Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial.

Venous thromboembolism occurs commonly in patients with cancer. Direct oral anticoagulants are non-inferior to conventional anticoagulants for the treatment of venous thromboembolism. We hypothesised that edoxaban, a direct oral inhibitor of activated clotting factor Xa, might be more suitable than conventional anticoagulants in the management of cancer-associated venous thromboembolism. The aim of this study was to assess the efficacy and safety of edoxaban compared with warfarin in a subgroup of patients with cancer enrolled in the Hokusai-VTE trial. We did a prespecified subgroup analysis in August, 2013, and a post-hoc analysis of non-inferiority and safety in March, 2016, of the patients with cancer enrolled in the randomised, double-blind, double-dummy, multicentre, Hokusai-VTE trial done between Jan 28, 2010, and Oct 31, 2012. In this study, patients aged at least 18 years with acute symptomatic deep-vein thrombosis or acute symptomatic pulmonary embolism (with or without deep-vein thrombosis) were assigned to receive edoxaban 60 mg once per day (or 30 mg once per day for patients with a creatinine clearance of 30-50 mL/min, bodyweight <60 kg, or who were receiving concomitant treatment with the P-glycoprotein inhibitors quinidine or verapamil) or warfarin (dose adjusted to maintain the international normalised ratio between 2·0 and 3·0) or placebos for either group for at least 3 months up to 12 months. All patients received initial therapy with open-label enoxaparin or unfractionated heparin for at least 5 days. Edoxoban (or placebo) was started after discontinuation of initial heparin; warfarin (or placebo) started concurrently with the study regimen of heparin. In our analysis we examined data for a subgroup of these patients who had a history of cancer or who had been categorised as having active cancer by the study physician at the time of enrolment. Additionally, all patients with a history of cancer were reviewed post hoc and categorised according to the presence or absence of active cancer. The primary efficacy outcome was the proportion of these patients with symptomatic recurrent venous thromboembolism during the 12-month study period, analysed in the modified intention-to-treat population, with an upper limit of the CI for the hazard ratio (HR) of 1·5. The principal safety outcome was the proportion of patients who had clinically relevant bleeding in the population of patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT00986154. Of 771 patients with cancer enrolled in the trial, 378 were assigned to edoxaban and 393 to warfarin. Recurrent venous thromboembolism occurred in 14 (4%) of 378 patients given edoxaban and in 28 (7%) of 393 patients given warfarin (hazard ratio [HR] 0·53, 95% CI 0·28-1·00; p=0·0007). The upper limit of this 95% CI did not exceed the non-inferiority margin of 1·5 that was prespecified for the trial. Clinically relevant bleeding (major or non-major) occurred in 47 (12%) of 378 patients who received edoxaban and in 74 (19%) of 393 patients who received warfarin; HR for clinically relevant bleeding 0·64, 95% CI 0·45-0·92; p=0·017. Major bleeding occurred in ten (3%) of 378 patients with a history of cancer who received edoxaban and in 13 (3%) of 393 who received warfarin (HR 0·80, 95% CI 0·35-1·83). Edoxaban might be as effective as warfarin for the treatment of patients with cancer with venous thromboembolism, and with less clinically relevant bleeding. Additional clinical trials of edoxaban versus low-molecular-weight heparin for the treatment of venous thromboembolism in patients with cancer are warranted. Daiichi Sankyo.

Raskob GE ，van Es N ，Segers A ，Angchaisuksiri P ，Oh D ，Boda Z ，Lyons RM ，Meijer K ，Gudz I ，Weitz JI ，Zhang G ，Lanz H ，Mercuri MF ，Büller HR ，Hokusai-VTE investigators ... -  《Lancet Haematology》

Recurrent venous thromboembolism in patients with pulmonary embolism and right ventricular dysfunction: a post-hoc analysis of the Hokusai-VTE study.

In patients with pulmonary embolism, right ventricular dysfunction is associated with early mortality. The Hokusai-VTE study used N-terminal pro-brain natriuretic peptide (NT-proBNP) and right to left ventricular diameter ratio on CT as indicators of right ventricular dysfunction and reported that recurrent venous thromboembolism rates were lower with edoxaban than warfarin. The aim of the current study was to further explore the significance of right ventricular dysfunction and investigate potential explanations for the superiority of edoxaban-ie, differences in baseline clinical characteristics, duration of initial heparin treatment, bleeding rates, or quality of warfarin treatment. The Hokusai-VTE trial was a randomised, double-blind, event-driven non-inferiority trial in patients from centres in 37 countries that compared edoxaban with warfarin in the treatment of acute venous thromboembolism. Patients received treatment for at least 3 months and up to a maximum of 12 months. Patients were followed up for 12 months. Outcome data at 12 months was collected for all patients irrespective of treatment duration. This prespecified subgroup analysis focuses on the included patients with pulmonary embolism. The primary efficacy outcome was the incidence of adjudicated symptomatic recurrent venous thromboembolism defined as a composite of deep vein thrombosis or non-fatal or fatal pulmonary embolism at 12 months. Recurrence rates with edoxaban and warfarin were compared in patients with and without right ventricular dysfunction. In those with NT-proBNP concentrations of 500 pg/mL or higher, we compared baseline characteristics, duration of heparin treatment, and bleeding leading to study drug discontinuation in the edoxaban and warfarin groups. We also assessed quality of warfarin treatment. All analyses were done with the modified intention-to-treat population. The Hokusai-VTE trial is registered with ClinicalTrials.gov, number NCT00986154. Between Jan 28, 2010, and Oct 5, 2012, 8292 patients were enrolled from 439 centres, of whom 8240 received at least one dose of study drug. 3319 patients had pulmonary embolism. NT-proBNP was 500 pg/mL or higher in 465 (30%) of 1565 patients given edoxaban and in 507 (32%) of 1599 given warfarin. Recurrent venous thromboembolism occurred in 14 (3%) of 465 patients in the edoxaban group and 30 (6%) of 507 in the warfarin group (hazard ratio [HR] 0·50, 95% CI 0·26-0·94; p=0·033). The right to left ventricular diameter ratio was 0·9 or higher in 414 (44%) of 937 patients in the edoxaban group and 427 (45%) of 946 in the warfarin group. Recurrent venous thromboembolism occurred in 11 (3%) of 414 and 20 (5%) of 427 patients in the edoxaban and warfarin groups (HR 0·57, 95% CI 0·27-1·17; p=0·13). Baseline characteristics, duration of heparin treatment, and rates of bleeding leading to study drug discontinuation were similar in the edoxaban and warfarin groups and the quality of warfarin management was adequate for patients with NT-proBNP concentrations of 500 pg/mL or higher. Findings from our analysis suggest that edoxaban is more effective than warfarin in the treatment and prevention of recurrent venous thromboembolism in patients with pulmonary embolism and evidence of right ventricular dysfunction. Daiichi Sankyo.

Brekelmans MP ，Ageno W ，Beenen LF ，Brenner B ，Buller HR ，Chen CZ ，Cohen AT ，Grosso MA ，Meyer G ，Raskob G ，Segers A ，Vanassche T ，Verhamme P ，Wells PS ，Zhang G ，Weitz JI ... -  《Lancet Haematology》

Extended duration of anticoagulation with edoxaban in patients with venous thromboembolism: a post-hoc analysis of the Hokusai-VTE study.

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. 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. 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. 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. Daiichi Sankyo.

Raskob G ，Ageno W ，Cohen AT ，Brekelmans MP ，Grosso MA ，Segers A ，Meyer G ，Verhamme P ，Wells PS ，Lin M ，Winters SM ，Weitz JI ，Büller HR ... -  《Lancet Haematology》

Efficacy and safety of edoxaban for treatment of venous thromboembolism: a subanalysis of East Asian patients in the Hokusai-VTE trial.

Direct oral anticoagulants have been evaluated for their efficacy and safety in the treatment of venous thromboembolism (VTE), which comprises deep vein thrombosis and pulmonary embolism. The randomized, double-blind Hokusai-VTE trial demonstrated that 60 mg of edoxaban once daily following initial heparin treatment is non-inferior to heparin overlapped with and followed by warfarin for the treatment of VTE, and is associated with significantly fewer bleeding events. To assess the efficacy and safety of edoxaban versus warfarin among East Asian patients enrolled in the Hokusai-VTE trial. The Hokusai-VTE trial enrolled 8292 patients from 439 centers worldwide, including 1109 patients from Japan, China, Korea, and Taiwan. The primary efficacy and safety outcomes were symptomatic recurrent VTE and clinically relevant bleeding, respectively. In the overall East Asian population, the primary efficacy outcome of symptomatic recurrent VTE occurred in 16 of 563 (2.8%) patients in the edoxaban group versus 24 of 538 (4.5%) patients in the warfarin group (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.34-1.19; P = 0.1601). The primary safety outcome of clinically relevant bleeding occurred in 56 of 563 (9.9%) patients in the edoxaban group versus 93 of 538 (17.3%) patients in the warfarin group (HR 0.56; 95% CI 0.40-0.78; P < 0.001). Edoxaban is an effective and safer alternative to warfarin in East Asian patients with acute VTE who require anticoagulant therapy, consistent with overall study findings from the Hokusai-VTE trial.

Nakamura M ，Wang YQ ，Wang C ，Oh D ，Yin WH ，Kimura T ，Miyazaki K ，Abe K ，Mercuri M ，Lee LH ，Segers A ，Büller H ... -  《-》

Outpatient Management in Patients with Venous Thromboembolism with Edoxaban: A Post Hoc Analysis of the Hokusai-VTE Study.

Medina A ，Raskob G ，Ageno W ，Cohen AT ，Brekelmans MPA ，Chen CZ ，Grosso MA ，Mercuri MF ，Segers A ，Verhamme P ，Vanassche T ，Wells PS ，Lin M ，Winters SM ，Weitz JI ，Büller HR ... -  《-》