药物：Eliquis（阿哌沙班，apixaban）
疾病：心血管病
开发商：辉瑞（Pfizer）和百时美施贵宝（Pfizer and Bristol-Myers Squibb）
欧洲药品监管机构已批准其备受瞩目的血管稀释剂ELIQUIS® (apixaban 阿哌沙班），该药用于接受过臀部或膝部置换手术患者的血栓预防。
该药由辉瑞与百时美施贵宝联合开发，两公司将分享利润，这一批准将意味着该药可以在欧盟的27个成员国使用。
临床研究结果表明，接受2次/天Eliquis治疗的效果要优于接受目前典型注射剂治疗的效果。
Eliquis能预防血栓，但出血的不良反应低于老药华法林，因而被认为是一只具有“重磅炸弹”潜力的药物。然而，辉瑞去年被迫停止一项有10000例心脏病史患者参与的临床试验，试验停止的原因是由于使用本品后，出现了许多意外的出血副作用。
Eliquis在美国还未上市，辉瑞和百时美施贵宝计划今年晚些时候向FDA提交上市申请，他们正争取将该有用于预防中风，主要用于有心脏病的患者。
同类药物中，勃林格殷格翰（Boehringer Ingelheim）的Pradaxa已经上市，拜耳（Bayer）和强生（J&J）的拜瑞妥（Xarelto）正在等待FDA的批准，辉瑞被抛在了后面。不过Eliquis还是很有可能最终获批，并成为一个巨型炸弹药物的有力竞争者。过不了多少日子，立普妥（Lipitor）就将失去专利保护，所以Eliquis对辉瑞来说是个好消息。对于百时美施贵宝，在今年好几个重要药物获得FDA批准后，Eliquis无疑是有一个明确的目标。
急性冠脉综合征使用阿哌沙班（一种口服的选择性活化Ⅹ因子抑制剂）联合抗血小板治疗。
背景：发生急性冠脉综合征后患者仍保持着再发的风险。阿哌沙班（一种口服的选择性活化Ⅹ因子抑制剂）作为新的抗凝剂，可能减少这些事件发生，但同时会增加出血风险。
方法与结果：APPRAISE是一项临床二期、随机双盲、剂量分类、对照试验。共有1,715名近期发生ST段抬高或非ST段抬高急性冠脉综合征患者入选，随机分为对照组和四个阿哌沙班不同剂量组：2.5 mg 每天两次 (317例), 10 mg 每天一次 (318例), 10 mg 每天两次(248例), 20 mg 每天一次 (221例)，疗程6月。几乎所有患者均接受阿司匹林治疗，76％使用氯吡格雷。
初级终点是国际血栓和止血学会规定的主要或临床相对非主要出血事件。次级终点是心血管死亡、心梗、严重再次缺血事件、缺血性卒中。
根据数据监管委员会推荐，两个高剂量组由于总出血事件过多而终止。
与对照组相比，阿哌沙班2.5mg 每天两次组（风险比1.78，95％可信区间0.91－3.48，P＝0.09）和10mg 每天一次组（风险比2.45，95％可信区间1.31－4.61，P＝0.005）结果导致主要出血或临床相对非主要出血事件患者剂量依赖的增加。
阿哌沙班2.5mg 每天两次组（风险比0.73，95％可信区间0.44－1.19，P＝0.21）和10mg 每天一次组（风险比0.61，95％可信区间0.35－1.04，P＝0.07）与对照组相比缺血事件发生率更低。
使用阿司匹林加氯吡格雷的患者与单用氯吡格雷患者相比，出血事件增加更显著，缺血事件减少证据不明显。
结论：近期发生急性冠脉综合征患者中，研究者观察到抗血小板治疗基础上加用阿哌沙班可引起剂量依赖的出血事件增加以及缺血事件减少的趋势。
阿哌沙班的安全性及有效性可能依赖于基础抗血小板治疗。再发缺血事件风险的患者使用阿哌沙班需要进一步试验。
来源：《Circulation》
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预防房颤患者卒中风险 阿哌沙班可补华法林之不足
房颤是常见的心律失常，会增加卒中的风险。维生素K拮抗剂（如华法林）具有预防房颤患者卒中的作用。然而，很多具有卒中高风险的房颤患者却不适合或不愿意接受维生素K拮抗剂治疗。阿哌沙班（Apixaban）是一种新型的凝血因子Xa抑制剂，AVERROES研究比较了其与阿司匹林在房颤患者中卒中预防效果，其结果表明阿哌沙班或许能克服传统抗凝药物的缺憾而成为这类患者的新选择。
维生素K拮抗剂被证实预防房颤患者卒中的效果优于阿司匹林。但是因为治疗获益的窗口窄且获益在不同人中差异很大，因此需要终身监测凝血。维持国际标准化比率（INR）在治疗范围是该类药物的一个挑战。对于很多患者而言，他们的INR低于正常60%，这抵消了维生素K拮抗剂的潜在获益，并增加了其大出血的风险。因此，至少1/3有卒中风险的房颤患者，或没有开始维生素K拮抗剂治疗，或开始治疗后又终止治疗。阿司匹林减低房颤患者卒中风险约20%而被用于治疗不适合维生素K拮抗剂治疗的房颤患者。在阿司匹林基础上加上氯吡格雷，进一步减少了卒中风险达28%，但是这一联合会增加大出血的风险。因此需要更好的抗血栓药物。
阿哌沙班是一种凝血Xa因子的直接、竞争性抑制剂，其生物利用度达50%，近25%经肾排泄。阿哌沙班（2.5mg，Bid）曾被证实预防骨科择期手术后静脉血栓栓塞安全有效。AVERROES研究(阿哌沙班相比乙酰水杨酸预防维生素K拮抗剂治疗失败或不适宜的心房颤动患者卒中研究)，旨在比较阿哌沙班（5mg，bid）和阿司匹林（81mg～324mg/d）在维生素K拮抗剂治疗失败或不适宜的心房颤动患者中预防卒中的作用。
AVERROES研究是一项随机、双盲、国际多中心的研究，涉及36个国家522个研究中心。时间跨度从2007年9月10日～2009年12月23日，共入组5599例卒中风险增高而不适合接受维生素K拮抗剂治疗的房颤患者。入组标准：年龄≥50岁以上；入组前6个月证实有房颤或者在入组筛选当天通过12导联心电图证实有房颤。此外应有以下至少一个卒中风险因素：以前有卒中或短暂性脑缺血病史；年龄≥75岁；高血压（正在接受治疗）；糖尿病（正在治疗）；心衰（NYHA分级≥2级）；左室射血分数（LVEF）≤35%；证实有外周血管疾病。患者不能接受维生素K拮抗剂治疗的原因是已经证实或预期不适合采用该药治疗。主要的排查标准：除外房颤，患者还有其他的需要长期抗凝的疾病或者需要外科手术的血管疾病；6个月内有严重的出血事件或有出血高风险（如活动性溃疡，血小板<100000/mm3，或血红蛋白<10g/dL，10d前有卒中，证实有出血倾向，血液紊乱）；目前有酒精或药物滥用的精神性疾病；预期寿命小于1年；严重的肾功能不全(Scr>2.5mg/dL或221μmol/L，计算肌酐清除率<25mL/min)；ALT或AST大于正常的上限的两倍；胆红素大于正常上限的1.5倍。
患者被随机分到阿哌沙班组（5mgbid）或阿司匹林组（81～324mg/d），平均随访时间是1.1年，主要研究终点是卒中或体循环栓塞的发生。入组前患者的基线临床特征基本一致。在入组筛选前30天，3/4的患者已经在服用阿司匹林治疗，15%的患者已经在服用维生素K拮抗剂治疗。在5599例患者中，2216例（40%）开始使用后又终止了维生素K拮抗剂治疗，其中932例（42%）INR不能维持在治疗范围。鉴于阿哌沙班的明显获益，数据和安全监测委员会建议提前终止研究。结果显示，阿哌沙班组有51例有效终点事件（年发生率1.6%），而阿司匹林组为113例（年发生率3.7%）阿哌沙班显著降低了卒中和体循环栓塞的风险（风险比HR0.4595CI:0.32~0.62,P<0.001）。阿哌沙班组的死亡率每年3.5%，而阿司匹林是4.4%（HR 0.79; 95%CI:0.62~1.02,P=0.07)。阿哌沙班还显著降低因为心血管原因首次住院的发生率（12.6%/年 vs. 15.9% /年, P<0.001)。在不良事件方面，阿哌沙班的重大出血事件为44例（1.4%/年），阿司匹林为39例（1.2%/年），没有显著差别（HR 1.13，95%CI: 0.74~1.75, P=0.57)。其中颅内出血阿哌沙班为11例，而阿司匹林是13例（HR 0.85, 95CI:0.38~1.90, P=0.69）。亚组分析显示，无论此前是否使用过维生素K拮抗剂，阿哌沙班的获益一致。在有卒中或短暂性脑缺血发作病史的764例患者中，阿哌沙班显著减少了卒中或系统血栓的发生（2.5%/年vs. 8.3%/年）。
因此，该研究提示，在维生素K拮抗剂治疗不适合的房颤患者中，阿哌沙班减低卒中和系统性栓塞的风险而不显著增加重大出血或颅内出血的风险，可作为维生素K拮抗剂或氯吡格雷+阿司匹林的安全替代药物。
新药阿哌沙班获批 意味着在成员国内使用
近期，由辉瑞与百时美施贵宝联合开发的新药血管稀释剂eliquis（阿哌沙班）已获得了欧洲药品监管机构的批准。早前，该药就受到了各界的广泛关注。据辉瑞表示，该药用于接受过臀部或膝部置换手术患者的血栓预防。
据了解，此药由辉瑞与百时美施贵宝联合开发的，利润也是由两公司共同分享，这一批准将意味着该药可以在欧盟的27个成员国使用。
据临床研究结果表明，接受2次/天eliquis治疗的效果要优于接受目前典型注射剂治疗的效果。
据有关专家介绍说，eliquis能预防血栓，但出血的不良反应低于老药华法林，因而被认为是一只具有“重磅炸弹”潜力的药物。然而，辉瑞去年被迫停止一项有10000例心脏病史患者参与的临床试验，试验停止的原因是由于使用本品后，出现了许多意外的出血副作用。
现阶段，在美国市场上还看不到新药血管稀释剂eliquis的身影，辉瑞和百时美施贵宝计划今年晚些时候向fda提交上市申请，他们正争取将该有用于预防中风，主要用于有心脏病的患者。
ELIQUIS® (apixaban) was Superior to Warfarin for the Reduction of Stroke or Systemic Embolism with Significantly Less Major Bleeding in Patients with Atrial Fibrillation in Phase 3 ARISTOTLE Trial
ARISTOTLE Demonstrated that ELIQUIS is the First Oral Anticoagulant to Significantly Reduce All-Cause Death
ELIQUIS, Compared to Standard of Care Warfarin, Significantly Reduced:
Risk of stroke or systemic embolism by 21 percent
Risk of major bleeding by 31 percent
Mortality by 11 percent
PRINCETON, N.J. & NEW YORK--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) and Pfizer Inc. (NYSE:PFE) today announced the main results of the Phase 3 clinical trial ARISTOTLE, which evaluated ELIQUIS® (apixaban) compared to warfarin for the prevention of stroke or systemic embolism in 18,201 patients with atrial fibrillation and at least one risk factor for stroke. In the ARISTOTLE trial, ELIQUIS as compared with warfarin significantly reduced the risk of stroke or systemic embolism by 21 percent, major bleeding by 31 percent, and mortality by 11 percent. Results were presented today during the Hot Line session at the European Society of Cardiology Congress in Paris, France, and published in The New England Journal of Medicine.
Conducted in 1,034 centers in 39 countries, the study was coordinated by the Duke Clinical Research Institute, Durham, N.C., and Uppsala Clinical Research Institute, Uppsala, Sweden.
“The risk for stroke in patients with atrial fibrillation is a major public health concern in an aging population,” said Dr. Christopher B. Granger, professor of medicine, Duke Clinical Research Institute, Duke University Medical Center, Durham, N.C., and lead investigator of the study. “We are therefore encouraged by the outcome of the ARISTOTLE trial, which showed that apixaban, as compared with warfarin, significantly reduced the risk of stroke or systemic embolism, major bleeding, and mortality.”
ELIQUIS, a new oral direct Factor Xa inhibitor, is part of a class of agents being studied for their potential to prevent and treat blood clots.
Atrial fibrillation is the most common sustained cardiac arrhythmia, or irregular heart beat. It is estimated that more than 5 million Americans and 6 million individuals in the European Union have atrial fibrillation. The lifetime risk of atrial fibrillation is estimated to be approximately one in four for individuals 40 years of age or older. The most serious medical issue for individuals with atrial fibrillation is the increased risk of stroke, which is five times higher in people with atrial fibrillation than those without atrial fibrillation. In fact, 15 percent of all strokes are attributable to atrial fibrillation in the U.S. Additionally, strokes due to atrial fibrillation are more burdensome than strokes not due to atrial fibrillation. Atrial fibrillation-related strokes are more severe than other strokes with an associated 30-day mortality of 24 percent and a 50 percent likelihood of death within one year.
About ARISTOTLE
ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation), a randomized, double-blind, multicenter, head-to-head trial, included 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The mean CHADS2 risk score for the study population was 2.1. Patients were randomized to receive either apixaban (n=9,120) 5 mg twice daily (2.5 mg twice daily in selected patients) or warfarin (n=9,081) dosed to achieve a target INR (International Normalized Ratio) of 2.0-3.0.
The key study outcomes were prespecified in a hierarchical manner that sequentially tested apixaban versus warfarin for noninferiority on the composite endpoint of stroke or systemic embolism; superiority on the composite endpoint of stroke or systemic embolism; superiority on major bleeding; and superiority on all-cause death. The efficacy analyses included all randomized patients (“intention to treat”); bleeding analyses were “on treatment” and included all randomized patients who received at least one dose of study drug. ELIQUIS demonstrated non-inferiority (p<0.001) for the primary efficacy outcome, composite of stroke or systemic embolism, compared with warfarin. The relative risk reduction was 21 percent with annual event rates of 1.27 percent for ELIQUIS and 1.60 percent for warfarin in an intention to treat analysis. Additionally, ELIQUIS met the key secondary objective of superiority for the primary outcome of the composite of stroke or systemic embolism (p=0.01). The predominant effect on stroke prevention was on hemorrhagic stroke, which was 49 percent lower with ELIQUIS than warfarin, along with an effect on ischemic or uncertain stroke that was 8 percent lower with ELIQUIS than with warfarin.
Results from ARISTOTLE also demonstrated that ELIQUIS was superior to warfarin for the primary safety outcome of ISTH major bleeding (p<0.001), yielding a significant relative risk reduction of 31 percent, with annual event rates of 2.13 for ELIQUIS and 3.09 for warfarin. Additionally, ELIQUIS significantly reduced the risk for ISTH major or clinically relevant non-major bleeding by 32 percent (p<0.001) compared to warfarin. Any bleeding was reduced 29 percent per year compared with warfarin (p<0.001). With ELIQUIS, the risk for intracranial hemorrhage was significantly reduced by 58 percent compared with warfarin (p<0.001). Fatal bleeding (including fatal hemorrhagic stroke) was numerically lower with ELIQUIS (10) than warfarin (27), in an on treatment analysis.
ARISTOTLE demonstrated that ELIQUIS is the first novel oral anticoagulant to significantly reduce all-cause death compared to warfarin. For the prespecified key secondary efficacy outcome of all-cause death, ELIQUIS was superior to warfarin (p=0.047). Specifically, there was a statistically significant 11 percent relative risk reduction with ELIQUIS compared to warfarin, with annual event rates of 3.52 percent and 3.94 percent, respectively.
In ARISTOTLE, adverse events were similar in the ELIQUIS (81.5 percent) and warfarin (83.1 percent) groups, as were serious adverse events (35.0 percent with ELIQUIS and 36.5 percent with warfarin). Discontinuation of study drug was significantly less common with ELIQUIS (25.3 percent of patients, 3.6 percent due to death) than with warfarin (27.5 percent of patients, 3.8 percent due to death)(p=0.001). Among patients on warfarin, time in therapeutic INR (International Normalized Ratio) range of 2.0–3.0 was a median of 66.0 percent and mean of 62.2 percent, excluding INR values during the seven days following randomization and during study drug interruptions.
Overall, safety and efficacy findings were consistent across subgroups, including geographical regions, warfarin experienced and naïve patients, age groups, sexes, differences in renal function, differences in risk for stroke, as well as in other predefined subgroups.
About ELIQUIS
ELIQUIS is the approved trade name for apixaban in Europe and the proposed trade name in the U.S. ELIQUIS is not approved for the prevention of stroke or systemic embolism in patients with atrial fibrillation in any country. Bristol-Myers Squibb and Pfizer recently announced the first regulatory approval for 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.
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 ARISTOTLE. The ELIQUIS atrial fibrillation clinical trial program, which includes ARISTOTLE and AVERROES, was designed to comprehensively evaluate ELIQUIS in approximately 24,000 patients with atrial fibrillation, including patients who are expected or demonstrated to be unsuitable for vitamin K antagonist (VKA) therapy.
In addition to stroke prevention in patients with atrial fibrillation and the prevention of VTE in patients who have undergone total hip or total knee replacement surgery, ELIQUIS is being investigated in Phase 3 trials for the treatment of VTE and the prevention of VTE in hospitalized acutely ill medical patients.
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.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.
Pfizer Inc.: Working together for a healthier world™
At Pfizer, we apply science and our global resources to improve health and well-being at every stage of life. We strive to set the standard for quality, safety and value in the discovery, development and manufacturing of medicines for people and animals. Our diversified global health care portfolio includes human and animal biologic and small molecule medicines and vaccines, as well as nutritional products and many of the world’s best-known consumer products. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as the world’s leading biopharmaceutical company, we also collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, Pfizer has worked to make a difference for all who rely on us.
Bristol-Myers Squibb Forward-Looking Statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding product development. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that apixaban will receive regulatory approval for an indication in stroke prevention in patients with atrial fibrillation. There is also no guarantee that, if approved in this indication, apixaban will become a commercially successful product. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2010, in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.
PFIZER DISCLOSURE NOTICE:
The information contained in this release is as of August 28, 2011. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments.
This release contains forward-looking information about various potential indications for ELIQUIS (apixaban), including their potential benefits, that involves substantial risks and uncertainties. Such risks and uncertainties include, among other things, the uncertainties inherent in research and development, including the ability to meet anticipated clinical trial completion dates and regulatory submission dates; decisions by regulatory authorities regarding whether and when to approve any drug applications that may be filed for any such indications as well as their decisions regarding labeling and other matters that could affect the availability or commercial potential of any such indications; and competitive developments.
A further description of risks and uncertainties can be found in Pfizer’s Annual Report on Form 10-K for the fiscal year ended December 31, 2010 and in its reports on Form 10-Q and Form 8-K.