利伐沙班预防ACS支架内血栓形成未获准

抗凝剂利伐沙班的生产商称，美国食品药品管理局(FDA)决定暂不批准利伐沙班用于降低急性冠状动脉综合征(ACS)患者支架内血栓形成的风险。

杨森研发有限公司(Janssen Research & Development)在6月28日发表的声明中宣布，FDA已经就公司提出的这一利伐沙班适应证申请发出了完整答复函。口服Xa因子抑制剂利伐沙班由杨森公司上市销售，商品名为拜瑞妥(Xarelto)。

FDA不会公布何时给厂家发出了完整答复函(针对批准前还有尚未解决的重大问题的药品)，但厂家可以公开相关信息。

杨森公司基于ATLAS ACS 2 TIMI 51(在急性冠脉综合征患者中应用阿司匹林联合/不联合噻吩并吡啶标准疗法加抗Xa因子治疗以降低心血管事件发生率)试验的结果提交了该适应证申请。这项试验总共纳入了15,526例近期确诊为ACS的患者。结果显示，利伐沙班降低了ACS患者的心血管死亡、心肌梗死(MI)或卒中风险，同时也增加了大出血和颅内出血的风险，但致命性出血风险无增加。该试验结果已于2012年1月公开发表(N. Engl. J. Med. 2012;366:9-19 )。

在杨森公司的声明中，杨森副总裁/心血管特许经营产品医学总监Christopher C. Nessel博士称：“我们对ATLAS ACS 2 TIMI 51试验的结果仍抱有信心，并且我们正与FDA就该产品的新药补充申请进行讨论。”杨森公司的声明并未阐述FDA拒绝批准该适应证的原因。

杨森公司基于同一项试验的数据还提交了利伐沙班另一种适应证的申请，即用于降低ACS患者的心血管事件风险，但已经收到了2封FDA针对该适应证发出的完整答复函，最近一次是在2013年3月。FDA审评专家在2012年5月召开的咨询委员会会议上以数据缺失和安全性担忧为由建议FDA不批准这一适应证，但杨森并未明确指出这是否就是FDA针对该ACS适应证发出2封完整答复函的原因。

自2011年获准用于膝关节或髋关节置换术患者深静脉血栓形成(DVT)的预防以及降低非瓣膜性房颤患者的卒中和全身性栓塞风险以来，利伐沙班又相继获得FDA的批准用于DVT和肺栓塞(PE)的治疗，以及用于降低DVT和PE的复发风险。

最近欧盟又批准利伐沙班联合抗血小板治疗预防ACS后动脉粥样硬化血栓形成事件。

爱思唯尔版权所有  未经授权请勿转载

By: ELIZABETH MECHCATIE, Cardiology News Digital Network

The Food and Drug Administration has decided not to approve rivaroxaban for reducing the risk of stent thrombosis in patients with acute coronary syndrome, according to the manufacturer of the anticoagulant.

In a statement issued on June 28, Janssen Research & Development announced that the FDA has issued a complete response letter regarding the company’s application to approve rivaroxaban for this indication. Janssen markets rivaroxaban, an oral factor Xa inhibitor, as Xarelto.

The FDA does not announce when they send a company a complete response letter, issued for a drug when there are outstanding issues that need to be resolved before approval, but manufacturers can make these announcements.

The company filed for approval of this indication based on the results of the ATLAS ACS 2 TIMI 51 (the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin With/Without Thienopyridine Therapy in Subjects With Acute Coronary Syndrome) study, of 15,526 patients with recent ACS. In the study, rivaroxaban reduced the risk of cardiovascular death, MI, or stroke in patients with ACS, with an increase in major bleeding and intracranial hemorrhage but not the risk of fatal bleeding. The study was published in January 2012 (N. Engl. J. Med. 2012;366:9-19).

In the Janssen statement, Dr. Christopher C. Nessel, vice president and medical leader of the cardiovascular franchise at Janssen, said, "We remain confident in the results of the ATLAS ACS 2 TIMI 51 trial and are in ongoing discussions with the FDA regarding" the supplemental new drug application. The Janssen statement did not elaborate on the reasons why the FDA did not approve this indication.

The company used data from the same study to file for approval of rivaroxaban for another indication – to reduce the risk of cardiovascular events in patients with ACS – but has received two complete response letters from the FDA for this indication, most recently in March 2013. Missing data and safety concerns were cited as concerns by FDA panelists recommending against the approval of this indication at an FDA advisory panel meeting in May 2012, but the company did not specify whether this was the reason for the two complete response letters for the ACS indication.

Since it was approved in 2011 for the prophylaxis of deep vein thrombosis in patients undergoing knee or hip replacement surgery and for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, rivaroxaban has been approved by the FDA for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; for the treatment of deep vein thrombosis (DVT), pulmonary embolism (PE); and for the reduction in the risk of recurrence of DVT and of PE.

It was recently approved in the European Union for in combination with antiplatelet therapy to help prevent atherothrombotic events after acute coronary syndrome.