[Current status of the management of venous thromboembolism in Japan].

In the past, unfractionated heparin and warfarin have been used as anticoagulants for treatment of venous thromboembolism in Japan. Although it has been effective anticoagulants, these uses are accompanied by several pitfalls, which have led to research and the discovery of new additional groups of anticoagulants: parenteral factor Xa inhibitors, such as fondaparinux, and oral direct factor Xa inhibitors, such as rivaroxaban, apixaban and edoxaban. These new anticoagulants are fast-acting, noninferior to heparin and warfarin in preventing recurrence of venous thromboembolism, and do not require monitoring. These new anticoagulants show promise for improvement of long-term outcome for venous thromboembolism.

The global Edoxaban Treatment in routine cliNical prActice (ETNA) noninterventional study program: rationale and design.

BACKGROUND: Randomized controlled trials showed the nonvitamin K oral anticoagulant (NOAC) edoxaban was effective and safe for stroke and systemic embolism prevention in nonvalvular atrial fibrillation (AF) and for the prevention and treatment of venous thromboembolism (VTE; including pulmonary embolism and deep vein thrombosis). Additional research is needed to evaluate the effects of edoxaban in routine clinical practice. Therefore, the Edoxaban Treatment in routine cliNical prActice (ETNA) program is being conducted to provide routine clinical care data on characteristics and outcomes in patients with AF or VTE receiving edoxaban. METHODS: The Global ETNA program integrates prospectively collected data from edoxaban patients in regional ETNA noninterventional studies across Europe, Japan, and East and Southeast Asia into indication-specific databases for AF and VTE. Targeted enrollment is >31 000 patients (AF >26 000; VTE >4500), with a follow-up of 2 years for AF and 1 year for VTE. Data integration will be possible using consistent terminology, parameter definitions, and data collection across the regional noninterventional studies. Safety and effectiveness data will be assessed. Crude rates of outcomes including bleeding and thromboembolic events will be reported. RESULTS: Globally, enrollment began in early 2015 and is ongoing. CONCLUSIONS: Global ETNA will generate the largest integrated prospective repository of routine clinical care data for a single NOAC in patients with AF or VTE. It will provide important information on the safety of edoxaban in routine clinical care and gather further information on its effectiveness.

[Guidelines for prevention of venous thromboembolism in the West and Japan].

Venous thromboembolism has been a common illness even in Japan and gets increased social as well as medical attention, especially during postoperative period, while guideline for prevention of the disease has been available in the West. Since the clinical experience has shown that there are ethnic differences between Japanese and westerners in coagulability, we need a Japanese own guideline. The guideline based on experts' views in Japan has been formulating, although it is difficult to prepare an ideal one based on reliable evidences for Japanese at present. We expect this first guideline be the foundation for establishment of an ideal one.

Safety and efficacy of edoxaban in patients undergoing hip fracture surgery.

INTRODUCTION: Edoxaban is an oral, direct, once-daily factor Xa inhibitor. This study evaluated the safety and efficacy of edoxaban compared to subcutaneous enoxaparin in Japanese patients undergoing hip fracture surgery. MATERIALS AND METHODS: In this multicenter, randomized, open-label, active-comparator, phase 3 trial, 92 patients were randomized 2:1 to receive edoxaban 30mg once daily (n=62) or enoxaparin sodium (enoxaparin) 2000IU (equivalent to 20mg) twice daily (n=30) for 11 to 14days. The primary endpoints were the incidence of major or clinically relevant non-major (CRNM) bleeding and incidence of any bleeding events (major, CRNM, or minor bleeding). Secondary efficacy endpoints included the incidence of thromboembolic events, venous thromboembolism-related deaths, and all-cause deaths. Additional adverse events were recorded throughout the study. RESULTS: In the edoxaban and enoxaparin treatment groups, the incidence of major or CRNM bleeding was 3.4% and 6.9%, respectively, while any bleeding event occurred in 25.4% and 17.2% of patients, respectively. The incidence of thromboembolic events was 6.5% in the edoxaban group and 3.7% in the enoxaparin group. All events were asymptomatic deep vein thrombosis. The incidence of adverse events was 72.9% and 82.8% in the edoxaban and enoxaparin groups, respectively. CONCLUSIONS: Compared to subcutaneous enoxaparin 2000IU twice daily, oral edoxaban 30mg once daily demonstrated similar safety and efficacy in the prevention of thromboembolic events in Japanese patients undergoing hip fracture surgery. CLINICAL TRIALS REGISTRATION NUMBER: NCT01181141.

Darexaban (YM150) prevents venous thromboembolism in Japanese patients undergoing major abdominal surgery: Phase III randomized, mechanical prophylaxis-controlled, open-label study.

INTRODUCTION: Darexaban (YM150) is an oral direct factor Xa inhibitor in clinical development for prophylaxis of venous thromboembolism (VTE) after major orthopaedic surgery. The objective of this study was to assess the efficacy and safety of darexaban 15 mg twice daily (bid) in Japanese patients undergoing major abdominal surgery. MATERIALS AND METHODS: In a Phase III, multicentre, randomized, open-label, mechanical prophylaxis-controlled, parallel-group study, adult patients (aged ≥ 40 years) were randomized to darexaban 15 mg bid or mechanical prophylaxis, for 28 days. The primary efficacy outcome was incidence of total VTE at Day 12. Adverse events (AEs) and bleeding events were recorded throughout the study. RESULTS: The total VTE incidence at Day 12 was 2.6% in the darexaban 15 mg bid group (95% confidence interval [CI]: 0.32, 9.07), compared with 15.0% (95% CI: 5.71, 29.84) in the mechanical prophylaxis group. During the investigational period, the incidence of all bleeding events was 9.5% in the darexaban 15 mg bid group and 3.9% in the mechanical prophylaxis group. In the darexaban 15 mg bid group, one patient experienced major bleeding and five patients experienced clinically relevant non-major (CRNM) bleeding. No patients in the mechanical prophylaxis group experienced major and/or CRNM bleeding. AEs were reported in 71.4% of patients in the darexaban 15mg bid group and 76.5% of patients in the mechanical prophylaxis group; the most frequent AEs across both treatment groups were constipation and insomnia. No patients died during the study. CONCLUSIONS: Based on these findings, darexaban is expected to be effective for the prevention of VTE in patients undergoing major abdominal surgery. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT00942435).

Clinical features of patients with left atrial thrombus undergoing anticoagulant therapy.

PURPOSE: Left atrial (LA) thrombus was sometimes found by transesophageal echocardiography (TEE) in non-valvular atrial fibrillation (AF), even in the setting of continuous warfarin therapy. A D-dimer cutoff level of 0.50 µg/mL appears to be a useful marker to rule out venous vein thrombosis. This study analyzed the clinical features of patients with LA thrombi who received anticoagulant therapy and whether the D-dimer test is useful to exclude LA thrombus. METHODS: Two hundred twenty-five consecutive patients with AF (149 with paroxysmal and 76 with persistent) were enrolled. All patients received continuous warfarin therapy with the prothrombin time-international normalized ratio (PT-INR) between 1.6 and 3.0 for more than 3 months and TEE was performed. RESULTS: LA thrombi were present in 23 and absent in 202 patients. Age, gender, and PT-INR (1.96 ± 0.59 vs. 1.98 ± 0.53) were not different between the two groups. Persistent AF (65 vs. 30%; p < 0.005), LA diameter (44 ± 5 vs. 40 ± 7 mm; p < 0.005), ejection fraction (57 ± 13 vs. 65 ± 9%; p < 0.005), brain natriuretic peptide levels (203 ± 209 vs. 105 ± 166 pg/mL; p < 0.05), D-dimer (0.55 ± 0.70 vs. 0.16 ± 0.20 µg/mL; p < 0.001), LA appendage flow velocity (33 ± 15 vs. 54 ± 19 cm/s; p < 0.001), CHADS(2) scores (2 ± 1 vs. 1 ± 1; p < 0.005), and CHA(2)DS(2)-VASc scores (3 ± 2 vs. 2 ± 1; p < 0.005) were significantly different in both groups. Although multivariate analysis showed that D-dimer and LA appendage flow velocity were significant independent predictors of LA thrombus, D-dimer levels below 0.5 µg/mL were found in 19 of 23 patients with LA thrombi. CONCLUSION: D-dimer levels below 0.5 µg/mL is not enough to rule out LA thrombus in AF patients with well-controlled anticoagulation.

Efficacy of linear block at the left atrial roof in atrial fibrillation.

BACKGROUND: After extensive encircling of ipsilateral pulmonary vein isolation (EEPVI) for atrial fibrillation (AF), we sometimes observe AF recurrence, or the occurrence of atrial tachycardia originating from the left atrium. This study examined the efficacy of additional linear ablation at the left atrial (LA) roof in combination with EEPVI to prevent arrhythmia recurrences. METHODS: This study included 104 patients with drug-refractory AF (75 with paroxysmal, 29 with persistent). The patients in Group A (n=70) underwent EEPVI treatment alone, and the patients in Group B (n=34) underwent linear ablation at the LA roof in addition to EEPVI treatment. At 1, 3, 6, and 12 months after ablation, patients underwent clinical review and 24-h ambulatory electrocardiogram monitoring to identify asymptomatic arrhythmias. Follow-up included daily trans-telephonic event monitoring, transmitted irrespective of the patient's symptoms. RESULTS: At 12 months, 57% of Group A and 79% of Group B were free of arrhythmias (p<0.05). Cox regression analysis demonstrated that among the variables of age, sex, duration of AF, types of AF (paroxysmal or persistent), LA size, ejection fraction, existence of hypertension, ischemic heart disease, valvular heart disease, history of stroke, and the ablation technique, only the ablation technique of the linear block at the LA roof was the independent predictor of arrhythmia-free recovery after ablation. CONCLUSIONS: EEPVI in combination with the linear ablation at the LA roof is associated with an improved clinical outcome compared with EEPVI alone.