title: Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial.
abstract: BACKGROUND
  Venous thromboembolism occurs commonly in patients with cancer. Direct oral anticoagulants are non-inferior to conventional anticoagulants for the treatment of venous thromboembolism. We hypothesised that edoxaban, a direct oral inhibitor of activated clotting factor Xa, might be more suitable than conventional anticoagulants in the management of cancer-associated venous thromboembolism. The aim of this study was to assess the efficacy and safety of edoxaban compared with warfarin in a subgroup of patients with cancer enrolled in the Hokusai-VTE trial.
  
  
  METHODS
  We did a prespecified subgroup analysis in August, 2013, and a post-hoc analysis of non-inferiority and safety in March, 2016, of the patients with cancer enrolled in the randomised, double-blind, double-dummy, multicentre, Hokusai-VTE trial done between Jan 28, 2010, and Oct 31, 2012. In this study, patients aged at least 18 years with acute symptomatic deep-vein thrombosis or acute symptomatic pulmonary embolism (with or without deep-vein thrombosis) were assigned to receive edoxaban 60 mg once per day (or 30 mg once per day for patients with a creatinine clearance of 30-50 mL/min, bodyweight <60 kg, or who were receiving concomitant treatment with the P-glycoprotein inhibitors quinidine or verapamil) or warfarin (dose adjusted to maintain the international normalised ratio between 2·0 and 3·0) or placebos for either group for at least 3 months up to 12 months. All patients received initial therapy with open-label enoxaparin or unfractionated heparin for at least 5 days. Edoxoban (or placebo) was started after discontinuation of initial heparin; warfarin (or placebo) started concurrently with the study regimen of heparin. In our analysis we examined data for a subgroup of these patients who had a history of cancer or who had been categorised as having active cancer by the study physician at the time of enrolment. Additionally, all patients with a history of cancer were reviewed post hoc and categorised according to the presence or absence of active cancer. The primary efficacy outcome was the proportion of these patients with symptomatic recurrent venous thromboembolism during the 12-month study period, analysed in the modified intention-to-treat population, with an upper limit of the CI for the hazard ratio (HR) of 1·5. The principal safety outcome was the proportion of patients who had clinically relevant bleeding in the population of patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT00986154.
  
  
  RESULTS
  Of 771 patients with cancer enrolled in the trial, 378 were assigned to edoxaban and 393 to warfarin. Recurrent venous thromboembolism occurred in 14 (4%) of 378 patients given edoxaban and in 28 (7%) of 393 patients given warfarin (hazard ratio [HR] 0·53, 95% CI 0·28-1·00; p=0·0007). The upper limit of this 95% CI did not exceed the non-inferiority margin of 1·5 that was prespecified for the trial. Clinically relevant bleeding (major or non-major) occurred in 47 (12%) of 378 patients who received edoxaban and in 74 (19%) of 393 patients who received warfarin; HR for clinically relevant bleeding 0·64, 95% CI 0·45-0·92; p=0·017. Major bleeding occurred in ten (3%) of 378 patients with a history of cancer who received edoxaban and in 13 (3%) of 393 who received warfarin (HR 0·80, 95% CI 0·35-1·83).
  
  
  CONCLUSIONS
  Edoxaban might be as effective as warfarin for the treatment of patients with cancer with venous thromboembolism, and with less clinically relevant bleeding. Additional clinical trials of edoxaban versus low-molecular-weight heparin for the treatment of venous thromboembolism in patients with cancer are warranted.
  
  
  BACKGROUND
  Daiichi Sankyo.
authors.affiliation: College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. Electronic address: gary-raskob@ouhsc.edu.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Raskob
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Nick
authors.initials: N
authors.lastname: van Es
authors.affiliation: ITREAS Clinical Research, Amsterdam, Netherlands.
authors.forename: Annelise
authors.initials: A
authors.lastname: Segers
authors.affiliation: Division of Hematology, Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Pantep
authors.initials: P
authors.lastname: Angchaisuksiri
authors.affiliation: Department of Internal Medicine, School of Medicine, CHA University, Seongnam, Korea.
authors.forename: Doyeun
authors.initials: D
authors.lastname: Oh
authors.affiliation: Department of Internal Medicine, Thrombosis and Hemostasis Center, University of Debrecen, Debrecen, Hungary.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Boda
authors.affiliation: Texas Oncology and US ONCOLOGY Research, San Antonio, Texas, USA.
authors.forename: Roger M
authors.initials: RM
authors.lastname: Lyons
authors.affiliation: University of Groningen, Department of Hematology, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: Karina
authors.initials: K
authors.lastname: Meijer
authors.affiliation: Department of Vascular Surgery, Ivano-Frankivsk National Medical University, Ivano-Frankivsk, Ukraine.
authors.forename: Ivan
authors.initials: I
authors.lastname: Gudz
authors.affiliation: McMaster University and the Thrombosis & Atherosclerosis Research Institute, Hamilton, Ontario, Canada.
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Weitz
authors.affiliation: Clinical Development, Daiichi Sankyo Pharma Development, Edison, NJ, USA.
authors.forename: George
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Global Medical Affairs, Daiichi Sankyo, Parsippany, NJ USA.
authors.forename: Hans
authors.initials: H
authors.lastname: Lanz
authors.affiliation: Clinical Development, Daiichi Sankyo Pharma Development, Edison, NJ, USA.
authors.forename: Michele F
authors.initials: MF
authors.lastname: Mercuri
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Harry R
authors.initials: HR
authors.lastname: Büller
mesh_terms: D000368:Aged; D004311:Double-Blind Method; D000074099:Equivalence Trials as Topic; D065427:Factor Xa Inhibitors / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications* / Q000473:pathology / Q000628:therapy; D011379:Prognosis; D011725:Pyridines / Q000627:therapeutic use*; D015996:Survival Rate; D013844:Thiazoles / Q000627:therapeutic use*; D054556:Venous Thromboembolism / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology
chemical_list: D065427:Factor Xa Inhibitors; D011725:Pyridines; D013844:Thiazoles; C552171:edoxaban