Rivaroxaban reduced the rates of major ischemic events in patients stabilized after acute coronary syndrome, but it was associated with an increased risk of bleeding in a dose-dependent manner, according to findings from a phase II, randomized, placebo-controlled trial published online June 17 in the Lancet.

In the double-blind study (known as ATLAS ACS-TIMI 46), 3,491 patients in 27 countries were randomized to either placebo or rivaroxaban, an oral direct factor Xa inhibitor, at doses of 5, 10, 15, or 20 mg total per day, administered either once or twice daily. Randomization occurred 1-7 days after hospitalization for acute coronary syndrome.

All patients also received background therapy of either low-dose aspirin alone or low-dose aspirin plus thienopyridine. Patients participated in the study for 6 months and were evaluated every 30 days (doi: 10.1016/S0140-6736(09)60738-8).

Overall, Dr. Jessica L. Mega of Brigham and Women’s Hospital, Boston, and associates found that 5.6% and 7.0% of patients in the rivaroxaban and placebo groups, respectively, (hazard ratio [HR], 0.79) met the primary efficacy endpoint, which was death, myocardial infarction, stroke, or severe recurrent ischemia requiring revascularization within 6 months of enrollment.

However, compared with placebo, treatment with rivaroxaban was associated with an HR of 3.6 for clinically significant bleeding among those patients also taking aspirin and a 3.66 HR in patients taking aspirin and thienopyridine.

The risk for bleeding was shown to be dose dependent, with an HR of 2.21 for 5 mg daily, increasing to an HR of 5.06 with 20 mg of rivaroxaban daily.

One fatal bleed occurred when a participant in the rivaroxaban 10 mg–once daily group had an intracranial hemorrhage.

In all patients, the most common adverse event was chest pain.

Increases in alanine aminotransferase levels greater than three times the upper limit of normal were noted in the placebo patients (4.5%) and the rivaroxaban patients (3.7%), but the difference was not significant.

Concerns about hepatotoxicity were previously raised by the U.S. Food and Drug Administration’s Cardiovascular and Renal Drugs Advisory Committee when the drug was being reviewed for the prevention of venous thromboembolism in patients who underwent hip or knee surgery. That approval is currently on hold while the manufacturer, Ortho-McNeil, evaluates a “complete response” letter issued by the FDA.

In an editorial accompanying the article, Dr. Hitinder S. Gurm and Dr. Kim Eagle, both of the University of Michigan Cardiovascular Center in Ann Arbor, said that, despite the increased risk of bleeding, “we should not be completely pessimistic about the future role of this drug in treating patients with acute coronary syndromes.” They added that rivaroxaban, a “promising drug,” could “potentially displace parenteral anticoagulants for early management of these syndromes,” though this indication hasn’t yet been tested (doi:10.1016/S0140-6736(09)60952-1).

The study was funded by Johnson & Johnson Pharmaceutical Research and Development and Bayer Healthcare. Several researchers, including Dr. Mega, reported receiving research grant support from Johnson & Johnson and other drug manufacturers. Ortho-McNeil is a subsidiary of Johnson & Johnson.

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

《柳叶刀》杂志6月17日在线刊出了一项随机的、以安慰剂为对照的Ⅱ期临床试验成果。根据该研究，口服Xa因子直接抑制剂利伐沙班，能降低急性冠状动脉综合征患者病情稳定后主要缺血事件的发生率，但出血的危险性也同时增加且呈现剂量依赖性趋势。

这项代号为ATLAS ACS-TIMI 46的双盲研究，涉及来自27个国家和地区的3,491名患者。将参试患者随机分到安慰剂组和利伐沙班治疗组。利伐沙班治疗组根据不同给药方式分为一天一次或一天两次给药，并根据不同给药日剂量分为5、10、15以及20 mg不同组别。随机分组过程在患者因急性冠状动脉综合征入院的第1~7天完成。

参试者均接受小剂量阿司匹林或小剂量阿司匹林加噻吩并吡啶的基础治疗。参试患者疗程为6个月，每30天接受一次评估。[文献doi号：10.1016/S0140-6736(09)60738-8]

该研究主要疗效终点为参试者注册6个月中发生死亡、心肌梗死、卒中或需要血管再通的严重再发性缺血。波士顿市布莱根妇女医院的Jessica L. Mega医生及其同事发现，利伐沙班治疗组和安慰剂组患者主要疗效终点发生率分别为5.6%和7.0%[危险比(HR)为0.79]。

然而，与安慰剂组相比，利伐沙班治疗组患者发生临床显著出血的危险比在服用小剂量阿司匹林者中为3.6，在服用小剂量阿司匹林加噻吩并吡啶者中为3.66。

出血的危险性也呈剂量依赖，利伐沙班日剂量5 mg组危险比为2.21，而20 mg组危险比则增加至5.06。

一位参试者每日一次口服利伐沙班10 mg，发生了致命的颅内出血。

所有患者最常见的不良反应是胸痛。

在安慰剂组和利伐沙班治疗组中，均出现丙氨酸转氨酶增加至正常上限数值三倍以上的患者，发生率分别为4.5%和3.7%，但两组间差异没有统计学意义。

早在美国食品药品管理局(FDA)下设的心脑血管病药物专家委员会复核该药用于预防髋关节或膝关节手术后患者静脉血栓栓塞情况时，就对药物的肝毒性给予了关注。对该药物的核准目前处于暂停状态，制造商Ortho-McNeil制药公司正对FDA出具的“完全响应”信函进行评估。

安娜堡市密歇根大学心血管疾病中心的Hitinder S. Gurm和Kim Eagle医生为该研究论文配发了述评。他们指出，尽管该药增加了出血的危险性，“我们完全没有必要对其在治疗急性冠状动脉综合征患者过程中所扮演的角色感到悲观。”他们还认为，利伐沙班可作为一种“有前途的”肠外抗凝药，“在早期处置此类综合征时展现其治疗潜力。”不过，这一观点尚未得到验证。[文献doi号：10.1016/S0140-6736(09)60952-1]

此项研究由强生公司药物研发部和拜耳医疗保健公司提供资金支持。包括Mega医生在内的多位研究者声明接受了强生公司和其他药物制造商的科研资金支持。Ortho-McNeil制药公司是强生公司的子公司。