Safety and Clinical Performance of the Drug- Eluting Orsiro Stent in the Treatment of Subjects With Single De Novo Coronary Artery Lesions-II (BIOFLOW-II , NCT01356888) Stephan Windecker, Bernhard Witzenbichler, Karl Stangl, Ton Slagboom, Franz-Josef Neumann, Thierry Lefévre, Rafael Ruiz-Salmeron, Manel Sabaté, Christophe Piot, Gert Richardt, Béla Merkely, Javier Goicolea, Johannes Bilger, Henrik Schneider, Paul Barragan, Stéphane Cook, Paul Erne, Ron Waksman, Michael Haude

Potential conflicts of interest Speaker's name: Stephan Windecker  I have the following potential conflicts of interest to report: Consultant: NA Employment in industry: NA Honorarium: NA Institutional grant/research support: Abbott, Biosensors, Biotronik, Boston Scientific, Cordis, Edwards Lifesciences, Medtronic, St Jude Owner of a healthcare company: NA Stockholder of a healthcare company: NA

Everolimus-Eluting Versus Sirolimus-Eluting Durable Polymer Stents Target Lesion Revasc Definite ST Favors EES Favors SES Favors EES Favors SES Meta-Analysis N = 11,167

Biodegradable Polymer DES Versus Durable Polymer SES @ 4 Years Target Lesion Revasc Definite ST Favors BP DES Favors SES Favors BP DES Favors SES N = 4,062 – IPD Pooled Analysis of LEADERS, ISAR-TEST 3 and 4 Stefanini G et al. Eur Heart J 2012; 33, 1214–1222

BIOFLOW-II Trial Primary Objective To compare the ORSIRO® sirolimus-eluting stent with biodegradale polymer (BIOTRONIK) with the XIENCE Prime® everolimus-eluting stents (Abbott Vascular) with durable polymer for the treatment of de novo coronary lesions with respect to non-inferiority for in-stent Late Lumen Loss (LLL) at 9 months

BIOFLOW-II Trial - Stent Platforms Co-Cr, L-605 60 µm Stent material Strut thickness Passive coating Silicon carbide Polymer coating Biodegradable (PLLA) Drug Sirolimus Orsiro 81 µm - Durable (PBMA/PVDF-HFP) Everolimus Xience Prime™

BIOFLOW II – Study Design 440 Patients with stable CAD 2:1 randomization Orsiro Xience Prime Clinical follow-up at 1 and 6- month Clinical, angiographic, IVUS* and OCT* at 9 months follow-up * Pre-specified subgroups with 60 patients in each Clinical follow-up at 12 months Clinical follow-up to 5 years Primary Endpoint: In-Stent Late Lumen Loss at 9 months follow-up

Patients Eligibility Inclusion Criteria Exclusion Criteria Single de novo lesions (≥ 50% and <100%) in up to 2 native coronary arteries RVD ≥2.25 mm and ≤4.0 mm Lesion lengths ≤26 mm Age ≥ 18 years 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 myocardial infarction within 72 hours prior to index procedure ≥2xURL CK level or in absence of CK a ≥3xURL CKMB <24 hours prior to PCI Unprotected left main 3-Vessel CAD Thrombotic lesions Ostial lesions Bifurcation lesions (SB > 2.0 mm) LVEF ≤ 30% Heavily calcified lesion Lesions in bypass graft Serum creatinine > 2.5 mg/dl

Sample Size Calculation Assumptions Mean in-stent late lumen loss 0.16 mm Standard deviation 0.40 mm Non-inferiority margin 0.16 mm Average number of lesion/patient 1.3 Ration of random allocation 2:1 Attrition rate 20% Sample Size Overall sample size of 440 randomised subjects (293 in the Orsiro group and 147 in the Xience Prime group) or 352 subjects with angiographic follow-up (234 in the Orsiro group and 118 in the Xience Prime group) will yield a power of 1-β = 80% at a two-sided α = 5%

Trial Organization Co-Principal Investigators Sponsor S. Windecker, Bern, Switzerland T. Lefèvre, Massy, France Sponsor Biotronik Core-Laboratories MedStar Health Research Institute (Angiography and IVUS) Cardialysis B.V. (OCT) Data Analysis Clinical Trials Unit Bern, Bern, Switzerland Clinical Event Committee Ralf Birkemeyer, Rostock, Germany Harald Rittger, Erlangen, Germany Zbigniew Siudak, Krakow, Poland

BIOFLOW II - Patient Flow 452 patients randomized (ITT*) between July 2011 and March 2012 Randomization 2:1 298 Orsiro Angio: n=298 IVUS: n=40 OCT: n=44 154 Xience Prime Angio: n=154 IVUS: n=26 OCT: n=21 1-month FUP Clinical: n =294 (99%) 1-month FUP Clinical: n =151 (98%) 6-month FUP Clinical: n =293(98%) 6-month FUP Clinical: n =151 (98%) 9-month FUP Clinical: n=288 (97%) Angio: n=252 (85%) IVUS: n=32 OCT: n=37 9-month FUP Clinical: n=151 (98%) Angio: n=131 (85%) IVUS: n=23 OCT: n=17 Clinical FUP yearly up to 5 years ongoing *ITT= Intention to treat

452 patients were enrolled across 24 centers in 8 European countries Investigator Country Patients M. Haude, MD Germany 57 P. Erne, MD Switzerland 41 B. Witzenbichler, MD 34 K. Stangl, MD 31 F.J. Neumann, MD 28 T. Slagboom, MD Netherlands S. Windecker, MD 24 T. Levefre, MD France R. Salmeron, MD Spain 20 M. Sabate, MD C. Piot, MD 18 G. Richardt, MD B. Merkely, MD Hungary 15 J. Goicolea, MD 14 H. Schneider, MD J. Bilger, MD P. Barragan, MD 12 S. Cook, MD 11 T. Moccetti, MD 9 A. Erglis, MD Latvia 8 W. Scholtz, MD 7 B. Eber, MD Austria 5 P. Radke, MD 3 M. Roffi, MD 452 patients were enrolled across 24 centers in 8 European countries Main study + OCT Main study Main study + IVUS

Baseline Clinical Characteristics Orsiro (N=298 Patients) Xience Prime (N=154 Patients) Age, years mean ± SD 62.7 ± 10.4 64.8 ± 9.2 Gender male (%) 78.2 74.7 Hypertension (%) 77.5 73.7 Hyperlipidemia (%) 67.8 73.4 History of MI (%) 30.2 20.1 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 (%) 6.5

Baseline Lesion Characteristics Lesion Location Lesion Type

Procedural Characteristics Orsiro (N=332 Lesions) Xience Prime (N=173 Lesions) Preprocedure Lesion length (mm) 13.36 ± 6.82 13.65 ± 5.58 Reference Vessel Diameter (mm) 2.78 ± 0.49 2.75 ± 0.49 Minimum Lumen Diameter (mm) 0.93 ± 0.46 0.96 ± 0.46 Diameter stenosis (%) 66.73 ± 14.27 65.34 ± 14.52 Postprocedure In-stent 2.62 ±0.45 2.58 ± 0.41 In-segment 2.33 ±0.48 2.31 ±0.45 6.91 ± 7.25 7.07 ± 7.70 17.44 ± 7.00 17.42 ± 6.64 Device success (%) 100 Procedure success (%) 97.5

P non-inferiority = <0.0001 Primary Endpoint In-stent LLL @ 9-Months 0 20 40 60 80 100 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 9 Month In-Stent LLL (mm) Cumulative Frequency (%) P non-inferiority = <0.0001 Difference = 0.00 95% CI = -0.06 to 0.06 0.10 ± 0.32 mm 0.11 ± 0.29 mm Orsiro Xience Prime

Angiographic Follow-up Findings Orsiro (N=278 Lesions) Xience Prime (N=149 Lesions) P Late loss (mm) In stent 0.10± 0.32 0.11 ± 0.29 0.99 In segment 0.09 ± 0.35 0.09 ± 0.33 0.86 MLD (mm) 2.52 ± 0.56 2.48 ± 0.50 0.40 2.25 ± 0.55 2.22 ± 0.56 0.59 Diameter stenosis (%) 9.52 ± 13.49 9.43 ± 10.78 0.89 19.48 ± 12.89 19.22 ± 12.25 0.96 Binary restenosis (%) 6 (2.16%) 2 (1.34%) 0.56 11 (3.96%) 7 (4.70%) 0.72 Remove In stent LLL Keep rest

Target Lesion Failure Through 9 Months TLF (%) 0.0% 5.0% 10% 15% Days after PCI 30 60 90 120 150 180 210 240 270 Orsiro Xience Prime 5.3% 4.8%

Target Lesion Failure Clinical Outcome @ 9 Months (%) P=0.40 P=0.95 P=0.66 P=0.47 TLF, composite of cardiac death, target vessel MI (Universal Definition), clinically driven TLR and emergent CABG - time to first event All events have been adjudicated by an independent clinical event committee 19

Stent Thrombosis Through 9 Months Definite ST Definite or Probable ST Orsiro (N=298) Xience Prime (N=154) Acute (0-48h) 0 % Subacute (48h-30d) Late (>30d-9m) Overall Orsiro (N=298) Xience Prime (N=154) Acute (0-48h) 0 % Subacute (48h-30d) Late (>30d-9m) Overall

Apposition and Coverage OCT Findings @ 9 Months Neointimal Area Apposition and Coverage 10 20 30 40 50 60 70 80 90 100 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 Median of Neo intimal area (mm2) Percent of lesions (%) Orsiro Xience Prime Mean value 1.00± 0.44 mm2 0.74± 0.38 mm2 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% 0.37 Covered Struts 98.3% 97.5% 0.042 P=0.024

Δ Neointimal hyperplasia IVUS Results @ 9 Months Stent apposition by IVUS @ 9-month FUP was 100.00 % in both study arms Δ Mean lumen area @ 9 M FUP Δ Neointimal hyperplasia mm2 P = 0.34 P = 0.043 Lesions N = 31 N = 25

Limitations BIOFLOW-II included patients with relatively simple clinical and angiographic characteristics Patients with AMI, CTO, bifurcation, ostial, SVG, unprotected LM, severely calcified lesions, or lesions with thrombus were excluded BIOFLOW-II was not powered to detect differences in clinical event rates However, an all-comer RCT powered for clinical endpoints directly comparing Orsiro and Xience has completed enrollment

Conclusions In this prospective, multicenter, randomized controlled trial the ORSIRO sirolimus-eluting stent with a biodegradable polymer was non-inferior to the XIENCE Prime everolimus-eluting stent with durable polymer for the primary angiographic endpoint of in-stent late loss at 9 months Clinical event rates were low and comparable with both ORSIRO and XIENCE Prime through 9 months These results will need to be extended to larger randomized trials powered for clinical endpoints including more complex patients