The oral factor Xa inhibitor apixaban has been found superior to enoxaparin in preventing venous thromboembolism after knee-replacement surgery, with similar rates of bleeding, in a randomized placebo-controlled phase III trial.

The findings, published March 5 in the Lancet, are from the manufacturer-sponsored ADVANCE-2 trial, the second randomized, controlled study comparing apixaban (Bristol-Myers Squibb, Pfizer) with enoxaparin (Sanofi-Aventis), a low molecular weight heparin, following knee-replacement surgery.

In an earlier trial, ADVANCE-1 (N. Engl. J. Med. 2009; 361:594–604), 2.5 mg oral apixaban taken twice daily was compared with 30 mg enoxaparin subcutaneously twice daily. In that trial rates of VTE or any-cause death – 9.0% with apixaban and 8.8% with enoxaparin – did not meet the statistical criteria for noninferiority for apixaban.

The size – both just over 3,000 patients each – and design of the first and second trials “was quite similar,” Dr. Michael Rud Lassen of the University of Copenhagen, Denmark, the lead investigator of both studies, said in an interview. In the current trial, however, the dosing for the comparator enoxaparin was changed to be in line with the drug’s European labeling. Patients scheduled for knee-replacement surgeries were randomized to receive either oral apixaban 2.5 mg twice daily (1,528 patients) of 40 mg subcutaneous enoxaparin once daily (1,529 patients).

The primary outcome, as in the previous trial, was a composite of symptomatic and asymptomatic deep vein thrombosis, nonfatal pulmonary embolism, and death from any cause, with onset during the intended treatment period of 12 days or within 2 days of the last dose of the study drug, whichever was longer. Apixaban was started 12 to 24 hours after wound closure, and enoxaparin 12 hours before surgery. Both drugs were continued for between 10 and 14 days, at the end of which bilateral venography was scheduled (Lancet 2010;375:807-15).

More than a third of patients in either group were not or could not be successfully assessed for the primary outcome. Of the 976 patients who were treated with apixaban and underwent surgery and successful subsequent analysis using venography, a primary outcome was reported for 147, or 15%. Of the 997 patients treated with enoxaparin who underwent surgery and successful analysis, a primary outcome was recorded for 243, or 24%. Compared with the earlier trial, “the advantages [of apixaban] were obvious,” Dr. Lassen said.

Bleeding was analyzed only for the intention-to-treat patients who had received one of the study drugs, regardless of whether they ultimately underwent surgery. Major or clinically relevant nonmajor bleeding occurred in 3.5% (53/1,501) of patients on apixaban and in 4.8% (72/1,508) of those receiving enoxaparin.

Xa inhibitors, a new class of antithrombotics, have the advantage of oral dosing, as opposed to injections, and noninteraction with food. Some, such as apixaban, are still in trials and one, rivaroxaban, manufactured by Bayer, already has marketing authority in Europe.

In an accompanying editorial, Jawed Fareed, Ph.D., of Loyola University Medical Center, Maywood, Illinois, and Dr. Russell Hull of the Thrombosis Research Unit, University of Calgary, Canada, wrote that further studies are needed to establish apixaban’s superiority against symptomatic venous thromboembolism, “which is widely accepted as the clinically relevant efficacy endpoint.”

Their editorial also described a need for “an antidote to allow immediate reversal in cases of severe bleeding,” and for “long-term safety analysis, especially for hepatic toxic effects.” One patient in the apixaban arm had died after evidencing abnormal liver levels, and the study authors concluded that contribution by apixaban was possible (Lancet 2010;375:779-780).

ADVANCE-2 was funded by Bristol-Myers Squibb and Pfizer. Several study authors either received consulting fees from these companies, among others, or were employed by Bristol-Myers Squibb.

Dr. Fareed acknowledged having served as a consultant to Sanofi-Aventis, among others, and Dr. Hull Sanofi-Aventis, Bayer, and Pfizer, among others.

 

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

一项随机、安慰剂对照III期试验的结果显示，口服因子Xa抑制剂预防膝关节置换术后静脉血栓栓塞(VTE)的疗效优于依诺肝素，并且这两种治疗的出血发生率相似。

 

由apixaban制造商发起的ADVANCE-2试验的这一结果于3月5日发表在《柳叶刀》(Lancet)上，这是第二项在膝关节置换术后患者中比较apixaban(百时美-施贵宝公司和辉瑞公司)与依诺肝素(赛诺菲-安万特公司)的随机、对照研究。依诺肝素是一种低分子量肝素制剂。

 

在之前的ADVANCE-1试验 (N. Engl. J. Med. 2009; 361:594–604)中，将apixaban 2.5 mg每日口服2次与依诺肝素30 mg每日皮下注射2次进行了比较。这项研究显示，apixaban 和依诺肝素组的VTE或全因死亡发生率分别为9.0%和8.8%，未达到apixaban的统计学非劣效性标准。

 

第一项和第二项研究的样本量相似，均为3,000例以上患者，两项研究的首席研究者、丹麦哥本哈根大学的Michael Rud Lassen博士在接受采访时说。不同之处在于，当前试验中对照药物依诺肝素的用药方法改为与该药物的欧洲标签保持一致。计划接受膝关节置换术的患者随机接受apixaban 2.5 mg每日口服2次(1,528例患者)或依诺肝素40 mg每日皮下注射1次治疗(1,529例患者)。

 

与前一试验相同，该研究的主要终点为由12天意向治疗期间或最后一次使用研究药物后2天内(取二者中时间较长者)发生的症状性和无症状深静脉血栓、非致死性肺栓塞和全因死亡组成的复合终点。在伤口闭合后12~24 h开始apixaban治疗，依诺肝素用药开始于术前12 h。两种药物治疗均持续10~14天，治疗结束时依照方案行双侧静脉造影检查(Lancet 2010;375:807-15)。

 

两组中均有1/3以上患者未成功评估主要终点或无法成功评估主要终点。在接受apixaban治疗和手术并成功完成后续静脉造影分析的976例患者中，有147例报告达到主要终点，发生率为15%。在接受依诺肝素治疗和手术并成功完成后续分析的997例患者中，共243例患者达到主要终点，发生率为24%。与前一项试验相比，“apixaban的优势显著，” Lassen博士说。

 

仅在接受一种研究药物治疗的意向治疗患者中进行出血分析，无论患者最终是否接受手术。Apixaban和依诺肝素组大出血或有临床意义的非大出血发生率分别为3.5% (53/1,501例)和4.8% (72/1,508例)。

 

Xa因子抑制剂是一类新型抗凝药物，与注射抗凝剂相比，具有可口服用药的优势，并且不会与食物发生相互作用。其中一些药物，如apixaban，仍处于试验阶段，但拜耳公司生产的同类药物利伐沙班已在欧洲获得上市授权。

 

在随刊编者按中，伊利诺伊州梅坞市罗耀拉大学医学中心的Jawed Fareed博士和加拿大卡尔加里大学血栓研究中心的Russell Hull博士写道，需要做进一步研究以确定apixaban预防症状性VTE的优势，“这是广为接受的有临床意义的疗效终点。”

 

编者按中还指出，需要“一种可迅速逆转严重出血的解毒剂，”以及“长期安全性分析，尤其是对肝脏的毒性反应。” Apixaban组中1例患者在发生明显肝功能指标异常后死亡，并且研究作者们总结认为可能与apixaban用药有关(Lancet 2010;375:779-780)。

 

ADVANCE-2试验由百时美-施贵宝公司和辉瑞公司资助。一些研究作者或接受了上述两家公司以及其他一些公司提供的顾问酬劳，或受雇于百时美-施贵宝公司。

 

Fareed博士称其担任赛诺菲-安万特以及其他一些公司的顾问，Hull博士则是赛诺菲-安万特、拜耳、辉瑞以及其他一些公司的顾问。

 

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