1. Randomised comparison of a novel, ultrathin strut biodegradable polymer sirolimus-eluting stent with a durable polymer everolimus-eluting stent for percutaneous coronary revascularization Thomas Pilgrim, MD; Dik Heg, PhD; Marco Roffi, MD; David Tüller, MD; Olivier Muller, MD; André Vuilliomenet, MD; Stéphane Cook, MD; Daniel Weilenmann, MD; Christoph Kaiser, MD; Peiman Jamshidi, MD; Bernhard Meier, MD; Peter Jüni, MD; Stephan Windecker, MD Department of Cardiology, Swiss Cardiovascular Center, University Hospital, Bern; Institute of Social and Preventive Medicine and Clinical Trials Unit Bern University Hospital, Switzerland NCT01443104

2. Speaker’s name: Thomas Pilgrim  I have the following potential conflicts of interest to report:  Research contracts  Consulting  Employment in industry  Stockholder of a healthcare company  Owner of a healthcare company  Other(s): travel expenses supported by Biotronik  I do not have any potential conflict of interest

3. Antiproliferative drug Sirolimus-analogues Paclitaxel Durable polymer Biodegradable polymer Stainless steel Cobalt-Chromium/Platinum-Chromium Polymer material P ROGRESS WITH METALLIC DRUG - ELUTING STENTS Taxus Cypher BioMatrix Nobori Endeavor Yukon PC Xience Promus Resolute Synergy Orsiro DESyne Combo Mistent Ultimaster 132 140 120 91 87 81 91 74 60 81 100 64 80 (μm) Platform material & strut thickness SES BES ZES SES EES ZES EES SES NES SES SirolimusBiolimusZotarolimusEverolimusNovolimus

4. D URABLE POLYMER EVEROLIMUS - ELUTING STENTS REDUCE THE RISK OF DEFINITE ST, MI AND TVR COMPARED TO NON -EES Baber U et al. J Am Coll Cardiol 2011;58:1569-77 Meta-analysis of 17 RCTs with 17,101 patients and mean follow-up of 22 months Definite ST: RR 0.55, 95% CI 0.38-0.78 TVR: RR 0.77, 95% CI 0.64-0.92 Definite stent thrombosis Target vessel revascularization

5. Definite stent thrombosis Target lesion revascularization B IODEGRADABLE POLYMER DES REDUCE THE RISK OF DEFINITE ST AND TLR COMPARED TO FIRST GENERATION DES Overall (I 2 = 0.0%, p=0.92) LEADERS ISAR-TEST 4 ISAR-TEST 3 0.58 (0.37-0.93) 20/857 9/1299 1/202 32/850 9/652 2/202 0.62 (0.36-1.08) 0.50 (0.20-1.26) 0.50 (0.05-5.47) 10.10.2250.5 Favours biodegradable polymer DES Favours durable polymer SES Risk ratio BP DESDP SESRR (95% CI) Overall (I 2 = 0.0%, p=0.79) LEADERS ISAR-TEST 4 ISAR-TEST 3 0.84 (0.71-0.99) 88/857 168/1299 17/202 111/850 95/652 21/202 0.79 (0.60-1.02) 0.89 (0.70-1.12) 0.81 (0.44-1.49) 10.10.225100.5 RR (95% CI)BP DESDP SES Risk ratio Favours biodegradable polymer DES Favours durable polymer SES Stefanini GG et al, Eur Heart J. 2012;33(10):1214-22 Studies

6. To compare the safety and efficacy of a novel, ultrathin strut, biodegradable polymer based sirolimus-eluting stent with a thin strut, durable polymer everolimus-eluting stent for percutaneous coronary revascularization. O BJECTIVE

7. S TENT PLATFORMS O RSIRO X IENCE PRIME / XPEDITION Cobalt-Chromium, L-605 Platform material Cobalt-Chromium, L-605 60 μm Strut thickness 81 μm Polymer material Passive coating Antiproliferative drug Silicon carbide layer Biodegradable Durable Sirolimus (1.4 μg/mm 2 ) Everolimus (1.0 μg/mm 2 ) PLLA: poly-L-lactic acid PBMA/PVDF-HFP

8. T RIAL DESIGN Patients with stable CAD or ACS undergoing PCI 1:1 Randomisation Biodegradable polymer sirolimus-eluting stent n = 1,030 Biodegradable polymer sirolimus-eluting stent n = 1,030 Durable polymer everolimus-eluting stent n = 1,030 Durable polymer everolimus-eluting stent n = 1,030 P RIMARY ENDPOINT Composite of cardiac death, target vessel myocardial infarction, and clinically-indicated target lesion revascularization at 12 months S ECONDARY ENDPOINTS Death, cardiac death, myocardial infarction, TLR, TVR, definite ST, definite and probable ST, target vessel failure Clinical follow-up at 30 days and 12 months

9. SponsorClinical Trials Unit and Department of Cardiology, University Hospital, Bern, Switzerland Steering committeeThomas Pilgrim, Peter Jüni, Stephan Windecker On-site data monitoringClinical Trials Unit, Bern, Switzerland (Brigitte Wanner, Lucia Kacina, Stefanie Hossmann) Central data monitoringClinical Trials Unit, Bern, Switzerland (Timon Spörri) Data coordination and analysis Clinical Trials Unit, Bern, Switzerland (Dik Heg, Peter Jüni) Clinical adjudication committee Pascal Vranckx, Hasselt, Belgium (Chair); Gerrit Hellige, Solothurn, Switzerland; Daniel Mattle, Münsterlingen, Switzerland FundingUnrestricted grant from Biotronik, Bülach, Switzerland S TUDY ORGANISATION

10. E LIGIBILITY FOR PATIENT ENROLLMENT Pregnancy Planned surgery within 6 months of PCI Intolerance to aspirin, clopidogrel, heparin, sirolimus, everolimus, contrast material Inability to provide informed consent Participation in another trial Exclusion criteria Age ≥ 18 years Coronary artery disease - stable CAD, silent ischemia - acute coronary syndromes: UA, NSTEMI, and STEMI At least one lesion with diameter stenosis >50% in a native coronary artery or a bypass graft - no. of vessels: no limitation - no. of lesions: no limitation - lesion length: no limitation Inclusion criteria

11. S AMPLE SIZE CALCULATION Assumptions based on COMPARE, RESOLUTE All-comers, and LESSON registry  Primary composite endpoint at 12 months8%  Non-inferiority margin3.5% Sample size 2,060 randomised subjects will yield a power of >80% to detect non-inferiority at a one-sided type I error of 0.05. Kedhi E, et al. Lancet 2010;375:201–09; Serruys PW, et al. N Engl J Med 2010;363:136–46; Räber L, et al. Circulation 2012;125:1110–21.

12. InvestigatorCityPatients Thomas Pilgrim, MDBern1,216 Marco Roffi, MDGeneva209 David Tüller, MDZurich179 André Vuilliomenet, MDAarau102 Olivier Muller, MDLausanne101 Stéphane Cook, MDFribourg100 Daniel Weilenmann, MDSt. Gallen99 Christoph Kaiser, MDBasel60 Peiman Jamshidi, MDLucerne53 2,119 patients were enrolled across 9 centers in Switzerland Geneva Lausanne Fribourg Bern Basel Lucerne Aarau Zurich St. Gallen P ATIENT RECRUITMENT February 2012 to May 2013

13. P ATIENT FLOW 2,129 patients randomised 2,119 patients included 10 provided preliminary consent but refused definite consent 1,063 allocated to biodegradable polymer sirolimus-eluting stent (1,594 lesions) 1,063 allocated to biodegradable polymer sirolimus-eluting stent (1,594 lesions) 1,056 allocated to durable polymer everolimus-eluting stent (1,545 lesions) 1,056 allocated to durable polymer everolimus-eluting stent (1,545 lesions) 1,031 follow-up information for primary endpoint available 1,036 follow-up information for primary endpoint available 1,056 analysed for primary clinical endpoint - 20 censored at timepoint of refusal or loss to follow-up 1,056 analysed for primary clinical endpoint - 20 censored at timepoint of refusal or loss to follow-up 1,063 analysed for primary clinical endpoint - 32 censored at timepoint of refusal or loss to follow-up 1,063 analysed for primary clinical endpoint - 32 censored at timepoint of refusal or loss to follow-up

14. Baseline characteristics BP SES (n=1,063) DP EES (n=1,056) Age (years) — mean ± SD 66.1 ± 11.665.9 ± 11.4 Male gender — n (%)818 (77%)816 (77%) Diabetes mellitus — n (%)257 (24%)229 (22%) Hypertension — n (%)728 (69%)706 (67%) Hypercholesterolemia — n (%)712 (67%)716 (68%) Previous PCI — n (%) 325 (31%)292 (28%) Previous CABG — n (%) 113 (11%)98 (9%) Renal Failure (GFR<60 ml/min) — n (%)151 (15%)130 (13%) Left ventricular ejection fraction (%) — mean ± SD55.7 ± 12.155.9 ± 12.6 Indication — n (%) Unstable angina78 (7%)74 (7%) Non ST-segment elevation MI288 (27%)284 (27%) ST-segment elevation MI211 (20%)196 (19%) Stable angina325 (31%)332 (31%) Silent ischemia 161 (15%)171 (16%)

15. Angiographic characteristics BP SES (n=1,594) DP EES (n=1,545) Target-vessel location per lesion — n (%) Left main artery29 (2%)27 (2%) Left anterior descending artery649 (41%)679 (44%) Left circumflex artery370 (23%)341 (22%) Right coronary artery505 (32%)452 (29%) Saphenous vein graft38 (2%)40 (3%) Arterial graft3 (0.2%)6 (0.4%) Number of treated lesions per patient — mean ± SD1.50 ± 0.791.46 ± 0.73 Number of stents per lesion — mean ± SD1.31 ± 0.611.34 ± 0.64 Total stent length per lesion (mm) — mean ± SD25.91 ± 15.4027.45 ± 16.77 Maximum stent diameter per lesion (mm) — mean ± SD3.05 ± 0.493.03 ± 0.49 Off-label stent use per lesion — n (%)690 (46%)735 (50%) Long lesion per lesion (>20 mm) — n (%)826 (54%)839 (57%) Small-vessel per lesion (<2.75 mm) — n (%)439 (29%)468 (32%)

16. 0 1 2 3 4 5 6 7 8 9 T ARGET LESION FAILURE (%) 1063102510041000993988980977967964960958941BP SES 1056102110041002998996994991985975971966945DP EES N UMBER AT RISK 0306090120150180210240270300330365 D AYS SINCE INDEX PROCEDURE P RIMARY ENDPOINT T ARGET LESION FAILURE A BSOLUTE RISK DIFFERENCE -0.14%, UPPER LIMIT OF ONE - SIDED 95% CI 1.97% P NON - INFERIORITY = 0.0004 6.7% - BP SES 6.7% - DP EES Rate ratio = 0.99 (95% CI 0.71-1.38), p=0.95

17. 0 1 2 3 4 5 6 7 8 9 C LINCALLY INDICATED TLR (%) 0306090120150180210240270300330365 C LINICALLY - INDICATED TLR N UMBER AT RISK D AYS SINCE INDEX PROCEDURE 0 1 2 3 4 5 6 7 8 9 T ARGET VESSEL MI (%) 0306090120150180210240270300330365 T ARGET VESSEL MYOCARDIAL INFARCTION N UMBER AT RISK D AYS SINCE INDEX PROCEDURE 0 1 2 3 4 5 6 7 8 9 C ARDIAC DEATH (%) 0306090120150180210240270300330365 C ARDIAC DEATH N UMBER AT RISK D AYS SINCE INDEX PROCEDURE Rate ratio = 0.91 (95% CI 0.50-1.67), p=0.77 106310441028102510221021101710161013100910061004987BP SES 1056104310311030102810271025 1024101810151012991DP EES Rate ratio = 0.97 (95%CI 0.58-1.60), p=0.90 106310271009100610021000993992986983979977959BP SES 10561024101010091006100510021001 997990986982961 DP EES Rate ratio = 1.42 (95%CI 0.85-2.37), p=0.18 106310381019101510081003996992984981976974957BP SES 105610381023102110181016101410121007997993988969DP EES I NDIVIDUAL COMPONENTS OF THE PRIMARY ENDPOINT Rate ratio = 0.99 (95%CI 0.71-1.38), p=0.95 0 1 2 3 4 5 6 7 8 9 T ARGET LESION FAILURE (%) 1063102510041000993988980977967964960958941BP SES 1056102110041002998996994991985975971966945DP EES N UMBER AT RISK 0306090120150180210240270300330365 D AYS SINCE INDEX PROCEDURE T ARGET LESION FAILURE 1.9% - BP SES 2.1% - DP EES 2.9% - DP SES 3.0% - DP EES 3.4% - BP SES 2.4% - DP EES 6.7% - BP SES 6.7% - DP EES

18. S TENT THROMBOSIS B IODEGRADABLE POLYMER SES D URABLE POLYMER EES 3 D AYS SINCE INDEX PROCEDURE D EFINITE OR PROBABLE STENT THROMBOSIS (%) 2.8% 3.4% 2.8% vs 3.4%; RR 0.83, 95% CI 0.50-1.35, p=0.45 D EFINITE OR PROBABLE STENT THROMBOSIS Cardiac death Myocardial infarction Target lesion revascularization D EFINITE STENT THROMBOSIS 0.9% vs 0.4%; RR 2.26 (95% CI 0.70-7.33), p=0.16

19. D EFINITE STENT THROMBOSIS p=0.66 p=0.15 p=0.16 D EFINITE STENT THROMBOSIS (%)

20. BP SESDP EESRR (95% CI)pp interaction Diabetes Acute Coronary Syndrome ST-elevation MI Off-label use Sex Renal failure Yes No Yes No Yes No Yes No Female Male Yes No Favours BP SESFavours DP EES 27/257 42/806 21/229 49/827 1.19 (0.67-2.10) 0.88 (0.58-1.33) 0.56 0.55 0.41 32/577 37/486 38/554 32/502 0.81 (0.51-1.30) 1.21 (0.75-1.95) 0.39 0.43 0.24 7/211 62/852 17/196 53/860 0.38 (0.16-0.91) 1.20 (0.83-1.73) 0.024 0.33 0.014 43/629 24/427 51/646 19/407 0.87 (0.58-1.31) 1.23 (0.67-2.24) 0.50 0.51 0.35 12/245 57/818 20/240 50/816 0.59 (0.29-1.21) 1.15 (0.79-1.68) 0.15 0.47 0.104 18/151 50/857 18/130 43/865 0.88 (0.45-1.70) 1.19 (0.79-1.79) 0.70 0.40 0.44 0.25 0.5 1 2 4 S TRATIFIED ANALYSIS OF PRIMARY ENDPOINT

21. Missing information on patients assessed for eligibility, but not included into the trial. The trial was powered for the primary composite outcome but not individual components. The primary endpoint results were determined at 12 months precluding conclusions regarding the long-term safety and efficacy. One third of patients had undergone previous PCI and some adverse events may have been related to previously implanted devices. L IMITATIONS

22. M ETA - ANALYSIS OF BIOSCIENCE AND BIOFLOW II Risk ratio (95% CI) Favours BP SESFavours DP EES Target lesion failure Bioflow-II Bioscience Overall Cardiac death Bioflow-II Bioscience Overall Target vessel myocardial infarction Bioflow-II Bioscience Overall Target lesion revascularisation Bioflow-II Bioscience Overall BP SESDP EES 0.82 (0.41-1.64) 0.98 (0.71 - 1.35) 0.95 (0.71 - 1.27) 19/298 69/1,063 12/154 70/1,056 1.03 (0.09 - 11.31) 0.90 (0.50 - 1.64) 0.91 (0.51 - 1.63) 2/298 20/1,063 1/154 22/1,056 1.03 (0.32 - 3.38) 0.96 (0.59 - 1.58) 0.97 (0.62 - 1.53) 8/298 30/1,063 4/154 31/1,056 0.74 (0.29 - 1.90) 1.51 (0.90 - 2.54) 1.18 (0.61 - 2.30) 10/298 35/1,063 7/154 23/1,056 0.25 0.5 1 2 4 Risk ratio (95% CI)

23. Ultrathin strut biodegradable polymer sirolimus- eluting stents were non-inferior to durable polymer everolimus-eluting stents for the primary endpoint target lesion failure at 1 year in a population with minimal exclusion criteria. The observed benefit in the subgroup of patients with ST-segment elevation myocardial infarction warrants confirmation in appropriately designed studies. C ONCLUSIONS

24. The Lancet, published online September 1, 2014