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FDA专家小组反对批准利伐沙班用于急性冠脉综合征

来源:环球医学编译    时间:2012年05月28日    点击数:    5星

5月28日消息 - 环球医学据悉,FDA的一个咨询委员会以6-4(1票弃权)的表决结果反对将Xa因子抑制剂利伐沙班(拜瑞妥)标签中的适应症扩大到治疗急性冠脉综合征(ACS)。

心血管和肾脏药物咨询委员的投票结果有些令人惊讶,因为两天前发布的FDA工作人员审查对利伐沙班用于ACS表示了肯定,但基于单一试验所得出的数据而扩大适应证变得越来越勉强。

在对利伐沙班的审查中,咨询专家可能已经特别谨慎,因为其他同类口服抗凝血剂——apixaban(Eliquis)(也是一种Xa因子抑制剂)和一种研究中的药物——darexaban在发现能够增加ACS人群的出血风险之后,均未能获批用于此人群。

利伐沙班已经获得FDA的上市批准用于非瓣膜性房颤患者预防卒中,以及用于关节置换手术患者预防深静脉血栓形成。

周三,专家委员会似乎一致地对利伐沙班可降低ACS患者的心血管死亡率表示认同,但对ATLAS ACS试验中缺失的数据表示担忧;该试验发现,利伐沙班可使由心血管疾病致死、心肌梗死及卒中所构成的复合终点的发生率降低至8.9%,相比之下,仅接受单独抗血小板治疗者的复合终点发生率为10.7%(p = 0.008)。

该研究在超过19000例ACS患者中对利伐沙班+阿司匹林同时联合噻吩并吡啶或不联合噻吩并吡啶的安全性及有效性进行了评估。

与服用安慰剂者相比,服用利伐沙班患者的复合终点(心血管疾病死亡、心肌梗死或卒中)发生率显著降低。导致该终点发生率下降的主要因素是心血管疾病死亡率的下降。

但总体来说,利伐沙班组的出血风险会增加三至四倍。

“我担心千上万的美国人会暴露于出血的风险,或许会导致卒中,”克利夫兰诊所心内科主任、小专家组成员、医学博士Steve Nissen说;他投票反对扩大利伐沙班的适应症。“对于扩大适应症,我还没有准备好走到那一步。”

Nissen说,如果FDA决定扩大利伐沙班的适应症,FDA将会认可治疗ACS患者的三联疗法(阿司匹林、噻吩并吡啶、利伐沙班)。

“在我们走到那一步之前,我需要确认在双重抗血小板治疗中加入其他疗法的这种策略更佳,”他说。“我只是不信服。”

他补充说,另外进行一项试验可能会改变他的观点。

周三大部分时间专家小组成员都在要求该药的开发商杨森公司(强生的子公司)就该研究缺失的数据进行工作,即超过2400名患者在试验早期就退出了研究,而且“随访不完整,未对死亡计数。”

专家小组成员对该公司表示,在研究结束后还有9%的患者不知是死是活,这是不可接受的。

Nissen甚至表示,该研究的设计可能会鼓励患者退出试验,这可能使公司受益,因为如果退出后患者死亡,就不会对总体结果产生负面影响了。

“在此缺失的数据令人困扰且值得关注,”洛杉矶Cedars-Sinai医疗中心的心脏病学家、医学博士Sanjay Kaul说;他投票反对批准利伐沙班用于ACS。

在当天早些时候,该专家小组听了Tom Marciniak的评价,他是FDA心血管和肾脏产品部的审查人员。Marciniak素以对心血管药物试验的审查严格而闻名,包括审查葛兰素史克关于罗格列酮的RECORD试验。

他在周三与以往并无不同。

“毫无疑问,ATLAS试验失败了,”他说。

专家小组成员还对试验中所研究的两种剂量的差异表示关注。

例如,与服用安慰剂者相比,接受2.5mg利伐沙班治疗者的复合终点(心血管疾病死亡、心肌梗死或卒中)发生率有所降低;但服用5mg利伐沙班者则未显示出其复合终点有统计学上显著的减少。此外,5mg利伐沙班还会增加出血的风险。

另一位FDA评审人员告诉专家小组,在每10000病人年中,预计使用利伐沙班治疗ACS可以防止115例复合终点(心血管疾病死亡、心肌梗死或卒中),但将会以516起出血事件作为代价。

预计FDA将在6月底之前对利伐沙班作出最终决定。FDA并非必须遵循其咨询委员会的意见,但通常还是会遵循的。

“我们感谢委员会的审查,我们将与FDA一起解决今天发现的问题,”杨森公司心血管专营部副总裁、医学博士、哲学博士Paul Burton在表决后发布的一篇新闻稿中说。(环球医学)

原文:

FDA Panel Narrowly Rejects Xarelto for ACS

WASHINGTON -- An FDA advisory committee has voted 6-4, with one abstention, against expanding the labeling for the factor Xa inhibitor rivaroxaban (Xarelto) to include treatment of acute coronary syndrome (ACS).

The vote by the Cardiovascular and Renal Drugs Advisory Committee was somewhat surprising given the positive review from FDA staff released two days before the meeting, but it signals a growing reluctance to expand indications based on data from a single trial.

In the case of rivaroxaban, the advisers may have been especially cautious since other oral anticoagulants in the same class -- apixaban (Eliquis) which is also a factor Xa inhibitor and an investigational agent, darexaban -- failed in ACS when both were found to increase bleeding in this population.

Rivaroxaban already has FDA marketing approval for prevention of stroke in patients with nonvalvular atrial fibrillation and for prevention of deep vein thrombosis in patients undergoing joint replacement surgery.

Wednesday's panel seemed in agreement that the drug worked well at reducing the rate of cardiovascular death in patients with ACS, but worried about missing data in the ATLAS ACS trial, which did find that the drug rivaroxaban reduced the composite rate of death from cardiovascular causes, myocardial infarction, and stroke to 8.9% compared with 10.7% among those on antiplatelet therapy alone (P=0.008).

The study evaluated the safety and efficacy of rivaroxaban in more than 19,000 ACS patients in addition to aspirin with or without thienopyridine therapy.

Patients taking rivaroxaban had a significant reduction in the occurrence of the composite primary endpoint of cardiovascular death, myocardial infarction, or stroke, compared with placebo (P=0.025). Most of that reduction was driven by a reduction in cardiovascular death.

But there was an increase in bleeding that was three to four times greater overall in the rivaroxaban group.

"I'm worried about exposing thousands of Americans to bleeding, maybe stroke," said panelist Steve Nissen, MD, chairman of the department of cardiology at the Cleveland Clinic, who voted against expanding rivaroxaban's indication. "I wasn't ready to go there yet."

Nissen said if the FDA decides to expand the indication for rivaroxaban, it would be an endorsement to treat ACS patients with three drugs (aspirin, thienopyridine, and rivaroxaban).

"Before we go that far, I want to make sure that this strategy of adding something else to dual antiplatelet therapy is robustly better," he said. "And I just wasn't convinced."

He added that a second trial might change his mind.

Panelists spent much of Wednesday taking the drug's sponsor -- Janssen, a Johnson & Johnson company -- to task for the missing data in the study, namely the more than 2,400 patients who dropped out of the trials early, and for "incomplete follow-up and uncounted deaths."

The panelists told the company it wasn't acceptable to not know whether 9% of their patients were alive or dead at the end of the study.

Nissen even suggested that the design of the study may have encouraged patients to drop out, which could benefit the company because then if the patient died, it wouldn't negatively effect the overall results.

"The missing data in this is troubling and concerning," said panelist Sanjay Kaul, MD, a cardiologist at Cedars-Sinai Medical Center in Los Angeles, who also voted against approving rivaroxaban for ACS.

Early in the day, the panel heard a review from Tom Marciniak, MD, a reviewer with the FDA's Department of Cardiovascular and Renal Products. Marciniak has been known to deliver a scathing review of cardiovascular drug trials in the past, including GlaxoSmithKline's RECORD trial for rosiglitazone).

Wednesday was no different.

"ATLAS failed, not shrugged," he said.

Panelists also were concerned with the differences between the two doses studied in the trial.

For instance, patients treated with the 2.5-mg dose of rivaroxaban had a reduced occurrence of the composite primary endpoint of cardiovascular death, myocardial infarction, or stroke, compared with placebo, but the 5-mg dose did not show a statistically significant reduction in the primary endpoint. In addition, the 5-mg dose also increased the risk of bleeding.

Another FDA reviewer told the panel that using rivaroxaban to treat ACS could be expected to prevent 115 cases of the composite endpoint of cardiovascular death, myocardial infarction, or stroke for every 10,000 patient years, but that would come at the cost of having an additional 516 bleeding events.

The FDA is expected to make a final decision on rivaroxaban by the end of June. The agency doesn't have to follow the advice of its advisory committees, but it often does.

"We appreciate the thoroughness of the committee's review and will ensure the questions raised today are addressed with the FDA," Paul Burton, MD, PhD, vice president of Janssen's cardiovascular franchise division, said in a press release sent after the vote.
 

相关链接:http://www.medpagetoday.com/Cardiology/AcuteCoronarySyndrome/32888 

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