Vorapaxar治疗利弊或由年龄、体重决定

一项在有心肌梗死(MI)病史的患者中开展的大规模、随机、安慰剂对照试验显示，在标准抗血小板治疗的基础上加用在研抗血小板药物vorapaxar可以降低心血管死亡和缺血性事件风险。这一作用在年龄＜75岁且体重≥60 kg的患者中最为显著，因此对于这类患者人群，vorapaxar治疗的收益可能大于相关中重度出血风险。

上述结果来自TRA 2°P(凝血酶受体拮抗剂在动脉粥样硬化性缺血性事件二级预防中的应用)–TIMI 50(心肌梗死溶栓治疗50)试验预设的一项亚组分析，首次证明了在阿司匹林的基础上强化抗血小板治疗用于MI后血栓形成事件的长期二级预防所能产生的效益。美国哈佛医学院的Benjamin M. Scirica博士以及TIMI研究小组的其他同事已于8月26日将上述结果发表在《柳叶刀》(The Lancet)上，与此同时也在欧洲心脏病学会(ESC)2012年会上同期发布(Lancet 2012 Aug. 26 [doi:10.1016/S0140-6736(12)61269-0])。

多国双盲TRA 2°P-TIMI 50试验于2007年9月~2009年11月招募既往有动脉粥样硬化性血栓形成病史的成年患者。因MI入选的患者在入组试验前2周~12个月内出现过自发性MI。在该试验所纳入的26,449例患者中，17,769例的既往MI病史符合纳入条件，因此组成了这项分析的亚组人群。这些患者被随机分配至接受口服vorapaxar或安慰剂，每日2.5 mg。在各组中，98%的患者同时服用阿司匹林，78%服用了噻吩吡啶，96%服用了降脂药物。在为期2.5年的中位随访期内，接受阳性药物治疗的8,898例患者中有610例发生心血管死亡、MI或卒中，而安慰剂组的8,881例患者中有750例出现了这类事件(3年Kaplan-Meier估值分别为8.1%和9.7%；危险比，0.80)。

不过，阳性药物治疗组的中重度出血事件的发生率显著高于安慰剂组，这是该试验的主要安全性终点，依照GUSTO(堵塞冠状动脉开通策略的全球使用情况)的标准来判定。服用了vorapaxar 的8,880例患者中有241例出现了这类出血，而服用安慰剂的8,849例患者中仅有151例出现了这类出血(3年Kaplan-Meier估值分别为3.4%和2.1%；危险比，1.61)。

在年龄＜75岁、体重≥60 kg且既往无短暂性脑缺血发作(TIA)或卒中病史的患者中(占试验亚组人群的84%)，接受阳性药物治疗的7,449例患者中有431例发生心血管死亡、MI或卒中，而接受安慰剂的7,640例患者中有570例出现了这类事件(3年Kaplan-Meier估值分别为6.8%和8.6%；危险比，0.75)。

研究者指出：“此外，在这些患者中，vorapaxar组的心血管死亡、MI、卒中、紧急冠脉血运重建或GUSTO中重度出血的发生率也低于安慰剂组(危险比，0.86)。相反，对于年龄≥75岁且既往有TIA或卒中病史或者体重＜60 kg的患者，vorapaxar的净临床结局较之安慰剂无显著差异。”

研究者写道，Vorapaxar是蛋白酶活化受体-1的一种选择性强拮抗剂，而蛋白酶活化受体-1是人体血小板上主要的凝血酶受体。研究结果表明，抑制该受体“成为了心肌梗死后长期二级预防的一个新的治疗靶点。即便完全依照现行指南来操作，vorapaxar所能产生的附加效益仍然存在。”研究者还指出，上述结果在现有证据的基础上进一步证实了阿司匹林结合长期抗血小板治疗在降低血栓形成事件风险方面的效益，同时也表明vorapaxar治疗的确会增加出血风险。

研究者总结道：“因此，要确定哪些患者适合接受这种治疗取决于缺血和出血风险之间的利弊权衡，而这在很大程度上需要根据临床情况、患者特征、抗凝剂伴随用药、药物剂量等因素来判断。”具体来说，年龄偏大和体重偏轻等临床特征预示着强化抗凝血治疗可能会增加出血风险。

TRA 2°P-TIMI 50试验由默克公司资助。TIMI研究小组以及各小组成员均声明与多家药企之间存在各种利益关系，包括接受研究经费资助、从事咨询工作以及加入企业的顾问委员会。利益冲突详情可参见www.thelancet.com上刊载的论文全文。

随刊述评：尚需更多数据以区分缺血和出血风险

瑞典乌普萨拉大学乌普萨拉临床研究中心的Stefan James博士和Claes Held博士指出，TIMI研究小组开展的这项亚组分析的结果支持在MI后加用长期抗凝血治疗。然而，目前还不清楚医生、患者以及支付机构是否会接受这种昂贵的药物，该药虽然能够降低MI风险且可能降低死亡风险，但同时也会增加重度出血的风险。

他们写道：“对于只存在中低度出血风险的患者，vorapaxar预防缺血的效益可能大于潜在的出血风险。但出血风险低的患者往往出现缺血性事件的风险也较低。因此，还需要确定能把缺血风险和出血风险区分开来的临床特征或生物标志物。”(Lancet 2012 Aug. 26 [doi:10.1016/S0140-6736(12)61383-X])。

“未来研究应该评估蛋白酶活化受体-1抑制剂等抗凝血药物作为单药治疗或者与小剂量阿司匹林联合使用的效果，以权衡其用于长期二级预防的安全性和疗效。此外，还应该探讨比TRA 2°P-TIMI 50试验所用剂量更小的vorapaxar治疗的效果。”

James博士和Held博士总结道，虽然TRA 2°P-TIMI 50试验的结果“让我们对这方面的课题有了进一步的了解，让我们向正确的方向又迈进了一步”，但是仍需针对蛋白酶活化受体-1抑制剂以及其他抗凝血药物开展进一步的研究以优化MI后的长期二级预防策略。

James博士声明接受了阿斯利康、礼来、默克、百时美-施贵宝、Terumo、美敦力和Vascular Solutions公司提供的研究经费和/或担任其顾问委员会成员。James博士还声明接受了阿斯利康、礼来和the Medicines Company提供的酬金。Held博士声明接受了阿斯利康、默克、百时美-施贵宝、葛兰素史克、罗氏和辉瑞公司提供的研究经费和/或担任其顾问委员会成员，并且接受了阿斯利康公司提供的酬金。

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By: SHARON WORCESTER, Cardiology News Digital Network

The investigational antiplatelet drug vorapaxar reduced the risk of cardiovascular death and ischemic events when it was added to standard antiplatelet treatment in a large, randomized, placebo-controlled trial of patients who had a previous myocardial infarction.

The findings, from a prespecified subgroup analysis of the TRA 2°P (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events)–TIMI 50 (Thrombolysis in Myocardial Infarction 50) trial, were most pronounced in patients younger than age 75 years with a body weight of at least 60 kg. Therefore, the benefits of treatment in this group may outweigh the risk of moderate or severe bleeding seen with treatment in this study, Dr. Benjamin M. Scirica of Harvard Medical School, Boston, and his colleagues from the TIMI Study Group reported Aug. 26 in the Lancet.

The study findings – the first to demonstrate the benefit of adding intense antiplatelet treatment to aspirin for long-term, secondary prevention of post-MI thrombotic events – were simultaneously presented at the annual congress of the European Society of Cardiology.

Of 26,449 patients in the TRA2°P–TIMI 50 trial, 17,769 experienced a qualifying MI and thus constituted the subgroup for the current analysis. These patients were randomized to receive treatment with 2.5 mg of a daily oral dose of either vorapaxar or placebo. In each group, 98% of patients concomitantly took aspirin, 78% took a thienopyridine, and 96% took a lipid-lowering agent. During a median follow-up of 2.5 years, cardiovascular death, MI, or stroke occurred in 610 of the 8,898 patients who received active treatment, compared with 750 of 8,881 patients who received placebo (3-year Kaplan-Meier estimates of 8.1% vs. 9.7%; hazard ratio, 0.80), the investigators said (Lancet 2012 Aug. 26 [doi:10.1016/S0140-6736(12)61269-0]).

However, the principal safety end point of moderate or severe bleeding, as defined by GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries), occurred significantly more often in the treatment group than in the placebo group, with 241 of 8,880 vorapaxar patients experiencing such bleeding, compared with 151 of 8,849 placebo patients (3-year Kaplan-Meier estimates of 3.4% vs. 2.1%; HR, 1.61).

Among those younger than age 75 years with no history of transient ischemic attack or stroke, and with a body weight of at least 60 kg (which represented 84% of the study subgroup), cardiovascular death, MI, or stroke occurred in 431 of 7,449 patients who received active treatment, compared with 570 of 7,640 who received placebo (3-year Kaplan Meier estimates of 6.8% vs. 8.6%; HR, 0.75), they noted.

"Moreover, cardiovascular death, myocardial infarction, stroke, urgent coronary revascularization, or GUSTO moderate or severe bleeding was less likely in the vorapaxar group than in the placebo group in these patients [HR, 0.86]. By contrast, for patients aged 75 years and older, with a history of transient ischemic attack or stroke, or patients weighing less than 60 kg, net clinical outcome was not significantly different with vorapaxar compared with placebo," the investigators wrote.

Patients in the multinational, double-blind TRA 2°P-TIMI 50 trial were adults with a history of atherothrombosis who were enrolled between September, 2007, and November, 2009. Those enrolled on the basis of MI had had a spontaneous MI in the 2 weeks to 12 months prior to enrollment.

Vorapaxar is a potent and selective antagonist of protease-activated receptor 1, which is the main receptor for thrombin on human platelets. The findings suggest that inhibiting this receptor "is a novel therapeutic target for long-term secondary prevention after myocardial infarction. The incremental benefit of vorapaxar existed even with high adherence to guidelines," the investigators wrote, noting that the findings add to existing evidence of a benefit of long-term antiplatelet treatment in addition to aspirin for reducing the risk of thrombotic events, and they also confirm the increased risk of bleeding with vorapaxar treatment.

"Identification of patients appropriate for treatment therefore depends on balance of the competing risks of ischemia and bleeding, which are largely based on the clinical setting, patient characteristics, concomitant anticoagulants, and drug dosing," they wrote.

Specifically, the findings of this and other studies indicate that clinical characteristics such as advanced age and low body weight are consistent predictor of increased bleeding risk with potent antithrombotic treatments.

"These simple clinical criteria seem to be useful for selection of patients with better potential for improved net clinical outcomes with vorapaxar," they wrote.

The TRA 2°P-TIMI 50 trial was supported by Merck. The TIMI Study Group and individual members of the group reported numerous disclosures with respect to grant funding, consulting work, and advisory board participation for various pharmaceutical companies. Details are available with the full text of the article at www.thelancet.com.

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Need More Data to Separate Risks

The findings of the TIMI Study Group’s TRA 2°P–TIMI 50 trial subgroup analysis support the addition of long-term antithrombotic treatment following MI, Dr. Stefan James and Dr. Claes Held wrote in an accompanying editorial.

However, it remains to be seen whether doctors, patients, health care providers, and funding agencies will accept the use of an expensive drug that reduces MI risk and possibly death, but also increases the risk of severe bleeding.

"For patients at low or moderate risk of bleeding, the ischemic benefit seems to outweigh the risk of bleeding. But patients at low risk of bleeding are also often at low risk of ischemic events. Therefore, clinical characteristics or biomarkers to separate ischemic risk and bleeding risk should be defined," they wrote (Lancet 2012 Aug. 26 [doi:10.1016/S0140-6736(12)61383-X]).

"Future research should assess antithrombotic drugs, such as inhibitors of protease-activated receptor 1, as monotherapy or in addition to low-dose aspirin, to balance safety and efficacy for long-term secondary prevention. Also, the effect of a lower dose of vorapaxar than that used in TRA 2°P-TIMI 50 should be investigated," they wrote.

Although the results of the TRA 2°P-TIMI 50 trial "provide data that [aid] our understanding of this topic and offer a step in the right direction," further research on blockade of protease-activated receptor 1 and other antithrombotic drugs is needed to optimize long-term, post-MI secondary prevention strategies, they concluded.

DR. JAMES and DR. HELD are with Uppsala (Sweden) Clinical Research Center at Uppsala University. Dr. James disclosed receiving institutional research grants from and/or serving on advisory boards for AstraZeneca, Eli Lilly, Merck, Bristol-Myers Squibb, Terumo, Medtronic, and Vascular Solutions. He also has received honoraria from AstraZeneca, Eli Lilly, and the Medicines Company. Dr. Held disclosed receiving institutional research grants from and/or serving on the advisory board for AstraZeneca, Merck, Bristol-Myers Squibb, GlaxoSmithKline, Roche, and Pfizer, and has received honoraria from AstraZeneca.