BACKGROUND: Whether the oral factor Xa inhibitor edoxaban can be an alternative to warfarin in patients with venous thromboembolism is unclear.
METHODS: In 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.
RESULTS: A 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).
CONCLUSIONS: Edoxaban 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.).
Low-molecular-weight heparin (LMWH) is recommended for long-term anticoagulant therapy in cancer patients with venous thromboembolism (VTE). These patients have been mostly excluded from clinical trials comparing new oral anticoagulants with vitamin-K antagonists. Hokusai-VTE was a global randomized, double-blind, non-inferiority trial (margin 1.5) that compared edoxaban, an oral factor Xa inhibitor, with warfarin for long-term therapy in 8,292 patients with acute symptomatic proximal deep-vein thrombosis and/or pulmonary embolism; all patients received initial LMWH treatment for at least 5 days. Patients with active cancer in whom long-term treatment with LMWH was anticipated were excluded, but patients with a history of cancer or with active cancer were eligible if long-term LMWH treatment was not planned due to availability, physician judgment or patient preference; the analysis of outcomes in these patients was pre-specified before the trial. The edoxaban dose was 60 mg once daily (30 mg in patients with body weight less than 60 kg or creatinine clearance 30 to 50 ml/min). Warfarin was adjusted to maintain the INR between 2.0 and 3.0. The primary efficacy outcome was recurrent symptomatic VTE. The efficacy analysis included all patients who received at least one dose of study drug, and included all outcomes through 12 months follow-up or study closure, regardless of the duration of treatment. The principal safety outcome was major or clinically relevant non-major bleeding, occurring on treatment or within 3 days of stopping treatment. All outcomes were adjudicated by an independent committee blinded to treatment allocation. A total of 771 cancer patients (9.3%) were enrolled (208 with active cancer and 563 with a history of cancer).The baseline clinical characteristics of patients in the edoxaban and warfarin groups were similar. The median duration of treatment in the edoxaban group was 267 days and in the warfarin group was 266 days (interquartile range 180 to 360 days in both groups). Among patients with active cancer, recurrent VTE occurred in 4 of 109 patients (3.7%) who received edoxaban and in 7 of 99 patients (7.1%) who received warfarin (hazard ratio 0.55, 95% CI 0.16 to 1.85). Clinically relevant bleeding (major or non-major) occurred in 20 patients (18.3%) given edoxaban (5 patients with major, 4.6%) and 25 patients (25.3%) given warfarin (3 patients with major, 3.0%) (hazard ratio for clinically relevant bleeding 0.72, 95% CI 0.40 to 1.30). Among all 771 cancer patients at entry, recurrent VTE occurred in 14 of 378 patients (3.7%) given edoxaban and in 28 of 393 patients (7.1%) who received warfarin (hazard ratio 0.53, 95% CI 0.28 to 1.00). Clinically relevant bleeding (major or non-major) occurred in 47 patients (12.4%) given edoxaban (10 patients with major, 2.6%) and 74 patients (18.8%) given warfarin (13 patients with major, 3.3%) (hazard ratio for clinically relevant bleeding 0.64, 95% CI 0.45 to 0.92). Among patients without cancer, either at entry or occurring during follow-up, recurrent VTE occurred in 103 of 3,658 patients (2.8%) given edoxaban and in 99 of 3,629 (2.7%) who received warfarin (hazard ratio 1.03, 95% CI 0.78 to 1.36, p=0.004 for non-inferiority). Clinically relevant bleeding (major or non-major) occurred in 280 of 3658 patients (7.7%) who received edoxaban (39 patients with major, 1.1%) and in 330 of 3629 patients (9.1%) given warfarin (48 patients with major, 1.3%) (hazard ratio for clinically relevant bleeding 0.83, 95% CI 0.71 to 0.97, p=0.022). The results suggest edoxaban is as effective, and possibly more effective, than warfarin in cancer patients with VTE. In such patients, bleeding is appreciable during anticoagulant therapy, and may potentially be reduced by edoxaban therapy. Additional studies of edoxaban for initial and long-term therapy of VTE in cancer patients are indicated, with LMWH as the comparator, and including lower doses of edoxaban to determine if bleeding can be further reduced without loss of efficacy.
Evaluation of heparin/edoxaban tosylate (DU176b) versus heparin/warfarin in preventing recurrence of blood clots in patients with acute symptomatic deep-vein blood clots in the legs and/or blood clots in the lungs.
BACKGROUND: There are few data on the relative efficacy and safety of direct oral anticoagulants, such as edoxaban, compared with vitamin K antagonists during extended therapy for venous thromboembolism. This analysis evaluates the risk-benefit of extended treatment for up to 12 months with edoxaban compared with warfarin among patients enrolled in the Hokusai-VTE study who continued therapy beyond 3 months.
METHODS: The Hokusai-VTE trial (NCT00986154) was a randomised, double-blind, event driven non-inferiority trial in 8292 patients comparing edoxaban with warfarin in the treatment of patients with acute venous thromboembolism. All patients were treated for at least 3 months and treatment was continued for up to 12 months. The outcomes at 12 months were documented in all patients irrespective of treatment duration. 3633 patients treated with edoxaban and 3594 treated with warfarin who completed 3 months of treatment were eligible for this analysis. The primary efficacy outcome was the incidence of adjudicated symptomatic recurrent venous thromboembolism evaluated for each of the time intervals of 3 months, greater than 3 months to 6 months, greater than 6 months to less than 12 months, and at 12 months, as well as the cumulative incidence occurring between 3 and 12 months. The principal safety outcome was the incidence of clinically relevant bleeding (composite of major or clinically relevant non-major bleeding). Both on-treatment and intention-to-treat analyses were done.
FINDINGS: In the on-treatment analysis, the incidence of recurrent venous thromboembolism at 3 months was 1·1% (0·8-1·4; 44 of 4118 patients) in the edoxaban-treated group versus 1·2% (0·9-1·6; 51 of 4122) in the warfarin-treated group; between greater than 3 months and 6 months, 0·7% (0·3-1·5; eight of 1076) versus 0·5% (0·2-1·1; five of 1084); between greater than 6 months and less than 12 months, 0·2% (0·0-0·8; two of 896) versus 0·8% (0·03-1·7; seven of 851); and at 12 months, <0·1% (0·0-0·3; one of 1661) versus 0·1% (0·0-0·4; two of 1659). In the on-treatment analysis, the cumulative incidence of recurrent venous thromboembolism between 3 and 12 months was 0·3% (95% CI 0·2-1·5; 11 of 3633 patients) in the edoxaban-treated group and 0·4% (0·2-1·7; 14 of 3594) in the warfarin-treated group (HR 0·78, 95% CI 0·36-1·72). The cumulative incidence of clinically relevant bleeding (major or non-major) between 3 and 12 months was 3·9% (95% CI 3·3-4·6; 143 of 3633 patients) in the edoxaban-treated group and 4·1% (3·5-4·8; 147 of 3594 patients) in the warfarin-treated group (HR 0·97, 95% CI 0·77-1·22); cumulative incidence of major bleeding was 0·3% (95% CI 0·2-0·5; 11 of 3633 patients) in the edoxaban-treated group and 0·7% (0·4-1·0; 24 of 3594 patients) in the warfarin-treated group (HR 0·45, 95% CI 0·22-0·92). Similar results were obtained in the intention-to-treat analysis.
INTERPRETATION: Extended treatment with edoxaban is effective and associated with less major bleeding than warfarin. Edoxaban once daily provides an attractive alternative to warfarin for patients with venous thromboembolism who require extended treatment for prevention of recurrent venous thromboembolism.
FUNDING: Daiichi Sankyo.
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.
