Thromb Haemost 2018; 118(08): 1439-1449
DOI: 10.1055/s-0038-1667001
Stroke, Systemic or Venous Thromboembolism
Georg Thieme Verlag KG Stuttgart · New York

Clinical Impact of Bleeding in Cancer-Associated Venous Thromboembolism: Results from the Hokusai VTE Cancer Study

Noémie Kraaijpoel
1  Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Marcello Di Nisio
2  Department of Medicine and Ageing Sciences, University G. D'Annunzio, Chieti, Italy
,
Frits I. Mulder
1  Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Nick van Es
1  Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Jan Beyer-Westendorf
3  Department of Medicine I, University Hospital Dresden, Dresden, Germany
,
Marc Carrier
4  Department of Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
,
David Garcia
5  Department of Hematology, University of Washington, Seattle, Washington, United States
,
Michael Grosso
6  Daiichi Sankyo Pharma Development, Basking Ridge, New Jersey, United States
,
Ajay K. Kakkar
7  Thrombosis Research Institute, University College London, London, United Kingdom
,
Michele F. Mercuri
6  Daiichi Sankyo Pharma Development, Basking Ridge, New Jersey, United States
,
Saskia Middeldorp
1  Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Cristhiam Rojas Hernandez
8  MD Anderson Cancer Center, University of Texas, Houston, Texas, United States
,
Amparo Santamaria
9  Department of Hematology, University Hospital Vall d'Hebron, Barcelona, Spain
,
Lee Schwocho
6  Daiichi Sankyo Pharma Development, Basking Ridge, New Jersey, United States
,
Annelise Segers
10  ITREAS, Academic Research Organization, Amsterdam, The Netherlands
,
Peter Verhamme
11  University Hospitals Leuven, University of Leuven, Leuven, Belgium
,
Tzu-Fei Wang
12  The Ohio State University Wexner Medical Center, Columbus, Ohio, United States
,
Jeffrey I. Weitz
13  Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
,
George Zhang
6  Daiichi Sankyo Pharma Development, Basking Ridge, New Jersey, United States
,
Jeffrey I. Zwicker
14  Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States
,
Harry R. Büller
1  Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Gary E. Raskob
15  University of Oklahoma Health Sciences Center, College of Public Health, University of Oklahoma, Oklahoma City, Oklahoma, United States
› Author Affiliations
Further Information

Publication History

09 April 2018

30 June 2018

Publication Date:
30 July 2018 (online)

Abstract

In the Hokusai VTE Cancer study, edoxaban was non-inferior to dalteparin for the composite outcome of recurrent venous thromboembolism (VTE) and major bleeding in 1,050 patients with cancer-associated VTE. The absolute rate of recurrent VTE was 3.4% lower with edoxaban, whereas the absolute rate of major bleeding was 2.9% higher. The present analysis focuses on the sites, clinical presentation, course and outcome of bleeding events, and the associated tumour types. Major bleeds and their severity (categories 1–4) were blindly adjudicated by a committee using a priori defined criteria, and data were analysed in the safety population. Major bleeding occurred in 32 of 522 patients given edoxaban (median treatment duration, 211 days) and in 16 of 524 patients treated with dalteparin (median treatment duration, 184 days); no patients had more than one major bleed. There were no fatal bleeds with edoxaban, and two with dalteparin. Severe bleeding at presentation (category 3 or 4) occurred in 10 (1.9%) and 11 (2.1%) patients in the edoxaban and dalteparin groups, respectively. The excess of major bleeding with edoxaban was confined to patients with gastrointestinal cancer. However, severe major bleeding at presentation (category 3 or 4) in this sub-group occurred in 5 of 165 (3.0%) and in 3 of 140 (2.1%) patients given edoxaban or dalteparin, respectively.

In conclusion, this analysis suggests that while oral edoxaban is an appropriate alternative to subcutaneous dalteparin for treatment of cancer-associated VTE, the use of edoxaban in patients with gastrointestinal cancer requires careful benefit–risk weighting.

Authors' Contributions

Study conception and design: N. Kraaijpoel, M. Di Nisio, M. Grosso, A. Segers, H.R. Büller and G.E. Raskob.


Data acquisition: M. Di Nisio, N. van Es, J. Beyer-Westendorf, M. Carrier, D. Garcia, M. Grosso, C. Rojas Hernandez, A. Santamaria, P. Verhamme, T.F. Wang and J.I. Zwicker.


Statistical analysis: G. Zhang.


Interpretation of the data: N. Kraaijpoel, M. Di Nisio, F.I. Mulder, N. van Es, J. Beyer-Westendorf, M. Carrier, D. Garcia, M. Grosso, A.K. Kakkar, M.F. Mercuri, S. Middeldorp, C. Rojas Hernandez, A. Santamaria, L. Schwocho, A. Segers, P. Verhamme, T.F. Wang, J.I. Weitz, G. Zhang, J.I. Zwicker, H.R. Büller and G.E. Raskob.


Drafting of the manuscript: N. Kraaijpoel, M. Di Nisio, F.I. Mulder, N. van Es, J. Beyer-Westendorf, M. Carrier, D. Garcia, M. Grosso, A.K. Kakkar, M.F. Mercuri, S. Middeldorp, C. Rojas Hernandez, A. Santamaria, L. Schwocho, A. Segers, P. Verhamme, T.F. Wang, J.I. Weitz, G. Zhang, J.I. Zwicker, H.R. Büller and G.E. Raskob.


Critical revision of the manuscript for important intellectual content: N. Kraaijpoel, M. Di Nisio, F.I. Mulder, N. van Es, J. Beyer-Westendorf, M. Carrier, D. Garcia, M. Grosso, A.K. Kakkar, M.F. Mercuri, S. Middeldorp, C. Rojas Hernandez, A. Santamaria, L. Schwocho, A. Segers, P. Verhamme, T.F. Wang, J.I. Weitz, G. Zhang, J.I. Zwicker, H.R. Büller and G.E. Raskob.


Final approval of the manuscript: N. Kraaijpoel, M. Di Nisio, F.I. Mulder, N. van Es, J. Beyer-Westendorf, M. Carrier, D. Garcia, M. Grosso, A.K. Kakkar, M.F. Mercuri, S. Middeldorp, C. Rojas Hernandez, A. Santamaria, L. Schwocho, A. Segers, P. Verhamme, T.F. Wang, J.I. Weitz, G. Zhang, J.I. Zwicker, H.R. Büller and G.E. Raskob.