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Original research article
Genetics and clinical response to warfarin and edoxaban in patients with venous thromboembolism
  1. Alexander G. Vandell1,
  2. Joseph Walker2,
  3. Karen S. Brown2,
  4. George Zhang3,
  5. Min Lin3,
  6. Michael A. Grosso4,
  7. Michele F. Mercuri4
  1. 1Translational Medicine Clinical Pharmacology, Daiichi Sankyo Pharma Development, Edison, New Jersey, USA
  2. 2Translational Medicine Clinical Pharmacology, Formerly of Daiichi Sankyo Pharma Development, Edison, New Jersey, USA
  3. 3Biostatistics, Daiichi Sankyo Pharma Development, Edison, NJ, USA
  4. 4Cardiovascular and Metabolism Therapeutic Area Development, Daiichi Sankyo Pharma Development, Edison, New Jersey, USA
  1. Correspondence to Dr Alexander G. Vandell, Translational Medicine & Clinical Pharmacology, Daiichi Sankyo Pharma Development, 399 Thornall St, Edison, NJ 08837, USA; avandell{at}


Objective The aim of this study was to investigate whether genetic variants can identify patients with venous thromboembolism (VTE) at an increased risk of bleeding with warfarin.

Methods Hokusai-venous thromboembolism (Hokusai VTE), a randomised, multinational, double-blind, non-inferiority trial, evaluated the safety and efficacy of edoxaban versus warfarin in patients with VTE initially treated with heparin. In this subanalysis of Hokusai VTE, patients genotyped for variants in CYP2C9 and VKORC1 genes were divided into three warfarin sensitivity types (normal, sensitive and highly sensitive) based on their genotypes. An exploratory analysis was also conducted comparing normal responders to pooled sensitive responders (ie, sensitive and highly sensitive responders).

Results The analysis included 47.7% (3956/8292) of the patients in Hokusai VTE. Among 1978 patients randomised to warfarin, 63.0% (1247) were normal responders, 34.1% (675) were sensitive responders and 2.8% (56) were highly sensitive responders. Compared with normal responders, sensitive and highly sensitive responders had heparin therapy discontinued earlier (p<0.001), had a decreased final weekly warfarin dose (p<0.001), spent more time overanticoagulated (p<0.001) and had an increased bleeding risk with warfarin (sensitive responders HR 1.38 [95% CI 1.11 to 1.71], p=0.0035; highly sensitive responders 1.79 [1.09 to 2.99]; p=0.0252).

Conclusion In this study, CYP2C9 and VKORC1 genotypes identified patients with VTE at increased bleeding risk with warfarin.

Trial registration number NCT00986154.

  • edoxaban
  • CYP2C9
  • VKORC1
  • warfarin sensitivity
  • venous thromboembolism

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  • Contributors AV, JW, KSB, GZ, ML, MAG and MFM made substantial contributions to the conception or design of the work and analysis or interpretation of data, drafted or critically revised the manuscript, and had final approval of the version to be published.

  • Funding The study was funded by Daiichi Sankyo, Inc (Parsippany, New Jersey, USA).

  • Competing interests AV, GZ, ML, MAG and MFM are employees of Daiichi Sankyo, Inc. JW and KSB were employees at Daiichi Sankyo, Inc at the time the study was conducted.

  • Patient consent This manuscript does not contain identifiable medical information.

  • Ethics approval The institutional review board at each participating centre approved the protocol.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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