HOKUSAI-VTE

Edoxaban for the long-term treatment of venous thromboembolism.
(2013)

Condition

Acute treatment and secondary prevention of symptomatic VTE

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Objective

Evaluation of efficacy and safety of heparin followed by edoxaban versus heparin overlapping with warfarin in patients with DVT and/or PE

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Trial design

Randomized, double-blind phase III non-inferiority study
Active treatment: heparin (LMW heparin s.c. 1 mg/kg twice daily or 1.5 mg/ kg once daily; UFH: 5000 IU bolus i.v., 1300 IU/h continuous infusion, minimum of 5 days and maximum of about 12 days treatment) plus edoxaban for 3-12 months (n=4118)
60 mg p.o. once daily edoxaban (30 mg once daily for patients with creatinine clearance of 30 to 50 ml per minute or a body weight of 60 kg or less or in patients who were receiving concomitant treatment with potent P glycoprotein inhibitors)
Control treatment: heparin as in active treatment plus warfarin
(INR 2.0–3.0) (n=4122)

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Endpoints

Primary efficacy endpoint: composite of DVT, non-fatal PE and fatal PE during 12 months, regardless of treatment duration
Secondary efficacy endpoint: composite outcome of symptomatic recurrent DVT, non-fatal recurrent PE and all-cause mortality during 12 months
Principal safety endpoint: major and clinically relevant non-major bleeding during 12 months

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Trial participants

8292 patients >18 years with confirmed DVT and/or symptomatic PE

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Results

Efficacy outcome: A recurrence of venous thromboembolism during the overall study period occurred in 130 of 4118 patients (3.2%) in the edoxaban group and in 146 of 4122 patients (3.5%) in the warfarin group. Among patients who qualified for the 30-mg dose of edoxaban, recurrent venous thromboembolism occurred in 22 of 733 patients (3.0%) receiving edoxaban, as compared with 30 of the 719 patients (4.2%) receiving warfarin.
Safety outcome: Clinically relevant bleeding (major or nonmajor) occurred in 349 of 4118 patients (8.5%) in the edoxaban group and in 423 of 4122 patients (10.3%) in the warfarin group. Major bleeding occurred in 56 patients (1.4%) in the edoxaban group and 66 patients (1.6%) in the warfarin group. Among patients who qualified for the 30-mg dose of edoxaban, clinically relevant bleeding occurred in 58 of 733 patients (7.9%) who received edoxaban, and in 92 of the 719 patients (12.8%) who received warfarin.

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Summary

Edoxaban administered once daily after initial treatment with heparin was non-inferior to high-quality standard therapy and caused significantly less bleeding in a broad spectrum of patients with venous thromboembolism, including those with severe pulmonary embolism

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Reference

The Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;369:1406-1415

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Corresponding author

Harry R. Buller, MD, Department of Vascular Medicine, Academic Medical Center, F4-275, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands,
e-mail: h.r.buller@amc.uva.nl

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