EuroSTAR II The European Randomized CoStar ™ Trial: Cobalt-Chromium Paclitaxel-eluting Stent vs. identical BMS

1. EuroSTAR II The European Randomized CoStar™ Trial:Cobalt-Chromium Paclitaxel-eluting Stent vs. identical BMS Sigmund Silber, MD, FACC, FESC Cardiology Practice and Hospital Munich, Germany sigmund@silber.com

2. EuroSTAR II Disclosure Consulting fees and honoraria from various companies, No stocks or patents, no conflict of interest related to this presentation

3. EuroSTAR II CoStar™ Stent Platform UniStar™ Cobalt Chromium stent platform Paclitaxel PLGA Bioresorbable polymer

4. EuroSTAR II CoStar™ Resorbable Polymer- Animal Data Explant In-vivo porcine model No residual polymer following tissue removal at 180 days

5. EuroSTAR II CoStar™ Stent Design Alternating hexagonal pattern Reservoirs Bridge Elements Ductile Hinges

6. EuroSTAR II CoStar™ Stent Design Alternating hexagonal pattern Reservoirs Bridge Elements Ductile Hinges highly deliverable

7. EuroSTAR II CoStar™ Stent Design Avoid possible cracking of polymer Reservoirs Bridge Elements Ductile Hinges

8. EuroSTAR II The Power of Reservoir Technology Bi-Directional Uni-Directional Single Drug Structure Drug Delivery Reservoirs Single Adjacent Multiple Drug Structures

9. EuroSTAR II EuroSTAR II TrialProspective, Multi-Center, Randomized, Study of the CoStar™ Paclitaxel-eluting Coronary Stent System in Patients with De Novo Lesions of Native Coronary Arteries Objective: • To compare the the CoStar™ Paclitaxel-Eluting Coronary Stent System to the same stent without a drug or polymer. • Dose: 10 µg / 30 days (in-vitro)

10. EuroSTAR II Study Administration Principal Investigator: Prof. Dr. S. Silber, Munich, Germany Data Coordinating Center: DATATRAK Deutschland GmbH Bonn, Germany Steering Committee: Prof. Dr. S. Silber, Munich, Germany Dr. Suryapranata, Zwolle, Netherlands Dr. B. Chevalier, Saint-Denis, France QCA Core Lab: Bio-Imaging Technologies Leiden, The Netherlands Data Safety Monitoring Committee / Clinical Events Committee Dr. Marcus Lins, Kiel, Germany Prof. Dr. Blanchard, France Jan Bart Hak, Netherlands (Chairman) Sponsor: BIOTRONIK GmbH & Co. KG

11. EuroSTAR II Study Design Prospective, Randomized, Multi-Center European Study Lesions  25 mm in length, 2.5 – 3.5 mm diameter303 Patients at 18 Centers Randomized 1:1 UniStar™ Coronary Stent(Control Group) N = 151 CoStar ™Paclitaxel-eluting Stent N = 152 Antiplatelet Therapy: Clopidogrel 300 mg loading dose, 75 mg QD for  6 monthsAspirin 100 mg QD for 6 months, and daily ASA indefinitely

12. EuroSTAR II Study Endpoints Primary • In-segment binary angiographic restenosis at 8 months Secondary • Angiographic Endpoints • In-stent late lumen loss at 8 months • In-stent and in-lesion minimum lumen diameter (MLD) • Clinical Endpoints • MACE at 30 days and 8 months • Target lesion revascularization (TLR) and target vessel revascularization (TVR) at 8 months

13. EuroSTAR II Statistical Assumptions • Assumptions: • 5% in treatment group • 15% in control group •  = 0.05 and  = 0.2 • 110 patients needed to provide 80% power to detect a difference in the primary endpoint of in-segment binary restenosis • A total of 150 patients will be needed in each group due to an assumed 25% lost to follow-up

14. EuroSTAR II Key Inclusion Criteria • Up to two discrete de-novo lesions in two native coronary arteries • Stenosis between 50-99% (visual estimate) • Reference vessel diameter (RVD) 2.5 – 3.5 mm • Lesion length  25 mm • TIMI flow 1 or higher

15. EuroSTAR II Study Investigators

16. EuroSTAR II Study Investigators 18 Sites in 3 European States

17. EuroSTAR II Demographics and Clinical Characteristics

18. EuroSTAR II QCA Analysis

19. 41.9% Reduction EuroSTAR II 8-Month Binary Angiographic Restenosis p=0.0002 p=0.0327 29/103 12/132 27/89 22/125 Primary Endpoint

20. EuroSTAR II Late Lossat 8 Months p<0.0001 p<0.0001 0.81 ± 0.49 0.64 ± 0.49 0.41 ± 0.48 0.29 ± 0.50

21. EuroSTAR II MACE at 30-Days p=NS for all comparisons MACE defined as composite of TVR, new Q- or non-Q-wave MI attributed to target vessel, or cardiac death attributed to target vessel

22. EuroSTAR II MACE at 8 Months p=0.0214 p=0.0079 p=0.0465 p=NS p=NS p=NS

23. EuroSTAR II Stent Thrombosis: Definitions per Protocol • Subacute: • Abrupt vessel closure of the treatment site that results in clinical manifestations of ischemia and occlusion occurring after the patient left the cath lab but with 30 days of index procedure • MI attributed to target vessel • ACS with angiographic evidence of thrombus • Death within 30 days that cannot be attributed to other obvious cause • Late: • MI attributable to the target vessel, with angiographic documentation or thrombus or total occlusion at the target lesion 31-120 days post-procedure

24. EuroSTAR II Stent Thrombosis p=NS for all comparisons

25. The four Studies with the Cobalt-Chromium CoStar™ Stentreleasing Paclitaxel 10µg/30 days (in-vitro)

26. The four Studies with the Cobalt-Chromium CoStar™ Stentreleasing Paclitaxel 10µg/30 days (in-vitro) different release kinetics ?

27. Angiography 1 month after the primary clinical endpoint at 8 months Angiography routinely performed at primary angiographic endpoint of 8 months The four Studies with the Cobalt-Chromium CoStar™ Stentreleasing Paclitaxel 10µg/30 days (in-vitro)

29. EuroSTAR II Conclusions • EuroSTAR II is a positive trial, having reached its primary endpoint. • The CoStar™ Paclitaxel-eluting stent had a significantly lower angiographic restenosis rate and a significantly lower late loss than the identically designed bare UniStar™. • With comparable vessel size and comparable lesion length in the TAXUS-IV trial, in-stent late loss of the CoStar™ Paclitaxel-eluting stent in the EuroSTAR II trial was in the range of the Taxus stent. • TLR, TVR and MACE were also significantly reduced. • No early or late stent thromboses were seen with the CoStar™ stent. • The reservoir technology combined with a completely absorbable polymer offers a great potential for further development using different drugs with modifiable optimization of release kinetics, specifically taylored to the patients’ needs.