利伐沙班的ACS适应证未获批准

正如人们预料的那样，美国食品药品管理局(FDA)拒绝批准口服抗凝剂利伐沙班治疗急性冠脉综合征(ACS)。

利伐沙班是一种Ⅹa因子抑制剂，商品名为拜瑞妥，已经获准用于一些适应证，包括降低非瓣膜病房颤患者的卒中和全身性栓塞风险、治疗深静脉血栓、预防髋关节或膝关节置换术后深静脉血栓形成以及降低深静脉血栓和肺栓塞风险。

利伐沙班的生产商杨森公司2月14日宣布，FDA已发出一份关于利伐沙班降低ACS患者继发性心血管事件(MI、脑卒中或死亡)风险的完全答复函。在此之前10天，FDA的心血管与肾脏药物顾问委员会以10-0的投票结果反对批准该适应证。该公司还宣布，FDA发布了一份关于利伐沙班联合标准抗血小板治疗降低ACS患者支架内血栓形成的ACS适应证的完全答复函，指出了在药物通过批准之前需要解决的突出问题。FDA未公开宣布何时发出这些信函，但生产商通常会这样做。

这些适应证均基于ATLAS ACS 2 TIMI 51（对急性冠脉综合征患者在阿司匹林伴有/不伴有噻吩吡啶类药物基础上联合抗Xa治疗降低心血管事件风险）试验，这是一项Ⅲ期研究，纳入了15,000余例近期发生ACS的患者，对两种剂量的利伐沙班联合标准抗血小板治疗（阿司匹林和一种噻吩吡啶类药物）与安慰剂联合标准治疗进行了比较。主要终点为心血管源性死亡、MI或脑卒中的复合风险。研究结果显示，2.5 mg每日2次剂量组的主要终点显著减少，较安慰剂组减少15%(P=0.039)(N. Engl. J. Med. 2012;366:9-19)。

这是FDA第三次拒绝核准将利伐沙班用于ACS适应证。杨森提交了新的数据分析，包括一些缺失数据，但在1月份的FDA会议上，专家小组认为仍存在缺失数据问题，并且主要终点的P值不够低，不足以支持单一试验基础上的批准。小组成员也表示仍然关注出血风险，并投票反对核准。

杨森未在声明中解释FDA决定拒绝核准的理由。杨森公司临床研发副总裁Paul Burton博士在公司声明中说：“我们正在评估信函内容，并将采取适当的后续行动。”

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By: ELIZABETH MECHCATIE, Cardiology News Digital Network

As expected, the Food and Drug Administration has declined to approve the oral anticoagulant rivaroxaban for treating acute coronary syndromes.

The manufacturer of the factor Xa inhibitor, Janssen Research & Development, announced on Feb. 14 that the FDA has issued a complete response letter regarding rivaroxaban, for reducing the risk of secondary cardiovascular events (MI, stroke, or death) in patients with ACS. This announcement came a month after the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 10-0 against approval. The company also announced that the FDA issued a complete response letter for the other ACS indication under review, to reduce the risk of stent thrombosis in patients with ACS, in combination with standard antiplatelet therapy.

The FDA issues complete response letters to manufacturers when it decides against approval, with explanations of outstanding issues that need to be resolved before the drug can be reconsidered for approval. The FDA does not publicly announce when these letters are issued, but manufacturers often do so.

Both indications are based on the ATLAS ACS 2 TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin With/Without Thienopyridine Therapy in Subjects With Acute Coronary Syndrome) trial, a phase III study of more than 15,000 patients with recent ACS, which compared two doses of rivaroxaban plus standard antiplatelet therapy (aspirin and a thienopyridine) to placebo plus standard therapy. The primary endpoint – the risk of a composite of cardiovascular death, MI, or stroke – was significantly reduced (P = .039) by 15% among patients on the 2.5-mg twice-daily dose, compared with patients on placebo (N. Engl. J. Med. 2012;366:9-19).

This is the third time the FDA has rejected approval of rivaroxaban for the ACS indication. The company submitted new analyses of the data which included some missing data, but at the FDA meeting in January, the panel said that missing data remained a problem and the P value for the primary endpoint was not low enough to support approval based on a single trial. Members also expressed continuing concerns about bleeding risk and voted against approval.

The company did not explain in the statement why the FDA had decided against approval.

"We are evaluating the contents of the letters and will determine the appropriate next steps," Dr. Paul Burton, vice president, clinical development, Janssen, said in the company’s statement.

Rivaroxaban, marketed as Xarelto, is approved for several indications, including reduction of the risk of stroke and systemic embolism in nonvalvular atrial fibrillation, treatment of deep vein thrombosis, prevention of deep vein thrombosis after hip or knee replacement surgery, and reduction in the risk of deep vein thrombosis and pulmonary embolism.