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Edoxaban for the Treatment of Acute Symptomatic Venous Thromboembolism the HOKUSAI-VTE study

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

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  1. 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.

  2. Disclosures for Harry R Büller

  3. 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

  4. 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

  5. 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

  6. 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 12 M 3 M 6 M initial (LMW)Heparin placebo warfarin placebo edoxaban

  7. 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

  8. 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

  9. Baseline characteristics

  10. Severity index event

  11. Efficacy outcomes * 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

  12. Primary Efficacy Outcome Overall On-Rx TTR : 63.5% 0.89 0.70 1.13 HazardRatio 0 1.00 1.50 Edoxaban superior Edoxaban non-inferior

  13. Safety outcomes † some patients have more than 1 bleeding

  14. Principal Safety Outcome Number of patients at risk

  15. 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

  16. Enrollment in 37 countries worldwide Europe, Middle East, and Africa (5183) North America (842) Asia/Pacific (2001) Latin America (266)

  17. Steering Management Coordination Committee (SMCC)

  18. Study Committees

  19. 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).

  20. Study sites cont. 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).

  21. 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).

  22. 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).

  23. 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).

  24. 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).

  25. 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)

  26. BACK UP slides

  27. Efficacy

  28. Safety

  29. 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

  30. Relative Efficacy over quartiles of center TTR

  31. Relative Efficacy/ Safety in 30 mg dose group

  32. 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).

  33. Cardiovascular events

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