NOBORI 2 Study Organization

Sponsor: Terumo Europe N.V. Leuven, Belgium

NOBORI 2 Principal Investigator: Gian Battista Danzi, Ospedale Santa Corona, Pietra Ligure, Italy

The NOBORI 2 Executive Operational Committee: G.B. Danzi, Ospedale Santa Corona, Pietra Ligure, Italy; B. Chevalier, Institut Cardiovasculaire Paris Sud, Massy/Quncy, France; P. Urban, Hopital de la Tour, Geneva, Switzerland; W. Wijns, Cardiovascular Center, Aalst, Belgium; M. Wiemer, Herz-und Diabeteszentrum Bad Oeynhausen, Bad Oeynhausen, Germany; J. R. Goicolea, Hospital Puerta de Hierro, Madrid, Spain; A. Serra, Hospital del Mar, Barcelona, Spain.

The NOBORI 2 Steering Committee: G.B. Danzi, Ospedale Santa Corona, Pietra Ligure, Italy; A. Stabile, Ospedale Civico Arnas, Palermo, Italy; K.E. Hauptmann, Krankenhaus der Barmherzigen Brüder, Trier, Germany; P. Kala, University Hospital Brno, Brno, Czech Republic; J. Koolen, Catharina Ziekenhuis, Eindhoven, The Netherlands; R. Koning, Clinique Saint Hilaire, Rouen, France; F. Fath-Ordoubadi, Royal Infirmary, Manchester, David Hildick-Smith, Royal Sussex County Hospital, Brighton, United Kingdom; D. Carrie, Centre Hospitalier Universitaire Rangueil, Toulouse, France.

The NOBORI 2 Clinical Event Commitee: C. Hanet, Cliniques Universitaire St.-Luc, Brussels, Belgium; G. Stankovic, Clinical Center of Serbia, Belgrade, Serbia; J. Vos, Amphia Ziekenhuis, Breda, The Netherlands; A. Vogt, Gemeinschaftspraxis Dres. Achim Vogt und Martin Diekmann, Köln, Germany; B. Rensing, St. Antonius Ziekenhuis, Nieuwegein, The Netherlands; C.J. Royaards, Maasstad Ziekenhuis, Rotterdam, The Netherlands.

The NOBORI 2 Participating Hospitals and Site Principal Investigators Belarus: P. Chernoglaz, Republican Research and Scientific Centre of Cardiology, Minsk; Belgium: W. Wijns, OLV Ziekenhuis, Aalst, M. Vrolix, ZOL Sint-Jan, Genk; Czech Republic: P. Kala, University Hospital, Brno, D. Horak, Krajska Nemocnice, Liberec; Denmark P. Thayssen, Odense Hospital, Odense; Estonia: P. Laanmets, North-Estonia Regional Hospital, Tallinn; Finland: A. Ylitalo, Satakunta Central Hospital, Pori, K. Korpilahti,Vaasa Central Hospital, Vaasa; France: E. Aptecar, Clinique les Fontaines, Melun, G. Finet, Hospital Cardiovasculaire Louis Pradel, Bron Cédex (Lyon), O. Darremont, Clinique Saint Augustin, Bordeaux, R. Koning, Clinique Saint Hilaire, Rouen, P. Brunel, Nouvelles Cliniques Nantaises, Nantes, C. Descaves, Clinique Saint Laurent, Rennes, J. Monségu, Clinique Val de Grâce, Paris, P. Joly, Polyclinique du Parc Rambot, Aix en Provence, J-P. Metzger, Hôpital Pitié Salpétrière, Paris, G. Lecoq, Clinique Saint Martin, Pessac, B. Aleil, Clinique de l’Orangerie, Strasbourg, R. Gabriel, Clinique Saint Pierre, Perpignan, T. Unterseeh, Hopital Claude Galien, Quincy Sous Senart, D. Carrie, CHU Rangeuil,

1 Toulouse, B. Glatt, Centre Cardiologique du Nord, Saint-Denis, A. Lafont, HEGP, Paris, E. Teiger, Henri Mondor, Créteil, P. Henry, Lariboisière, Paris; Germany: M. Wiemer, Herz- und Diabeteszentrum Bad Oeynhausen, Bad Oeynhausen, W. Jung, Schwarzwald-Baar Klinikum, Villingen- Schwennigen, H. Schneider, Universitätsklinikum Rostock, Rostock, K. Oppenländer, St. Elisabeth Klinikum, Saarlouis, G. Strupp, Klinikum Fulda gAG, Fulda, P. Lanzer, Gesundheitszentrum Bitterfeld/Wolfen, Bitterfeld, E. Vester, Evangelisches Krankenhaus Düsseldorf, Düsseldorf, G. Richardt, Segeberger Kliniken GmbH, Bad Segeberg, S. Hoffmann, Vivantes Netzwerk für Gezundheit GmbH, Berlin, A. Klein, Oberschwabenklinik GmbH, Krankenhaus St. Elisabeth, Ravensburg, K-E. Hauptmann, Krankenhaus der Barmherzigen Brüder, Trier, H. Schwacke, Krankenhaus der ev. Diakonieanstalt, Speyer, B. Saurbier, Kardiologische Gemeinschaftspraxis Saurbier, Freiburg, A. Elsässer, Klinikum Oldenburg, Oldenburg, R. Wessely, Johaniter-Klinikum Duisburg, Duisburg, F. Hartmann, Universitätskliniken Schleswig Holstein, Kiel, D. Pfeiffer, Universitätsklinikum Leipzig, Leipzig, R. Blank, GPR Klinikum Rüsselsheim, Rüsselsheim, M. Hennersdorf, SLK-Kliniken Heilbronn GmbH, Heilbronn; Greece: D. Alexopoulos, University Hospital Rio-Patras, Rio-Patras, V. Voudris, Onassis Cardiac Surgery Center, Athens; Hungary: D. Apró, State hospital for Cardiology, Balatonfüred, Béla Merkely, Semmelweis University of Budapest, Budapest, G. Fontos, Hungarian Institute of Cardiology, Budapest; Indonesia: T. Santoso, Medistra Hospital, Jakarta; Israel: A. Roguin, Rambam Hospital, Haifa, C. Lotan, Hadassah Medical Organization, Jerusalem, M. Mosseri, Meir Medical Centre, Kfar-Saba, R. Kornowski, Rabin Medical Centre, Petah-Tikvah, I. Herz, Lanadio Hospital, Netanya, I. Tamari, Wolfson Medical Center, Holon; Italy: G.B. Danzi (PI), Ospedale Maggiore Policlinico, Milan, A. Manari, Ospedale S. Maria Nuova, Reggio Emilia, A. Marzocchi, Policlinico S. Orsola Malpighi, Bologna, P. Sangiorgio, Ospedale Maggiore Bologna, Bologna, S. Tondi, Nuovo Ospedale di Modena, Baggiovara (Modena), Tricoli, A.O.V. Cervello, Palermo, P. Bellone, Ospedale San Paolo, Savona, C. Pierli, A.O. Senese- Pol Le Scotte, Siena, M. Lombardi, Azienda Ospedaliera Villa Sofia, Palermo, A. Stabile, Ospedale Civico Arnas, Palermo, S. Ierna, Ospedale Sirai, Carbonia, C. Trani, Policlinico A. Gemelli Univ. Cattolica del Sacro Cuore, Roma, B. Tuccillo, Loreto Mare, Napoli, B. Reimers, Ospedale Civile di Mirano, Mirano, C. Indolfi, Policlinico Universitario Mater Domini, Catanzaro, R. Ceravolo, Azienda Ospedaliera Pugliese - Ciaccio, Catanzaro, L. Moretti, Ospedale C.G. Mazzoni, Ascoli Piceno, A. Santarelli, Ospedale Degli Infermi, Rimini, F. Romea, Policlinico Universitario Di Tor Vergata, Roma; Latvia: A. Erglis, Riga University Hospital, Riga; Macau: X-M. Zhang, Kiang Wu Hospital, Macau; Serbia: N. Jagic, Clinical Centre Kragujevac, Kraguje- vac, A. Neskovic, Clinical Hospital Centre Zemum, Zemun, D. Sagic, Centre for CVD, Dedinje, M. Ostojic, Clinical Center n 10 EuroIntervention 2012; 7-online publish-ahead- of-print January 2012 Belgrade, Belgrade, Z. Perisic, University Clinical Center Niš, Niš; Singapore: V. Lim, National Heart Centre, Singapore; Spain: R. Lezaun, Hospital General de Navarra, Pamplona, R.J. Goicolea, Hospital Puerta de Hierro, Madrid, E. Garciá Jiménez, Hospital Guadalajara, Guadalajara, A.R. Valdesuso, Hospital de Torrevieja, Torrevieja, F. Bosa, Hospital Universitario de Canarias, Tenerife, A. Serra, Hospital del Mar, Barcelona, F.F. Mauri, Hospital Universitari Germans Trias I Pujol, Badalona, R.A. Iñiguez, MEDTEC Vigo,

2 Vigo, R. Trillo Nouche, Hospital Clinico Universitario de Santiago, Santiago de Compostela, M. Mohandes, Hospital Joan XXIII, Taragona, I. Santos, Hospital Clinico Universitari de Salamanca, Salamanca, R. Lazaro Garcia, C.H. Torrecardenas, Almeria, H. Perez, Hospital La Candelaria, Tenerife, J.M. Duran, Hospital General Yagüe, Burgos, E. Garcia, Clinical Moncloa, Madrid, J.R. Lopez-Minguez, Hospital Infanta Christina, Badajoz, N. Batalla, Angiocor, Barcelona; Sweden: S. James, Uppsala Akademiska Sjukhus, Uppsala; Switzerland: O. Bertel, Klinik im Park, Zurich, C. Roguelov, C.H.U. Vaudois, Lausanne, C. Kaiser, University Hospital Basel, Basel, G. Sutsch, Hirslanden Klinik, Zürich, A. Vuilliomenet, Kantonsspital Aarau, Aarau; Thailand: D. Tresukosol, Siriraj Hospital, Bangkok; The Netherlands: J.J. Koolen, St. Catharina Eindhoven, Eindhoven; Tunisia: M. Sghaier, Clinique El Amen Coeur, Ben Arous; Turkey: I. Ates, Ozel Antalya Yasam Hospital, Sokak, A. Tastan, Sifa Hospital, Izmir, S. Dagdelen, Acibadem Hospital, Istanbul; United Kingdom: F. Fath-Ordoubadhi, Manchester Royal Infirmary, Manchester, P. Lim, St George’s Healthcare NHS trust, London, D. Gorog, E & N Hertfordshire NHS Trust, - Lister Hospital, Hertfordshire, S. Talwar, Royal Bournemouth, Bournemouth, D. Hildick-Smith, Royal Sussex County Hospital, Sussex, F. Witherow, Dorset County hospital, Dorset, N. West, Papworth Hospital, Papworth, N. Spyrou, Royal Berkshire, Berkshire; Vietnam: P.H. Manh, Vietnam Heart Institute, Hanoi, H. Do Quan, Heart institute of HCMC, Ho Chi Minh.

3 Definitions of study endpoints

Cardiac death:

Any death due to proximate cardiac cause (e.g. MI, low-output failure, fatal arrhythmia) un-witnessed death and death of unknown cause, and all procedure-related deaths, including those related to concomitant treatment.

Myocardial infarction (MI):

Q-wave MI: Development of new, pathological Q waves in 2 or more contiguous leads (as assessed by the ECG core laboratory).

Non-Q-wave Myocardial Infarction: For the purpose of this study there will be two definitions of non-Q-Wave Myocardial Infarction: • The myocardial infarction occurring during the procedure or within 48h after the procedure at either the baseline procedure or at any repeated percutaneous coronary intervention. • Spontaneous Myocardial infarction occurring any time after baseline procedure and in between any repeated percutaneous interventions.

Pre-procedural Myocardial Infarction: The baseline enzyme values will be used to assess elevation before the index procedure. Recurrent MI may be diagnosed when: enzyme levels are stable on 2 samples which are > 6 hours apart; or are in decline; and subsequent value 3 to 6 hours after the procedure is increased by ≥20% compared to the baseline sample. If the baseline value is not stable, the event will be considered as a pre-procedural MI.

Target-lesion revascularization (TLR): is defined as any repeat percutaneous intervention of the target lesion or bypass surgery of the target vessel performed for restenosis or other complication of the target lesion. All TLRs should be classified prospectively as clinically indicated* or not clinically indicated by the investigator prior to repeat angiography. An independent angiographic core laboratory should verify that the severity of percent diameter stenosis meets requirements for clinical indication and will overrule in cases where investigator reports are not in agreement. The target lesion is defined as the treated segment from 5 mm proximal to the stent and to 5 mm distal to the stent.

*A revascularization is considered clinically indicated if angiography at follow-up shows a percent diameter stenosis ≥50% (core lab QCA assessment) and if one of the following occurs: (1) a positive history of recurrent angina pectoris, presumably related to the target vessel; (2) objective signs of ischemia at rest (ECG changes) or during exercise test (or equivalent), presumably related to the target vessel; (3) abnormal results of any invasive functional

4 diagnostic test (e.g. Doppler flow velocity reserve, fractional flow reserve); (4) A TLR with a diameter stenosis ≥70% even in the absence of the above-mentioned ischemic signs or symptoms.

Target-vessel revascularization (TVR): is defined as any clinically driven repeat percutaneous intervention or surgical bypass of any segment of the target vessel. The target vessel is defined as the entire major coronary vessel proximal and distal to the target lesion, which includes upstream and downstream branches and the target lesion itself. TLR indicates target lesion revascularization; TVR, target vessel revascularization; and QCA, quantitative coronary angiographic.

*A revascularization is considered clinically driven if angiography at follow-up shows a percent diameter stenosis ≥50% (core lab QCA assessment) and if one of the following occurs: (1) a positive history of recurrent angina pectoris, presumably related to the target vessel; (2) objective signs of ischemia at rest (ECG changes) or during exercise test (or equivalent), presumably related to the target vessel; (3) abnormal results of any invasive functional diagnostic test (e.g. Doppler flow velocity reserve, fractional flow reserve); (4) A TVR with a diameter stenosis ≥70% even in the absence of the above-mentioned ischemic signs or symptoms.

5 Table S1. Baseline characteristics in the overall cohort

Variable All patients (N=3,067) Age, years 64.4±11 Male gender 2,391 (78%) Dyslipidemia 2,092 (71%) Hypertension 2,080 (69.1%) Current smoker 707 (25.6%) Diabetes mellitus 888 (29.5%) Insulin-requiring 210 (7.0%) Previous PCI 973 (32.1%) Previous CABG 267 (8.8%) Previous MI 987 (33.2%) Indication to PCI Stable CAD 1,424 (46.5%) Acute coronary syndrome 1,643 (53.5%) Unstable angina 1,066 (34.7%) MI at presentation 577 (18.8%) STEMI 248 (8.1%) NSTEMI 329 (10.7%) Age adjusted Charlson 3.2±1.8 Comorbidity Index Charlson Comorbidity Index 1.24±1.24 Heart failure 114 (3.9%)

PCI: percutaneous coronary intervention. CABG: coronary artery bypass grafting. MI: myocardial infarction. CAD: coronary artery disease. STEMI: ST-segment elevation myocardial infarction.

NSTEMI: Non-ST-segment elevation myocardial infarction.

6 Table S2. Angiographic characteristics in the overall cohort

All patients (N=3,067) No. diseased vessels, per patient 1.7±0.8 Extent of coronary artery disease 1 Vessel, % 1,431 (46.6) 2 Vessels, % 1,031 (33.7) 3 Vessels, % 602 (19.7) No. treated lesions, per patient 1.4±0.7 No. implanted stents, per patient 1.7±1.1 Reference vessel diameter, mm 2.6±0.6 Lesion length, mm 15.6±9.6 Baseline diameter stenosis, % 68.2±17.5 Post-procedural diameter stenosis, % 13.1±7.0 Baseline minimal lumen diameter, mm 0.8±0.5 Post-procedural minimal lumen diameter, mm 2.5±0.5 Lesion classification A 142 (3.7%) B1 913 (23.6%) B2 1,610 (41.9%) C 1,184 (30.8%) Lesion location Left anterior descending 1,835 (40.9%) Left circumflex 1,167 (26.0%) Right coronary 1,327 (29.8%) Left main 63 (1.4%) Saphenous vein graft 87 (1.9%) Lesion type Bifurcation 786 (20.4%) Ostial 419 (10.9%) Occlusion 389 (10.2%) Thrombus 373 (9.7%) Ulceration 248 (8.4%) Calcification 1,003 (26.1%) Direct stenting, per lesion 1,284 (28.6%) Post-dilation, per lesion 1,531 (34.2%) Maximum stent deployment, atm 14.75±3.3 Categorical data are expressed as count and percentages. Continues variable are shown as mean ± standard deviation.

7 Table S3. Baseline characteristics of patients with vs. without follow-up at 5-year.

Follow-up at 5-year Variable Available or death Not available p-value Age, years 64.89±10.89 63.33±11.00 0.0009 Male gender 77.78% 78.32% 0.75 Dyslipidemia 72.19% 68.74% 0.06 Hypertension 69.55% 68.17% 0.45 Current smoker 23.57% 29.62% 0.001 Diabetes mellitus 29.83% 28.73% 0.55 Previous PCI 33.38% 29.68% 0.05 Previous CABG 8.90% 8.61% 0.84 Previous MI 32.99% 33.51% 0.80 Indication to PCI Stable angina 47.34% 42.54% 0.01 Unstable angina 37.66% 42.14% 0.02 STEMI 7.45% 9.39% 0.07 NSTEMI 12.10% 7.89% 0.0004 Charlson Comorbidity 3.26±1.80 3.04±1.71 0.002 Index Charlson Comorbidity 1.26±1.28 1.20±1.16 0.53 Index without age scoring

8 Table S4. Clinical characteristics between patients with vs. without very late definite or probable stent thrombosis after 12 months.

Very late definite or probable stent thrombosis Yes No Variable p-value (N=11) (N=3056) Age, years 59.23±10.20 (11) 64.40±10.95 (3,053) 0.14 Male gender 72.73% (8/11) 77.98% (2,383/3,056) 0.72 Dyslipidemia 70.00% (7/10) 71.06% (2,085/2,934) 1 Hypertension 63.64% (7/11) 69.12% (2,073/2,999) 0.75 Current smoker 27.27% (3/11) 25.56% (704/2,754) 1 Diabetes mellitus 36.36% (4/11) 29.45% (884/3,002) 0.74 Previous PCI 36.36% (4/11) 32.17% (969/3,012) 0.75 Previous CABG 18.18% (2/11) 8.77% (265/3,020) 0.25 Previous MI 36.36% (4/11) 33.14% (983/2,966) 0.76 Indication to PCI Stable angina 27.27% (3/11) 45.84% (1,400/3,054) 0.24 Unstable angina 63.64% (7/11) 39.03% (1,192/3,054) 0.12 STEMI 9.09% (1/11) 8.08% (247/3,056) 0.61 NSTEMI 18.18% (2/11) 10.70% (327/3,056) 0.33 Charlson Comorbidity 2.82±1.78 (11) 3.19±1.78 (3,056) 0.45 Index Charlson Comorbidity Index without age 1.36±1.43 (11) 1.24±1.24 (3,056) 0.82 scoring

9 Table S5. Angiographic characteristics between patients with vs. without very late definite or probable stent thrombosis after 12 months.

Very late definite or probable stent thrombosis Yes No Variable p-value (N=11) (N=3056) No. diseased vessel, per patient 2.18±0.87 1.73±0.77 0.07 No. treated lesions, per patient 1.45±0.82 1.40±0.69 0.98 No. implanted study stents, per patient 1.55±0.82 1.49±0.90 0.72 Reference vessel diameter, mm 2.71±0.74 2.61±0.58 0.77 Lesion length, mm 13.54±9.66 15.60±9.57 0.21 Baseline diameter stenosis, % 70.86±18.17 68.19±17.51 0.71 Post-procedural diameter stenosis, % 10.87±6.06 13.05±7.01 0.29 Baseline minimal lumen diameter, mm 0.77±0.54 0.83±0.50 0.57 Post-procedural minimal lumen 2.58±0.61 2.51±0.47 0.46 diameter, mm Lesion classification A 0.00% 3.70% 1 B1 38.46% 23.66% 0.20 B2 30.77% 41.84% 0.58 C 30.77% 30.75% 1 Lesion location Left anterior descending 58.82% 40.90% 0.15 Left circumflex 5.88% 26.13% 0.09 Right coronary 29.41% 29.63% 1 Left main 0.00% 1.41% 1 Saphenous vein graft 5.88% 1.93% 0.28 Lesion type Bifurcation 15.38% 20.42% 1 Ostial 7.69% 10.89% 1 Occlusion 15.38% 10.23% 0.64 Thrombus 23.08% 9.64% 0.12 Ulceration 30.77% 8.28% 0.02 Calcification 15.38% 26.07% 0.53 Direct stenting, per lesion 17.65% 28.73% 0.43 Maximum stent deployment pressure, 14.00±3.27 14.74±3.32 0.39 atm

10 Figure S1. Kaplan-Meier curve of target-lesion revascularization (Panel A) and definite or probable stent thrombosis (Panel B). Landmark analysis of target-lesion revascularization (Panel C) and definite or probable stent thrombosis (Panel D).

Figure S1, Panel A

11 Figure S1, Panel B

12 Figure S1, Panel C

Figure S1, Panel D

13 Figure S2. Rate of dual antiplatelet therapy discontinuation throughout the 5-year follow-up.

14 Figure S3. Kaplan-Meier curves for the primary composite endpoint in patients with on- label vs. off-label indication.

15