Edoxaban for the  Treatment of Acute Symptomatic Venous Thromboembolism the HOKUSAI-VTE study
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Edoxaban for the Treatment of Acute Symptomatic Venous Thromboembolism the HOKUSAI-VTE study. On behalf of the HOKUSAI -VTE Investigators.

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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 b ller
Disclosures for Harry R Thromboembolism the HOKUSAI-VTE study Büller


Introduction
Introduction Thromboembolism the HOKUSAI-VTE study

  • 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
Edoxaban Thromboembolism the HOKUSAI-VTE study

  • 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
Background Hokusai-VTE study Thromboembolism the 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: Thromboembolism the HOKUSAI-VTE study 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

12 M

3 M

6 M

initial (LMW)Heparin

placebo warfarin

placebo edoxaban


Study outcomes
Study Outcomes Thromboembolism the HOKUSAI-VTE study

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
Statistics and analyses Thromboembolism the HOKUSAI-VTE study

  • 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
Baseline characteristics Thromboembolism the HOKUSAI-VTE study


Severity index event
Severity index event Thromboembolism the HOKUSAI-VTE study


Efficacy outcomes
Efficacy outcomes Thromboembolism the HOKUSAI-VTE study

* Denominator is number of patients with index DVT: 2468 and 2453 in edoxaban and warfarin grouprespectively

** Denominator is number of patientswith index PE : 1650 and 1669 in edoxaban and warfarin grouprespectively


Primary Efficacy Outcome Thromboembolism the HOKUSAI-VTE study

Overall

On-Rx

TTR : 63.5%

0.89

0.70

1.13

HazardRatio

0

1.00

1.50

Edoxaban superior

Edoxaban non-inferior


Safety outcomes
Safety outcomes Thromboembolism the HOKUSAI-VTE study

† some patients have more than 1 bleeding


Principal Safety Outcome Thromboembolism the HOKUSAI-VTE study

Number of patients at risk


Conclusion
Conclusion Thromboembolism the HOKUSAI-VTE study

(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 Thromboembolism the HOKUSAI-VTE study

Europe, Middle East, and Africa (5183)

North America (842)

Asia/Pacific

(2001)

Latin America (266)


Steering Management Coordination Committee (SMCC) Thromboembolism the HOKUSAI-VTE study


Study committees
Study Committees Thromboembolism the HOKUSAI-VTE study


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. countries enrolled 8292 patients

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. countries enrolled 8292 patients

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. countries enrolled 8292 patients

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. countries enrolled 8292 patients

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. countries enrolled 8292 patients

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. countries enrolled 8292 patients

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)


Back up slides
BACK UP slides countries enrolled 8292 patients


Efficacy countries enrolled 8292 patients


Safety countries enrolled 8292 patients


Pre specified subgroups of interest
Pre-specified subgroups of interest countries enrolled 8292 patients

  • 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 over quartiles of center TTR countries enrolled 8292 patients


Relative efficacy safety in 30 mg dose group
Relative Efficacy/ Safety in 30 mg dose group countries enrolled 8292 patients


Liver function tests: on-treatment period countries enrolled 8292 patients

* 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 countries enrolled 8292 patients


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