欧洲药品管理局建议羟乙基淀粉退市

钟医生

6月14日，欧洲药品管理局（EMA）发布声明指出，药品风险评估委员会（PRAC）建议将羟乙基淀粉退市。

PRAC对于羟乙基淀粉的裁决是基于发表在NEJM上的三项重要研究，这些研究对比了HES以及其他液体复苏液对危重症患者的疗效和安全性。

第一项研究表明，6%HES用于液体复苏并不优于生理盐水，而且HES还与患者肾脏损伤的高风险率有关。（NEJM：Hydroxyethyl starch or saline for fluid resuscitation in intensive care.)

第二项研究表明，使用羟乙基淀粉的危重症患者与使用乳酸林格液的患者相比有更高的死亡风险。（NEJM：通过羟乙基淀粉进行复苏治疗的ICU患者存在更高的肾脏损伤风险）

第三项研究表明，HES对于严重毒血症患者“有害并且毒副作用会随着累积剂量增加而升高”。（NEJM：羟乙基淀粉130/0.4治疗严重脓血症效果不佳）

基于以上研究结果，EMA授权 PRAC对这些研究结果进行评估，并评估羟乙基淀粉在低血容量性患者中的风险收益比。PRAC指出，羟乙基淀粉临床收益不比高于临床风险，建议羟乙基淀粉在欧洲退市。

EMA指出，除非有权威部门有足够的证据可以证明羟乙基淀粉对一些患者群体的临床收益高于风险，否则退市的裁决应该不会改变。

欧盟下属的协调机构（the Coordination Mutual Recognition and Decentralised Procedures–Human）将酌情考虑EMA的这一建议，并作出最终裁决。

需要指出的是，与欧洲药品管理局的作出一系列举措相比，中国这方面的进展相对滞后，羟乙基淀粉在国内指南的建议级别至今没有太大变动。

针对近来关于羟乙基淀粉的报道，以及发表在NEJM上面的研究。我们对NEJM：羟乙基淀粉130/0.4治疗严重脓血症效果不佳 这项研究的通讯作者Dr. Perner进行了采访：

编者按：针对近来关于羟乙基淀粉的报道，以及发表在NEJM上面的研究。丁香园对 NEJM：羟乙基淀粉130/0.4治疗严重脓血症效果不佳.这项研究的通讯作者Dr. Perner进行了采访：

DXY: 近期，多家顶级期刊（如NEJM, BMJ, JAMA) 发表了对HES不利的研究结果。这是否意味着HES的终结。

Dr. Perner:有可能，这取决于的欧洲药品管理局实施的地域。详见附件。

DXY: 为了了解中国医生对羟乙基淀粉的临床使用情况和态度，我们做了一项调查。这份调查有7000余名医生参与。调查结果表明，非常多的中国医生在临床中经常使 用羟乙基淀粉，ICU医生和麻醉科医生甚至常规使用。而且，很多医生认为羟乙基淀粉临床效果尚可，且不良反应轻微。这与研究结果并不一致，您怎么看待临床 医生实践与研究结果之间的差异？

Dr. Perner:关于羟乙基淀粉的高质量数据仅在去年发表过，这些数据表明，羟乙基淀粉与晶体溶液相比，没有优势，而且在危重症病人中副作用明显。现在，临 床医师、指南委员会成员以及策略制定者应吸纳这些研究结果，并使其在临床应用的转变中有所体现，以确保患者的安全。

DXY: 羟乙基淀粉在中国市场份额巨大，这种消息对于羟乙基淀粉无疑是致命一击。羟乙基在欧洲的市场份额有多大，这将会对欧洲医药界产生多大的影响？

Dr. Perner:在我看来，羟乙基淀粉在欧洲的应用已经急剧下降，在一些国家的销售量相比该大型试验结果发表之前下降到仅剩三成。

DXY: 不少研究表明羟乙基淀粉对肾脏有一定毒性，我注意到您在研究中的首要终点为死亡率和90天后末期肾功能衰竭，这里的死亡率应该是全因死亡率吧？如果对肾脏引起的死亡率进行单独的分析，结果会有所不同么？

Dr. Perner:该死亡率指的是全因死亡率。我们并没有评估“肾脏相关死亡率”，但接受透析病人的死亡率比未接受透析病人的死亡率有明显的升高。

DXY: 您在研究中选择了“改良后意向治疗（Modified Intention-to-treat, ITT）人群”，也就是基于最初的治疗意愿进行分析的方法，不考虑患者在试验中实际接受的治疗。您为何会选择意向治疗人群呢？如果按“符合方案集 （Pre-protocol, PP）分析”进行研究对结果会有怎样的影响呢？

Dr. Perner:我们一般首选ITT分析，因为它的偏倚风险率药低于其他符合方案分析。我们进行了两种符合方案分析，其结果与ITT分析结果相符。

DXY: 目前学术界对羟乙基淀粉引起肾脏损伤风险有没有什么解释？其机制大致如何呢？

Dr. Perner:在我们的研究数据中并没有解释其机制，但其他研究有在肾脏及其他组织中发现羟乙基淀粉，这可能是由于羟乙基淀粉进入到不能被代谢或排除的组织中，成为了体内异物。

DXY: 您在文章中提到，不论患者最初应接受HES还是醋酸钠林格，一旦患者需要的剂量超出了最大剂量，直接给与患者醋酸钠林格溶液。我的问题是，是在患者分配到 的药的基础上联合醋酸钠林格溶液，还是直接换用醋酸钠林格，不接受分配的药？如果是前一种情况，HES和醋酸钠林格之间有没有什么相互影响，研究有没有进 行“HES+Ringer”亚组分析？

Dr. Perner:患者被给予最大剂量（33ml/kg/d）的羟乙基淀粉或林格溶液，如果一天内他们还需要更大剂量，则继续给予林格溶液。

DXY: 在如今严重脓血症的治疗中，您推荐哪种血容量扩张药？

Dr. Perner:这要依据高质量试验结果和系统回顾，我推荐使用晶体溶液（生理盐水或林格溶液）作为脓血症的抢救措施。

DXY:感谢您接受我们的采访！

DXY: Recently, several famous medical journals (such as NEJM, BMJ, JAMA) have pointed out that HES has many adverse reactions. However, HES has been used in clinical for a long time. My question is, does this indicate the end of HES in the treatment of all its indications?

Dr. Perner: Maybe, depending on the postion taken by EMA, see the attachment.

DXY: To get a general understanding of Chinese doctor's usage and attitudes towards HES, we have done a survey among professional members of our DXY.CN. More than seven thousand doctors participated in this survey, and the result shows that large numbers of Chinese doctors use HES normally in their medical orders, especially in ICU and Anesthesiology. Many doctors think HES has a good clinical effect and the adverse reaction is slim, and this is obviously contrary to the results of many researches. What's your opinion on such a difference between the clinic practice and research results？

Dr. Perner: For HES, high quality data have only been published in the last year. These data indicate that the effects of HES is only marginally better than crystalloid solutions, if at all, and that the side effects results in overall harm at least in critically ill patients. Now clinicians, guideline committee members and policy-makers should adopt these results and translate them into a change in clinical practice to ensure patient safety.

DXY: HES holds large proportion of the market in China, and such bad news may be fatal to this medicine . I wonder what's the size of HES's market in Europe and what difference has this result made in the medical circle of Europe?

Dr. Perner: Here in Europe my impression is that HES use has declined dramatically; in some countries sale no. are down to 30% of what they were prior to the publications of the large trials.

DXY: Some studies showed that HES is related to increased risk of kidney injuries. And I have noticed that the primary outcome in your study was “either death or end-stage kidney failure”. Does the death rate here mean “all-cause mortality”? If we do a “kidney-related mortaliy” subgroup analysis, would it make a difference on the results?

Dr. Perner: The mortality rates are all cause mortality. We have not assessed ‘kidney-related mortality’, but those patients that received dialysis had markedly increased mortality compared to those who did not.

DXY: In this study, you chose “Modified Intention-to-treat (ITT) population” for analysis, which means the analysis was based on patients’ assigned treatment, regardless of what treatment they really got. I was wondering why chose Modified ITT over pre-protocol analysis, which was based on the actual treatment patients got?

Dr. Perner: ITT analyses are preferred in general because the risk of bias is lower than with per-protocol analyses. We did two per-protocol analyses and found results comparable to the ITT analysis.

DXY: Are there any explanations or mechanism studies about the impaired kidney function related to HES?

Dr. Perner: In our data, we have no mechanistic explanations, but others have found HES in kidney and other biopsies, so it may be that HES is deposited in tissues where it cannot be metabolised or excreted and therefore act as a foreign body.

DXY: In the article published in NEJM, you mentioned that “if (the trial fluid) doses higher than the maximum daily dose were required, unmasked Ringer’s acetate was used, regardless of the treatment assignment”. My question is, should these patients use HES and Ringer’s acetate together to achieve the required dose, or should they only take Ringer’s acetate without assigned treatment? If it’s the former situation, could there be any interaction between HES and Ringer’s acetate? Have you done a subgroup analysis of “HES+ Ringer’s acetate” combined therapy?

Dr. Perner: The patients recieved either masked HES or Ringers to the maximum dose (33 ml/kg/d). If they then needed more on that day they received Ringers.

DXY: What kind of plasma volume expander would you recommend in the condition of severe sepsis?

Dr. Perner: Based on the results of the high quality trials and systematic reviews, I recommend to use crystalloids (saline or Ringers) as the Surviving Sepsis Campaign do.

DXY:Many thanks for all the good things you have done in helping us !