Thromb Haemost 2010; 104(03): 633-641
DOI: 10.1160/TH10-01-0066
New Technologies, Diagnostic Tools and Drugs
Schattauer GmbH

Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation

Jeffrey I. Weitz
1   Thrombosis & Atherosclerosis Research Institute, Hamilton General Hospital, Ontario, Canada
,
Stuart J. Connolly
2   Division of Cardiology, McMaster University, Ontario, Canada
,
Indravadan Patel
3   Daiichi Sankyo Pharma Development, Edison, New Jersey, USA
,
Daniel Salazar
3   Daiichi Sankyo Pharma Development, Edison, New Jersey, USA
,
Shashank Rohatagi
4   Daiichi Sankyo India (Private) Ltd., Chembur, Mumbai, India
,
Jeanne Mendell
3   Daiichi Sankyo Pharma Development, Edison, New Jersey, USA
,
Helen Kastrissios
5   Pharsight Corporation, Mountain View, California, USA
,
Jianqing Jin
3   Daiichi Sankyo Pharma Development, Edison, New Jersey, USA
,
Satoshi Kunitada
3   Daiichi Sankyo Pharma Development, Edison, New Jersey, USA
› Author Affiliations
Financial support:This study was sponsored by Daiichi Sankyo.
Further Information

Publication History

Received: 26 January 2010

Accepted after major revision: 30 April 2010

Publication Date:
23 November 2017 (online)

Summary

The primary objective of this study was to compare the safety of four fixed-dose regimens of edoxaban with warfarin in patients with nonvalvular atrial fibrillation (AF). In this 12-week, parallel-group, multi-centre, multinational study, 1,146 patients with AF and risk of stroke were randomised to edoxaban 30 mg qd, 30 mg bid, 60 mg qd, or 60 mg bid or warfarin dose-adjusted to a target international normalised ratio of 2.0–3.0. The study was double-blind to edoxaban dose, but open-label to warfarin. Primary outcomes were occurrence of major and/or clinically relevant non-major bleeding and elevated hepatic enzymes and/or bilirubin. Mean age was 65 ± 8.7 years and 64.4% were warfarin-naïve. Whereas major plus clinically relevant non-major bleeding occurred in 3.2% of patients randomised to warfarin, the incidence of bleeding was significantly higher with the edoxaban 60 mg bid (10.6%; p=0.002) and 30 mg bid regimens (7.8%; p=0.029), but not with the edoxaban 60 mg qd (3.8%) or 30 mg qd regimens (3.0%). For the same total daily dose of 60 mg, both bleeding frequency and trough edoxaban concentrations were higher in the 30-mg bid group than in the 60-mg qd group. There were no significant differences in hepatic enzyme elevations or bilirubin values among the groups. The safety profiles of edoxaban 30 and 60 mg qd in patients with AF were similar to warfarin. In contrast, the edoxaban bid regimens were associated with more bleeding than warfarin. These results suggest that in this three-month study, edoxaban 30 or 60 mg qd are safe and well-tolerated.

ClinicalTrials.gov Registration Number: NCT00504556

 
  • References

  • 1 Naccarelli GV, Varker H, Lin J. et al. Increasing prevalence of atrial fibrillation and flutter in the United States. Am J Cardiol 2009; 104: 1534-1539.
  • 2 Fuster V, Ryden LE, Cannom DS. et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006; 114: e257-e354.
  • 3 Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007; 146: 857-867.
  • 4 Gross CP, Vogel EW, Dhond AJ. et al. Factors influencing physicians’ reported use of anticoagulation therapy in nonvalvular atrial fibrillation: a cross-sectional survey. Clin Ther 2003; 25: 1750-1764.
  • 5 Ansell J, Hirsh J, Hylek E. et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 160S-198S.
  • 6 Singer DE, Albers GW, Dalen JE. et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 546S-592S.
  • 7 Weitz JI. New oral anticoagulants in development. Thromb Haemost 2010; 103: 62-70.
  • 8 Ogata K, Mendell-Harary J, Tachibana M. et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol 2010; 50: 743-753.
  • 9 Fuji T, Fujita S, Tachibana S. et al. Randomized, double-blind, multi-dose efficacy, safety and biomarker study of the oral factor Xa inhibitor DU-176b compared with placebo for prevention of venous thromboembolism in patients after total knee arthroplasty (Abstract). Blood (ASH Annual Meeting Abstracts). 2008 112. Abstract 34.
  • 10 Raskob G, Cohen A, Eriksson B. et al. Oral directa factor Xa inhibition with edoxaban for thromboprophylaxis after total hip replacement. Thromb Haemost. 2010 epub ahead of print.
  • 11 Gage BF, Waterman AD, Shannon W. et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. J Am Med Assoc 2001; 285: 2864-2870.
  • 12 Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3: 692-694.
  • 13 Alexander JH, Becker RC, Bhatt DL. et al. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation 2009; 119: 2877-2885.
  • 14 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
  • 15 Salazar DCT, Shi J, Green M. et al. Population pharmacokinetic/pharmacodynamic (PK/PD) analysis of exposure and bleeding in edoxaban, a novel oral factor Xa inhibitor, in patients with atrial fibrillation (Abstract). AAPS J 2009; 11: 35-42.
  • 16 Rosendaal FR, Cannegieter SC, van der Meer FJ. et al. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69: 236-239.
  • 17 US Food and Drug Administration.. Rivaroxaban for prophylaxis of deep vein thrombosis and pulmonary embolism in patients undergoing hip and knee replacement surgery. Advisory Committee Briefing Book. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM138385.pdf. Accessed November 1, 2009.
  • 18 Eriksson BI, Dahl OE, Buller HR. et al. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost 2005; 3: 103-111.
  • 19 Giugliano RRS, Kasstrissios H, Green M, Carrothers TJ, Mendell J, Antman E, Salazar D. The relationship between oral factor Xa (FXa) inhibitor DU-176b pharmacokinetics and the probability of bleeding events in patients with atrial fibrillation (Abstract). J Thromb Haemost 2009; 7: 200.
  • 20 Buller H, Deitchman D, Prins M. et al. Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study. J Thromb Haemost 2008; 6: 1313-1318.
  • 21 Mega JL, Braunwald E, Mohanavelu S. et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 2009; 374: 29-38.
  • 22 Agnelli G, Gallus A, Goldhaber SZ. et al. Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59–7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59–7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis) study. Circulation 2007; 116: 180-187.
  • 23 Ezekowitz MD, Reilly PA, Nehmiz G. et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol 2007; 100: 1419-1426.
  • 24 Connolly SJ, Pogue J, Eikelboom J. et al. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation 2008; 118: 2029-2037.