Edoxaban for the long-term treatment of venous thromboembolism: rationale and design of the Hokusai-venous thromboembolism study--methodological implications for clinical trials.

Abstract : BACKGROUND: New oral anticoagulants may simplify long-term therapy by eliminating the need for laboratory monitoring. Edoxaban is an oral, direct inhibitor of factor Xa that is given in a fixed dose once daily. OBJECTIVE AND METHODS: The Hokusai-VTE study is a randomized, double-blind trial to evaluate whether initial low molecular weight heparin (LMWH) followed by edoxaban (60 mg once daily) is non-inferior to LMWH followed by warfarin (International Normalized Ratio of 2.0-3.0) for the prevention of recurrent thromboembolism in patients with acute symptomatic venous thromboembolism (VTE). The primary efficacy outcome is symptomatic recurrent VTE during the 12-month study period. The principal safety outcome is clinically relevant bleeding (major or non-major) occurring during or within 3 days of stopping study treatment. A clinical events committee adjudicates all suspected outcome events. A unique study design feature is the flexible treatment duration of between 3 and 12 months to simulate usual clinical practice, and enabled by: (i) double-blinding to minimize bias that could occur if knowledge of the patient's treatment influenced the duration of therapy; and (ii) follow-up for 12 months of all patients and inclusion in the primary efficacy analysis, regardless of the duration of therapy received. A second innovative design feature is the strategy for achieving an appropriate time in therapeutic range in the warfarin group, with central tracking for each participating center and feedback to the investigators. CONCLUSION: The standard methods combined with innovative design features should achieve study results that are both scientifically valid and relevant to clinical practice.