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. Durable Polymer Coated Stent Bioabsorbable Polymer Coated Stent BIOTRONIK Orsiro CoCr-SES 60 µm Circumferential 4-8 µm/side Boston Synergy PtCr-EES 74 µm Abluminal 4 µm/side Terumo Ultimaster CoCr-SES 80 µm Abluminal 15 µm/side Biosensors BioMatrix 316L-BES 120 µm Abluminal 10 µm/side Medtronic Resolute CoNi-ZES 91 µm Circumferential 6 µm/side Abbott/Boston Xience/Promus CoCr/PtCr-EES 81 µm Circumferential 7-8 µm/side Strut Thickness Polymer Coating Company Device Name Material-Drug Device Design

BIOFLOW II Study Design Orsiro 452 Patients (Intention To Treat) with de novo lesions in up to two coronary arteries All 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 Prime 2:1 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: NCT

Stent Platforms Co-Cr, L µm Stent material Strut thickness Passive coatingSilicon carbide Polymer coatingBiodegradable (PLLA) DrugSirolimus Orsiro Co-Cr, L µm - Durable (PBMA/PVDF-HFP) Everolimus Xience Prime™ Source: Lefèvre T., Oral presentation, TCT 2013, San Francisco, USA.

Inclusion/Exclusion Criteria Inclusion 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: NCT

Orsiro N= 332 Xience Prime N= 173 Preprocedure Lesion Length (mm) 13.4 ± ± 5.6 Reference Vessel Diameter (mm) 2.8 ± ± 0.5 Minimum Lumen Diameter (mm) 0.9 ± ± 0.5 Diameter stenosis (%)66.7 ± ± 14.5 Postprocedure Minimum Lumen Diameter (mm) In-stent2.6 ± ± 0.4 In-segment2.3 ± 0.5 Diameter stenosis (%) In-stent6.9 ± ± 7.7 In-segment17.4 ± ± 6.6 Device Success (%) 100 Procedure Success (%) 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 Characteristics Lesion Location Lesion Type Orsiro (N=332) Xience Prime (N=173) Orsiro (N = 298) Xience Prime (N = 154) Age, years mean ± SD62.7 ± 10.4¹64.8 ± 9.2¹ Gender male (%) Hypertension (%) Hyperlipidemia (%) History of MI (%)30.2²20.1² Renal Insufficiency (%) Congestive Heart Failure (%) Diabetes (%) Insulin dependent (%) Non-insulin dependent (%) Smoking (%) History of stroke TIA (%) Patient Characteristics Source: Ruiz-Salmeron R. Poster presentation. TCT, Washington DC, USA, September ¹p=0.0344, ²p=

Angiographic Results at 9 Months Orsiro N = 278 Xience Prime N = 149 Late loss (mm) In-stent 0.10± ± 0.29 In-segment 0.09 ± ± 0.33 MLD (mm) In stent 2.52 ± ± 0.50 In segment 2.25 ± ± 0.56 Diameter stenosis (%) In stent 9.52 ± ± In segment ± ± 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 Primary Enpoint: In-Stent LLL at 9 Months P non-inferiority = < Difference = % CI = to 0.06 Orsiro Xience Prime Major Secondary Endpoints: Angiographic Results at 9 Months 0.11 ± 0.29 mm 0 In-Stent LLL (mm) Cumulative Frequency (%) 0.10 ± 0.32 mm No statistical significance between study arms

Xience Prime ™ (N=154) Orsiro (N=298) TLF univ. def. (%) 8.4% 10.0% P = 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 % 10% 20% % 9.1% P = 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 TLF univ. def. (%) Xience Prime ™ (N=91) Orsiro (N=168) 9.4% 13.3% P = % 10% 20% Days after PCI

Stent thrombosis (%) % Days after PCI 0.7% P = 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 Xience Prime ™ (N=154) Orsiro (N=298)

0.0% Days after PCI P = > P = 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 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 Stent Thrombosis at 24 months Source: Ruiz-Salmeron R. Poster presentation. TCT, Washington DC, USA, September Orsiro Xience Prime

Stent Thrombosis at 24 Months Orsiro N = 298 Xience Prime N = 154 Acute (0-48h)0 % Subacute (48h-30d)0 % Late (>30d-12m)0 % Very late (>12m)0% Overall 0 % Orsiro N = 298 Xience Prime N = 154 Acute (0-48h)0 % Subacute (48h-30d)0 % Late (>30d-12m)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.

Diabetic Subgroup Analysis OrsiroXience Prime Subjects = 84Subjects = 44 Age, years mean ± SD63.7 ± ± 7.5 Hypertension (%) Hyperlipidemia (%) History of MI (%) Congestive heart failure (%) Insulin dependent DM(%) Non-insulin dependent DM (%) Lesions = 93Lesions = 49 Lesion length (mm) ± ± 6.21 RVD (mm) 2.71 ± ± 0.51 Diameter stenosis (%)67.6 ± ± p = 0.047, Remaining values show no statistical significance between the study arms 2 Analysis only possible for Orsiro n=91 Source: Sabate M. Oral presentation. EuroPCR, Paris, France, May Oral Presentation. Ruiz-Salmeron R. Poster presentation. TCT, Washington DC, USA, September Diabetic Subgroup Demographics & Lesion Characteristics 0% 10% 20% TLF 9.7% 9.1% P = Days after PCI Xience Prime Orsiro Diabetic Subgroup TLF at 24 months Diabetic Subgroup Results at 24 months

Small Vessel Subgroup Analysis OrsiroXience Prime N = 168 SubjectsN = 91 Subjects Age, years mean ± SD62.9 ± ± 9.0 Hypertension (%) Hyperlipidemia (%) History of MI (%) Diabetes (%) Insulin dependent (%) Non-insulin dependent (%) Lesions = 195Lesions = 109 Lesion length (mm) ± 6.88*13.08 ± 5.22* RVD (mm) 2.49 ± ± 0.33 Diameter stenosis (%) ± ± *Analysis only possible for Orsiro n=191, Xience Prime n=108 Small Vessel Subgroup Demographics & Lesion CharacteristicsSmall Vessel Subgroup TLF at 24 months Small Vessel Subgroup Results at 24 mos. 9.4% 13.3% P = % 10% 20% TLF Days after PCI Xience Prime Orsiro Source: Sabate M. Oral presentation. EuroPCR, Paris, France, May Oral Presentation. 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 Oral Presentation. Source: Windecker S. TCT, San Francisco, USA, October Oral presentation. Maturity: 58.8% [13.5 – 92.9] Maturity: 64.2% [8.9 – 97.0] Adjusted p value = 0.62 Orsiro 27 lesions with 3501 ROIs Xience Prime 11 lesions with 1271 ROIs Mature Immature 9-month OCT Results

OCT and IVUS results at 9 Months Source: Byrne R., EuroPCR, Paris, France, May Oral Presentation. Source: Windecker S. TCT, San Francisco, USA, October Oral presentation. Maturity: 58.8% [13.5 – 92.9] Maturity: 64.2% [8.9 – 97.0] Adjusted p value = 0.62 OrsiroXience PrimeP Well-apposed struts98.6%98.8%0.62 Incomplete Strut Apposition 1.0%0.6%0.32 Non-apposed side branch 0.4%0.6%0.37 Covered Struts98.3%97.5%0.042 Neointimal Area 1.00 ± 0.44 mm ± 0.38 mm 2 P=0.024 Apposition and coverage

IVUS results at 9 Months Source: Byrne R., EuroPCR, Paris, France, May Oral Presentation. Source: Windecker S. TCT, San Francisco, USA, October Oral presentation. Mature Immature 9-month IVUS Results Orsiro (N=31) Xience Prime (N=25) Δ Mean lumen 9 M FUP Δ Neointimal 9 M FUP P = 0.34 P =  Stent apposition by 9-month FUP was 100% in both study arms

OCT appearance at 9 Months Orsiro Neointima coverage Xience Prime Neointima coverage *With the courtesy of Prof. Haude/Neuss Source: Lefèvre T., Oral presentation, TCT 2013, San Francisco, USA.

OCT findings at 9 Months Source: Windecker S. TCT, San Francisco, USA, October Oral presentation. OrsiroXience PrimeP Well-apposed struts98.6%98.8%0.62 Incomplete Strut Apposition 1.0%0.6%0.32 Non-apposed side branch 0.4%0.6%0.37 Covered Struts98.3%97.5%0.042 Neointimal Area 1.00 ± 0.44 mm ± 0.38 mm 2 P non-inferiority = < Difference = % CI = to 0.06 P=0.024 Apposition and coverage

Neointimal Maturity Source: Byrne R., EuroPCR, Paris, France, May Oral Presentation. Maturity: 58.8% [13.5 – 92.9] Maturity: 64.2% [8.9 – 97.0] Adjusted p value = 0.62 Orsiro 27 lesions with 3501 ROIs Xience Prime 11 lesions with 1271 ROIs Mature Immature

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.