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NEJM:阿哌沙班可安全降低长期VTE复发风险

2012-12-17 我要评论0

        一项近2500例患者的随机试验显示,抗凝治疗静脉血栓栓塞(VTE)6个月-12个月后,进行为期12个月的两种不同剂量的阿哌沙班(Eliquis, Bristol-Myers Squibb/Pfizer)治疗,与安慰剂相比,可显著降低复发性静脉血栓栓塞风险。该研究结果发表在《新英格兰医学杂志》上。
 
       在世界各地,口服抗凝药物----凝血因子Xa抑制剂作为华法林替代药品的患者越来越多,这些患者的VTE复发或任何原因所致死亡主要终点指标明显下降,但大出血或或混合性大出血或临床上重要的轻微出血风险并未升高。

       研究人员指出,对于连续治疗受益和风险不确定的VTE患者来说,本研究结果,为延长进行12个月的连续抗凝治疗提供了理论基础。更重要的是,阿哌沙班(2.5mg/5mg,2/d)安全、有效、简单易用。

       据Giancarlo Agnelli(意大利佩鲁贾大学)报告,延长的一年用药期间,需要进行阿哌沙班治疗以预防VTE复发的患者为14例,但引起一次大出血或临床相关的轻微出血多达200人次。

       AMPLIFY-EXT研究招募了2482例静脉血栓栓塞患者,这些患者正要完成6-12个月的抗凝治疗,在此期间一直保持无症状。以双盲的方式对上述患者随机进行两种不同剂量的阿哌沙班,(2.5mg/5.0mg,每日两次),或安慰剂治疗,为期12个月。但不允许进行双重抗血小板治疗。如果患者对确诊的症状性深静脉血栓形成(DVT)或有/无DVT的肺栓塞已完成为期6-12个月的抗凝治疗以及如果对继续或停止抗凝治疗保持临床均势的话。患者则有资格入选该研究。

       这项研究在欧洲、亚洲、北美洲、南美洲以及澳大利亚、以色列、南非等26个国家,328个治疗点进行。

       在为期一年的随机治疗期间,840例患者接受阿哌沙班2.5mg每日两次治疗,其中3.8%达到主要终点指标;813例接受5.0mg治疗,4.2%达到主要终点指标;安慰剂组829例患者中11.6%达到主要终点指标(与两个阿哌沙班剂量组相比,P <0.001)。三组中分别有13例,19例,20例发生意向治疗主要事件,均已失访。

表1 阿哌沙班剂量疗效和安全性终点指标的相对危险度(95%CI)
终点指标 2.5 mg组与安慰剂组 5 mg组与安慰剂组 2.5mg组与5mg组
VTE复发或任何原因引起的死亡(主要终点指标) 0.33 (0.22-0.48) 0.36(0.25-0.53) NA
非VTE相关性心血管死亡,心肌梗死或死亡 0.36 (0.11-1.12) 0.47(0.16-1.33) 0.77(0.21-2.88)
复发性VTE、VTE相关的死亡、心肌梗死、卒中或心血管死亡 0.21 (0.13-0.35) 0.23(0.14-0.38) 0.92 (0.48-1.74)
大出血 0.49 (0.09-2.64) 0.25(0.03-2.24) 1.93(0.18-21.25)
大出血或临床相关性非大出血 1.20 (0.69-2.10) 1.62(0.96-2.73)  0.74 (0.46-1.22)
VTE/VTE相关性死亡,心肌梗塞/卒中/心血管死亡或大出血(主要临床净效益) 0.23(0.14-0.37)  0.24(0.15-0.38) 0.97 (0.52-1.79)
            注:VTE=静脉血栓栓塞

       亚组分析表明,试验中阿哌沙班的疗效大多与性别,年龄,体重和肾功能以及最初是否因静脉血栓栓塞或肺栓塞而抗凝治疗无关。

      作者告诫称,这项研究中,只有15%的患者年龄超过75岁,少数患者体重低于60kg,所以关于此类患者出血方面的问题需要更多的数据都来更好的确定阿哌沙班的利益-风险谱。



Background
Apixaban, an oral factor Xa inhibitor that can be administered in a simple, fixed-dose regimen, may be an option for the extended treatment of venous thromboembolism.
Methods
In this randomized, double-blind study, we compared two doses of apixaban (2.5 mg and 5 mg, twice daily) with placebo in patients with venous thromboembolism who had completed 6 to 12 months of anticoagulation therapy and for whom there was clinical equipoise regarding the continuation or cessation of anticoagulation therapy. The study drugs were administered for 12 months.
Results
A total of 2486 patients underwent randomization, of whom 2482 were included in the intention-to-treat analyses. Symptomatic recurrent venous thromboembolism or death from venous thromboembolism occurred in 73 of the 829 patients (8.8%) who were receiving placebo, as compared with 14 of the 840 patients (1.7%) who were receiving 2.5 mg of apixaban (a difference of 7.2 percentage points; 95% confidence interval [CI], 5.0 to 9.3) and 14 of the 813 patients (1.7%) who were receiving 5 mg of apixaban (a difference of 7.0 percentage points; 95% CI, 4.9 to 9.1) (P<0.001 for both comparisons). The rates of major bleeding were 0.5% in the placebo group, 0.2% in the 2.5-mg apixaban group, and 0.1% in the 5-mg apixaban group. The rates of clinically relevant nonmajor bleeding were 2.3% in the placebo group, 3.0% in the 2.5-mg apixaban group, and 4.2% in the 5-mg apixaban group. The rate of death from any cause was 1.7% in the placebo group, as compared with 0.8% in the 2.5-mg apixaban group and 0.5% in the 5-mg apixaban group.
Conclusions
Extended anticoagulation with apixaban at either a treatment dose (5 mg) or a thromboprophylactic dose (2.5 mg) reduced the risk of recurrent venous thromboembolism without increasing the rate of major bleeding. (Funded by Bristol-Myers Squibb and Pfizer; AMPLIFY-EXT ClinicalTrials.gov number, NCT00633893.)



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