Rosiglitazone Increases MI and CV Death in Meta-Analysis
罗格列酮增加心梗和心源性死亡的Meta分析
A new meta-analysis has suggested that the diabetes drug rosiglitazone (Avandia, GlaxoSmithKline) may increase the risk of MI and cardiovascular death [1].
一项新的Meta分析显示：糖尿病药物罗格列酮（文迪雅，葛兰素史克公司生产)可能会增加患心肌梗塞和心血管病的死亡[1] 。
The analysis, published online today in the New England Journal of Medicine, shows a significant increase in the risk of MI and an increase in cardiovascular death of borderline significance with rosiglitazone.
该研究分析，今天在新英格兰医学杂志上公布，显示出在使用罗格列酮后显著的界限，在心肌梗塞和心源性死亡上一个明显的风险增加。
The authors, led by Dr Steven Nissen (Cleveland Clinic, OH), say these new findings are "worrisome" because of the high incidence of cardiovascular events in patients with diabetes. "Because exposure of such patients to rosiglitazone is widespread, the public-health impact of an increase in cardiovascular risk could be substantial if our data are borne out by further analysis and the results of larger controlled trials," they write.
作者为Dr Steven Nissen (克利夫兰诊所)说道，这一新的发现是“令人担忧的” ，因为糖尿病患者心血管疾病是高发事件。 “因为接触罗格列酮的这类病人是很普遍的，他们写道，如果我们进一步的分析和大量的对照实验结果都证实了这一数据，那么心血管疾病风险的增加对公众健康的影响可能是重大的。
Nissen commented to heartwire: "The FDA must now evaluate all the data they have, and they have more data than we had access to. I was working with one arm tied behind my back, as we did not have original source data. In my view, the risks we saw are correct, but the FDA will have to make a decision on this. In the meantime, individual physicians should look at our data and make up their own minds about whether to continue using this drug."
Nissen在heartwire做了评论: “ FDA现在必须对他们所有的资料进行评估， 他们比我们获得的数据更多。就象工作时一只手臂绑在背后一样，因为我们没有原始数据。以我看来，我们见到的风险是正确的，但是，FDA将必须对该事件作出决定。在此期间，个别医师应该看看我们的数据，并做出他们自己的决定，是否继续使用这种药物。”
Editorial: "Rationale for rosiglitazone now unclear"
评论：“罗格列酮的机理现在尚不清楚“
In an accompanying editorial, Drs Bruce Psaty (University of Washington, Seattle) and Curt Furberg (Wake Forest University, Winston-Salem, NC) share Nissen’s concerns [2]. "In view of the potential cardiovascular risks and in the absence of evidence of other health advantages, except for laboratory measures of glycemic control, the rationale for prescribing rosiglitazone at this time is unclear. Unless new data provide a different picture of the risk/benefit profile, regulatory action by the FDA is now warranted," they say.
在随后的一篇评论中，Drs Bruce Psaty (华盛顿大学，西雅图)，Curt Furberg ( 维克森林大学，温斯顿塞勒姆，北卡罗莱那州)同样关注了Nissen的担忧 [2]。他们说道， “鉴于潜在的心血管系统风险，及在没有其他健康利益证据缺失下，除血糖控制实验方法外，在这一时期罗格列酮处方的合理性尚不清楚，除非新的数据提供了不同的风险图像/利益轮廓，由FDA规范行为是正当的”。
Nissen and his coauthor, Kathy Wolski, note that rosiglitazone was approved based on its ability to lower blood glucose levels, and studies so far conducted have not been large enough to assess its impact on long-term events. Noting that the effect of any diabetes therapy on cardiovascular outcomes is particularly important given that 65% of deaths in diabetic patients are from cardiovascular causes, they performed a meta-analysis of trials comparing rosiglitazone with placebo or an active comparator to assess its effect on cardiovascular outcomes.
Nissen及其合做者Kathy Wolski，提出罗格列酮获得批准是基于其能够降低血糖浓度，迄今为止的研究不能知道其对长远事件的影响。任何影响糖尿病治疗心血管病的成果尤为重要，因为糖尿病患65%的死亡率是心血管原因造成的，他们进行了一个Meta分析比较了，罗格列酮与安慰剂或一个活性对比药物，以此评估其对心血管的结果。
The source material for this analysis consisted of publicly available data submitted to the FDA as part of the approval package, another series of trials performed by the sponsor after approval, and two large prospective randomized trials designed to study additional indications for the drug (DREAM and ADOPT). In all, 42 trials met the inclusion criteria of a follow-up period of at least 24 weeks, the use of a randomized control group, and the availability of outcome data on MI and cardiovascular death. In these trials, 15 560 patients were assigned to rosiglitazone and 12 283 received placebo or an active comparator.
这项分析的原始材料包括，程交给FDA的公开发表数据，作为认可包装的一部分，另一连串的实验在批准后有发起者实行，和两项大型前瞻性随机试验，设计以研究附加的药物适应症(做梦和采纳) 。在符合选择标准的所有42个至少24个星期时间的后续实验，试验采用随机对照组，有效的心梗与心血管死亡数据。在这些试验中， 15560名受试者被分配到罗格列酮组，12283接受安慰剂或活性对比药物组。
Results showed that rosiglitazone-treated patients had an odds ratio of 1.43 for MI and 1.64 for cardiovascular death compared with the control group.
结果表明接受罗格列酮治疗的患者对比对照控制组患者在心梗和心血管死亡上的优势比分别是1.43和1.64
Nissen and Wolski note that the increased risk associated with rosiglitazone is the same when compared with placebo or with an active comparator, suggesting that this observation was not due to a protective effect of comparator drugs.
Nissen and Wolski指出，使用罗格列酮相关的风险增加，对比与接受安慰剂或活性对照药物，结果是一样的。显示这个观测不是由于活性药物的保护效应原因。
They point out that this meta-analysis is limited by a lack of access to original source data, which would have enabled time-to-event analysis, and on a relatively small number of events (there were 86 MIs and 39 cardiovascular deaths in the rosiglitazone patients vs 72 MIs and 22 cardiovascular deaths in control patients). But they say that despite these limitations, patients and providers should consider the potential for serious adverse cardiac effects of treatment with rosiglitazone.
他们指出,这一Meta分析是有限的，因为缺少原始数据的获得， 这将使得时间-事件的分析，和在事件中相对小的数目(接受罗格列酮治疗中有86例心梗和39例心血管病死亡的患者对比对照控制组72例心梗和22例心血管病死亡的患者) 。但他们说，尽管有这些限制，病人和供者应考虑到用罗格列酮治疗中潜在的严重不良的心脏治疗。
Nissen explained to heartwire that he requested the original data from these trials from the manufacturer but they were unable to reach agreement over the terms.
Nissen向heartwire解释道，他要求从生产厂商得到这些试验得的原始数据，但最终却未能达成协议的条款。
Nissen and Wolski say the mechanism for the increased risk remains uncertain and could be due to several factors, including an adverse effect on lipid levels, precipitation of heart failure, and a reduction in hemoglobin levels.
Nissen and Wolski说风险增加得机制仍然不明，可能是规因若干因素，包括血脂水平的不良影响，心力衰竭充盈量下降，血红蛋白水平的减少。
What about other drugs in this class?
那么其它药物也在这一类吗？
Rosiglitazone belongs to a class of drugs known as peroxisome proliferator-activated receptor (PPAR) agonists. Nissen and Wolski point out that it is not the first of this drug class to be associated with cardiovascular events, as the investigational agent muraglitazar was dropped from late-stage development because of adverse cardiovascular events, and development of many other PPAR agonists has also been stopped after early evidence of toxicity.
罗格列酮属于称为过氧化物酶体活化受体( PPAR ) 促效剂一类药物。Nissen and Wolski指出，这不是这类药物是与心血管事件第一次关联，作为一种实验药Muraglitazar在后期发展中是下降的，因为对心血管事件的不良，在最近毒性反应证据下许多PPAR 类促效剂的开展都被停止。
To heartwire, Nissen commented: "These drugs are very complex, and every one is different in that they all turn on or off different genes, so you can’t really talk about a class effect. They all have to be evaluated separately." He noted that the other major drug in this class--pioglitazone--has shown a reassuring effect on cardiovascular outcomes in a large-scale trial (PROACTIVE). "The PROACTIVE data went in the right direction, so I would say pioglitazone was probably safe," he said.
Nissen对heartwire评论道: “这些药品是非常复杂的，每一种都是不同的，他们都是开启或关闭不同基因，因此你不能确切的评论这一类药物的效果。这些都必须单独进行评估。” 他指出，在一个大型试验中，其他主要的匹格列酮类药物呈现对心血管结果一种安慰剂效果。“在正确的方向显示积极的数据，所以我要说匹格列酮类药物可能是安全的。”
Nissen noted that such a large-scale trial has not been conducted with rosiglitazone, but that one is under way--the RECORD study. ‘However, the RECORD results are not due out until 2009, and even then this trial may not be adequately powered," he added.
Nissen指出，这种大规模的试验尚未对罗格列酮进行，但是，一个正在着手进行记录的研究。他补充说，不过，记录的结果，直至2009年不会完成，即使如此，这次试验可能不会得到充分的证据“
Another failure of the regulatory process?
该调节过程的另一种失败？
In their paper, Nissen and Wolski call for more stringent evaluation of diabetes drugs preapproval. "The FDA considers demonstration of a sustained reduction in blood glucose levels with an acceptable safety profile adequate for approval of antidiabetic agents. However, the ultimate value of antidiabetic therapy is the reduction of the complications of diabetes, not improvement in a laboratory measure of glycemic control. . . . After the failure of muraglitazar and the apparent increase in adverse cardiovascular outcomes with rosiglitazone, the use of blood glucose measurements as a surrogate end point in regulatory approval must be carefully reexamined," they write.
在他们的文件中。Nissen and Wolsk要求对糖尿病药物的使用性采取更严格的评价。“FDA认为血糖水平持续降低实证可接受的安全评论足够批准降糖药。不过，最终有效的降血糖疗法是减少糖尿病并发症，不是改善在实验室中血糖控制 . . . 匹格列酮类失败后，使用罗格列酮不良心血管结果的增加，使用血糖检测作为最终的监管机构批准，必须认真反思。“
This view is shared by Psaty and Furberg, who write: "Ongoing trials using rosiglitazone may provide important new data, but for a drug approved in 1999, the delay in obtaining information about health outcomes has already been considerable." They add that tens of millions of prescriptions for rosiglitazone have been written, and if the current findings represent a valid estimate of the risk of cardiovascular events, rosiglitazone represents a "major failure of the drug-use and drug-approval process in the United States."
这个观点得到Psaty and Furberg支持，他们写道: "我们正在用罗格列酮进行试验，可能可提供新的资料，但1999年核准的药物，关于健康结果信息的延迟也已经被考虑到。“他们还补充说，数以百万计的罗格列酮处方已经开出，如果当前的结果证明了心血管事件的有效评估，在美国罗格列酮是“一个药物使用和药物审批的过程中的重大失败。”
FDA: No action recommended at this time
FDA：在这一时期没有一种行为是推荐的。
In a statement released at the same time as this paper, the US FDA notes that it is aware of this meta-analysis but that other published and unpublished data from long-term clinical trials of rosiglitazone, including an interim analysis of data from the RECORD trial and unpublished reanalyses of data from DREAM, provide contradictory evidence about the risks in patients treated with Avandia.
在一项声明中同时公布这个文件，美国FDA指出，这一Meta-分析是很清楚，但来自罗格列酮长远临床试验的其他已出版和未公布的数据，包括一个临时的数据进行分析，记录试验和来自DREAM数据的重分析，关于使用艾迪雅患者的风险提供矛盾性证据.
The agency advises patients taking rosiglitazone, especially those who are known to have underlying heart disease or who are at high risk of heart attack, to talk to their doctor about this new information.
该机构建议病人服用罗格列酮，特别是那些已知有心脏病或有高危险性心脏病,需要向他们的医生询问这种新的资料。
The FDA says its analyses of all available data are ongoing, and it has not confirmed the clinical significance of the reported increased risk in the context of other studies. Noting that there is inherent risk associated with switching patients with diabetes from one treatment to another, the agency says it is not asking GlaxoSmithKline to take any specific action at this time.
FDA说，所有数据的分析都在进行，在其他研究的内容中关于临床显著的风险增加还没有得到证实，所有数据的分析都在进行。注意到糖尿病患者从这种治疗到另一种有内在风险相关，该机构说道，在这一时期没有对葛兰素史克公司进行任何特殊的特定动作。
“FDA is carefully weighing several complex sources of data, some of which show conflicting results, related to the risk of heart attack and heart-related deaths in patients treated with Avandia," said Steven Galson, director of the FDA's Center for Drug Evaluation and Research. "We will complete our analyses and make the results available as soon as possible. FDA will take the issue of cardiovascular risk associated with Avandia and other drugs in this class to an advisory committee as soon as one can be convened," he added.
FDA正仔细权衡数个复杂的数据来源，其中一些显示相反的结果，相关接受文迪亚治疗的患者心脏病发作风险和心脏相关的死亡" Steven Galson说道，FDA药物评价和研究中心主任。我们将完成我们的分析和尽快提出有效的结果。FDA将采取发行使用艾迪亚心血管相关危险和其它这一类药品提交给咨询委员会，以尽快的收集证据，他补充说道。
The statement notes that since rosiglitazone was approved, the FDA has been monitoring several heart-related adverse events (fluid retention, edema, and congestive heart failure) based on signals seen in previous controlled clinical trials and from postmarketing reports. The most recent labeling change for Avandia also included a new warning about a potential increase in heart attacks and heart-related chest pain in some individuals using Avandia, which was based on the result of a controlled clinical trial in patients with existing congestive heart failure.
声明指出，自罗格列酮被批以来，FDA一直监控数起与心脏有关的不良事件(体液储留，水肿和充血性心力衰竭)基于这些现象在几次对照临床试验出现，并从上市后研究承诺报告。最近关于艾迪雅的标示变更还包括一项新的警告，在一些使用艾迪亚的个体中可能会增加心脏病发作和与心脏有关的胸痛，这是基于临床对照试验中充血性心脏衰竭患者的结果。
GSK disagrees with Nissen’s conclusions
葛兰素史克公司不同意Nissen的结论
GlaxoSmithKline also issued a statement strongly disagreeing with the conclusions reached in the article, which it says are based on “incomplete evidence and a methodology that the author admits has significant limitations.”,
葛兰素史克公司也发表声明，强烈反对文章中得到的结论。因为文章结果示基于“不完整的证据和方法论，作者坦承有很大的局限性。
The company notes that the totality of its data show that Avandia has a comparable cardiovascular profile to other oral antidiabetic medicines, adding that “GSK stands firmly behind the safety of Avandia when used appropriately, and we believe its significant benefits continue to outweigh any treatment risks.”
公司提示其全部数据显示迪雅对比其它口服降糖药的心血管概况有可比性。他补充说: "葛兰素史克公司坚定支持如果使用得当艾迪亚示安全的，我们相信其显著利益仍然大于任何治疗风险 "
Nissen SE and Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;DOI 10.1056/NEJMoa072761. Available at: >
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