FDA专家组拒绝推荐利伐沙班治疗ACS

马里兰州银泉——杨森制药在收集大规模研究缺失数据和提交补充分析后，仍未能说服美国食品药品管理局(FDA)专家组建议批准利伐沙班用于急性冠脉综合征(ACS)。

FDA心血管和肾病药物专家组在1月16日的会议上，以10:0的投票结果(1票弃权) 不建议批准Xa因子抑制剂利伐沙班(Xarelto)用于ACS治疗。利伐沙班制造商杨森制药基于ATLAS ACS 2 TIMI 51(ACS患者阿司匹林联合/不联合噻吩并吡啶类药物治疗添加抗Xa因子治疗以降低心血管事件)试验结果，申请将该药物用于减少ACS患者血栓形成性心血管事件风险的新适应证。

该试验比较了15,000余例近期确诊ACS的患者接受两种剂量的利伐沙班(2.5和5 mg，2次/日，前者为推荐剂量) 或安慰剂+标准抗血小板治疗(阿司匹林+噻吩并吡啶类药物)的治疗情况。结果显示，与安慰剂组相比，2.5 mg利伐沙班组主要终点(心血管死亡、心梗或卒中复合风险)显著下降15%( P=0.039)，这一差异主要来自利伐沙班组患者心血管死亡减少。

但在2012年5月，FDA专家组以4:6的投票结果反对批准利伐沙班用于ACS适应证，理由是对安全性表示担心以及该研究大量数据缺失。同年6月，FDA拒绝批准该适应证。2013年3月，FDA在杨森提供更多资料后再次做出拒绝批准的决定。杨森对此提出异议并继续推动批准事宜，随后提交了补充分析并将治疗时间限于90天。

在1月16日的会议上，专家组成员虽然对试验研究者以及杨森的新工作表示赞赏，但仍投票反对批准该新适应证。他们认为缺失数据问题仍然存在，仅凭单次试验的主要终点P值尚不足以支持批准，并对出血风险仍表示担忧。

FDA专家组成员、旧金山心脏安全研究联盟学术委员会主席Philip Sager医生指出，补充工作实际上没有对主要终点事件分析带来实质性帮助。总体上，从显著性差异方面来看，该研究不足以被认为是一项阳性研究。

FDA已批准利伐沙班多种适应证，包括降低非瓣膜房颤患者卒中和全身性栓塞风险，治疗深静脉血栓形成以及预防髋关节或膝关节置换术术后深静脉血栓形成。

根据这家强生子公司的声明，将与FDA合作解决这次会议所提出的质疑。

去年5月，欧洲药品管理局(EMA)已批准利伐沙班的ACS适应证，用于预防心脏生物标志物升高的ACS成人患者动脉粥样硬化血栓形成事件(心血管死亡、心梗或卒中)。用法用量为利伐沙班2.5 mg，2次/日，与阿司匹林或阿司匹林+氯吡格雷或噻氯匹定同服。

FDA通常遵循专家组推荐意见。专家组成员中已排除与会议主题存在潜在利益冲突者，但偶尔也会有1名成员被豁免，不过此次会议没有豁免者参加。

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By: ELIZABETH MECHCATIE, Cardiology News Digital Network

SILVER SPRING, MD. – Collection of missing data and additional analyses from a large study on rivaroxaban failed to convince a Food and Drug Administration advisory panel to recommend approval of the anticoagulant drug for acute coronary syndrome.

At a meeting Jan. 16, the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 10 to 0, with 1 abstention, that the factor Xa inhibitor rivaroxaban (Xarelto) should not be approved as a treatment for acute coronary syndromes (ACS). Rivaroxaban maker Janssen Pharmaceuticals had proposed an indication to reduce the risk of thrombotic cardiovascular events in patients with ACS, based on the results of 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.

That study compared two doses of rivaroxaban (2.5 mg twice a day, the proposed dose, and 5 mg twice a day) plus standard antiplatelet therapy (aspirin and a thienopyridine) to placebo plus standard therapy in more than 15,000 people with recent ACS. 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. The difference was primarily driven by a reduction in cardiovascular deaths among rivaroxaban patients.

But in May 2012, the FDA panel voted 4 to 6 against approval of rivaroxaban for the ACS indication, citing safety concerns and the large amount of missing data from the study. In June 2012, the FDA declined to approve the indication, and the agency refused again in March 2013, after Janssen provided more information. The company disputed the decision and continued to pursue approval. Janssen submitted new analyses and proposed that treatment be limited to 90 days.

At the Jan. 16 advisory committee meeting, panel members commended the study investigators and Janssen for that new work. But they still voted against approval, noting that the missing data remained a problem, the P value for the primary endpoint was not low enough to support approval based on a single trial, and concerns continued about bleeding risk.

The additional work "didn’t really add in a substantial way to the primary endpoint analysis," explained advisory panel member Dr. Philip Sager. Overall, the study "wasn’t robust enough in terms of statistical significance to be considered as a positive study," added Dr. Sager, chair of the scientific programs committee at the Cardiac Safety Research Consortium, San Francisco.

The FDA has approved rivaroxaban for several indications, including reduction of the risk of stroke and systemic embolism in nonvalvular atrial fibrillation, treatment of deep vein thrombosis, and prevention of deep vein thrombosis after hip or knee replacement surgery.

Janssen will work with the FDA to address the questions raised at the meeting, according to a statement issued by the Johnson & Johnson subsidiary.

In May 2013, European Union drug regulators approved an ACS indication for rivaroxaban, to prevent atherothrombotic events (cardiovascular death, myocardial infarction, or stroke) after an ACS in adults with elevated cardiac biomarkers, at a dose of 2.5 mg twice a day, co-administered with acetylsalicylic acid alone or with acetylsalicylic acid plus clopidogrel or ticlopidine.

The FDA usually follows the recommendations of its advisory panels. Advisory panel members have been cleared of potential conflicts related to the meeting topic. Occasionally, a panelist is given a waiver, but no waivers were given at this meeting.