Randomised comparison of a novel, ultrathin strut biodegradable polymer sirolimus-eluting stent with a durable polymer everolimus-eluting stent for percutaneous coronary revascularization NCT01443104 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

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

Progress with metallic drug-eluting stents Antiproliferative drug Paclitaxel Sirolimus-analogues SES BES ZES EES NES Sirolimus Biolimus Zotarolimus Everolimus Novolimus Polymer material Durable polymer Biodegradable polymer Platform material & strut thickness 132 140 120 91 87 81 74 60 100 64 80 (μm) Stainless steel Cobalt-Chromium/Platinum-Chromium Taxus Cypher BioMatrix Nobori Endeavor Yukon PC Xience Promus Resolute Synergy Orsiro DESyne Combo Mistent Ultimaster

Baber U et al. J Am Coll Cardiol 2011;58:1569-77 Durable 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

Biodegradable polymer DES reduce the risk of definite ST and TLR compared to first generation DES Stefanini GG et al, Eur Heart J. 2012;33(10):1214-22 Definite stent thrombosis Target lesion revascularization Studies BP DES DP SES RR (95% CI) Studies BP DES DP SES RR (95% CI) ISAR-TEST 3 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) ISAR-TEST 3 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) ISAR-TEST 4 ISAR-TEST 4 LEADERS LEADERS Overall (I2 = 0.0%, p=0.92) 0.58 (0.37-0.93) Overall (I2 = 0.0%, p=0.79) 0.84 (0.71-0.99) 0.1 0.2 0.5 1 2 5 0.1 0.2 0.5 1 2 5 10 Risk ratio Risk ratio Favours biodegradable polymer DES Favours durable polymer SES Favours biodegradable polymer DES Favours durable polymer SES

Objective 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.

PLLA: poly-L-lactic acid Stent platforms Orsiro Xience prime/xpedition Platform material Cobalt-Chromium, L-605 Cobalt-Chromium, L-605 Strut thickness 60 μm 81 μm Silicon carbide layer Passive coating Biodegradable Durable Polymer material PLLA: poly-L-lactic acid PBMA/PVDF-HFP Antiproliferative drug Sirolimus (1.4 μg/mm2) Everolimus (1.0 μg/mm2)

Trial design Primary endpoint Secondary endpoints Patients with stable CAD or ACS undergoing PCI 1:1 Randomisation Biodegradable polymer sirolimus-eluting stent n = 1,030 Durable polymer everolimus-eluting stent n = 1,030 Clinical follow-up at 30 days and 12 months Primary endpoint Composite of cardiac death, target vessel myocardial infarction, and clinically-indicated target lesion revascularization at 12 months Secondary endpoints Death, cardiac death, myocardial infarction, TLR, TVR, definite ST, definite and probable ST, target vessel failure

Study organisation Sponsor Clinical Trials Unit and Department of Cardiology, University Hospital, Bern, Switzerland Steering committee Thomas Pilgrim, Peter Jüni, Stephan Windecker On-site data monitoring Clinical Trials Unit, Bern, Switzerland (Brigitte Wanner, Lucia Kacina, Stefanie Hossmann) Central data monitoring Clinical 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 Funding Unrestricted grant from Biotronik, Bülach, Switzerland

Eligibility for patient enrollment Masterlayout 23.07.2018 Eligibility for patient enrollment 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 Exclusion criteria 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 © BIOTRONIK

Sample size calculation Assumptions based on COMPARE, RESOLUTE All-comers, and LESSON registry Primary composite endpoint at 12 months 8% Non-inferiority margin 3.5% 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.

2,119 patients were enrolled across 9 centers in Switzerland Patient recruitment February 2012 to May 2013 2,119 patients were enrolled across 9 centers in Switzerland Investigator City Patients Thomas Pilgrim, MD Bern 1,216 Marco Roffi, MD Geneva 209 David Tüller, MD Zurich 179 André Vuilliomenet, MD Aarau 102 Olivier Muller, MD Lausanne 101 Stéphane Cook, MD Fribourg 100 Daniel Weilenmann, MD St. Gallen 99 Christoph Kaiser, MD Basel 60 Peiman Jamshidi, MD Lucerne 53 Basel Aarau Zurich St. Gallen Lucerne Bern Fribourg Lausanne Geneva

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

Baseline characteristics BP SES (n=1,063) DP EES (n=1,056) Age (years) — mean ± SD 66.1 ± 11.6 65.9 ± 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 ± SD 55.7 ± 12.1 55.9 ± 12.6 Indication — n (%)   Unstable angina 78 (7%) 74 (7%) Non ST-segment elevation MI 288 (27%) 284 (27%) ST-segment elevation MI 211 (20%) 196 (19%) Stable angina 332 (31%) Silent ischemia 161 (15%) 171 (16%)

Angiographic characteristics BP SES (n=1,594) DP EES (n=1,545) Target-vessel location per lesion — n (%)   Left main artery 29 (2%) 27 (2%) Left anterior descending artery 649 (41%) 679 (44%) Left circumflex artery 370 (23%) 341 (22%) Right coronary artery 505 (32%) 452 (29%) Saphenous vein graft 38 (2%) 40 (3%) Arterial graft 3 (0.2%) 6 (0.4%) Number of treated lesions per patient — mean ± SD 1.50 ± 0.79 1.46 ± 0.73 Number of stents per lesion — mean ± SD 1.31 ± 0.61 1.34 ± 0.64 Total stent length per lesion (mm) — mean ± SD 25.91 ± 15.40 27.45 ± 16.77 Maximum stent diameter per lesion (mm) — mean ± SD 3.05 ± 0.49 3.03 ± 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%)

Primary endpoint Target lesion failure 9 Absolute risk difference -0.14%, upper limit of one-sided 95% CI 1.97% Pnon-inferiority = 0.0004 8 7 6.7% - DP EES 6 6.7% - BP SES Target lesion failure (%) 5 4 3 2 1 Rate ratio = 0.99 (95% CI 0.71-1.38), p=0.95 30 60 90 120 150 180 210 240 270 300 330 365 Days since index procedure Number at risk 1056 1021 1004 1002 998 996 994 991 985 975 971 966 945 DP EES 1063 1025 1004 1000 993 988 980 977 967 964 960 958 941 BP SES

Individual components of the primary endpoint Rate ratio = 0.99 (95%CI 0.71-1.38), p=0.95 1 2 3 4 5 6 7 8 9 Target lesion failure (%) 1063 1025 1004 1000 993 988 980 977 967 964 960 958 941 BP SES 1056 1021 1002 998 996 994 991 985 975 971 966 945 DP EES Number at risk 30 60 90 120 150 180 210 240 270 300 330 365 Days since index procedure Target lesion failure 1 2 3 4 5 6 7 8 9 Cardiac death (%) 30 60 90 120 150 180 210 240 270 300 330 365 Cardiac death Number at risk Days since index procedure 6.7% - DP EES Rate ratio = 0.91 (95% CI 0.50-1.67), p=0.77 6.7% - BP SES 2.1% - DP EES 1.9% - BP SES 1056 1043 1031 1030 1028 1027 1025 1024 1018 1015 1012 991 DP EES 1063 1044 1028 1025 1022 1021 1017 1016 1013 1009 1006 1004 987 BP SES 1 2 3 4 5 6 7 8 9 Target vessel MI (%) 30 60 90 120 150 180 210 240 270 300 330 365 Target vessel myocardial infarction Number at risk Days since index procedure 1 2 3 4 5 6 7 8 9 Clincally indicated TLR (%) 30 60 90 120 150 180 210 240 270 300 330 365 Clinically-indicated TLR Number at risk Days since index procedure Rate ratio = 0.97 (95%CI 0.58-1.60), p=0.90 Rate ratio = 1.42 (95%CI 0.85-2.37), p=0.18 3.0% - DP EES 3.4% - BP SES 2.9% - DP SES 2.4% - DP EES 1056 1024 1010 1009 1006 1005 1002 1001 997 990 986 982 961 DP EES 1056 1038 1023 1021 1018 1016 1014 1012 1007 997 993 988 969 DP EES 1063 1027 1009 1006 1002 1000 993 992 986 983 979 977 959 BP SES 1063 1038 1019 1015 1008 1003 996 992 984 981 976 974 957 BP SES

Stent thrombosis Definite or probable stent thrombosis 2.8% vs 3.4%; RR 0.83, 95% CI 0.50-1.35, p=0.45 Durable polymer EES 3.4% 2.8% Definite or probable stent thrombosis (%) Biodegradable polymer SES Cardiac death Myocardial infarction Target lesion revascularization Definite stent thrombosis 0.9% vs 0.4%; RR 2.26 (95% CI 0.70-7.33), p=0.16 3 Days since index procedure

Definite stent thrombosis Definite stent thrombosis (%) p=0.16 Definite stent thrombosis (%) p=0.15 p=0.66

Stratified analysis of primary endpoint BP SES DP EES RR (95% CI) p pinteraction Diabetes Acute Coronary Syndrome ST-elevation MI Off-label use Sex Renal failure Yes No Female Male 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 Favours BP SES 0.25 0.5 1 2 4 Favours DP EES

Masterlayout 23.07.2018 Limitations 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. © BIOTRONIK

Meta-analysis of BIOSCIENCE and BIOFLOW II BP SES DP EES Risk ratio (95% CI) Target lesion failure Bioflow-II Bioscience Overall 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 Cardiac death Bioflow-II Bioscience Overall 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 Target vessel myocardial infarction Bioflow-II Bioscience Overall 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 Target lesion revascularisation Bioflow-II Bioscience Overall 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) Favours BP SES Favours DP EES

Masterlayout 23.07.2018 Conclusions 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. © BIOTRONIK

The Lancet, published online September 1, 2014