Edoxaban Study 018

A study to assess the safety of a potential new drug in comparison to the standard practice of dosing with warfarin for non-valvular atrial fibrillation (2011)

Condition

Stroke prevention in patients with non-valvular AF

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Objective

To evaluate the safety of 4 fixed-dose regimens of edoxaban versus warfarin in patients with atrial fibrillation (CHADS2 score ≥2)

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Trial design

Randomized phase II dose-finding study (double-blind for edoxaban, open label for warfarin); treatment period 3 months
Active treatment: edoxaban 30 or 60 mg p.o. once daily or twice daily (n=235, n=244, n=234, n=180, respectively)
Control treatment: warfarin (INR 2.0–3.0) (n=250)

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Endpoints

Primary outcome measure: occurrence of major and/or clinically relevant non-major bleeding, elevated hepatic enzymes and/or bilirubin 
Secondary outcome measure: composite of stroke, systemic embolic events, myocardial infarction, cardiovascular death and hospitalisation for any cardiac condition; edoxaban pharmacokinetic and -dynamic markers, adverse events

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Trial participants

1146 patients between 18 and 85 years with persistent non-valvular AF and risk of stroke

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Results

Primary outcome results: Major and clinically relevant non-major bleeding occurred in 7 of 235 patients (3.0%) receiving 30 mg edoxaban once daily, 11 of 234 patients (3.8%) receiving 60 mg edoxaban once daily, 19 of 244 patients (7.8%) receiving 30 mg edoxaban twice daily and 19 of 180 patients (10.6%) receiving 60 mg edoxaban twice daily. In the warfarin group, major and clinically relevant non-major bleeding was observed in 8 of 250 patients (3.2%). Also the incidence of all bleeding showed a dose-related increase. The incidence of other adverse events (increased liver enzymes, bilirubin) was similar in all edoxaban groups and in the warfarin group

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Summary

Safety:

  • The 60 mg twice daily dose regimen was prematurely discontinued because of an excess of bleedings
  • Major and clinically relevant non-major bleeding occurred significantly more often in patients receiving 30 and 60 mg edoxaban twice daily compared to warfarin
  • 60 mg edoxaban once daily: bleeding similar to warfarin
  • 30 mg edoxaban once daily: major and clinically relevant non-major bleeds similar to warfarin, rate of all bleeding numerically lower than with warfarin
  • Rates of liver enzyme and bilirubin elevation similar in all arms; no signals of significant concern
  • The dose regimens with 30 mg and 60 mg edoxaban once daily were safe and well tolerated

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Reference

Weitz JL, Connolly SJ, Patel I, Salazar D, Rohatagi S, Mendell J, Kastrissios H, Jin J, Kunitada S. 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. Thromb Haemost 2010;104:633-641

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Corresponding author

Jeffrey I. Weitz, MD, Thrombosis and Atherosclerosis Research Institute, 237 Barton Street East, Hamilton Ontario L8L 2X2, Canada, e-mail: weitzj@taari.caJeffrey I. Weitz, MD, Thrombosis and Atherosclerosis Research Institute, 237 Barton Street East, Hamilton Ontario L8L 2X2, Canada, e-mail: weitzj@taari.ca

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