阿哌沙班可有效预防复发性静脉血栓栓塞

亚特兰大——美国血液病学会(ASH)年会上公布的AMPLIFY-EXT随机双盲研究显示，阿哌沙班(Eliquis)延长治疗1年，可使静脉血栓栓塞(VTE)复发事件风险降低80%，而大出血发生率与安慰剂组相同。阿哌沙班每治疗14例患者，就可预防1例致死性或非致死性复发性VTE，而每治疗200例患者才导致1例大出血或具有临床意义的非大出血。该研究同时在《新英格兰医学杂志》上发表(2012 Dec. 8 [doi: 10.1056/NEJMoa1207541])。

Giancarlo Agnelli博士

这项研究由佩鲁贾大学内科学与心血管医学/卒中科主任Giancarlo Agnelli博士及其同事进行，阿哌沙班2.5 mg组842例患者，阿哌沙班5 mg组815例，安慰剂组829例，所有组均为每日给药2次，疗程12个月。3/4患者的初始诊断为深静脉血栓形成，1/4为肺栓塞。所有患者已接受抗凝治疗6~12个月并达到了临床稳态。

结果显示，在不到10%的患者中，VTE与短暂性或可逆性危险因素相关。两个阿哌沙班组各有2例患者被排除出意向治疗疗效分析。他们的平均年龄约为56岁。

阿哌沙班2.5 mg组和5 mg组复合主要疗效终点(症状性VTE复发或全因死亡)的发生率分别为3.8%和4.2%，而安慰剂组为11.6%。两个阿哌沙班组的症状性复发性VTE或VTE性死亡发生率均为1.7%，而安慰剂组为8.8%。阿哌沙班2.5 mg组和5 mg组的大出血发生率分别为0.2%和0.1%，而安慰剂组为0.5%。两个阿哌沙班组具有临床意义的非大出血发生率分别为3.0%和4.2%，稍高于安慰剂组的2.3%。

研究者表示，由于该研究人群中仅2%患有活动性癌症，因此需开展进一步研究，以确定上述结果是否可直接外推至因癌症而VTE风险增加的癌症患者。对于无复发事件的VTE患者，是应该延长还是停止标准抗凝治疗，临床医生对此不太确定，AMPLIFY-EXT研究结果为此提供了一些指导。在无可逆危险因素的患者中，停止华法林治疗不仅可导致VTE复发风险增加10%及增加出血风险，而且需要经常实验室监测。口服因子Xa抑制剂阿哌沙班为固定剂量给药，不需实验室监测。

加拿大英属哥伦比亚大学血栓形成项目医学主任Agnes Lee博士表示，从AMPLIFY-EXT研究观察到的疗效结果来看，与另外两种固定剂量抗凝剂利伐沙班(Xarelto)和达比加群(Pradaxa)相比，阿哌沙班较少依赖于肾脏清除，因此可能也是肾功能损害VTE患者的较好治疗选择。值得注意的是，ARISTOLE的一项近期分支研究显示，在合并肾功能不全和房颤的患者中，阿哌沙班组大出血事件发生率降低35%~52%。

阿哌沙班目前已被欧洲和加拿大批准用于房颤患者预防卒中和全身性栓塞，以及用于大型骨科手术后VTE的预防，但尽管ARISTOTLE研究证明阿哌沙班治疗房颤患者的效果优于华法林，阿哌沙班仍未获得美国食品药品管理局(FDA)批准。预计FDA将在2013年初对是否批准该药作出决定。

AMPLIFY-EXT研究获百时美施贵宝和辉瑞公司资助。Agnelli博士声明与百时美施贵宝、第一三共和其他公司存在利益关系。其他研究者声明与研究申办者存在关系。Lee博士声明是百时美施贵宝公司的顾问。

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By: PATRICE WENDLING, Cardiology News Digital Network

ATLANTA – An extra year of apixaban reduced the risk of recurrent events in patients with venous thromboembolism by 80%, while keeping major bleeding rates in line with placebo in the randomized AMPLIFY-EXT trial.

The number needed to treat with apixaban (Eliquis) to prevent one fatal or nonfatal recurrent VTE was only 14, while the number needed to treat to cause one episode of major or clinically relevant nonmajor bleeding was 200, Dr. Giancarlo Agnelli reported in a late-breaking abstract at the annual meeting of the American Society of Hematology.

"We really believe this study, for its design and results, is a remarkable achievement, and [may lead to a] change in clinical practice," he said during a press briefing at the meeting.

Apixaban is approved in Europe and Canada for the prevention of stroke and systemic embolism in patients with atrial fibrillation, and for prevention of VTE after major orthopedic surgery, but it has struggled to gain approval in the United States despite demonstrating superiority to warfarin in patients with AF in the ARISTOTLE trial. A decision by the Food and Drug Administration is expected in early 2013.

In the meantime, the results of AMPLIFY-EXT (Apixaban After the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis with First-Line Therapy–Extended Treatment) provide some guidance for physicians uncertain about whether to extend or stop standard anticoagulation therapy in patients with VTE in the absence of recurrent events. Stopping warfarin therapy increases the risk of recurrent VTE by up to 10% in patients without reversible risk factors, but also requires frequent laboratory monitoring and increases the risk of bleeding.

Apixaban, an oral factor Xa inhibitor, is given in fixed doses without the need for laboratory monitoring, said Dr. Agnelli, director of the internal and cardiovascular medicine/stroke unit at the University of Perugia, Italy.

Given the efficacy demonstrated in AMPLIFY-EXT, apixaban may also be an attractive option for those VTE patients with renal impairment, because it is the least dependent on renal clearance compared with two other fixed-dose anticoagulants, rivaroxaban (Xarelto) and dabigatran (Pradaxa), said press briefing moderator Dr. Agnes Lee, medical director of the thrombosis program and associate professor of medicine at the University of British Columbia, Vancouver, and Vancouver Coastal Health.

Notably, a recent prespecified substudy of ARISTOLE demonstrated that apixaban produced 35%-52% fewer major bleeding events in patients with renal dysfunction and atrial fibrillation.

The double-blind AMPLIFY-EXT trial randomized 842 patients to apixaban 2.5 mg, 815 to apixaban 5 mg, and 829 to placebo, all twice daily for 12 months. Three-fourths had an initial diagnosis of deep vein thrombosis and one-fourth pulmonary embolism. All had received 6-12 months of anticoagulation therapy and reached clinical equipoise about the continuation or cessation of anticoagulation therapy.

VTE was associated with a transient or reversible risk factor in less than 10% of patients. Two patients from each apixaban group were excluded from the intention-to-treat efficacy analysis. Their average age was roughly 56.

The composite primary efficacy endpoint of symptomatic VTE recurrence or all-cause death occurred in 3.8% of patients on apixaban 2.5 mg and in 4.2% of patients on apixaban 5 mg, compared with 11.6% of patients given placebo, Dr. Agnelli said.

Symptomatic recurrent VTE or death from VTE occurred in 1.7% of patients in both apixaban groups vs. 8.8% of placebo-treated patients.

Major bleeding was reported in 0.2% of the 2.5-mg apixaban group, 0.1% of the 5-mg group, and 0.5% of the placebo group. Clinically relevant nonmajor bleeding rates were slightly higher at 3.0% and 4.2% in the apixaban groups vs. 2.3% in the placebo group, he said.

Further study will be needed to determine if the results can be directly applied to cancer patients who face an increased risk of VTE because of the disease, as only about 2% of the study population had active cancer, Dr. Agnelli said in an interview.

The study was simultaneously published in the New England Journal of Medicine (2012 Dec. 8 [doi: 10.1056/NEJMoa1207541]).

AMPLIFY-EXT was funded by Bristol-Myers Squibb and Pfizer. Dr. Agnelli reported commercial relationships with Bristol-Myers Squibb, Daiichi Sankyo, and other companies. His coauthors reported relationships with the study sponsors. Dr. Lee disclosed consulting for Bristol-Myers Squibb.