Treatment with intravenous alteplase improves outcomes for acute ischemic stroke patients only within the first 4.5 hours after stroke, a U.K.-led team of investigators has found, and should not routinely be administered later.

The findings, published online May 13 in the Lancet, suggest that there is no benefit to administering alteplase after 270 minutes and that considerable risk to patients is involved. The risks include an increased likelihood of intracranial hemorrhage when administered at any time, and when administered after the 270-minute window, the investigators found a higher risk of death.

For their research, Dr. Kennedy Lees of the University of Glasgow, and colleagues pooled data from 3,670 patients in eight randomized controlled trials to assess the relationship of stroke onset to the timing of treatment with alteplase and subsequent 3-month outcomes as measured by Rankin scores, as well as incidence of parenchymal hemorrhage and overall mortality.

While six of the included trials had been combined in an earlier analysis (Lancet 2004;363:768-74), Dr. Lees and colleagues were able to incorporate results from two newer trials, further updating the findings and increasing the number of study subjects by 32%. Their study had no funding source, although Dr. Lees and four of his coauthors disclosed that they had received honoraria or had ongoing consulting arrangements with Boehringer Ingelheim, the manufacturer of alteplase, along with Lundbeck, Thrombogenics and others. One coauthor is an employee of Boehringer Ingelheim.

Dr. Lees and colleagues found that 3 months after stroke, 36% of patients treated with alteplase within the first 90 minutes had a favorable recovery without significant disability (a Rankin score of 0 or 1), about 2.5 times more than placebo. Only 18% of those treated in the second 90-minute window, by comparison, saw favorable recoveries, as did only 9% of those in the third window (Lancet2010;375:1695-703).

Though the outcomes for the last group may be slight, they nonetheless represent a benefit over placebo, and “it is nice to know that for those patients who live further away from hospital we have solid information that it’s still justifiable to treat them before 4.5 hours,” Dr. Lees said in an interview.

For people treated beyond that window, however, the benefits are nil and the risks are serious. Patients treated with alteplase after 270 min (n = 1,118) saw a 6.8% incidence of parenchymal hemorrhage, compared with 1% of controls. Dr. Lees and colleagues wrote in their analysis that they did not consider this to be significant evidence that late treatment increases the likelihood of hemorrhage. Parenchymal hemorrhage is a known risk of the medication and was shown to have higher incidence, 5.2%, in the alteplase group overall (n = 1,850), compared with 1% in the placebo group (n = 1,820).

All-cause mortality at 90 days was higher in the alteplase group overall, except for people treated within the first 180 minutes, who saw slightly less than in the control groups. At between 90 and 270 minutes, mortality rates differed little between the groups. In the late-treated groups, all-cause mortality was markedly higher among patients who had received treatment (15%) than among controls (10.2%).

Though incidence of mortality did not correlate strongly to incidence of hemorrhage in this study, “it’s possible that there is a relationship but we didn’t have the statistical power to detect it,” Dr. Lees said. “Or there is something else [causing mortality].” The bottom line, Dr. Lees said, is that “there is a relationship between the time you start treatment and the chance of dying. You’re more likely to die if you begin treatment after 4.5 hours.”

The median time to treatment for patients in the study was a fairly late 240 minutes; however, Dr. Lees said, “many of the trials took place years ago when we didn’t know what the time window would be.” Later trials had difficulty recruiting in the later time slots, Dr. Lees said, as patients and clinicians knew to arrive and initiate treatment as early as possible. “I think we would have a very high proportion being treated and completely cured if people could get to hospital within 20 minutes of a stroke, and treated within 1 hour.”

In an accompanying editorial, Dr. Jeffrey L. Saver of the University of California, Los Angeles, and Dr. Steven R. Levine of the Mount Sinai School of Medicine, New York, echoed that hopeful sentiment. “We need to increase the proportion of patients arriving at hospital in the first, golden hour after ischemia onset by better educating the public to recognize stroke warning signs,” they wrote. “In thrombolytic stroke therapy, sooner is much, much better.” (Lancet2010;375:1667-8).

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

一个以英国为首的研究小组发现，对于急性缺血性脑卒中患者，静脉注射阿替普酶治疗仅在卒中发作后的最初4.5 h内能够改善转归，而此后则不应该常规应用。

 

5月13日在线发表于《柳叶刀》的研究结果表明，在卒中发作270 min后应用阿替普酶不但无益反而会对患者造成相当大的风险。这些风险包括在这段时间后任何时间应用阿替普酶都会增加颅内出血的风险，并且研究者发现，在270 min的时间窗外应用阿替普酶时死亡风险升高。

 

格拉斯哥大学的Kennedy Lees博士及其同事汇总了8项随机对照试验中3,670例患者的数据， 旨在评估卒中发作距阿替普酶治疗的时间与随后3个月的转归(采用Rankin评分系统评定)以及脑实质出血发生率和总病死率之间的关系。

 

虽然所纳入的试验中有6项已经在早期的分析中被引用(Lancet 2004;363:768-74)，但是Lees博士及其同事能够结合两项较新的试验对研究结果做进一步的更新，并增加了32%的受试者。尽管Lees博士和4个合著者披露他们收到酬金或与勃林格殷格翰药业有限公司 (阿替普酶生产商) 、 丹麦灵北药厂、Thrombogenics公司和其他公司有顾问协议且仍在进行之中，但是本研究没有资金来源。其中一位合著者是勃林格殷格翰药业有限公司的职员。

 

Lees博士及其同事发现，卒中发作后最初90 min内接受阿替普酶治疗的患者中有36%在3个月后恢复良好且无严重致残事件发生(Rankin评分为0或1)，较对照组高2.5倍以上。相比之下，在第2个90 min时间窗内给药治疗的患者中仅有18%恢复良好，而在第3个90min时间窗内治疗的患者中只有9%恢复良好 (Lancet2010;375:1695-703)。

 

尽管最后一组的疗效可能微不足道，但收益仍高于对照组，而且“欣喜的是，据现有的可靠资料，对那些远离医院居住的患者在卒中发作后的4.5h内应用阿替普酶治疗仍有效。” Lees博士在一次受访中说道。

 

然而，超出时间窗应用阿替普酶治疗的收益为零且风险较大。据观察，卒中发作270 min后接受阿替普酶治疗的患者(n=1,118)脑实质血的发生率为6.8%，而对照组为1%。Lees博士及其同事在分析中写到，他们认为这并非延迟治疗可增加出血风险的重要证据。脑实质出血是该药物的已知风险之一，研究表明，整体阿替普酶治疗组(n=1，850)脑实质出现的发生率高达5.2%，而对照组(n=1,820)为1%。

 

总体上，阿替普酶治疗组卒中发作90天时的全因病死率较高，而最初180 min内应用阿替普酶治疗的患者例外(病死率略低于对照组)。若在90~180 min之间用药，则病死率的组间差异极小。在延迟治疗组中，阿替普酶治疗组全因病死率(15%)明显高于对照组(10.2%)。

 

虽然在本研究中病死率与脑实质出血发生率之间无强相关性，但仍“可能存在关系，只是我们不具备检测这种关系的统计学效能，”Lees博士说，“或者还有其他情况(导致死亡)。””Lees博士说，至少是“开始治疗时间与死亡风险之间有关。如果你在卒中发作4.5 h后开始治疗，则会有较高的死亡风险”。

 

本研究中患者开始治疗的中位时间很晚，为240 min以后；但Lees博士说，“其中许多试验在数年前开展，那时我们不知道具体的治疗时间窗。”新试验很难募集到受试者，Lees博士说，因为患者和医生都知道应尽早开始治疗。“我认为，如果患者在卒中发作20 min内到达医院并且在1h内接受治疗，则会有非常高的治愈率。”

 

美国洛杉矶加利福尼亚大学的Jeffrey L. Saver博士和纽约西奈山医学院的Steven R. Levine博士在随刊编者按中对这一前景乐观的观点表示认同。“我们需要通过向公众宣传卒中征兆的识别方法，以提高在第一时间(即缺血发作后的黄金治疗时间)到达医院的患者比例。”他们写到，“在卒中溶栓治疗中治疗越早预后越好。” (Lancet2010;375:1667-8)。

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