1. N Engl J Med. 2018 Feb 15;378(7):615-624. doi: 10.1056/NEJMoa1711948. Epub 2017
Dec 12.

Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism.

Raskob GE(1), van Es N(1), Verhamme P(1), Carrier M(1), Di Nisio M(1), Garcia
D(1), Grosso MA(1), Kakkar AK(1), Kovacs MJ(1), Mercuri MF(1), Meyer G(1), Segers
A(1), Shi M(1), Wang TF(1), Yeo E(1), Zhang G(1), Zwicker JI(1), Weitz JI(1),
Büller HR(1); Hokusai VTE Cancer Investigators.

Collaborators: Beyer-Westendorf J, Boda Z, Chlumsky Y, Gibbs H, Kamphuizen PW,
Monreal M, Ockleford P, Pabinger-Fasching I, Sinnaeve P, Beenen L, Gerdes V,
Laleman W, Larrey D, van Mechelen R, Roos Y, Scheerder M, Slagboom T, Thijs V,
Eikelboom JW, Crowther M, Roberts RS, Vanassche T, Vandenbriele C, Debaveye B,
Dani V, Schwocho L, Duggal A, Baker R, Carroll P, Chan N, Coughlin P, Crispin P, 
Gallus A, Hugman A, Tran H, Brodmann M, Mathies R, Rossmann D, Deeren D, Hainaut 
P, Jochmans K, Vercauter P, Wautrecht JC, Champion P, Gross P, Lee A, Shivakumar 
S, Tagalakis V, Zed E, Kovarova K, Lastuvka J, Matoska P, Prosecky R, Achkar A,
Aquilanti S, Chatellain P, Cony-Makhoul P, Del Piano F, Elias A, Falvo N, Ferrari
E, Mahé I, Merle P, Mismetti P, Muron T, Pernod G, Quere I, Schmidt J, Stephan D,
Espinola-Klein C, Horacek T, Kröning R, Oettler W, Schellong S, Schön N,
Zwemmrich C, Farkas K, Gurzo M, Nyirati G, Pecsvarady Z, Riba M, Becattini C,
Cattaneo M, Falanga A, Ghirarduzzi A, Imberti D, Lodigiani C, Parisi R, Porreca
E, Squizzato A, Tassoni MI, Villalta S, Visonà A, Beeker A, Boersma W, Brouwer R,
Dees A, Huisman M, Kuijer P, Mairuhu R, Meijer K, Middeldorp S, Otten HM, van
Marwijk-Kooy M, van Wissen S, Westerweel P, Harper P, Merriman E, Ockelford P,
Royle G, Smith M, Cereto Castro F, de Oña Navarrete R, Font Puig C, Gallardo Díaz
E, Garcia-Bragado Dalmau F, Ruiz Artacho P, Santamaria A, Baumann Kreuziger L, De
Sancho M, Gaddh M, Metjian A, Rojas Hernandez CM, Shah V, Smith W, Wun T, Xiang
Z.

Author information: 
(1)From the University of Oklahoma Health Sciences Center, College of Public
Health, Oklahoma City (G.E.R.); the Department of Vascular Medicine, Academic
Medical Center, University of Amsterdam (N.E., H.R.B.), and ITREAS, Academic
Research Organization (A.S.) - both in Amsterdam; the Department of Vascular
Medicine and Hemostasis, University Hospitals Leuven, Leuven, Belgium (P.V.);
Ottawa Hospital Research Institute, Ottawa (M.C.), London Health Sciences
Centre-Victoria Hospital, London, ON (M.J.K.), University Health Network,
University of Toronto, Toronto (E.Y.), and McMaster University and the Thrombosis
and Atherosclerosis Research Institute, Hamilton, ON (J.I.W.) - all in Canada;
the Department of Medicine and Aging Sciences, University G. D'Annunzio, Chieti, 
Italy (M.D.N.); the Department of Medicine, Division of Hematology, University of
Washington, Seattle (D.G.); Daiichi Sankyo Pharma Development, Basking Ridge, NJ 
(M.A.G., M.F.M., M.S., G.Z.); Thrombosis Research Institute and University
College London, London (A.K.K.); the Department of Respiratory Disease, Hôpital
Européen Georges-Pompidou, Assistance Publique-Hôpitaux de Paris, Paris (G.M.);
the Department of Internal Medicine, Division of Hematology, Ohio State
University Wexner Medical Center, Columbus (T.-F.W.); and Beth Israel Deaconess
Medical Center, Harvard Medical School, Boston (J.I.Z.).

Comment in
    N Engl J Med. 2018 Feb 15;378(7):673-674.
    N Engl J Med. 2018 Jul 05;379(1):93.
    N Engl J Med. 2018 Jul 05;379(1):93-4.
    N Engl J Med. 2018 Jul 05;379(1):94.
    N Engl J Med. 2018 Jul 05;379(1):94-5.

BACKGROUND: Low-molecular-weight heparin is the standard treatment for
cancer-associated venous thromboembolism. The role of treatment with direct oral 
anticoagulant agents is unclear.
METHODS: In this open-label, noninferiority trial, we randomly assigned patients 
with cancer who had acute symptomatic or incidental venous thromboembolism to
receive either low-molecular-weight heparin for at least 5 days followed by oral 
edoxaban at a dose of 60 mg once daily (edoxaban group) or subcutaneous
dalteparin at a dose of 200 IU per kilogram of body weight once daily for 1 month
followed by dalteparin at a dose of 150 IU per kilogram once daily (dalteparin
group). Treatment was given for at least 6 months and up to 12 months. The
primary outcome was a composite of recurrent venous thromboembolism or major
bleeding during the 12 months after randomization, regardless of treatment
duration.
RESULTS: Of the 1050 patients who underwent randomization, 1046 were included in 
the modified intention-to-treat analysis. A primary-outcome event occurred in 67 
of the 522 patients (12.8%) in the edoxaban group as compared with 71 of the 524 
patients (13.5%) in the dalteparin group (hazard ratio, 0.97; 95% confidence
interval [CI], 0.70 to 1.36; P=0.006 for noninferiority; P=0.87 for superiority).
Recurrent venous thromboembolism occurred in 41 patients (7.9%) in the edoxaban
group and in 59 patients (11.3%) in the dalteparin group (difference in risk,
-3.4 percentage points; 95% CI, -7.0 to 0.2). Major bleeding occurred in 36
patients (6.9%) in the edoxaban group and in 21 patients (4.0%) in the dalteparin
group (difference in risk, 2.9 percentage points; 95% CI, 0.1 to 5.6).
CONCLUSIONS: Oral edoxaban was noninferior to subcutaneous dalteparin with
respect to the composite outcome of recurrent venous thromboembolism or major
bleeding. The rate of recurrent venous thromboembolism was lower but the rate of 
major bleeding was higher with edoxaban than with dalteparin. (Funded by Daiichi 
Sankyo; Hokusai VTE Cancer ClinicalTrials.gov number, NCT02073682 .).

DOI: 10.1056/NEJMoa1711948 
PMID: 29231094  [Indexed for MEDLINE]