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.

Edoxaban for the Treatment of Acute

Symptomatic Venous Thromboembolism the

HOKUSAI-VTE study

On behalf of the HOKUSAI -VTE Investigators

Disclosures for Harry R Büller

Research Support/P.I. Sanofi-aventis, Bayer HealthCare, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Pfizer, Roche, Isis, Thrombogenics

Employee No relevant conflicts of interest to declare

Consultant Sanofi-aventis, Bayer HealthCare, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, 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 HealthCare, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Pfizer, Roche, Isis, Thrombogenics

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 half-

life 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 (CrCl 30 - 50mL/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 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

R

edoxaban

warfarin

3 M 6 M 12 M

initial (LMW)Heparin placebo warfarin placebo edoxaban

Day 6- 12

Sham INR

INR

Day 1- 5

Symptomatic confirmed VTE event

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

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-

proBNP; 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 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 characteristicsEdoxaban(N=4118)

Warfarin(N=4122)

Mean age, years (SD) 56 (16) 56 (16)

Male gender, n (%) 2360 (57) 2356 (57)

Qualifying diagnosis, n (%)DVTPE

2468 (60)1650 (40)

2453 (60)1669 (40)

Clinical presentation and risk factors, n (%)

Unprovoked CancerPrevious VTE

2713 (66)378 (9)784 (19)

2697 (65)393 (10)736 (18)

Dose of 30 mg ( e.g ≤ 60 kg, CrCl≥30 ≤50 ml/min), n (%) 733 (18) 719 (17)

Severity index event

Edoxaban(N=4118)

Warfarin(N=4122)

DVT – no. (%) 2468 (60) 2453 (60)

Most proximal site – no. (%)

Popliteal Vein 603 (24) 596 (24)

Superficial Femoral Vein 795 (32) 773 (32)

Femoral or Iliac Vein 1035 (42) 1049 (43)

PE – no. (%) 1650 (40) 1669 (40)

Anatomical extent – no. (%)

Limited 128 (8) 123 (7)Intermediate 679 (41) 682 (41)Extensive 743 (45) 778 (47)

Concomitant DVT – no. (%) 410 (25) 404 (24)

NT pro-BNP ≥500 pg/ml – n/N (%) 454/1484 (28) 484/1505 (29) Right Ventricular Dysfunction – n/N (%) 172/498 (35) 179/504 (36)

Efficacy outcomes Edoxaban(N=4118)

Warfarin(N=4122)

Hazard ratio(95% CI) P Value

First recurrent VTE - no. (%)

Overall study period 130 (3.2) 146 (3.5) 0.89 (0.70-1.13)

<0.001

Noninferiority

Patients with index DVT* 83 (3.4) 81 (3.3) 1.02 (0.75-1.38)

Patients with index PE** 47 (2.8) 65 (3.9) 0.73(0.50-1.06)

On-treatment period 66 (1.6) 80 (1.9) 0.82 (0.60-1.14)

<0.001noninferiority)

Subgroup severe PE (RV dysfunction ProBNP) n/N (%)

15/454 (3.3) 30/485 ( 6.2) 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

13

Primary Efficacy Outcome

1.00 0

0.70 1.130.89

Hazard Ratio

Edoxaban superior Edoxaban non-inferior

1.50

hep / edoxaban

(n / N)

hep / warfarin

(n / N)

HR

(95% CI)

mITT

Overall

130 / 4,118

3.2%

146 / 4,122

3.5%

0.89

(0.70–1.13)

mITT

On-Rx

66 / 4,118

1.6%

80 / 4,122

1.9%

0.82

(0.60-1.14)

Overall

On-Rx

TTR : 63.5%

Safety outcomes Edoxaban(N=4118)

Warfarin(N=4122)

Hazard ratio(95% CI) P Value

First major or clinically relevant non major – no. (%) 349 (8.5) 423 (10.3) 0.81

(0.71-0.94)

0.004

superiority

Major – no. (%) 56 (1.4) 66 (1.6)0.84 (0.59-1.21)

0.35

superiority

Fatal 2 (<0.1) 10 (0.2)

Intracranial 0 6 (0.1)

Non-Fatal in Critical Sites 13 (0.3) 25 (0.6)

Intracranial 5 (0.1) 12 (0.3) Non-Fatal in Non-Critical Sites 41 (1.0) 33 (0.8) †

Clinically Relevant Non-Major– no. (%)

298 (7.2) 368 (8.9) 0.80(0.68-0.93)

0.004

superiority† some patients have more than 1 bleeding

Principal Safety Outcome

hep / edoxaban

(n / N)

hep / warfarin

(n / N)

HR

(95% CI)

349 / 4,118

8.5%

423 / 4,122

10.3%

0.81

(0.71–0.94)

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

Number of patients at risk

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

North America (842)

Asia/Pacific (2001)

Europe, Middle East, and Africa (5183)

Latin America (266)

Enrollment in 37 countries worldwide

Europe, Middle East and Africa

Austria 168Belarus 85Belgium 177Czech Republic 427Denmark 268Estonia 76France 714Germany 476Hungary 464Israel 233Italy 153Netherlands 387Norway 30Poland 43Russia 519South Africa 365Spain 27Sweden 60Switzerland 49Turkey 54Ukraine 292United Kingdom 116

Latin AmericaArgentina 47Brazil 93Mexico 126

Asia/PacificIndia 515China 487Korea 272Japan 209Australia 180New Zealand 113Taiwan 141Thailand 42Philippines 32Singapore 11

North AmericaCanada 219USA 623

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

Yanushko

Wei-Hsian Yin

Steering Management Coordination Committee (SMCC)

Study Committees

Data Monitoring Committee

Central Adjudication Committee 24/7 Medical Support Line

John Eikelboom (Chair) Martin Prins (chair) Peter Verhamme (Chair)

Mark Crowther Ludo Beenen Thomas VanasscheRobin Roberts Dees Brandjes Christophe Vandenbriele

Melvin MacGillavry Barbara Debaveye

Neil Kaplowitz Hans-Martin Otten Dominique Pessayre Ron Peters Yvo Roos Ton Slagboom

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).

From January 2010 through October 2012, 439 centers in 37

countries enrolled 8292 patients Study sites

Canada (219 patients, 6 centers) - S.R. Kahn, Montreal (14); M. Kovacs, A. Lazo Langner, H. VanSpronsen, 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. 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. 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. 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 (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); 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. MacCallum, 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. DiBella, 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)

Study sites cont.

BACK UP slides

Efficacy

Safety

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

Relative Efficacy/ Safety in 30 mg dose group

EdoxabanN = 733 (%)

Warfarin N = 719

(%)

Hazard ratio

(95 % CI)

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)

Outcome Edoxaban

no. / Total no. (%)

Warfarin

no. /Total no. (%)

ALT ≥ 3x ULN 81/3901 (2.1) 90/3903 (2.3)

ALT ≥ 5x ULN 26/3901 (0.7) 28/3903 (0.7)

ALT or AST ≥ 3x ULN + bilirubin ≥ 2x ULN

9/3878 (0.2) 4/3865 (0.1)

ALT or AST ≥ 3x ULN + concurrent bilirubin ≥ 2x ULN

6/3878 (0.2) 3/3865 (<0.1)

Number of subjects with events satisfying Hy’s Rule * per adjudication

0/3878 2/3865 (<0.1)

Liver failure 0/4118 1/4122

Percentages based on number of subjects with these tests available

Liver function tests: on-treatment period

* 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).

On treatment periodEdoxaban

N = 4118 (%)Warfarin

N = 4122 (%)

Acute coronary event20 (0.5) 13 (0.3)

Cerebrovascular event26 (0.6) 26 (0.6)

Systemic embolism4 (<0.1) 0

30 day post study treatment periodEdoxaban

N = 4061 (%)Warfarin

N = 4077 (%)

Acute coronary event1 (<0.1) 3 (<0.1)

Cerebrovascular event2 (<0.1) 8 (0.2)

Systemic embolism1 (<0.1) 2 (<0.1)

Cardiovascular events