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N Engl J Med. 2013 Oct 10;369(15):1406-15. doi: 10.1056/NEJMoa1306638. Epub 2013 Aug 31.

Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.

Collaborators (680)

Büller H, Agnelli G, Angchaisuksiri P, Banyai M, Bauersachs R, van Bellen B, Blüguermann J, Boda Z, Bounameaux H, Brenner B, Brighton T, Castañon JD, Chechulov P, Chlumský Y, Cohen A, Davidson B, Decousus H, Eriksson H, Gallus A, Gudz I, Jacobson B, Heng LL, Lyons R, Meijer K, Minar E, Monreal M, Nakamura M, Oh D, Öngen G, Parakh R, Piovella F, Raskob G, Rehm J, Sandset PM, Schellong S, Smith M, Sokurenko G, Tomkowski W, Torp-Pedersen C, Verhamme P, Wang C, Wang Y, Weitz J, Wells P, Yanushko V, Yin WH, Prins M, Beenen L, Brandjes D, MacGillavry M, Kaplowitz N, Otten HM, Pessayre D, Peters R, Roos Y, Slagboom T, Eikelboom J, Crowther M, Roberts R, Verhamme P, Vanassche T, Vandenbriele C, Debaveye B, Segers A, Dani V, van Bergen P, Gerrits P, Mercuri M, van Kranen R, Lanz H, Grosso M, Schwocho L, Kappelhoff J, Franc J, Shi M, Zhang G, Lin M, Crerand W, Giordano C, Skinner M, Hurley S, Lovelace G, Barrier R, Betcher J, Alvarez C, Amuchastegui LM, Blüguermann J, Cassettari A, Ceressetto J, Hrabar, Macin S, Mahuad C, Oberti P, Santini F, Baker RI, Blombery P, Brighton T, Carroll P, Chong B, Coughlin P, Crispin P, Fletcher J, Gallus A, Serisier DJ, Tran H, Chan N, Stafford L, Ward C, Baghestanian M, Kyrle PA, Eischer L, Traby L, Marschang P, Mathies R, Pilger E, Brodmann M, Roithinger F, Weltermann A, Adzerikho I, Davidovskaya E, Gorokhovsky S, Maslianski B, Kulik A, Yanushka A, De Vleeschauwer P, Debing E, Duchateau J, Gustin M, Hainaut P, Vandekerkhof J, Verhamme P, Peerlinck K, Verstraeten P, Wautrecht JC, Motte S, Annichino-Bizzacchi JM, Mello TB, Menezes FH, Burihan M, Cavalcanti M, Correa J, Correa de Carvalho F, Cukier A, Manenti E, Manenti ER, Sacilotto R, Timi JM, van Bellen B, Kahn SR, Kovacs M, Langner A, VanSpronsen H, Ritchie B, Shafai-Sarshar R, Shivakumar S, Anderson D, Robinson K, Gallant B, Wells P, Karovitch A, Scarvelis D, Carrier M, Bai CX, Chen RC, Cheng ZZ, Du YC, Hu XY, Gu YQ, Hao QL, Sun SB, Wang C, Jiang L, Liu CJ, Liu CW, Liu S, Wang XX, Ye XF, Ma Z, Qin ZQ, Qin XJ, Tian HY, Wang YQ, Shi ZY, Wen FQ, Wu Q, Yang YH, Kuang TG, Yang H, Ying KJ, Ma GF, Yuan YD, Yu J, Gong XW, Zhang FX, Zhang J, Zhang S, Zhang JW, Zhang L, Zhao JC, Huang B, Zhao J, Chlumsky J, Hola D, Hirmerova J, Hutyra M, Klimsa Z, Holub M, Kovarova K, Lang P, Ryba M, Podoubský R, Matoska P, Mayer O, Patek F, Tupa M, Spacek R, Urbanova R, Blazejova S, Vitovec M, Andersen B, Brønnum-Schou J, Dominguez H, Egstrup K, Auscher S, Jeppesen J, Asferg C, Vishram J, Nielsen H, Galsgaard I, Michaelsen M, Haugaard-Nielsen B, Ostergaard O, Poulsen SH, Torp-Pedersen C, Masik S, Kadarik M, Meriste S, Paumets M, Laheäär M, Raidjuk L, Accassat S, Buchmuller A, Mismetti P, Achkar A, Aquilanti S, Rifaï A, Breuil N, Schmidt J, Brisot D, Brousse C, de la Fuentes P, Chakra M, Crestani B, Desormais I, Lacroix P, Diamand JM, El Kouri D, Clairand R, Elias A, Ferrari E, Doyen D, Chiche O, Grange C, Guenneguez H, Lacut K, Couturaud F, Mottier D, Leroux L, Lorcerie B, De Maistre E, Berthier S, Mahe I, Martin M, Meneveau N, Meyer G, Sanchez O, Montaclair K, Pavic M, Pernod G, Imbert B, Quere I, Galanaud JP, Roy PM, Sevestre MA, Simoneau G, Stephan D, Aleil B, Mirea C, Trinh-Duc A, von Bilderling P, Beyer-Westendorf J, Werth S, Köhler C, Halbritter K, Diehm C, Espinola-Klein C, Weisser G, Franke D, Heuer H, Horacek T, Kahrmann G, Kroening R, Lawall H, Roecken M, Schellong SM, Pomper L, Voigts B, Bernhard S, Frommhold R, Stellbrink C, Boda Z, Ilonczai P, Olah Z, Razso K, Schlammadinger A, Farkas K, Kolossváry E, Szabó I, Frankfurter Z, Gasztonyi B, Gurzó M, Klucsik Z, Kovacs A, Szigeti S, Varga C, Landi A, Nyirati G, Pecsvarady Z, Riba M, Sámson Z, Sipos G, Szigyártó M, Sebő N, Szabó T, Toth K, Agarwal S, Arneja J, Babhulkar S, Balaji R, Banker D, Bhagavan NK, Bhonagiri S, Mehta A, Dayasagar Rao V, Desai P, Desai SC, Chandrashekar AR, Singh R, Deshpande A, Dharmadhikari A, Durairaj N, Ghaisas N, Gupta S, Jain R, Jindal R, Kamerkar D, Kothiwale VA, Kothurkar A, Kulkarni R, Kumar S, Mody B, Nagabhushan KN, Pandharpurkar HK, Joshi S, Parakh R, Grover T, Patel J, Patel K, Dudhagra N, Pawar N, Penurkar M, Pinjala R, Rai K, Rao B, Raval M, Raval A, Mehta P, Ravi Kishore AG, Saravanan S, Shetty P, Srinivas A, Suresh KR, Sumanthraj K, Girija KR, Vinod M, Gavish D, Ashkenazy B, Braester A, Caraco Y, Elias M, Goldstein L, Grossman E, lahav M, Lishner M, Lugassy G, Oliven A, Rachmilevitz R, Tzoran I, Brenner B, Yeganeh S, Zeltser D, Zimlichman R, Ageno W, Barillari G, Pasca S, Bortoluzzi C, Cattaneo M, Falanga A, Ghirarduzzi A, Lodigiani C, Picchi C, Iosub DI, Porreca E, Prandoni P, Quintavalla R, Siragusa S, Akita T, Aoyama T, Fujimoto K, Hanzawa K, Ikeda U, Iwata H, Kobayashi T, Kondo K, Kurimoto T, Maeda H, Mo M, Munemasa M, Murakami H, Nishi Y, Nishibe T, Nishigami K, Nunohiro T, Obayashi T, Satoh T, Satokawa H, Shimizu K, Shiroma H, Sonoda M, Suzuki Y, Taniguchi S, Tsujita K, Yamada N, Yasuda C, Yoshida H, Chang HJ, Choi WI, Kwon KY, Rho BH, Choi JS, Hong YS, Joh JH, Kim DJ, Kim HS, Kim SH, Kim YK, Kim KU, Kim JY, Kwon TW, Lee TS, Lim SY, Mun YC, Oh DY, Park KH, Yun WS, Yoon HI, Diaz-Castañon J, Flota LF, Galindo J, Gomez Lara J, Jerjes-Sanchez C, Palomar-Lever A, Rodriguez D, Higareda I, Boersma WG, de Graaff CS, Oudeman L, Brans E, Bredie SJ, Dees A, Erdkamp F, Peters F, Fijnheer R, Gerdes VE, Griffioen A, Jie KS, Meijer K, Kooistra H, Wiewel-Verschueren S, Middeldorp S, Kamphuisen PW, van Es J, Eerenberg ES, Swart Heikens J, Ten Cate H, ten Wolde M, Hes R, Atalay S, Harper P, Merriman E, Ockelford P, Hulton MH, Phillips J, Royle G, Ford A, Smith M, Ghanima W, Amundsen H, Sandset PM, Abola MT, Ganzon MS, Germar A, Checinski P, Kwasniewski A, Tomkowski W, Zechowicz T, Apartsin K, Arutyunov G, Barbarash O, Burov Y, Chechulov P, Varaksina E, Chernyatina M, Gladchenko M, Belikov L, Fokin A, Gubenko A, Igor K, Olga M, Kazakov Y, Kazakov A, Krasavin V, Linev K, Plechev V, Shesternya P, Shkurin V, Shvalb P, Sokurenko G, Sonkin I, Remizov A, Chernykh K, Staroverov I, Subbotin Y, Zeltser M, Seletsky A, Iliynykh A, Zilber A, Zubareva N, Tkachenko I, Pakhomova A, Raghuram J, Ng HJ, Sin K, Adler D, Weber F, van der Jagt R, Basson M, Becker J, Ellis G, Isaacs R, Jacobson B, Louw S, van Rensburg J, Siebert H, Skosana F, van Marle J, van Zyl L, le Roux R, Williams P, Cereto F, Garcia-Bragado F, Miranda R, Carlsson A, Eriksson H, Villegas-Scivetti M, Ottosson E, Sjalander A, Torstensson I, Banyai M, Afarideh R, Gallino A, Mazzolai L, Righini M, Staub D, Chen CJ, Chiang CE, Wang KL, Chiu KM, Huang J, Lai WT, Pai PY, Lin KH, Wang JH, Wu CC, Yin WH, Huang CL, Angchaisuksiri P, Kulpraneet M, Rojnuckarin P, Öngen G, Duman B, Ozkan S, Savas I, Selçuk T, Tuncay E, Gerasymov V, Gubka O, Gudz I, Voloshyn M, Nikulnikov P, Danylets A, Prasol V, Rusyn V, Sergeev O, Shtutin O, Skupyy O, Tatarin A, Venger I, Cohen AT, Patel R, Hunt BJ, Kesteven P, Robson L, MacCallum P, Nokes T, Rose P, Acs P, Gordan L, Bhatia A, Ali M, Amin D, Masson J, Gavi E, Ayele E, Ayeni O, Canosa R, Chavous D, Chen D, Comerota A, Concha M, Cunanan-Bush M, Daboul N, Daggubati S, Dang N, DiBella N, Driver A, Dulgeroff A, Fraiz J, Friedlander A, Galvez A, Jani C, Johnson S, Khandelwal P, Kingsley E, Kingsley J, Hutchinson L, Lavender R, Lyons R, Guzley G, Martinez R, Metjian A, Moran J, Nadar V, Pish R, Pullman J, Quaranta AJ, Ravi C, Refaai M, Rehm J, Richards D, Richwine R, Sachdeva S, Seibert A, Sharma A, Stricklin D, Tannenbaum A, Tin-U C, Vora K, Watkins D, Willms D.

Erratum in

  • N Engl J Med. 2014 Jan 23;370(4):390.

Abstract

BACKGROUND:

Whether the oral factor Xa inhibitor edoxaban can be an alternative to warfarin in patients with venous thromboembolism is unclear.

METHODS:

In a randomized, double-blind, noninferiority study, we randomly assigned patients with acute venous thromboembolism, who had initially received heparin, to receive edoxaban at a dose of 60 mg once daily, or 30 mg once daily (e.g., in the case of patients with creatinine clearance of 30 to 50 ml per minute or a body weight below 60 kg), or to receive warfarin. Patients received the study drug for 3 to 12 months. The primary efficacy outcome was recurrent symptomatic venous thromboembolism. The principal safety outcome was major or clinically relevant nonmajor bleeding.

RESULTS:

A total of 4921 patients presented with deep-vein thrombosis, and 3319 with a pulmonary embolism. Among patients receiving warfarin, the time in the therapeutic range was 63.5%. Edoxaban was noninferior to warfarin with respect to the primary efficacy outcome, which occurred in 130 patients in the edoxaban group (3.2%) and 146 patients in the warfarin group (3.5%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.70 to 1.13; P<0.001 for noninferiority). The safety outcome occurred in 349 patients (8.5%) in the edoxaban group and 423 patients (10.3%) in the warfarin group (hazard ratio, 0.81; 95% CI, 0.71 to 0.94; P=0.004 for superiority). The rates of other adverse events were similar in the two groups. A total of 938 patients with pulmonary embolism had right ventricular dysfunction, as assessed by measurement of N-terminal pro-brain natriuretic peptide levels; the rate of recurrent venous thromboembolism in this subgroup was 3.3% in the edoxaban group and 6.2% in the warfarin group (hazard ratio, 0.52; 95% CI, 0.28 to 0.98).

CONCLUSIONS:

Edoxaban administered once daily after initial treatment with heparin was noninferior to high-quality standard therapy and caused significantly less bleeding in a broad spectrum of patients with venous thromboembolism, including those with severe pulmonary embolism. (Funded by Daiichi-Sankyo; Hokusai-VTE ClinicalTrials.gov number, NCT00986154.).

PMID:
23991658
DOI:
10.1056/NEJMoa1306638
[Indexed for MEDLINE]
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