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。
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。
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。
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）。
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.
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.
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.
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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.