clinical Performance Of The Drug Eluting Orsiro Stent In The Treatment Of Subjects With Single De Novo Coronary Artery

Lesions(BIOFLOW-II)

Michael Haude, Rafael Ruiz-Salmeron, Thierry Lefévre, Bernhard Witzenbichler, Karl Stangl, Ton Slagboom, Franz-Josef Neumann,

Manel Sabaté, Jean-Cristophe Macia, Gert Richardt, Béla Merkely, Javier Goicolea, Johannes Bilger, Dimitar Divchev, Paul Barragan,

Stéphane Cook, Ron Waksman, Stephan Windecker

Prof. Michael Haude. MD I have the following potential conflicts of interest

to report:

Consultant: BIOTRONIK, ORBUSNEICH Institutional grant/research support: ABBOTT

VASCULAR, BIOTRONIK,MEDTRONIC, ORBUSNEICH,VOLCANO, CARDIAC

DIMENSIONS

Orsiro Hybrid Drug Eluting Stent With Bioabsorbable Polymer

The hybrid structure:

A combination of passive and active components

The underlying PK Energy Stent with thin strut (60μm) design

Passive component encapsulates the stent

Active component contains bioabsorbable PLLA and sirolimus

Overview of Current Stent Designs

Source: Stefanini G., Taniwaki M., Windecker S., Heart 2013; 0:1-11.

DurablePolymer Coated Stent

BioabsorbablePolymer Coated Stent

BIOTRONIK

OrsiroCoCr-SES

60 µm

Circumferential 4-8 µm/side

Boston

SynergyPtCr-EES

74 µm

Abluminal4 µm/side

Terumo

UltimasterCoCr-SES

80 µm

Abluminal15 µm/side

Biosensors

BioMatrix316L-BES

120 µm

Abluminal 10 µm/side

Medtronic

ResoluteCoNi-ZES

91 µm

Circumferential 6 µm/side

Abbott/Boston

Xience/PromusCoCr/PtCr-EES

81 µm

Circumferential 7-8 µm/side

Strut Thickness

PolymerCoating

Company

Device NameMaterial-Drug

DeviceDesign

BIOFLOW II Study Design

Orsiro

452 Patients (Intention To Treat) with de novo lesions in up to two coronary arteriesAll subjects stratified for diabetes

Annual clinical follow-up to 5 years

1,6-month clinical follow-up

Prospective, multicenter, international, randomized, non-inferiority design

Co-PIs: Stephan Windecker, University Hospital Bern, Switzerland Thierry Lefevre, Hospital Jacques Cartier, Massy, France

Xience Prime2:1

9-month clinical and angiographic follow-up IVUS and OCT follow-up in pre-specified subgroups with 60 patients in each

12-month clinical follow-up

ClinicalTrials.gov Identifier: NCT01356888.

Stent Platforms

Co-Cr, L-605

60 µm

Stent material

Strut thickness

Passive coating Silicon carbide

Polymer coating Biodegradable (PLLA)Drug Sirolimus

Orsiro

Co-Cr, L-605

81 µm

-

Durable (PBMA/PVDF-HFP)Everolimus

Xience Prime™

Source: Lefèvre T., Oral presentation, TCT 2013, San Francisco, USA.

Inclusion/Exclusion CriteriaInclusion Criteria

Exclusion Criteria

Co-PIs: Stephan Windecker, University Hospital Bern, Switzerland Thierry Lefevre, Hospital Jacques Cartier, Massy, France

Single de novo lesions in up to 2 native coronary arteries RVD ≥2.25 mm and ≤4.0 mm, lesion lengths ≤26 mm Age ≥18 and ≤80 years old Target vessel(s) TIMI flow ≥ 2 Eligible for DAPT therapy with ASA plus either, Clopidogrel, Prasugrel, Ticlopidine, or

Ticagrelor

Evidence of MI within 72 hours prior to index procedure ≥2xURL CK level or in absence of CK, ≥3xURL CKMB <24 hours prior to PCI Unprotected left main, 3-vessel CAD, thrombotic, ostial or bifurcation (SB>2.0mm), heavily

calcified or lesions in bypass graft LVEF ≤ 30% Serum creatinine > 2.5 mg/dl

ClinicalTrials.gov Identifier: NCT01356888.

OrsiroN= 332

Xience PrimeN= 173

Preprocedure

Lesion Length (mm) 13.4 ± 6.8 13.6 ± 5.6

Reference Vessel Diameter (mm) 2.8 ± 0.5 2.7 ± 0.5

Minimum Lumen Diameter (mm) 0.9 ± 0.5 1.0 ± 0.5

Diameter stenosis (%) 66.7 ± 14.3 65.3 ± 14.5Postprocedure Minimum Lumen Diameter (mm) In-stent 2.6 ± 0.5 2.6 ± 0.4 In-segment 2.3 ± 0.5 2.3 ± 0.5 Diameter stenosis (%) In-stent 6.9 ± 7.2 7.1 ± 7.7 In-segment 17.4 ± 7.0 17.4 ± 6.6 Device Success (%) 100 100Procedure Success (%) 97.7 97.4

Baseline Procedural Characteristics

No statistical significance between study arms

Procedural Characteristics: All Lesions

Source: Ruiz-Salmeron R. Poster presentation. TCT, Washington DC, USA, September 2014.

Baseline & Lesion CharacteristicsLesion Location

Lesion Type

Orsiro (N=332)

Xience Prime (N=173)Orsiro

(N = 298)Xience Prime

(N = 154)

Age, years mean ± SD 62.7 ± 10.4¹ 64.8 ± 9.2¹

Gender male (%) 78.2 74.7

Hypertension (%) 77.5 77.3

Hyperlipidemia (%) 67.8 73.4

History of MI (%) 30.2² 20.1²

Renal Insufficiency (%) 7.0 4.5

Congestive Heart Failure (%) 10.1 13.6

Diabetes (%) 28.2 28.6

Insulin dependent (%) 21.4 34.1

Non-insulin dependent (%) 78.6 65.9

Smoking (%) 66.4 57.8

History of stroke TIA (%) 7.0 6.5

Patient Characteristics

Source: Ruiz-Salmeron R. Poster presentation. TCT, Washington DC, USA, September 2014.

¹p=0.0344, ²p=0.0219.

Angiographic Results at 9 Months

OrsiroN = 278

Xience PrimeN = 149

Late loss (mm) In-stent 0.10± 0.32 0.11 ± 0.29 In-segment 0.09 ± 0.35 0.09 ± 0.33

MLD (mm) In stent 2.52 ± 0.56 2.48 ± 0.50 In segment 2.25 ± 0.55 2.22 ± 0.56

Diameter stenosis (%) In stent 9.52 ± 13.49 9.43 ± 10.78 In segment 19.48 ± 12.89 19.22 ± 12.25

Binary restenosis (%) In stent 6 (2.16%) 2 (1.34%) In segment 11 (3.96%) 7 (4.70%)

Source: Windecker S. Oral presentation. EuroPCR, Paris, France. 21 May 2013.

Primary Enpoint: In-Stent LLL at 9 Months

P non-inferiority = <0.0001Difference = 0.0095% CI = -0.06 to 0.06

OrsiroXience Prime

Major Secondary Endpoints: Angiographic Results at 9 Months

0.11 ± 0.29 mm

0

-1.0In-Stent LLL (mm)

Cum

ulati

ve F

requ

ency

(%) 0.10 ± 0.32 mm

20

40

60

80

100

-0.5 0.0 0.5 1.0 1.5 2.0

No statistical significance between study arms

Xience Prime™ (N=154)Orsiro (N=298)

0.0

10

20

0 180 365 730

TLF

univ

. def

. (%

)

8.4%10.0%

P = 0.5648

Days after PCI

Clinical Results at 24 Months All Subjects

TLF at 24 months – All Subjects

Source: Ruiz-Salmeron R. Poster presentation. TCT, Washington DC, USA, September 2014.

Clinical Results at 24 Months Diabetic Subgroup

TLF at 24 months – Diabetic Subgroup

Source: Ruiz-Salmeron R. Poster presentation. TCT, Washington DC, USA, September 2014.

0%

10%

20%

0 180 365 730

9.7%9.1%

P = 0.8975

Days after PCI

TLF

univ

. def

. (%

)

Xience Prime™ (N=44)Orsiro (N=84)

Clinical Results at 24 Months Small Vessel Subgroup

TLF at 24 months – Small Vessel Subgroup

Source: Ruiz-Salmeron R. Poster presentation. TCT, Washington DC, USA, September 2014.

TLF

univ

. def

. (%

)

Xience Prime™ (N=91)Orsiro (N=168)

9.4%13.3%

P = 0.3153

0%

10%

20%

0 180 365 730Days after PCI

Sten

t thr

ombo

sis

(%)

0.0

10

0 180 365 7300.0%

Days after PCI

0.7%P = 0.3407

Stent Thrombosis at 24 Months All Subjects

Stent Thrombosis at 24 months – All Subjects

Source: Ruiz-Salmeron R. Poster presentation. TCT, Washington DC, USA, September 2014.

Xience Prime™ (N=154)Orsiro (N=298)

0.0%0.0%

Days after PCI

0.0

10

0 180 365 730

P = >0.9999

0.0

10

0 180 365 730

P = 0.3437

Days after PCI

ST (%

)

0.0%2.3%

Stent Thrombosis at 24 Months Subgroups

Stent Thrombosis at 24 months – Diabetic Subgroup

Source: Ruiz-Salmeron R. Poster presentation. TCT, Washington DC, USA, September 2014.

Xience Prime™ (N=91)Orsiro (N=168)

Stent Thrombosis at 24 months – Small Vessel Subgroup

ST (%

)

Xience Prime™ (N=44)Orsiro (N=84)

Stent Thrombosis at 24 Months

Orsiro

N = 298

Xience Prime

N = 154

Acute (0-48h) 0 % 0 %

Subacute (48h-30d) 0 % 0 %

Late (>30d-12m) 0 % 0 %

Very late (>12m) 0% 0%

Overall 0 % 0 %

Orsiro

N = 298

Xience Prime

N = 154

Acute (0-48h) 0 % 0 %

Subacute (48h-30d) 0 % 0 %

Late (>30d-12m) 0 % 0 %

Very late (>12m) 0% 0.7%

Overall 0 % 0.7 %

Definite Stent Thrombosis Definite, Probable and Possible Stent Thrombosis

Source: Ruiz-Salmeron R. Poster presentation. TCT, Washington DC, USA, September 2014.

OCT and IVUS results at 9 Months

Source: Byrne R., EuroPCR, Paris, France, May 2014. Oral Presentation.Source: Windecker S. TCT, San Francisco, USA, October 2013. Oral presentation.

Maturity: 58.8% [13.5 – 92.9]

Maturity: 64.2% [8.9 – 97.0]

Adjusted p value = 0.62

Orsiro Xience Prime P

Well-apposed struts 98.6% 98.8% 0.62

Incomplete Strut Apposition 1.0% 0.6% 0.32

Non-apposed side branch 0.4% 0.6% 0.37

Covered Struts 98.3% 97.5% 0.042

Neointimal Area

1.00 ± 0.44 mm2

0.74 ± 0.38 mm2

P=0.024

Apposition and coverage

IVUS results at 9 Months

Source: Byrne R., EuroPCR, Paris, France, May 2014. Oral Presentation.Source: Windecker S. TCT, San Francisco, USA, October 2013. Oral presentation.

Mature

Immature

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

0.3

0.4

0.5

-0.10

0.16

-0.34

0.43

9-month IVUS Results

Orsiro (N=31)

Xience Prime (N=25)

Δ Mean lumen area @ 9 M FUP

Δ Neointimal hyperplasia @ 9 M FUP

P = 0.34 P = 0.043

Stent apposition by IVUS @ 9-month FUP was 100% in both study arms

OCT appearance at 9 MonthsOrsiro 

Neointima coverage

Xience Prime 

Neointima coverage

*With the courtesy of Prof. Haude/Neuss

Source: Lefèvre T., Oral presentation, TCT 2013, San Francisco, USA.

Conclusion Orsiro is a thin-strut cobalt-chromium sirolimus-eluting stent with a biodegradable

polymer coating. In this randomized controlled trial the clinical event rates of the Orsiro SES with a

biodegradable polymer were low and comparable to the Xience Prime up to 24 months in all three analyzed populations.

One possible late stent thrombosis occurred in the Xience Prime™ diabetic cohort. No stent thrombosis was observed in the Orsiro cohorts through 24 months.

The BIOFLOW-II OCT/IVUS sub group analysis showed similar results between the Orsiro and Xience Prime.

Safe inhibition of neointimal hyperplasia was seen in both arms with struts well covered with a thin, uniform neointima.

Orsiro was associated with a significantly lower area of neointimal hyperplasia than Xience Prime.

Orsiro achieved an excellent strut apposition.