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Edoxaban for the Treatment of Acute Symptomatic Venous Thromboembolism the HOKUSAI-VTE study On behalf Edoxaban for the Treatment of Acute Symptomatic Venous Thromboembolism the HOKUSAI-VTE study On behalf of the HOKUSAI -VTE Investigators Breaking Wave Off Kanagawa. Katsushika Hokusai 1831 (25. 4 x 37. 1 cm) colour woodblock print from Hokusai's series Thirty-six Views of Fuji, which are the high point of Japanese prints. The original is at the Hakone Museum in Japan.

Disclosures for Harry R Büller Research Support/P. I. Sanofi-aventis, Bayer Health. Care, Bristol-Myers Squibb, Disclosures for Harry R Büller Research Support/P. I. Sanofi-aventis, Bayer Health. Care, Bristol-Myers Squibb, Daiichi-Sankyo, Glaxo. Smith. Kline, Pfizer, Roche, Isis, Thrombogenics Employee No relevant conflicts of interest to declare Consultant Sanofi-aventis, Bayer Health. Care, Bristol-Myers Squibb, Daiichi-Sankyo, Glaxo. Smith. Kline, Pfizer, Roche, Isis, Thrombogenics Major Stockholder No relevant conflicts of interest to declare Speakers Bureau No relevant conflicts of interest to declare Scientific Advisory Board Sanofi-aventis, Bayer Health. Care, Bristol-Myers Squibb, Daiichi-Sankyo, Glaxo. Smith. Kline, Pfizer, Roche, Isis, Thrombogenics

Introduction • Venous thromboembolism (VTE) is the third most common cardiovascular disease after MI Introduction • Venous thromboembolism (VTE) is the third most common cardiovascular disease after MI and stroke • Current standard of treatment : heparin/vitamin K antagonist (VKA) • New oral anticoagulants with and without heparin are effective and safe in the treatment of VTE • Uncertainty exists about representation of more severe VTE in previous studies

Edoxaban • Oral direct factor Xa inhibitor with a rapid onset of action and Edoxaban • Oral direct factor Xa inhibitor with a rapid onset of action and halflife of 10– 14 hours • 60 mg once daily dose was selected based on phase II data • Dose of 30 mg in case of • moderate renal impairment (Cr. Cl 30 - 50 m. L/min) • low body weight, i. e. , ≤ 60 Kg • concomitant use of P-gp inhibitors

Background Hokusai-VTE study • Randomized, double blind, event driven, non-inferiority study • Designed to Background Hokusai-VTE study • Randomized, double blind, event driven, non-inferiority study • Designed to broaden applicability to real world practice, by encouraging physicians to enroll all VTE patients • Starting with standard parenteral heparin • At least 3 months treatment, duration flexible • All patients followed for 12 months • Halving the dose for patients perceived to be at higher risk for bleeding

Aim: To evaluate whether initial (LMW)heparin followed by edoxaban only is non-inferior to initial Aim: To evaluate whether initial (LMW)heparin followed by edoxaban only is non-inferior to initial (LMW)heparin overlapping with warfarin, followed by warfarin only in the treatment of subjects with acute symptomatic venous thromboembolism for the prevention of symptomatic recurrent venous thromboembolism during a 12 -month study period edoxaban Sham INR Symptomatic confirmed VTE event R INR warfarin Day 1 - 5 Day 6 - 12 initial (LMW)Heparin placebo warfarin placebo edoxaban 3 M 6 M 12 M

Study Outcomes Efficacy • Primary : symptomatic recurrent VTE, i. e. , the composite Study Outcomes Efficacy • Primary : symptomatic recurrent VTE, i. e. , the composite of DVT, non-fatal PE and fatal PE in the overall study period • Secondary: symptomatic recurrent VTE , in the on-treatment period, in DVT and PE separately, and in severe PE with right ventricular dysfunction (NT-pro. BNP; spiral CT) Safety • Principal : composite of major or clinically relevant non-major bleeding in the on-treatment period All outcomes were adjudicated by an independent clinical event committee

Statistics and analyses • Hypothesis: LMW(Heparin)/edoxaban is non-inferior to LMW(Heparin)/warfarin for prevention of recurrent Statistics and analyses • Hypothesis: LMW(Heparin)/edoxaban is non-inferior to LMW(Heparin)/warfarin for prevention of recurrent VTE • Estimated incidence of primary efficacy outcome with LMW(Heparin)/warfarin : 3% at 12 months • Noninferiority margin of 1. 5 for hazard ratio (corresponds to retention of at least 70 % of treatment effect of warfarin) • Power 85%, two sided alpha of 0. 05 • Sample size at least 7500

Baseline characteristics Edoxaban (N=4118) Warfarin (N=4122) 56 (16) Male gender, n (%) 2360 (57) Baseline characteristics Edoxaban (N=4118) Warfarin (N=4122) 56 (16) Male gender, n (%) 2360 (57) 2356 (57) Qualifying diagnosis, n (%) DVT PE 2468 (60) 1650 (40) 2453 (60) 1669 (40) 2713 (66) 378 (9) 784 (19) 2697 (65) 393 (10) 736 (18) 733 (18) 719 (17) Mean age, years (SD) Clinical presentation and risk factors, n (%) Unprovoked Cancer Previous VTE Dose of 30 mg ( e. g ≤ 60 kg, Cr. Cl≥ 30 ≤ 50 ml/min), n (%)

Severity index event Edoxaban (N=4118) Warfarin (N=4122) 2468 (60) 2453 (60) Popliteal Vein 603 Severity index event Edoxaban (N=4118) Warfarin (N=4122) 2468 (60) 2453 (60) Popliteal Vein 603 (24) 596 (24) Superficial Femoral Vein 795 (32) 773 (32) Femoral or Iliac Vein 1035 (42) 1049 (43) 1650 (40) 1669 (40) 128 (8) 679 (41) 743 (45) 410 (25) 123 (7) 682 (41) 778 (47) 404 (24) 454/1484 (28) 484/1505 (29) 179/504 (36) DVT – no. (%) Most proximal site – no. (%) PE – no. (%) Anatomical extent – no. (%) Limited Intermediate Extensive Concomitant DVT – no. (%) NT pro-BNP ≥ 500 pg/ml – n/N (%) Right Ventricular Dysfunction – n/N (%) 172/498 (35)

Efficacy outcomes Edoxaban (N=4118) Warfarin (N=4122) Hazard ratio (95% CI) P Value 130 (3. Efficacy outcomes Edoxaban (N=4118) Warfarin (N=4122) Hazard ratio (95% CI) P Value 130 (3. 2) 146 (3. 5) 0. 89 (0. 70 -1. 13) <0. 001 First recurrent VTE - no. (%) Overall study period Patients with index DVT* 83 (3. 4) 81 (3. 3) Patients with index PE** 47 (2. 8) 65 (3. 9) 66 (1. 6) 80 (1. 9) On-treatment period Subgroup severe PE (RV dysfunction Pro. BNP) n/N (%) * ** 15/454 (3. 3) 30/485 ( 6. 2) Noninferiority 1. 02 (0. 75 -1. 38) 0. 73 (0. 50 -1. 06) 0. 82 (0. 60 -1. 14) 0. 52 (0. 28 to 0. 98) Denominator is number of patients with index DVT: 2468 and 2453 in edoxaban and warfarin group respectively Denominator is number of patients with index PE : 1650 and 1669 in edoxaban and warfarin group respectively <0. 001 noninferiority)

Primary Efficacy Outcome hep / edoxaban Overall m. ITT On-Rx HR (n / N) Primary Efficacy Outcome hep / edoxaban Overall m. ITT On-Rx HR (n / N) m. ITT hep / warfarin (n / N) (95% CI) 130 / 4, 118 146 / 4, 122 0. 89 3. 2% 3. 5% (0. 70– 1. 13) 66 / 4, 118 80 / 4, 122 0. 82 1. 6% 1. 9% (0. 60 -1. 14) Overall On-Rx TTR : 63. 5% 0. 70 0 0. 89 1. 13 1. 00 13 Edoxaban superior Hazard Ratio 1. 50 Edoxaban non-inferior

Safety outcomes Edoxaban (N=4118) Warfarin (N=4122) First major or clinically relevant non major – Safety outcomes Edoxaban (N=4118) Warfarin (N=4122) First major or clinically relevant non major – no. (%) 349 (8. 5) Major – no. (%) 56 (1. 4) 66 (1. 6) Fatal 2 (<0. 1) Hazard ratio (95% CI) P Value 0. 0 10 (0. 2) Intracranial Non-Fatal in Critical Sites Intracranial 0 13 (0. 3) 5 (0. 1) Non-Fatal in Non-Critical Sites 41 (1. 0) Clinically Relevant Non-Major – no. (%) 298 (7. 2) 423 (10. 3) 0. 81 (0. 71 -0. 94) 0. 84 (0. 59 -1. 21) 04 superiority 0. 35 superiority 6 (0. 1) 25 (0. 6) 12 (0. 3) 33 (0. 8) † 368 (8. 9) 0. 80 (0. 68 -0. 93) 0. 004 superiority † some patients have more than 1 bleeding

Principal Safety Outcome hep / edoxaban hep / warfarin HR (n / N) (95% Principal Safety Outcome hep / edoxaban hep / warfarin HR (n / N) (95% CI) 349 / 4, 118 423 / 4, 122 0. 81 8. 5% 10. 3% (0. 71– 0. 94) Number of patients at risk warfarin 4122 3757 3627 3522 3313 3218 2979 2165 2007 1883 1754 1613 1212 edoxaban 4118 3840 3695 3587 3382 3308 3038 2192 2043 1904 1767 1650 1241

Conclusion (LMW)heparin/edoxaban regimen – non-inferior to standard therapy for preventing recurrent VTE – consistent Conclusion (LMW)heparin/edoxaban regimen – non-inferior to standard therapy for preventing recurrent VTE – consistent efficacy in patients with DVT and PE – clinically significant reduction in recurrent VTE in right ventricular dysfunction subgroup – less clinically relevant bleeding – constant effect over center TTR quartiles – dose adaptation (30 mg) effective and safer Attractive regimen for full spectrum of VTE- patients

Enrollment in 37 countries worldwide Europe, Middle East and Africa Europe, Middle East, and Enrollment in 37 countries worldwide Europe, Middle East and Africa Europe, Middle East, and Africa (5183) North America (842) Latin America (266) Asia/Pacific (2001) Asia/Pacific North America Canada USA 219 623 Latin America Argentina Brazil Mexico 47 93 126 India China Korea Japan Australia New Zealand Taiwan Thailand Philippines Singapore 515 487 272 209 180 113 141 42 32 11 Austria Belarus Belgium Czech Republic Denmark Estonia France Germany Hungary Israel Italy Netherlands Norway Poland Russia South Africa Spain Sweden Switzerland Turkey Ukraine United Kingdom 168 85 177 427 268 76 714 476 464 233 153 387 30 43 519 365 27 60 49 54 292 116

Steering Management Coordination Committee (SMCC) Harry Büller (Chair) Giancarlo Agnelli Pantep Angchaisuksiri Martin Banyai Steering Management Coordination Committee (SMCC) Harry Büller (Chair) Giancarlo Agnelli Pantep Angchaisuksiri Martin Banyai Rupert Bauersachs Bonno van Bellen Julio Blüguermann Zoltán Boda Henri Bounameaux Benjamin Brenner Tim Brighton Javier Diaz Castañon Pavel Chechulov Yaromir Chlumský Alexander Cohen Bruce Davidson Hervé Decousus Henry Eriksson Alexander Gallus Ivan Gudz Barry Jacobson Lee Lai Heng Roger Lyons Karina Meijer Erich Minar Manuel Monreal Mashio Nakamura Doyeun Oh Gül Öngen Rajiv Parakh Franco Piovella Gary Raskob Jeffery Rehm Per Morten Sandset Sebastian Schellong Mark Smith German Sokurenko Witold Tomkowski Christian Torp-Pedersen Peter Verhamme Chen Wang Yuqi Wang Jeff Weitz Phil Wells Vyacheslav Wei-Hsian Yin Yanushko

Study Committees Data Monitoring Committee Central Adjudication Committee 24/7 Medical Support Line John Eikelboom Study Committees Data Monitoring Committee Central Adjudication Committee 24/7 Medical Support Line John Eikelboom (Chair) Mark Crowther Robin Roberts Martin Prins (chair) Ludo Beenen Dees Brandjes Melvin Mac. Gillavry Neil Kaplowitz Hans-Martin Otten Dominique Pessayre Ron Peters Yvo Roos Ton Slagboom Peter Verhamme (Chair) Thomas Vanassche Christophe Vandenbriele Barbara Debaveye

From January 2010 through October 2012, 439 centers in 37 countries enrolled 8292 patients From January 2010 through October 2012, 439 centers in 37 countries enrolled 8292 patients Study sites Argentina (47 patients, 10 centers) – C. Alvarez, Bahia Blanca (2); L. M. Amuchastegui, Cordoba (16); J. Blüguermann, Buenos Aires (1); A. Cassettari, Santa Fe (1); J. Ceressetto, Buenos Aires (3); Hrabar, Quilmes (7); S. Macin, Corrientes (4); C. Mahuad, Buenos Aires (2); P. Oberti, Buenos Aires (4); F. Santini, Mar del Plata (7). Australia (180 patients, 12 centers) – R. I. Baker, Perth (6); P. Blombery, Melbourne (5); T. Brighton, Sydney (6); P. Carroll, Redcliffe (16); B. Chong, Sydney (19); P. Coughlin, Box Hill (45); P. Crispin, Garran (17); J. Fletcher, Sydney (1); A. Gallus, Adelaide (10); D. J. Serisier, South Brisbane (5); H. Tran, N. Chan, L. Stafford, Melbourne (42); C. Ward, Sydney (8). Austria (168 patients, 7 sites) - M. Baghestanian, Vienna (27); P. A. Kyrle, L. Eischer, L. Traby, Vienna (43); P. Marschang, Innsbruck (16); R. Mathies, Feldkirch (18); E. Pilger, M. Brodmann, Graz (34); F. Roithinger, Moedling (19); A. Weltermann, Linz (11). Belarus (85 patients, 4 centers) - I. Adzerikho, E. Davidovskaya, Minsk (26); S. Gorokhovsky, B. Maslianski, Gomel (30); A. Kulik, Mogilev (19); A. Yanushka, Minsk (10). Belgium (177 patients, 9 centers) - P. De Vleeschauwer, Lier (19); E. Debing, Brussels (11); J. Duchateau, Duffel (20); M. Gustin, Liege (9); P. Hainaut, Brussels (27); J. Vandekerkhof, Hasselt (14); P. Verhamme, K. Peerlinck, Leuven (38); P. Verstraeten, Aalst (10); J. C. Wautrecht, S. Motte, Brussels (29). Brazil (93 patients, 11 centers) - J. M. Annichino-Bizzacchi, T. B. T. Mello, F. H. Menezes, Campinas (25); M. Burihan, São Paulo (2); M. Cavalcanti, Porto Alegre (3); J. Correa, São Bernardo do Campo/SP (20); F. Correa de Carvalho, São Paulo (3); A. Cukier, Sao Paulo (18); E. Manenti, Porto Alegre (3); E. R. Manenti, Porto Alegre (2); R. Sacilotto, Sao Paulo (7); J. M. Timi, Curitiba (4); B. van Bellen, São Paulo (6).

Study sites cont. Canada (219 patients, 6 centers) - S. R. Kahn, Montreal (14); Study sites cont. Canada (219 patients, 6 centers) - S. R. Kahn, Montreal (14); M. Kovacs, A. Lazo Langner, H. Van. Spronsen, London Ontario (41); B. Ritchie, Edmonton (31); R. Shafai-Sarshar, Newmarket (1); S. Shivakumar, D. Anderson, K. Robinson, B. Gallant, Halifax (69); P. Wells, A. Karovitch, D. Scarvelis, M. Carrier, Ottawa (63). China (486 patients, 25 centers) - C. X. Bai, Shanghai (2); R. C. Chen, Guangzhou (14); Z. Z. Cheng, Qingdao (14); Y. C. Du, X. Y. Hu, Taiyuan (22); Y. Q. Gu, Beijing (18); Q. L. Hao, S. B. Sun, C. Wang, Kunming (41); L. Jiang, Jiangyin (4); C. J. Liu, Nanjing (2); C. W. Liu, Beijing (20); S. Liu, X. X. Wang, X. F. Ye, Beijing (56); Z. Ma, Shenyang (1); Z. Q. Qin, X. J. Qin, Nanning (36); H. Y. Tian, Xi'an (6); Y. Q. Wang, Z. Y. Shi, Shanghai (21); F. Q. Wen, Chengdu (3); Q. Wu, Tianjin (4); Y. H. Yang, T. G. Kuang, Beijing (25); H. Yang, Beijing (10); K. J. Ying, G. F. Ma, Hangzhou (34); Y. D. Yuan, J. Yu, X. W. Gong, Shijiazhuang (53); F. X. Zhang, Beijing (9); J. Zhang, S. X. Zhang, Yinchuan (23); J. W. Zhang, L. Zhang, Shanghai (35); J. C. Zhao, B. Huang, Chengdu (23); J. Zhao, Shanghai (10). Czech Republic (427 patients, 11 centers) - J. Chlumsky, D. Hola, Prague (54); J. Hirmerova, Plzen (9); M. Hutyra, Olomouc (9); Z. Klimsa, M. Holub, Jihlava (33); K. Kovarova, Ostava (93); P. Lang, M. Ryba, R. Podoubský, Liberec (50); P. Matoska, Ostrava Poruba (6); O. Mayer, Plzen-Bory (13); F. Patek, M. Tupa, Usti nad Labem (54); R. Spacek, R. Urbanova, S. Blazejova, Prague (61); M. Vitovec, Prague (45). Denmark (268 patients, 9 centers) - B. Andersen, Aarhus C (13); J. Brønnum-Schou, Copenhagen (46); H. Dominguez, Herlev (19); K. Egstrup, S. Auscher, Svendborg (26); J. Jeppesen, C. Asferg, J. Vishram, Glostrup (53); H. Nielsen, I. Galsgaard, M. Michaelsen, B. Haugaard-Nielsen, Kopenhagen (70); O. Ostergaard, Roskilde (12); S. H. Poulsen, Aarhus (3); C. Torp-Pedersen, Hellerup (26). Estonia (76 patients, 3 centers) S. Masik, M. Kadarik, Tallinn (23); S. Meriste, Tartu (7); M. Paumets, M. Laheäär, L. Raidjuk, Tallinn (46).

Study sites cont. France (714 patients, 29 centers) - S. Accassat, A. Buchmuller, P. Study sites cont. France (714 patients, 29 centers) - S. Accassat, A. Buchmuller, P. Mismetti, Saint Etienne (42); A. Achkar, Vernon (12); S. Aquilanti, A. Rifaï, Arras (34); N. Breuil, J. Schmidt, Clermont -Ferrand (31); D. Brisot, C. Brousse, P. Tarodo de la Fuentes, M. Chakra, Castelnau le lez (72); B. Crestani, Paris (2); I. Desormais, P. Lacroix, Limoges (35); J. M. Diamand, Grenoble (5); D. El Kouri, R. Clairand, Nantes (21); A. Elias, Toulon (9); E. Ferrari, D. Doyen, O. Chiche, Nice (53); C. Grange, Lyon Sud (15); H. Guenneguez, Gruchet st. Simeon (3); K. Lacut, F. Couturaud, D. Mottier, Brest (42); L. Leroux, Pessac (7); B. Lorcerie, E. De Maistre, S. Berthier, Dijon (66); I. Mahe, Colombes (15); M. Martin, Annecy (8); N. Meneveau, Besancon (19); G. Meyer, O. Sanchez, Paris (27); K. Montaclair, Le Mans (18); M. Pavic, Lyon (10); G. Pernod, B. Imbert, Grenoble (25); I. Quere, J. P. Galanaud, Montpellier (23); P. M. Roy, Angers (14); M. A. Sevestre, Amiens (4); G. Simoneau, Paris (7); D. Stephan, B. Aleil, C. Mirea, Strasbourg (76); A. Trinh-Duc, Agen (19). Germany (476 patients, 12 centers) P. Baron von Bilderling, Munchen (13); J. Beyer-Westendorf, S. Werth, C. Köhler, K. Halbritter, Dresden (90); C. Diehm, Karlsbad (19); C. Espinola-Klein, G. Weisser, Mainz (25); D. Franke, Magdeburg (69); H. Heuer, Dortmund (13); T. Horacek, G. Kahrmann, Witten (24); R. Kroening, Paderborn (41); H. Lawall, Hamburg (11); M. Roecken, Tübingen (5); S. M. Schellong, L. Pomper, B. Voigts, S. Bernhard, R. Frommhold, Dresden (144); C. Stellbrink, Bielefeld (22). Hungary (464 patients, 12 centers) - Z. Boda, P. Ilonczai, Z. Olah, K. Razso, A. Schlammadinger, Debrecen (118); K. Farkas, E. Kolossváry, I. Szabó, Budapest (51); Z. Frankfurter, Balassagyarmat (7); B. Gasztonyi, Zalaegerszeg (12); M. Gurzó, Z. Klucsik, Kecskemét (31); A. Kovacs, S. Szigeti, C. Varga, Szentes (50); A. Landi, Budapest (15); G. Nyirati, Baja (17); Zs. Pecsvarady, Kistarcsa (3); M. Riba, Z. Sámson, Szombathely (35); Gy. Sipos, M. Szigyártó, N. Sebő, T. Janossikné Szabó, Miskolc (112); K. Toth, Pecs (13).

Study sites cont. India (515 patients, 39 centers) - S. Agarwal, Lucknow (6); J. Study sites cont. India (515 patients, 39 centers) - S. Agarwal, Lucknow (6); J. Arneja, Nagpur (13); S. Babhulkar, Nagpur (6); R. Balaji, Hyberadad (7); D. Banker, Vadodara (12); N. K. Bhagavan, Bangalore (3); S. Bhonagiri, A. Mehta, Pune (25); V. Dayasagar Rao, Secunderbad A. P. (2); P. Desai, Vadodara (20); S. C. Desai, A. R. Chandrashekar, R. Singh, Bangalore (47); A. Deshpande, Aurangabad (4); A. Dharmadhikari, Nashik (11); N. Durairaj, Madurai (4); N. Ghaisas, Nashik (10); S. Gupta, Lucknow (14); R. Jain, Indore (4); R. Jindal, Mohali (8); D. Kamerkar, Pune (5); V. A. Kothiwale, Belgaum (17); A. Kothurkar, Pune (7); R. Kulkarni, Pune (6); S. Kumar, Hyberadad (1); B. Mody, Vadodara (7); K. N. Nagabhushan, Bangalore (4); H. K. Pandharpurkar, S. Joshi, Bangalore (24); R. Parakh, T. Grover, New Delhi (26); J. Patel, K. Patel, N. Dudhagra, Surat (53); N. Pawar, Nagpur (1); M. Penurkar, Pune (31); R. Pinjala, Hyderabad (3); K. Rai, New Delhi (3); B. Rao, Vishakapattnam (2); M. Raval, A. Raval, P. Mehta, Ahmedabad (52); A. G. Ravi Kishore, Bangalore (3); S. Saravanan, Chennai (4); P. Shetty, Bangalore (6); A. Srinivas, Mysore (4); K. R. Suresh, K. Sumanthraj, K. R. Girija, Bangalore (41); M. Vijan Vinod, Nashik (19). Israel (233 patients, 14 centers) - D. Gavish, B. Ashkenazy, Holon (22); A. Braester, Nahariya (14); Y. Caraco, Jerusalem (1); M. Elias, L. Goldstein, Afula (38); E. Grossman, Tel-Hashomer (6); M. lahav, Petah Tikva (20); M. Lishner, Kfar Saba (21); G. Lugassy, Ashkelon (3); A. Oliven, Haifa (20); R. Rachmilevitz, Haderra (10); I. Tzoran, B. Brenner, Haifa (28); S. Yeganeh, Tiberias (15); D. Zeltser, Tel Aviv (32); R. Zimlichman, Holon (3). Italy (153 patients, 12 centers) - W. Ageno, Varese (11); G. Barillari, S. Pasca, Udine (27); C. Bortoluzzi, Venezia (13); M. Cattaneo, Milano (10); A. Falanga, Bergamo (3); A. Ghirarduzzi, Reggio Emilia (17); C. Lodigiani, Rozzano (5); C. Picchi, D. I. Iosub, Pavia (34); E. Porreca, Francavilla Chieti (5); P. Prandoni, Padua (18); R. Quintavalla, Parma (6); S. Siragusa, Palermo (4).

Study sites cont. Japan (209 patients, 29 centers) - T. Akita, Uchinada (10); T. Study sites cont. Japan (209 patients, 29 centers) - T. Akita, Uchinada (10); T. Aoyama, Shimada (7); K. Fujimoto, Kumamoto (2); K. Hanzawa, Niigata (6); U. Ikeda, Matsumoto (4); H. Iwata, Nagakute (8); T. Kobayashi, Hatsukaichi (7); K. Kondo, Kitakyushu (12); T. Kurimoto, Nishinomiya (4); H. Maeda, Tokyo (15); M. Mo, Yokohama (10); M. Munemasa, Okayama (7); H. Murakami, Sapporo (6); Y. Nishi, Tokyo (8); T. Nishibe, Tokyo (7); K. Nishigami, Kumamoto (11); T. Nunohiro, Nagasaki (4); T. Obayashi, Musashino (4); T. Satoh, Mitaka (4); H. Satokawa, Fukushima (9); K. Shimizu, Sakura (15); H. Shiroma, Tomigusuku (10); M. Sonoda, Kagoshima (6); Y. Suzuki, Yonago (4); S. Taniguchi, Hirosaki (2); K. Tsujita, Kumamoto (7); N. Yamada, Tsu (5); C. Yasuda, Osakasayama (10); H. Yoshida, Sapporo (5). Korea (272 patients, 17 centers) - H. J. Chang, Seoul (18); W. I. Choi, K. Y. Kwon, B. H. Rho, Daegu (52); J. S. Choi, Cheonan (3); Y. S. Hong, Suwon (3); J. H. Joh, Seoul (22); D. J. Kim, Bucheon (3); H. S. Kim, Seoul (3); S. H. Kim, Busan (8); Y. K. Kim, K. U. Kim, Seoul (22); J. Y. Kim, Seoul (4); T. W. Kwon, Seoul (13); T. S. Lee, Seongnam (13); S. Y. Lim, Seoul (10); Y. C. Mun, Seoul (12); D. Y. Oh, Seongnam (18); K. H. Park, W. S. Yun, Daegu (57); H. I. Yoon, Seongnam (11). Mexico (126 patients, 7 centers) - J. Diaz-Castañon, Zapopan (5); L. F. Flota, Merida (28); J. Galindo, Monterrey (4); J. Gomez Lara, Guadalajara (15); C. Jerjes-Sanchez, Monterrey (25); A. Palomar-Lever, Mexico City (16); D. Rodriguez, I. Higareda, Guadalajara (33). Netherlands – (387 patients, 13 centers) - W. G. Boersma, C. S. de Graaff, L. Oudeman, E. Brans, Alkmaar (80); S. J. H. Bredie, Nijmegen (13); A. Dees, Rotterdam (10); F. Erdkamp, F. Peters, Sittard (29); R. Fijnheer, Amersfoort (3); V. E. A. Gerdes, Amsterdam (12); A. Griffioen, Hoofddorp (20); K-S. G. Jie, Heerlen (18); K. Meijer, H. Kooistra, S. Wiewel-Verschueren, Groningen (53); S. Middeldorp, P. W. Kamphuisen, J. van Es, E. S. Eerenberg, Amsterdam (61); J. Swart Heikens, Assen (27); H. Ten Cate, Maastricht (18); M. ten Wolde, R. Hes, S. Atalay, Almere (43). New Zealand (113 patients, 6 centers) - P. Harper, Palmerston North (12); E. Merriman, North Shore City (16); P. Ockelford, M. H. Hulton, Auckland (45); J. Phillips, Wellington (5); G. Royle, A. Ford, Auckland (21); M. Smith, Christchurch (14). Norway (30 patients, 2 centers) - W. Ghanima, H. Amundsen, Fredrikstad (22); P. M. Sandset, Oslo (8).

Study sites cont. Philippines (32 patients, 3 centers) - M. T. Abola, Quezon City Study sites cont. Philippines (32 patients, 3 centers) - M. T. Abola, Quezon City (19); M. S. Ganzon, Quezon City (6); A. Germar, Pasig City (7). Poland (43 patients, 4 centers) - P. Checinski, Poznan (17); A. Kwasniewski, Lubin (1); W. Tomkowski, Warsaw (16); T. Zechowicz, Olsztyn (9). Russia (519 patients, 23 centers) - K. Apartsin, Irkutsk (17); G. Arutyunov, Moscow (1); O. Barbarash, Kemerovo (10); Y. Burov, Saratov (21); P. Chechulov, E. Varaksina, St. Petersburg (40); M. Chernyatina, M. Gladchenko, L. Belikov, Kursk (51); A. Fokin, Chelyabinsk (13); A. Gubenko, Omsk (5); K. Igor, M. Olga, Novosibirsk (26); Y. Kazakov, A. Kazakov, Tver (23); V. Krasavin, Yaroslavl (13); K. Linev, Krasnoyarsk (2); V. Plechev, Ufa (5); P. Shesternya, Krasnoyarsk (9); V. Shkurin, Pskov (20); P. Shvalb, Ryazan (57); G. Sokurenko, Saint-Petersburg (8); I. Sonkin, A. Remizov, K. Chernykh, Saint-Petersburg (41); I. Staroverov, Yaroslavl (20); Y. Subbotin, Barnaul (32); M. Zeltser, A. Seletsky, A. Iliynykh, Sochi (53); A. Zilber, Petrozavodsk (3); N. Zubareva, I. Tkachenko, A. Pakhomova, Perm (49). Singapore (11 patients, 3 centers) - J. Raghuram, Singapore (1); H. J Ng, Singapore (9); K. Sin, Singapore (1). South Africa (365 patients, 12 centers) - D. Adler, F. Weber, R. van der Jagt, Johannesburg (52); M. Basson, Cape Town Western Cape (2); J. Becker, Pretoria (56); G. Ellis, Somerset West (27); R. Isaacs, Johannesburg (29); B. Jacobson, S. Louw, Johannesburg (130); Jansen van Rensburg, Centurion (9); H. Siebert, Pretoria (24); F. Skosana, Olivedale Randburg (8); J. van Marle, Lyttelton Pretoria (2); L. van Zyl, R. le Roux, Worcester (22); P. Williams, Johannesburg (4). Spain (27 patients, 3 centers) - F. Cereto, Barcelona (10); F. Garcia-Bragado, Girona (16); R. Tirado Miranda, Cabra (1). Sweden (60 patients, 5 centers) - A. Carlsson, Stockholm (4); H. Eriksson, M. Villegas-Scivetti, Gothenburg (24); E. Ottosson, Stockholm (11); A. Sjalander, Sundsvall (6); I. Torstensson, Kristianstad (15). Switzerland (49 patients, 5 centers) - M. Banyai, R. Afarideh, Lucerne (24); A. Gallino, Bellinzona (8); L. Mazzolai, Lausanne (7); M. Righini, Geneva (8); D. Staub, Basel (2).

Study sites cont. Taiwan (141 patients, 8 centers) - C. J. Chen, Kaohsiung (9); Study sites cont. Taiwan (141 patients, 8 centers) - C. J. Chen, Kaohsiung (9); C. E. Chiang, K. L. Wang, Taipei (32); K. M. Chiu, J. H. Huang, New Taipei City (25); W. T. Lai, Kaohsiung (3); P. Y. Pai, K. H. Lin, Taichung (27); J. H. Wang, Hualien (3); C. C. Wu, Taipei (9); W. H. Yin, C. L. Huang, Taipei (33). Thailand (42 patients, 3 centers) - P. Angchaisuksiri, Bangkok (25); M. Kulpraneet, Ong-Karuk (6); P. Rojnuckarin, Bangkok (11). Turkey (54 patients, 5 centers) - G. Öngen, B. Duman, Istanbul (23); S. Ozkan, Izmir (5); I. Savas, Ankara (6); T. Selçuk, Ankara (6); E. Tuncay, Istanbul (14). Ukraine (292 patients, 10 centers) - V. Gerasymov, Chernigiv (35); O. Gubka, Zaporizhzhya (18); I. Gudz, M. Voloshyn, Ivano-Frankivsk (46); P. Nikulnikov, A. Danylets, Kiev (37); V. Prasol, Kharkiv (63); V. Rusyn, Uzhgorod (7); O. Sergeev, Dnipropetrovsk (9); O. Shtutin, Donetsk (2); O. Skupyy, A. Tatarin, Vinnitsa (68); I. Venger, Ternopil (7). United Kingdom (116 centers, 6 centers) - A. T. Cohen, R. Patel, London (40); B. J. Hunt, London (12); P. Kesteven, L. Robson, Newcastle Upon Tyne (37); P. Mac. Callum, London (11); T. Nokes, Plymouth (8); P. Rose, Coventry (8). United States (623 patients, 50 centers) - P. Acs, L. Gordan, A. Bhatia, Gainesville, FL (20); M. Ali, Saint Petersburg, FL (1); D. Amin, J. Masson, E. Gavi, Clearwater, FL (53); E. Ayele, Los Alamitos, CA (8); O. Ayeni, Jonesboro, GA (11); R. Canosa, Lancaster, PA(26); D. Chavous, Palm Springs, CA (7); D. Chen, Tacoma, WA (16); A. Comerota, Toledo, OH (1); M. Concha, Sarasota, FL(30); M. Cunanan-Bush, Baltimore, MD (7); N. Daboul, Maumee, OH (25); S. Daggubati, New Braunfels, TX (20); N. Dang, Anaheim, CA (21); N. Di. Bella, Aurora, CO (7); A. Driver, Sellersville, PA (13); A. Dulgeroff, Lancaster, PA (7); J. Fraiz, Indianopolis, IN (26); A. Friedlander, Savannah, GA (6); A. Galvez, Park Ridge, IL (2); C. Jani, Albany, NY (3); S. Johnson, Salt Lake City, UT (7); P. Khandelwal, Odessa, TX (2); E. Kingsley, Las Vegas, NV (24); J. Kingsley, L. Hutchinson, Columbus, GA (21); R. Lavender, Little Rock, AR (5); R. Lyons, G. Guzley, San Antonio, TX (50); R. Martinez, Brandon, FL (21); A. Metjian, Durham, NC (11); J. Moran, Statesville, NC (9); V. Nadar, Harrisburg, PA (32); R. Pish, Uniontown, PA (10); J. Pullman, Butte, MT (9); A. J Quaranta, Norfolk, VA (9); C. Ravi, Randallstown, MD (8); M. Refaai, Rochester, NY (2); J. Rehm, Fredericksburg, VA (20); D. Richards, Tyler, TX (2); R. Richwine, Ft. Worth, TX (14); S. Sachdeva, Seattle, WA (2); A. Seibert, Mobile, AL (4); A. Sharma, Montgomery, AL (18); D. Stricklin, Paducah, KY (5); A. Tannenbaum, Cape Coral, FL (6); C. Tin-U, Sugarland, TX (6); K. Vora, Owensboro, KY (6); D. Watkins, Midland, TX (7); D. Willms, San Diego, CA (3)

BACK UP slides BACK UP slides

Efficacy Efficacy

Safety Safety

Pre-specified subgroups of interest • DVT and PE separately • PE with right ventricular Pre-specified subgroups of interest • DVT and PE separately • PE with right ventricular dysfunction • Relative efficacy over quartiles of center TTR • Relative efficacy/safety in 30 mg dose group

Relative Efficacy over quartiles of center TTR Edoxaban Warfarin HR (95% CI) 3. 9 Relative Efficacy over quartiles of center TTR Edoxaban Warfarin HR (95% CI) 3. 9 3. 6 1. 09 (0. 64 -1. 85) 2. 6 3. 4 0. 77 (0. 50 -1. 20) 3. 7 3. 6 1. 05 (0. 68 -1. 61) 2. 5 3. 7 0. 66 (0. 38 -1. 13) 1 st Quartile <56% First Recurrent VTE % 2 nd Quartile ≥ 56% to <64% First Recurrent VTE % 3 rd Quartile ≥ 64 % to< 70% First Recurrent VTE % 4 th Quartile ≥ 70% First Recurrent VTE %

Relative Efficacy/ Safety in 30 mg dose group Edoxaban N = 733 (%) Warfarin Relative Efficacy/ Safety in 30 mg dose group Edoxaban N = 733 (%) Warfarin N = 719 (%) Hazard ratio First recurrent VTE 22 (3. 0) 30 (4. 2) 0. 73 (0. 42 -1. 26) Clinically relevant non major or major bleeding 58 (7. 9) 92 (12. 8) 0. 62 (0. 44 -0. 86) (95 % CI)

 Liver function tests: on-treatment period Outcome Edoxaban Warfarin no. /Total no. (%) 90/3903 Liver function tests: on-treatment period Outcome Edoxaban Warfarin no. /Total no. (%) 90/3903 (2. 3) ALT ≥ 3 x ULN no. / Total no. (%) 81/3901 (2. 1) ALT ≥ 5 x ULN 26/3901 (0. 7) 28/3903 (0. 7) ALT or AST ≥ 3 x ULN + bilirubin ≥ 2 x ULN ALT or AST ≥ 3 x ULN + concurrent bilirubin ≥ 2 x ULN 9/3878 (0. 2) 4/3865 (0. 1) 6/3878 (0. 2) 3/3865 (<0. 1) Number of subjects with events satisfying Hy’s Rule * per adjudication Liver failure 0/3878 2/3865 (<0. 1) 0/4118 1/4122 Percentages based on number of subjects with these tests available * For a case to be considered to meet Hy’s Rule in the Hokusai study, a case must have ALT or AST ≥ 3 x ULN with concurrent TBL ≥ 2 x ULN and the CEC reviewer deems the nature of liver injury to be primarily hepatocellular and the injury attributable to study drug by excluding other known causes (e. g. , viral hepatitis, Gilbert’s syndrome, concomitant use of / exposure to agents known to cause liver injury).

Cardiovascular events On treatment period Acute coronary event Cerebrovascular event Systemic embolism 30 day Cardiovascular events On treatment period Acute coronary event Cerebrovascular event Systemic embolism 30 day post study treatment period Acute coronary event Cerebrovascular event Systemic embolism Edoxaban N = 4118 (%) Warfarin N = 4122 (%) 20 (0. 5) 13 (0. 3) 26 (0. 6) 4 (<0. 1) 0 Edoxaban N = 4061 (%) Warfarin N = 4077 (%) 1 (<0. 1) 3 (<0. 1) 2 (<0. 1) 8 (0. 2) 1 (<0. 1) 2 (<0. 1)