University Hospital of Caen ClinicalTrials.gov Identifier: NCT01214148 First-in-man experience with the DES Orsiro in the treatment of patients with single de novo coronary artery lesions (BIOFLOW-I) Martial Hamon, MD, FESC University Hospital of Caen Normandy, France ClinicalTrials.gov Identifier: NCT01214148

Potential conflicts of interest Speaker’s name: Martial Hamon  I have the following potential conflicts of interest to report:  Research contracts  Consulting for BIOTRONIK AG  Employment in industry  Stockholder of a healthcare company  Owner of a healthcare company  Other(s)  I do not have any potential conflict of interest 2

Background Early generations of DES have reduced restenosis, but have been associated with an increased risk of late events Efforts to resolve these problems have been made including improvements in stent platforms, polymer carriers as well as drug selection A hybrid combination of active and passive coatings on a DES aim to optimize effectiveness of results and also mediate the threat of late events The aim of the BIOFLOW-I study was to evaluate the safety and efficacy of the Orsiro Hybrid Drug Eluting Stent with a bioabsorbable polymer, in patients with a single de novo lesion in a native coronary artery lkjlökj 3 3

The device: Orsiro Hybrid Drug Eluting Stent PROBIO® passive coating encapsulates the stent and minimizes interaction between the metal stent and the surrounding tissue BIOlute® active coating contains a highly biocompatible polymer which delivers a Limus drug via a biodegradable matrix PRO-Kinetic Energy Stent System brings good deliverability for reaching complex lesions BIOlute® achieves a controlled drug release Quick facts Passive coating PROBIO® amorphous silicon carbide coating Active coating BIOlute® bioabsorbable PLLA eluting Sirolimus Drug dose 1.4 µg/mm2 Stent material Cobalt chromium L-605 Strut thickness 60 µm (3.00 mm stent) Approval status CE approved The BIOlute® polymer matrix gently degrades into CO2 and H2O Only a PROBIO® sealed stent is left in the arterial wall

Investigational centers & core lab Principal investigator Rodica Niculescu, MD, PhD, FESC Spitalul Clinic de Urgenţă Bucureşti, Romania 15 Subjects enrolled 100% Angio & IVUS FUP @ 4month 100% Angio & IVUS FUP @ 9month Angiography Corelab Ron Waksman MD MedStar Health Research Institute, Washington DC, USA Principal investigator Dan Deleanu, MD, FESC Institutul de Urgenţă pentru Boli Cardiovasculare, Romania 15 Subjects enrolled 100% Angio FUP @ 4month 100% Angio FUP @ 9month IVUS Corelab Neil J. Weissman MD MedStar Health Research Institute, Washington DC, USA lkjlökj 5 5

BIOFLOW-I trial design Design: Prospective, multi-centre, first in man trial Patient Number: 30 Patents with angiographic follow-up: 30 Patients with IVUS follow-up: 15 Follow-up rate: 100% Enrollment time: Between 02 – 23 July 2009 Clinical endpoint assessment 30 d 4 mo 9 mo 12 mo 2 yr 3 yr Angiographic & IVUS endpoint assessment

Study endpoints Primary Endpoint Secondary Endpoints Definitions In-stent late lumen loss at 9 months by QCA Secondary Endpoints  In-stent and in-segment binary restenosis rate at 4 and 9 months post procedure Clinically driven target lesion revascularization (TLR) at 1, 4 and 9 months and at 1, 2 and 3 years post-procedure Composite of cardiac death, MI attributed to the target vessel and clinically driven target lesion revascularization at 1, 4 and 9 month post-procedure, and yearly up to 3 years Stent thrombosis at 1, 4 and 9 months, and at 1, 2 and 3 years post-procedure. Definitions Lesion Treatment Success is defined as the attainment of <30% residual stenosis by offline QCA using any percutaneous method Device Success defined as achievement of a final residual diameter stenosis of <30% by offline QCA, using the assigned device only

Patient eligibility Exclusion Criteria Inclusion Criteria Patient is ≥18 years old Clinical evidence of ischemic heart disease and / or a positive functional study. Documented stable angina pectoris, or documented silent ischemia Single de novo lesion with ≥50% and <90% stenosis in 1 coronary artery Exclusion Criteria Documented left ventricular ejection fraction (LVEF) ≤ 30% ACS (NSTE-MI or STEMI) Three-vessel coronary artery disease Evidence of myocardial infarction within 72 hours prior to the index procedure Total occlusion (TIMI 0 or 1) Target lesion is located in or supplied by an arterial or venous bypass graft Target lesion involves a side branch >2.0mm in diameter Unprotected Left main coronary artery disease (stenosis >50%)

Baseline clinical characteristics Age, years 58.10 yrs ± 9.80 Male sex 60.0% 18/30 Hyperlipidemia 93.3% 28/30 History of MI 73.3% 22/30 Hypertension 66.6% 20/30 Smoker 53.3% 16/30 Diabetes 23.3% 7/30 CHF 20.0% 6/30

Baseline lesion characteristics Pre-Procedure N=30 RVD (mm) 2.75 ± 0.34 MLD (mm) 0.95 ± 0.29 % Diameter stenosis 65.52 ± 9.47 Mean Lesion length (mm) 11.71 ± 4.40 Procedural Stent length per lesion (mm) 19.93 ± 5.33 Stent diameter per lesion (mm) 3.08 ± 0.37 Direct stenting 20.0% Device success* 100.0% * Defined as In-Stent < 30% residual stenosis by offline QCA

Angiographic follow-up results 4-month FUP 9-month FUP RVD (mm) 2.81 ± 0.28 2.81 ± 0.30 Minimal Lumen Diameter In-stent (mm) 2.50 ± 0.36 2.56 ± 0.38 In-segment (mm) 2.20 ± 0.35 2.21 ± 0.31 Diameter Stenosis In-stent (%) 15.19 ± 4.55 13.60 ± 4.27 In-segment (%) 23.66 ± 9.80 23.55 ± 8.06 Late Loss 0.12 ± 0.19 0.05 ± 0.22 0.06 ± 0.23 0.05 ± 0.26 Binary Restenosis 0%

Cumulative frequency of Diameter Stenosis lkjlökj 12 12

Cumulative Frequency of Minimum Lumen Diameter lkjlökj 13 13

Cumulative Frequency of In-Stent Late Lumen Loss Mean In-Stent LLL: 4 Months 0.12 ± 0.21 9 Months 0.05 ± 0.22 lkjlökj 14 14

IVUS results Mean net volume obstruction: 0.00% @ 4 months

Clinical outcomes at 9 months 9-month clinical results N % Death 0.0 Stent thrombosis MI TLR (clinically driven) 2 6.7 MACE 16

BIOFLOW-I results in perspective Overview of in stent late lumen loss in FIM trials FIM SR3 4 m n=15 Nevo Nevo Res-I2* 6 m n=186 XienceV SPIRIT First1 n=28 Endeavor Resolute Orsiro BIOFLOW-I 9 m n=30 FIM FR3 FIM4 FIM5 n=92 Cypher ± 0.21 ± 0.31 ± 0.30 ± 0.26 ± 0.27 ± 0.22 (mm) 0.10 0.13 0.09 -0.01 0.12 0.22 0.05 * Randomized trial. Only number of patients in device arm displayed 1 Serruys et al. A randomized comparison of a durable polymer Everolimus-eluting stent with a bare metal coronary stent: The SPIRIT first trial; Eurointervention 2 Ormiston et al. Six-month results of the NEVO Res-Elution I (NEVO RES-I) trial: a randomized, multicenter comparison of the NEVO sirolimus-eluting coronary stent with the TAXUS Liberte paclitaxel-eluting stent in de novo native coronary artery lesions; Circ.Cardiovasc.Interv. 3 Sousa et al. Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries: a quantitative coronary angiography and three-dimensional intravascular ultrasound study; Circulation 4 Meredith et al. The next-generation Endeavor Resolute stent: 4-month clinical and angiographic results from the Endeavor Resolute first-in-man trial; EuroIntervention 5 Meredith et al. Clinical and angiographic results with the next-generation resolute stent system: a prospective, multicenter, first-in-human trial; JACC.Cardiovasc.Interv.

Pre-procedural angiography BIOFLOW-I Case report Pre-procedural angiography Medical history & risk factors Male, 53 yrs MI (April-2009), smoker, hyperlipidemia, DM (insulin) Procedure 09 JUL 2009 RCA mid Lesion length 16 mm Source: BIOFLOW-i case, patient ROM001-009 lkjlökj 18 18

Post-procedural angiography BIOFLOW-I Case report Post-procedural angiography Medical history & risk factors Male, 53 yrs MI (April-2009), smoker, hyperlipidemia, DM (insulin) Procedure 09 JUL 2009 RCA mid Lesion length 16 mm Post-dilatation Stent size 3.5 x 18 mm Max pressure 21 atm Source: BIOFLOW-i case, patient ROM001-009 lkjlökj 19 19

Four-month follow-up angiography BIOFLOW-I Case report Four-month follow-up angiography Medical history & risk factors Male, 53 yrs MI (April-2009), smoker, hyperlipidemia, DM (insulin) Procedure 09 JUL 2009 RCA mid Lesion length 16 mm Post-dilatation Stent size 3.5 x 18 mm Max pressure 21 atm Source: BIOFLOW-i case, patient ROM001-009 lkjlökj 20 20

Nine-month follow-up angiography BIOFLOW-I Case report Nine-month follow-up angiography Medical history & risk factors Male, 53 yrs MI (April-2009), smoker, hyperlipidemia, DM (insulin) Procedure 09 JUL 2009 RCA mid Lesion length 16 mm Post-dilatation Stent size 3.5 x 18 mm Max pressure 21 atm Source: BIOFLOW-i case, patient ROM001-009 lkjlökj 21 21

BIOFLOW Clinical Program for Orsiro Hybrid Drug Eluting Stent A prospective, multi-centre, single treatment clinical trial Endpoint: LLL 9 months, N=30 A prospective, multi-center, non-inferiority, randomized study, Orsiro vs. Xience Prime Endpoint: LLL at 9 months, N=440 Study design Clinical strategy First-in-man study evaluating safety and efficacy, data submitted during CE approval (TÜV) Comparative, non-inferiority trial evaluating safety and efficacy A prospective, multi-centre, single treatment clinical study Endpoint: LLL at 9 months, N=120 A prospective, multi-centre, single treatment clinical registry Endpoint: TLF at 9 months, with long term follow-up, N=1000+ Study design Clinical strategy Study to evaluate safety and efficacy in a complex patient population Post marketing surveillance to demonstrate long term outcomes

Conclusions In this FIM study with a primary angiographic endpoint, the Orsiro Hybrid DES showed excellent results in terms of late lumen loss in the overall patient population This mixed population of patients is atypical for a FIM study, with its high rate of diabetic patients and complex lesions At 9 months follow-up, no late catch-up was seen in the LLL values and a narrow standard deviation suggests that these study results are quite robust A larger randomized, comparative study is currently running to prove the safety and effectiveness of this promising device