ESTAT:蛇毒药物使用于中风3小时后治疗期是无效的


  November 23, 2006 — 一项新研究发现,Ancrod,一种来自蛇毒的天然抑制血栓形成剂,不应该使用于缺血性中风发生3小时后。
  
  使用Ancrod欧洲中风治疗临床试验(ESTAT)发现,相较于安慰剂,使用该药物来延长标准缺血性中风治疗时间至中风发生后3至6个小时,会增加颅内出血(ICH)以及3个月死亡率。
  
  该试验发表于2006年11月23日的Lancet上。
  
  作者表示,根据我们的发现,Ancrod不应该使用于缺血性中风发生3个小时之后。
  
  【延长治疗黄金时间】
  研究者受到发表于2000年JAMA的北美Ancrod中风治疗研究(STAT)结果鼓舞,该试验收纳500名病患,且试验设计与ESTAT几乎相同;STAT发现当Ancrod于急性中风缺血性中风发生3小时内给与,预后将会比控制组佳。
  
  作者表示,我们(ESTAT试验)的目的是要研究Ancrod是否可以用于缺血性中风发作3小时后、6小时内,就如同STAT试验的用法。
  
  德国海德堡大学Michael Hennerici医师领导这项多中心、随机分派、双盲、安慰剂控制第三期临床试验,共收纳了1,222位来自欧洲、澳洲与以色列的病患;这些病患中,604位被随机分派接受Ancrod,剩下的618位接受安慰剂。
  
  该试验收纳条件为18岁以上病患,发生急性中重度神经功能丧失,且可能肇因自缺血性事件者;症状发生6个小时内进行治疗;具有脑实质出血、或于计算机断层出现出血影像、或其它发生梗塞的重大病征,接排除于试验之外。
  
  【高死亡率】
  接受Ancrod或安慰剂病患,以72小时持续输注,接著以单一持续约1小时的注射方式连续两天,以达到目标纤维蛋白酶原浓度1.2-2.1 μmol/L的目标。
  
  Ancrod起始注射剂量为每六小时1.00(治疗前纤维蛋白酶原>13.2μmol/L)、0.75(治疗前纤维蛋白酶原10.3–13.2μmol/L)与0.50 IU/kg(治疗前纤维蛋白酶原<10.3μmol/L),根据纤维蛋白酶原浓度决定投予剂量。
  
  受试者于试验期间不得使用抗血小板药物、口服抗凝血药物、血栓分解药物、肝素、或其它影响血栓分解系统之药物。
  
  试验主要终点为功能性成功,定义为达到Barthel指标95-100分时的存活率、或是至少等于中风前的分数;次要试验终点包括修改后Scandinavian中风指标、修改后Rankin指数、第3与12个月时的存活率、以及第7天时的断层扫描梗塞体积。
  
  后续追踪3个月时,使用Ancrod病患与安慰剂组的功能性成功比例并无差异;作者表示,这两组病患中约42%的Barthel指标大于95分,或是回到中风前分数;然而,安慰剂组病患的神经学功能恢复较差。
  
  使用Ancrod病患(20%)的90天死亡率比安慰剂组(14%)高,然而,作者表示12个月死亡率并无差异。
  
  【时间仍然决定一切】
  Ancrod组于28天时发生有症状与无症状ICH比例为13%,相较于安慰剂组则是4%;但是,安慰剂组的神经学功能恢复较差。
  
  作者表示,使用Ancrod病患发生有症状ICH的比例相较于安慰剂组病患显著较高,且大部分在7天内发生;Ancrod组发生无症状ICH的比例相较于安慰剂组也显著较高。
  
  然而,作者指出,尽管这两组死亡率与ICH的结果令人沮丧,ESTAT试验的整体死亡率也较之前的控制组试验低,包括神经异常与中风(NINDS)tPA试验,该试验控制组的死亡率为21%,相较于STAT试验的23%。
  
  芬兰赫尔辛基大学Markku Kaste博士在随后的评论中表示,虽然该试验是失败的,但它传达了一项重要讯息:症状发生到治疗之间的时间是很重要的,且ESTAT试验中显然是太长了。
  
  【强调负面讯息】
  作为该试验的附件,作者表示报导负面讯息与报导正面讯息一样重要,他们举出必须要发表ESTAT试验结果的挣扎,该试验的初期结果发表于2001年伦敦神经学大会。
  
  他们表示,在那次会议之后,赞助该试验的药厂(Knoll,AG)被卖掉,因此,该试验的数据并未完全提供给研究者,因此增加了分析的困难。
  
  根据作者表示,唯有许多研究者的奉献、以及再三详细地分析最终数据,他们才有办法完成目前的报告。
  
  这样的情况突显了可理解的、但通常是赞助者与研究者之间可惜的差异,造成科学上的损失以及病患与研究者不符合道德的付出;正面结果试验较容易发表,甚至有时候是早期的研究结果,另一方面应该思考的是,发表这项研究报告因此认可了所有临床试验在科学与医学上的价值。

ESTAT: Snake-Venom Drug Ineffe

By Caroline Cassels
Medscape Medical News

November 23, 2006 — Ancrod, a natural defibrinogenating agent derived from snake venom, should not be used to treat ischemic stroke more than 3 hours after symptom onset, a new study has found.

The European Stroke Treatment with Ancrod Trial (ESTAT) found that attempting to extend the standard ischemic-stroke treatment window from 3 to 6 hours using this agent increased the rate of intracerebral hemorrhage (ICH) and 3-month mortality, compared with placebo.

The study was published in the November 23, 2006 issue of The Lancet.

"On the basis of our findings, ancrod should not be recommended for use in acute ischemic stroke beyond 3 hours," the authors write.

Widening the Treatment Window

Investigators were encouraged by the results of the North American Stroke Treatment with Ancrod Trial (STAT). Published in 2000 in JAMA, it included 500 patients and had an almost identical design to ESTAT. STAT found that when ancrod was given within 3 hours after acute ischemic stroke, outcomes were better than they were in the control group.

"Our aim [with the ESTAT study] was to see whether ancrod was effective with a 6-hour window rather than a 3-hour window, as was used in STAT," the authors write.

Led by Michael Hennerici, MD, from the University of Heidelberg in Germany, the multicenter, randomized, double-blind, placebo controlled phase 3 study included 1222 patients from Europe, Australia, and Israel. Of these, 604 subjects were randomly assigned to receive ancrod and the remaining 618 received placebo.

Patients over age 18 with an acute moderate or severe neurological deficit suggestive of an ischemic event were eligible for the study. Treatment was started within 6 hours of symptom onset. Those with evidence of parenchymal hemorrhage and hemorrhagic transformation on CT imaging, or with major signs of developing infarction, were excluded from the study.

Higher Mortality

Patients received ancrod or placebo as a continuous 72-hour intravenous infusion, followed by daily single infusions lasting approximately 1 hour for 2 days, to reach and maintain a target fibrinogen concentration of 1.2–2.1 µmol/L.

Ancrod was given at initial infusion rates of 1.00, 0.75, and 0.50 IU/kg, per 6 hours, based on pretreatment fibrinogen concentrations of >13.2 µmol/L, 10.3–13.2 µmol/L, or <10.3 µmol/L, respectively.

Patients were not allowed to receive antiplatelet agents, oral anticoagulants, thrombolytics, heparin, or other drugs that might affect the fibrinolytic system.

Functional success at 3 months was the study's primary outcome, which was defined as survival to follow-up with a Barthel index score of 95 to 100, or at least equal to prestroke value. Secondary outcomes included the modified Scandinavian Stroke Scale, the modified Rankin Scale, death rates at 3 and 12 months, and CT infarct-volume at day 7.

At 3-month follow-up, functional outcomes in the ancrod and placebo groups were the same. The authors report that 42% of patients in both groups had a Barthel index score >95 or had returned to prestroke values. However, neurological recovery was worse in the placebo group.

At 20%, 90-day mortality was worse in the ancrod group than in the placebo group (14%). However, the authors report that 12-month mortality did not differ significantly between the 2 groups.

Timing (Still) Matters

Symptomatic and asymptomatic ICH at day 28 occurred in 13% of patients in the ancrod group and 4% in the placebo group. However, neurological recovery was worse in the placebo group.

"Symptomatic intracranial hemorrhage occurred significantly more often in patients given ancrod, compared with those given placebo, and mainly arose within 7 days. Asymptomatic intracranial hemorrhage also occurred more often in the ancrod group than the placebo group," the authors write.

However, the authors note that despite the discouraging differences in death and intracranial hemorrhage rates between the 2 groups, the overall death rate in ESTAT was lower than in the control groups of earlier controlled trials, including the Neurological Disorders and Stroke (NINDS) tPA trial, which reported a death rate of 21% among controls, and STAT's 23% death rate.

In an accompanying editorial, Markku Kaste, MD, PhD, from Helsinki University Central Hospital in Finland, notes that "although the study was unsuccessful, it delivers an important message: that time from onset of symptoms to treatment matters, and in ESTAT it was too long."

Accentuate the Negative

As an addendum to the study, the authors note that it is just as important to report negative results as it is positive results. They cite the struggle they had to publish the ESTAT trial results, the preliminary findings of which were originally reported in 2001 at the World Federation of Neurology Congress in London.

After this conference, they write, the pharmaceutical company that supported the trial (Knoll AG) was sold. Thereafter, the data from the study were not fully available to the investigators, making further analysis difficult.

According to the authors, "only with the support of many dedicated investigators and after careful reassessment of the material finally provided" were they able to prepare the current report.

"This situation illustrates the understandable but often regrettable divergences between sponsor and investigators' interest, leading to scientific losses and unethical waste of patients' and investigators' efforts. The bias towards easier publication of successful trials, sometimes at too early a stage, is another important issue to consider: the publication of this report is therefore an important recognition of the scientific and medical value of all clinical trials," they write.

Lancet 2006; 368:1871-1878.

JAMA 2000; 283:2395-2403.

    
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