Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism

BackgroundWhether the oral factor Xa inhibitor edoxaban can be an alternative to warfarin in patients with venous thromboembolism is unclear. MethodsIn a randomized, double-blind, noninferiority study, we randomly assigned patients with acute venous thromboembolism, who had initially received heparin, to receive edoxaban at a dose of 60 mg once daily, or 30 mg once daily (e.g., in the case of patients with creatinine clearance of 30 to 50 ml per minute or a body weight below 60 kg), or to receive warfarin. Patients received the study drug for 3 to 12 months. The primary efficacy outcome was recurrent symptomatic venous thromboembolism. The principal safety outcome was major or clinically relevant nonmajor bleeding. ResultsA total of 4921 patients presented with deep-vein thrombosis, and 3319 with a pulmonary embolism. Among patients receiving warfarin, the time in the therapeutic range was 63.5%. Edoxaban was noninferior to warfarin with respect to the primary efficacy outcome, which occurred in 130 patients in the edoxaban group (3.2%) and 146 patients in the warfarin group (3.5%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.70 to 1.13; P <0.001 for noninferiority). The safety outcome occurred in 349 patients (8.5%) in the edoxaban group and 423 patients (10.3%) in the warfarin group (hazard ratio, 0.81; 95% CI, 0.71 to 0.94; P=0.004 for superiority). The rates of other adverse events were similar in the two groups. A total of 938 patients with pulmonary embolism had right ventricular dysfunction, as assessed by measurement of N-terminal pro-brain natriuretic peptide levels; the rate of recurrent venous thromboembolism in this subgroup was 3.3% in the edoxaban group and 6.2% in the warfarin group (hazard ratio, 0.52; 95% CI, 0.28 to 0.98). ConclusionsEdoxaban administered once daily after initial treatment with heparin was noninferior 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. (Funded by Daiichi-Sankyo; Hokusai-VTE ClinicalTrials.gov number, NCT00986154.) The anticoagulant edoxaban, an oral inhibitor of activated factor X, does not require monitoring. As initial treatment for acute venous thromboembolism, heparin-edoxaban was noninferior to heparin-warfarin and caused less bleeding. Venous thromboembolism is the third most common cardiovascular disease after myocardial infarction and stroke, affecting at least 700,000 persons annually in North America.(1)-(3) The standard treatment consists of low-molecular-weight heparin followed by vitamin K antagonists.(4) A number of studies have established that new oral anticoagulants with or without initial heparin therapy are effective alternatives.(5)-(8) Edoxaban is a direct inhibitor of activated factor X with a rapid onset of action. It is administered orally once daily and has proven antithrombotic efficacy.(9)-(11) The Hokusai-VTE study was a randomized, double-blind clinical trial that was conducted to evaluate edoxaban for the ..