2013年9月1日讯 --第一三共株式会社（Daiichi Sankyo）9月1日在荷兰阿姆斯特丹举行的2013年欧洲心脏病学会年会（ESC 2013）上，公布了有关新型口服抗凝血剂—Xa因子抑制剂edoxaban的一项全球性III期Hokusai-VTE研究的数据。该项研究在8292例急性症状性深静脉血栓（DVT）和/或肺栓塞（PE）患者中开展，评价了edoxaban相对于华法林（warfarin）的疗效和安全性。

研究中，2组最初使用肝素治疗，随后分别接受edoxaban和华法林治疗，用于治疗和预防症状性静脉血栓栓塞（VTE）的复发，结果表明，该项研究达到了edoxaban相较于华法林的非劣效性主要疗效终点。

Hokusai-VTE研究数据同时已在线发表于《新英格兰医学杂志》（NEJM）。

Edoxaban是一种新颖的实验性、口服、每日一次、直接作用的Xa因子抑制剂，是新型口服抗凝血剂市场中的新成员，将与强生（JNJ）拜瑞妥（Xarelto，rivaroxban）、辉瑞（Pfizer）和百时美施贵宝（BMS）Eliquis（apixaban，阿哌沙班）、勃林格殷格翰（Boehringer Ingelheim）Pradaxa（dabigatran，达比加群）展开竞争。

Hokusai-VTE研究旨在广泛的静脉血栓栓塞（VTE）患者（包括那些严重PE患者）中，反映一种灵活的治疗时长（3个月~12个月）的临床实践，包括初始肝素治疗。主要疗效数据包括，edoxaban组症状性VTE复发发病率略低于华法林组（3.2% vs 3.5%，p＜0.001），证明了edoxaban相对于华法林的非劣效性。此外，临床相关出血的既定主要安全性结果表明，edoxaban优于华法林（8.5% vs 10.3%，p=0.004）。

Hokusai-VTE研究中，患者的具体剂量根据研究方案而定，edoxaban给药量为每日口服60mg，但对于伴有通常会影响口服抗凝剂反应的临床因素（肾功能不全、低体重、同时使用某些P-糖蛋白抑制剂）的患者，则每日口服30mg。研究数据表明，30mg edoxaban治疗组的疗效属性与整体研究一致，与华法林组（n=719）相比，30mg edoxaban组（n=733）具有较低的VTE复发事件（VTE复发，3.0% vs 4.2%，HR=0.73，95%CI,0.42-1.26）。临床相关出血发生率，30mg edoxaban组显着低于华法林组（7.9% vs 12.8%，HR=0.62，95％CI，0.44-0.86）。

在DVT患者（n=4921）中，edoxaban组和华法林组VTE复发发病率相似（3.4% vs 3.3%,HR=1.02，95％CI，0.75-1.38）。在PE患者（n=3319）中，edoxaban组VTE复发发病率低于华法林组（2.8% vs 3.9%，HR=0.73,95%CI，0.50-1.06）。此外，在亚组分析中，严重PE和右心功能不全迹象（定义为NT-ProBNP≥500pg/mL，n=938）edoxaban治疗组比华法林组症状性VTE复发风险低48%（3.3% vs 6.2%，HR=0.52, 95%CI,0.28-0.98）。

关于Edoxaban：

Edoxaban是一种实验性、口服、每日一次的抗凝血剂，能够可逆性抑制凝血因子Xa。全球性edoxaban临床项目包括2个III期研究：Hokusai-VTE和ENGAGE AF-TIMI48。前者在深静脉血栓（DVT）和/或肺栓塞（PE）患者中开展，评价edoxaban对症状性静脉血栓栓塞（VTE）复发的治疗和预防。后者在非瓣膜性心房颤动（AF）患者中开展，评价edoxaban对中风和全身性栓塞事件（SEE）的预防。

目前，edoxaban已于2011年4月在日本批准，用于预防骨科大手术后静脉血栓栓塞（VTE），该药于2011年7月以商品名Lixiana上市。此外，在其他地方，包括欧洲和美国，edoxaban目前正处于III期临床开发，尚未获批任何适应症。ENGAGE AF-TIMI 48研究将提交至2013年11月19日召开的美国心脏学会（AHA）科学年会。

关于Hokusai-VTE试验：

Hokusai-VTE是一项全球性、事件驱动的、随机、双盲、平行组III期临床研究，涉及全球38个国家和地区439个临床试验点的8292例症状性深静脉血栓（DVT）和/或肺栓塞（PE）患者中开展。

研究中，患者被随机分配至2个治疗组之一。2组都接受至少5天开放标签依诺肝素（enoxaparin）或未级分肝素（unfractionated heparin，UFH）治疗，以及华法林（warfarin）或安慰剂（edoxaban组），随后进行双盲edoxaban 60mg（n=4118）（肾功能不全患者或低体重患者或使用P-糖蛋白抑制剂的患者，edoxaban给药量为30mg）或华法林（n=4122）治疗至少3个月至最长12个月（由研究者根据患者的临床特点决定）。随后对患者随访12个月，以更好地了解临床实践的预后。

研究的主要疗效终点是症状性VTE复发，定义为为期12周研究期间症状性DVT、非致死性症状性PE、致死性PE复合复发率。主要的安全性终点是治疗期间或中断/终止治疗3天内临床相关性出血（重大或非重大）的发生率。次要疗效终点包括症状性DVT复发、非致死性PE复发、全因死亡的复合临床预后。

Positive Results for New Anticoagulant From Daiichi Sankyo

Daiichi Sankyo’s Once-Daily Edoxaban Shows Comparable Efficacy and Superiority for the Principal Safety Endpoint Compared to Warfarin in a Phase 3 Study for the Treatment of Symptomatic VTE and Prevention of its Recurrence

?Hokusai-VTE, the first global phase 3 double-blind study for once-daily edoxaban and the largest single comparative study for this patient population, achieves these results in a broad spectrum of VTE patients, including those with severe pulmonary embolism

?Efficacy and safety findings were consistent with the overall results for patients administered edoxaban 30 mg for renal impairment or low body weight

?Results from Hokusai-VTE presented during ESC Congress 2013 Hot Line session and published in the New England Journal of Medicine

Tokyo, Japan, September 1, 2013 – Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) today announced results from the global phase 3 Hokusai-VTE study of 8,292 patients with either acute symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE), or both. The study found that the investigational, oral, once-daily direct factor Xa-inhibitor edoxaban met the primary efficacy endpoint of non-inferiority compared to warfarin, following initial use of heparin in both arms, for the treatment and prevention of recurrent symptomatic venous thromboembolism (VTE). Once-daily edoxaban also demonstrated superiority compared to warfarin for the principal safety outcome of clinically relevant bleeding (the composite of major or clinically relevant non-major bleeding).1 Results from Hokusai-VTE were presented today at the ESC Congress 2013 in Amsterdam and published online in the New England Journal of Medicine.

The Hokusai-VTE study was designed to reflect clinical practice using a flexible treatment duration of three to 12 months, including initial heparin treatment, in a broad spectrum of VTE patients, including those with severe PE. For the primary efficacy outcome, edoxaban demonstrated non-inferiority with a numerically lower incidence of recurrent symptomatic VTE compared to warfarin (3.2% vs. 3.5%, respectively) (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.70 to1.13; P<0.001 for non-inferiority).1 Edoxaban was also found to be superior to warfarin for the pre-specified principal safety outcome of clinically relevant bleeding (8.5% vs. 10.3%, respectively) (HR, 0.81; 95% CI, 0.71 to 0.94; P=0.004 for superiority).1

In the Hokusai-VTE study, patient specific dosing was applied according to the study protocol. Edoxaban was dosed at 60 mg once-daily, except for those patients with clinical factors that commonly impact response to oral anticoagulants (renal impairment, low body weight, or concomitant use of certain p-glycoprotein inhibitors) who received edoxaban 30 mg according to the study protocol. The reduced dose of edoxaban was found to have an efficacy profile consistent with the overall study cohort, with fewer recurrent VTE events in patients receiving 30 mg edoxaban (n=733) compared to warfarin (n=719) (VTE recurrence of 3.0% vs. 4.2%; HR, 0.73; 95% CI, 0.42 to 1.26). Clinically relevant bleeding in patients receiving edoxaban 30 mg was significantly lower compared to warfarin (7.9% vs. 12.8%, respectively) (HR, 0.62; 95% CI, 0.44 to 0.86).1

Among patients with DVT (n=4,921), VTE recurrence was similar in the edoxaban and warfarin groups (3.4% vs. 3.3%, respectively) (HR, 1.02; 95% CI, 0.75 to 1.38), while the incidence of recurrent VTE among patients with PE (n=3,319) was numerically lower for patients treated with once-daily edoxaban compared to warfarin (2.8% vs. 3.9%, respectively) (HR, 0.73; 95% CI, 0.50 to 1.06). Additionally, in a sub-group analysis, patients with severe PE and evidence of right ventricular dysfunction (defined as NT pro-BNP ≥ 500 pg/mL, n=938) treated with edoxaban had a 48% lower risk of recurrent symptomatic VTE compared to warfarin (3.3% vs. 6.2%, respectively) (HR, 0.52; 95% CI, 0.28 to 0.98).1

“Hokusai-VTE was designed to include a broad range of VTE patients, including those with severe pulmonary embolism, and we are therefore pleased that the study found that edoxaban administered once-daily is as efficacious as warfarin for the prevention of recurrent symptomatic VTE while significantly reducing the risk of bleeding,” said Harry Büller, MD, PhD, Professor of Internal Medicine, Chairman of the Department of Vascular Medicine at the Academic Medical Center in Amsterdam, The Netherlands and Chairman of the Hokusai-VTE steering committee. “A promising finding was the sizeable reduction in recurrent symptomatic VTE among patients with severe pulmonary embolism who were treated with edoxaban.”

“We are excited about the results from the Hokusai-VTE study demonstrating that once-daily edoxaban may provide a new treatment option for a broad range of VTE patients. Daiichi Sankyo plans to submit New Drug Applications for edoxaban for VTE by the first quarter of 2014 in the US, Japan and Europe,” said Glenn Gormley, MD, PhD, Global Head of Research and Development and Senior Executive Officer, Daiichi Sankyo. “Daiichi Sankyo is committed to continuing the global development of edoxaban and looks forward to the presentation of the results from the phase 3 ENGAGE AF-TIMI 48 study in patients with atrial fibrillation at the 2013 American Heart Association Scientific Sessions in November.”

About Hokusai-VTE

Hokusai-VTE was a global, event-driven, randomized, double-blind, parallel-group phase 3 clinical study involving 8,292 patients in 439 clinical sites across 37 countries to evaluate once-daily edoxaban in patients with symptomatic DVT and/or PE.1

Patients were randomized to one of two different treatment groups. Both groups received open-label enoxaparin or unfractionated heparin for at least five days, and either warfarin or placebo (administered to edoxaban group), followed by double-blind edoxaban 60 mg (n=4,118) (edoxaban 30 mg for patients with renal impairment or low body weight or p-glycoprotein inhibitor use) or warfarin (n=4,122) for at least three months and up to a maximum of one year (duration of study treatment was determined by the investigator based on the patient’s clinical features). Patients were followed for 12 months regardless of treatment duration to provide investigators with a better understanding of outcomes in clinical practice relative to an on-treatment analysis only.1

The primary efficacy outcome was the recurrence of symptomatic VTE, defined as the composite of recurrent symptomatic DVT, non-fatal symptomatic PE and fatal PE in patients during the 12-month study period. The principal safety outcome was clinically relevant bleeding (major or non-major) occurring during or within three days of interrupting or stopping study treatment. Secondary efficacy outcomes included the composite clinical outcome of symptomatic recurrent DVT, non-fatal symptomatic recurrent PE and all-cause mortality.1

The study is named after the famous Japanese artist and painter Katsushika Hokusai.

About Venous Thromboembolism

VTE is an umbrella term for two conditions, DVT and PE. DVT is a blood clot found anywhere in the deep veins of the legs, while PE occurs when part of a clot detaches and lodges in the pulmonary arteries, causing a potentially fatal condition.2

VTE is a major cause of morbidity and mortality worldwide with an annual incidence of approximately one per 1,000 in developed countries, including an estimated 430,000 PE events, 680,000 DVT events and 540,000 deaths each year in the EU.3,4 In the U.S., it is currently estimated that more than 950,000 VTE events and approximately 300,000 VTE related deaths occur each year.5,6 Thirty percent of people with VTE die within one month of diagnosis and about 20% of those with PE experience sudden death.7

About Edoxaban

Edoxaban is an investigational, oral, once-daily anticoagulant that specifically and reversibly inhibits factor Xa, which is an important factor in the coagulation system that leads to blood clotting.8 The global edoxaban clinical trial program includes two phase 3 clinical studies, Hokusai-VTE and ENGAGE AF-TIMI 48 (Effective aNticoaGulation with Factor XA Next GEneration in Atrial Fibrillation), which are evaluating edoxaban, administered once-daily, for treatment and prevention of recurrence of venous thromboembolism (VTE) in patients with deep vein thrombosis (DVT) and/or pulmonary embolism (PE), and for the prevention of stroke and systemic embolic events (SEE) in patients with non-valvular atrial fibrillation, respectively.9

Edoxaban is currently approved only in Japan, since April 2011, for the prevention of VTE after major orthopedic surgery, and was launched in July 2011 under the brand name Lixiana?. Elsewhere, including Europe and the U.S., edoxaban is currently in phase 3 clinical development and has not been approved in any indication.10 Results from the ENGAGE AF-TIMI 48 study will be presented at the American Heart Association Scientific Sessions on November 19th, 2013.

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