FDA顾问小组一致投票赞成普拉格雷

FDA顾问小组一致投票赞成普拉格雷

 

 

 

       美国食品药品管理局（FDA）顾问小组一致投票批准通过普拉格雷用于治疗急性冠脉综合征（ACS）。此次投票是由来自心血管和肾脏药物咨询委员会9名小组成员参与的，就目前治疗策略而言，它标志着抗血管药物的重大突破。

 

       “我认为，这是对比氯吡格雷更好的药代动力学和药效动力学的药物的迫切需要，而促使的。”顾问小组成员理查德•卡农博士说，“我认为氯吡格雷抵抗的观点是真实且紧要的，并且此药物是在关注下取得的重要进展。”

 

         关于普拉格雷的数据是基于非常重要的TRITON-TIMI 38试验。此试验首先由Dr Steven Wiviott带领，发表于2007年AHA大会并且此试验轰动一时，它的重大意义在于与氯吡格雷相比，新药可明显减少由副作用引起的局部缺血事件，但是付出了ACS患者行PCI的主要出血事件增加的代价。

 

        但是增加了患有ACS经PCI手术在控制出血方面的费用。 “伴随每个新抗血小板或抗凝血药物的出现，都会产生益处利润和风险的纷争，”顾问小组主席Dr Marvin Konstam博士说，现在存在一些基于第二阶段处方过程中药剂用量数据的预测，但我们应指出事实并不是那样的。

 

       应用普拉格雷有明显的益处，也就是更显著的抗血小板效果，但它也伴随着代价。“一些基于那两组关于处方过程中药剂用量数据，还要继续观察，但应指出它的副作用。在普拉格雷明显的抗血小板的巨大作用的同时，它也带来了巨大的利润。” 专家建议在先前有中风或短暂性脑缺血发作的病人，应用普拉格雷是有禁忌的。

 

         一些人则关心亚组和能否引发癌症。 早在此周二早上，Dr Elliott M Antman，TRITON-TIMI-38的研究者，提供给专家小组一个详细的风险和效益权衡的分析，表明他相信在ACS的治疗方面普拉格雷有了重要的突破。顾问小组成员也对此表示认同。 TRITON-TIMI-38试验中，普拉格雷在整个ACS人群心血管死亡、MI和中风的主要复合终点减少了19%。

 

       在不稳定心绞痛伴非ST段抬高MI组和ST段抬高的MI患者中，是有着几乎相同的好处。关于主要安全终点，普拉格雷与氯吡格雷相比，非CABG相关的TIMI主要出血风险有明显增加，而且出血死亡风险也有所增加。

 

         在评论此项决议时，大多数专家称他们在支持在ACS病人中普拉格雷代替氯吡格雷的决议时感觉还是很轻松的，尽管有出血风险的增加。Mori Krantz博士称普拉格雷是一个“科学的进步”，并说“很高兴能看到新的治疗方法，而不是在原来的治疗方法中添加新的使治疗更加复杂。”

 

       Michael Domanski博士也是顾问组成员，在适当选择的病人中，他说赞助商和研究者都说了普拉格雷对选择适当的患者是安全有效的。 一直以来对于年龄小和/或老的患者，特别是那些体重在60公斤或以下和那些年龄75岁或更大的患者，质疑一直存在。

 

       许多小组成员说患者可能应该使用更少的剂量的普拉格雷，用5-mg来替代原来推荐的10-mg维持量，尽管关于此策略只有有限的临床数据。他们认为在这些人群中如何使用普拉格雷的决定，应该留给那些谨慎的内科医生，并且因为在这些患者中数据是支持用普拉格雷替代氯吡格雷的，他们这么做会感觉相对轻松。

 

         不同解释 尽管一致通过，血小板研究者Victor Serebruany博士，在论坛期间对公众说，对TRITON-TIMI-38试验中对局部缺血的好处是表示质疑的，因为去年三月他已经给《新英格兰》杂志的编辑写了一封信。普拉格雷可见的主要优势是使非致命性心梗有所减少。

 

         Serebruany说在TRITON-TIMI-38试验中心梗的比率是夸大的并其包括的不仅是临床相关MI而且有围手术期MI包含心脏缺血的生物标记物的增加。另外，出血风险是通过非CABG TIMI主要出血事件来评价，紧急测量出血情况。在这种情况下，所有对普拉格雷的风险/利益评价是有偏颇的。

 

       “如果你想分析TIMI主要出血事件，那么就只要分析患者死亡和ST段抬高MI。” Serebruany说，“如果你想分析那些新的MI，那么你也需要包括小量的出血。” 他也告知顾问小组，如果仅仅把研究者所知的MI包括在分析之内，在试验中心血管死亡，心梗或中风就没有明显统计学意义的减少。

 

       只有包括了临床终点委员会评定后的MI，才能证明普拉格雷的优势。

 

        总之，Serebruany批评了FDA的决定，称它为theheart.org’s 论坛的 “家庭聚会”他说这项决定就像事先约定好的投票。 也说在论坛期间，美国心血管学学院院长Doug Weaver博士，表示近来的研究已经表明许多患者对氯吡格雷有抵制，并且药物间是有相互作用，包括质子泵抑制剂。尽管需要新的治疗方案，但是也要小心。

 

        “我们相信如果药物被通过，那么另外的研究就应该提上日程，以确保它的安全性和确保此药对病人是有益处并且没有害处。”他说。 癌症标志应被讨论但被取消 Ellis Unger博士的分析，他是心血管病和肾脏药物在新药物委员会的代理理事，表明他对此药的可能的致癌风险表示担心，因为有33例普拉格雷组患者死于恶性肿瘤，在氯吡格雷组中有21例死于恶性肿瘤。

 

         基于各种各样的评估，但是，FDA表示他们不相信普拉格雷有致癌作用，或它可以催生已有的恶性肿瘤。顾问小组成员几乎一致同意癌症标志物不应该被过分关注。大多数认为试验观察到的的肿瘤标志物应该被分在有标签的相**，并“尽可能的不显著”，因为这个发现很可能是不真实的。但是一个小组成员说此结果不应被忽视。

 

         “我不认为癌症数据是强有力的，但是它是有点可疑的，并且问题是如果你对事物的分析仅仅是基于对机制的一般性理解，那么就永远不会学到新的知识，”小组成员John Flack博士说。“我认为结论已经出现，但是出现的低水平标志物应该包含在某种低水平的警告中。我不认为标志物数据是有足够说服力的，而且我还想把此药介绍给我的家人。”

 

        Dr Eugene Braunwald，另一个TRITON-TIMI-38试验研究者，他提供数据给顾问小组，表示此项决议的通过普拉格雷的使用每年可能防止23，000例MI患者和4，000例患者死亡，但增加2，300例主要出血事件。 “我可以说这是一个非常、非常好的权衡，并且作为一名内科医生，我可能非常愿意把这个药物提供给我的病人，”Braunwald.说。

 

soucre：www.theheart.org

 

 《医心评论》编辑：呼唤 翻译 毛新罡 校对

 

FDA advisory panel votes unanimously in favor of prasugrel

 

Silver Spring, MD - A US Food and Drug Administration advisory panel voted unanimously to recommend approval of prasugrel (Lilly/Daiichi Sankyo) for the treatment of acute coronary syndromes.

 

The vote, by the nine panel members of the Cardiovascular and Renal Drugs Advisory Committee, was based largely on the premise that the antiplatelet agent represents an advance over existing treatment strategies.

 

"I think there is a compelling need for a drug that has more predictable pharmacokinetics and pharmacodynamics than clopidogrel," said advisory panel member Dr Richard Cannon (National Institutes of Health, Bethesda, MD). "I think the issue of clopidogrel resistance is real and it matters, and this drug is a major advance in that regard."

 

Data on prasugrel were based largely on the pivotal Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON-TIMI 38).

 

That study, first presented by Dr Steven Wiviott (Brigham and Women’s Hospital, Boston, MA) at the American Heart Association 2007 Scientific Sessions and reported by heartwire at that time, showed significantly reduced ischemic events with the new drug compared with clopidogrel, but at the expense of an increase in major bleeding in ACS patients scheduled for PCI.

 

"With every new antiplatelet or antithrombotic agent that came along, there’s often been a promise of dissociation between benefit and risk," panel chair Dr Marvin Konstam (Tufts University School of Medicine, Boston, MA) said today. "There was some anticipation based on phase 2 data that this might be the case with the dosing regimen prescribed, but we should point out that it didn’t work that way.

 

There was incremental benefit, what was clearly a greater antiplatelet effect, but it came with a cost." The panel recommended that prasugrel be contraindicated in patients with a prior stroke or transient ischemic attack Some concerns about subgroups and cancer signal Early Tuesday morning, Dr Elliott M Antman (Brigham and Women’s Hospital), a TRITON-TIMI-38 investigator, provided a detailed analysis of the risk/benefit trade-off with the antiplatelet agent, saying he believes that the drug represents an advance in the treatment of ACS.

 

Many panel members thought the same. In the TRITON-TIMI-38 trial, prasugrel was associated with a 19% reduction in the primary composite end point of cardiovascular death, MI, and stroke in the entire ACS population. There was a nearly identical benefit in the unstable-angina and non-ST-segment elevation (non-STEMI) MI cohort and in patients with STEMI.

 

Regarding the primary safety end point, the risk of non-CABG-related TIMI major bleeding was significantly increased with prasugrel compared with clopidogrel, and there was also an increased risk of fatal hemorrhages. Commenting on the decisions, most panel members said they felt comfortable supporting a superiority claim for prasugrel over clopidogrel in ACS patients, despite the increased risk of bleeding.

 

 Dr Mori Krantz (University of Colorado Medical Center, Denver), calling prasugrel a "scientific advance," said that "it was nice to see incremental value rather than a new add-on therapy that creates more complexity for care." Dr Michael Domanski (National Institutes of Health, Bethesda, MD), who was also part of the advisory panel, said the sponsor and investigators showed prasugrel to be effective and safe in appropriately selected patients.

 

Throughout the day questions were raised about small and/or elderly patients, specifically those who weigh 60 kg or less and those 75 years and older. Many panel members said these patients should probably take a lower dose of prasugrel, 5-mg instead of the recommended 10-mg maintenance dose, although there are limited clinical data on the effectiveness of this strategy.

 

They felt the decision of how to use prasugrel in these subsets should be left to discretion of the physician and felt comfortable doing so as the data still favor prasugrel over clopidogrel in these patients. A different interpretation Despite the unanimous vote, platelet researcher Dr Victor Serebruany (Johns Hopkins University, Baltimore, MD), who spoke during a forum open to the public, took issue with the observed ischemic benefits in the TRITON-TIMI-38 trial, as he did in a letter to the New England Journal of Medicine editor last March [1].

 

The major benefit seen with prasugrel was a reduction in nonfatal MI. Serebruany said that the rate of MI in TRITON-TIMI-38 was inflated and included not just clinically relevant MIs but also periprocedural MIs comprising increases in cardiac ischemic biomarkers.

 

Bleeding risks, on the other hand, were assessed by non-CABG TIMI major bleeds, a stringent measure of hemorrhage. In this way, any risk/benefit assessment of prasugrel is skewed. "If you want to deal with TIMI-major bleeds, then pick up death and ST-segment-elevated MIs only," said Serebruany. "If you deal with these green, juicy MIs that are there, then you need to include minor bleeds."

 

 He also told the panel that if only investigator-site-acknowledged MIs are included in the analysis, there is no statistically significant reduction in cardiovascular death, MI, or stroke in TRITON. It is only when MIs adjudicated by the clinical-end-points committee are included is an advantage with prasugrel observed.

 

Overall, Serebruany was critical of the FDA hearing, calling it a "family picnic" in theheart.org’s forum [2]. He said the hearing felt as if a vote for approval was a foregone conclusion. Also speaking during the open forum, Dr Doug Weaver (Henry Ford Hospital, Detroit, MI), president of the American College of Cardiology, noted that recent studies have shown that many patients are resistant to clopidogrel and that the drug has interactions with other commonly prescribed medications, including proton-pump inhibitors.

 

Despite the need for new therapies, Weaver expressed caution. "We believe that if the drug is approved, additional studies should be conducted to ensure its safety as well as to ensure that it is prescribed to patients who might benefit and who are unlikely to be harmed," he said.

 

Cancer signal debated but dismissed An analysis by Dr Ellis Unger, deputy director of cardiovascular and renal products in the Office of New Drugs, showed that there were also concerns about a possible cancer risk, since there was an excess of malignancy deaths with prasugrel—33 cancer deaths in the prasugrel group and 21 in the clopidogrel group.

 

Based on various assessments, however, the FDA said that it does not believe prasugrel is carcinogenic or that it enhances existing tumors. Panel members agreed almost unanimously that the cancer signal should not be emphasized in a black box or in a section on warnings or precautions.

 

Most agreed that the cancer signal observed in trials should be placed as "inconspicuously as possible" under the adverse-events section of the label, as the finding was likely spurious. One panel member, however, said the finding shouldn’t be ignored. "I don’t think the cancer data are strong, but it’s a little suspicious, and the problem is that if you assess things based only on currently understood mechanisms you never learn anything new," said panel member Dr John Flack (Wayne State University, Detroit, MI).

 

"I think the verdict is out, but it’s a low-level signal that ought to be included in some type of low-level warning. I don’t believe [the signal] is strong enough, nor would I have a problem giving this drug to one of my family members." Dr Eugene Braunwald (Brigham and Women’s Hospital), another TRITON-TIMI-38 investigator who presented data to the advisory panel, said the approval and use of prasugrel would prevent 23 000 MIs and 4000 deaths annually at a cost of an additional 2300 major bleeding events.

 

"I would say that this is a very, very good trade-off, and as a physician I would very much like to be able to offer this to my patients," said Braunwald.