Apixaban是施贵宝和辉瑞双方合作研发的最新抗凝制剂，是一种口服的高选择性Xa因子抑制剂。目前正处于研发阶段，如果Apixaban研发成功，有望取代使用时间已长达50年的老抗凝剂华法林，为临床防治静脉血栓栓塞提供一种更安全有效的抗凝药物。

这次实验被命名为ADVANCE-3，为期35天，研究人员主要观察那些正接受全髋关节置换术的患者用药治疗之后在降低静脉血栓栓塞方面的效果。在实验过程中，Apixaban受试者每天用药两次，每次服用2.5毫克进行治疗，而对照组则每天使用一次经皮给药的依诺肝素进行治疗，剂量为40毫克。

结果发现，Apixaban受试组中有1.4%的人出现下肢深静脉血栓，未出现具有致命性的肺部血栓和死亡病例，而依诺肝素钠对照组有3.9%的人出现下肢深静脉血栓。这些数据表明，与依诺肝素钠对照组相比，Apixaban受试组能将静脉血栓栓塞的风险降低64%。

此外，对于那些正接受膝关节置换术的患者，Apixaban在防止静脉血栓栓塞方面的效果也优于依诺肝素钠。实验中，两个组别在出现大出血和临床非大出血等副作用方面相差无几。
ELIQUIS® (apixaban) Approved In Europe For Preventing Venous Thromboembolism After Elective Hip Or Knee Replacement

• ELIQUIS demonstrated superior efficacy versus enoxaparin 40 mg once daily without increased bleeding
• ELIQUIS is the only oral anticoagulant with a 12- to 24-hour post surgery initiation window
• First approval for ELIQUIS, a new oral direct Factor Xa inhibitor

PRINCETON, N.J. & NEW YORK--(BUSINESS WIRE)-- The European Commission has approved ELIQUIS® in the 27 countries of the European Union (EU) for the prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery. This decision marks the first approval for ELIQUIS®, a new oral direct Factor Xa inhibitor being developed by the alliance of Bristol-Myers Squibb Company and Pfizer Inc.

"Major orthopedic surgery, such as total knee replacement or total hip replacement, puts patients at a very high risk of developing VTE or pulmonary embolism. The absolute risk of deep vein thrombosis for these patients ranges from 40 to 60 percent when these patients do not receive preventive care," said Michael Rud Lassen, M.D., Glostrup Hospital in Copenhagen, Denmark, and lead investigator for the Phase 3 orthopedic trials for ELIQUIS. "The approval of ELIQUIS gives European orthopedic surgeons a new option in VTE prevention that is more effective than the current standard of care, enoxaparin 40 mg once daily, and importantly, without increasing bleeding."

The approval of ELIQUIS is based on the ADVANCE-2 and ADVANCE-3 clinical trials, part of the EXPANSE clinical trial program. In these trials, ELIQUIS given orally twice daily demonstrated superior efficacy versus enoxaparin 40 mg given once daily by injection in the prevention of VTE in total knee and total hip replacement, and did not increase the risk of bleeding versus enoxaparin. These trials randomized over 8,000 patients and assessed the safety and efficacy of ELIQUIS compared to enoxaparin. The primary efficacy endpoint of ADVANCE-2 and ADVANCE-3, which studied patients undergoing elective total knee or hip replacement, respectively, was defined as the composite of asymptomatic and symptomatic deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and death from any cause during study treatment. The principal safety measure in the trials was the composite of major and clinically relevant non-major bleeding.

ELIQUIS is the only oral anticoagulant with a 12- to 24-hour post surgery initiation window, which may help physicians to observe and stabilize post-surgical patients before beginning treatment. ELIQUIS is dosed 2.5 mg twice daily, requires no routine platelet or liver monitoring, and requires no dose adjustment in indicated patients. In patients undergoing hip replacement surgery, the recommended duration of treatment is 32 to 38 days. In patients undergoing knee replacement surgery, the recommended duration of treatment is 10 to 14 days.

"As the first ELIQUIS approval worldwide, today marks an important milestone for the Bristol-Myers Squibb/Pfizer Alliance," said Beatrice Cazala, senior vice president, Commercial Operations, and president, Global Commercialization, Europe and Emerging Markets, Bristol-Myers Squibb. "We are confident that our shared resources and leadership in the treatment of cardiovascular disease will help make the European launch a success and continue to bring value to the development of ELIQUIS."

"The approval of ELIQUIS provides a new oral option for patients in the EU undergoing elective hip or knee replacement surgery, where the risk of bleeding is a significant concern," said Olivier Brandicourt, president and general manager, Primary Care, Pfizer Inc. "We are excited to bring this new agent to market in Europe and provide orthopedic surgeons with an option that will help them to prevent VTE in patients undergoing elective total knee or total hip replacement surgery."

About Venous Thromboembolism

VTE encompasses two serious conditions: DVT, a blood clot in a vein, usually in the leg that partially or totally blocks the flow of blood; and PE, a blood clot blocking one or more vessels in the lungs. DVT causes multiple symptoms including pain, swelling and redness and, more importantly, can progress to PE, which carries the risk of sudden death.

About the ELIQUIS® Clinical Trial Program

ELIQUIS® is being investigated within the EXPANSE Clinical Trials Program, which is projected to include nearly 60,000 patients worldwide across multiple indications and patient populations and includes a total of nine completed or ongoing, randomized, double-blind Phase 3 trials, including the ADVANCE trials.

In addition to prevention of VTE in orthopedic surgery, ELIQUIS is being investigated in Phase 3 trials for the treatment of VTE, the prevention of VTE in hospitalized acutely ill medical patients and the prevention of stroke and other thromboembolic events in patients with atrial fibrillation.

About the Bristol-Myers Squibb/Pfizer Collaboration

In 2007, Pfizer and Bristol-Myers Squibb entered into a worldwide collaboration to develop and commercialize ELIQUIS, an investigational oral anticoagulant discovered by Bristol-Myers Squibb. This global alliance combines Bristol-Myers Squibb's long-standing strengths in cardiovascular drug development and commercialization with Pfizer's global scale and expertise in this field.
阿哌沙班用于髋关节及膝关节术后获批准

欧盟已经批准口服直接Xa因子抑制剂阿哌沙班（Apixaban，Eliquis，百时美施贵宝/辉瑞公司制造）在欧盟27个成员国使用，用于预防接受择期髋关节或膝关节置换术的成年患者出现静脉血栓栓塞症（VTE）事件。这是全球首个获批用于此的药物。

阿哌沙班获批是基于ADVANCE-2和ADVANCE-3临床试验，试验结果表明，与每日注射一次40mg伊诺肝素（Enoxaparin）相比，每日口服两次阿哌沙班对预防全膝和全髋关节置换术出现VTE的疗效更优，而且还不会增加出血风险。

阿哌沙班的推荐剂量是2.5mg（每日两次）。对接受髋关节置换手术和膝关节置换手术的患者，推荐的治疗时间分别为32-38天和10-14天。

阿哌沙班是即将或已经上市的众多新型口服抗凝剂中的一种。还有两种新型抗凝剂，在一些国家已经获批用于预防VTE一段时间，一种是Xa因子抑制剂利伐沙班（Rivaroxaban，商品名Xarelto，拜耳/强生制造），另一种是直接凝血酶抑制剂达比加群（Dabigatran，商品名Pradaxa，德国勃林格殷格翰制造）。

在欧洲批准的这三种口服抗凝剂中，与目前骨科手术后预防VTE的护理标准伊诺肝素相比，利伐沙班和阿哌沙班分别在RECORD试验和ADVANCE试验中突显优势。加拿大安大略省汉密尔顿市麦克玛司特大学Alexander Turpie博士是此领域的专家，他曾表示，将这些试验的结果并排来看，利伐沙班的疗效似乎略好，但出血情况比阿哌沙班严重。他将这些差异归因于用药时间，在RECORD试验中利伐沙班是在手术后6-8个小时用药，而在ADVANCE试验中阿哌沙班是在手术后18个小时用药，这些药物的用药时间离手术越近，其疗效越好，但出血风险越高。

百时美施贵宝/辉瑞公司拿ADVANCE试验中阿哌沙班的用药时间进行宣传，称该药是唯一一种术后首次用药窗口期为12-24小时的口服抗凝药，可帮助医师在术后病人开始治疗前对其进行观察并稳定病情。然而，一天一次的新型口服抗凝剂——利伐沙班，也有其优势。

达比加群在骨科方面未显示出与上述两种抗凝剂相当的效果，它仅在两项研究中表现得不逊于当前的标准护理，在其他试验中仍较为逊色。

但是达比加群已率先获得较大适应症，该药已在美国与加拿大获批用于预防房颤患者出现中风。利伐沙班虽对此适用范围也显示出很好结果，但还没有获得批准。

阿哌沙班的III期临床试验正进行的研究是针对VTE的治疗、重病住院医疗患者出现VTE的预防、及房颤患者出现中风和其他血栓栓塞事件的预防。因在APPRAISE-2试验中发现该药有不可接受的出血风险，所以不再开发它用于急性冠状动脉综合征（ACS）。

阿哌沙班（apixaban）减少54%卒中、血栓意外
8月31日，研究人员在2010年欧洲心脏病学会年会（ESC）报告时称：高危患者使用Xa因子抑制剂阿哌沙班（apixaban）与服用阿司匹林者相比，卒中或全身性栓塞事件风险减少54％。
汉密尔顿大学Stuart Connolly博士介绍了阿哌沙班与乙酰水杨酸比较预防卒中研究（AVERROES）的结果，以阿司匹林预防的病人卒中和全身性栓塞发生率均为3.9％ - 这两项组合即为该研究的主要考核指标 – 而使用阿哌沙班患者中发生率为1.7％（P <0.001）。
研究者招募的病人患有心房颤动，并至少有另外一种卒中危险因素，他们无法成功地使用维生素K拮抗剂作为抗凝剂，或者他们不适宜使用维生素K拮抗剂。
患者随机接受阿哌沙班 5毫克，每日两次（809例）或阿司匹林81至324毫克/天（2791例）。
这些患者的中位年龄为70岁，约60％为男性。超过85％患者有高血压，约40％有心脏衰竭，约20％有糖尿病。
21个月后该患者人群中以阿哌沙班治疗明显优于阿司匹林时该试验被中止。
Connolly 博士指出：“如果我们以阿哌沙班不是阿司匹林治疗1000名患者，就可以防止18例卒中事件，10人死亡，免除31例因心血管事件住院，这实在是一个很了不起的数字。”在一年治疗中出现2起大出血事件。
除了达到上述主要指标的肯定结果外，以阿哌沙班治疗还有以下：
与阿司匹林比较，显著减少卒中、全身栓塞事件、心肌梗死或血管性死亡，达34％（P <0.001）。
心血管疾病住院率明显降低（P <0.001）。
总死亡率趋于减少（P =0.07）。
没有增加严重出血风险（P =0.56）。