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歐洲急性卒中合作3研究的新分析支持在中風之後達4.5小時時仍可使用劑
作者：蘇珊杰弗裡
出處：一家醫療網站醫學新聞

09年10月20號（2009年10月21日更新） - “第3次歐洲急性卒中協作研究（歐洲急性卒中合作3）”這項研究的資料進行的次級分析結果，支持對符合治療規範，但是錯過症狀發生後0-3小時治療黃金時間的中風病患，使用重組組織胞漿素原活化劑（重組組織型纖溶酶原激活物[激活劑，鏈激酶]）進行治療。

第一作者，德國海德堡大學神經科主席，教授，維爾納哈克博士結論表示，我們所有的附加結果分析幾乎都強力支持歐洲急性卒中合作3試驗的初級和次級結果。

作者們指出，雖然個別分析並不顯著，但所有的附加效果終點顯示，鏈激酶至少清楚呈現有利的模式，特別是不論病患中風嚴重度如何，確認治療有效。

不過，哈克博士向Medscape神經表示，就他的觀點，現在這些次分析所支持之有關歐洲急性卒中合作3的重點，並非意味著劑的治療時間視窗可以安全地延展到4.5小時。

他表示，急性缺血性中風的血栓治療觀念現在是由一個簡單明確，謹慎的隨機臨床試驗所支持，這個試驗的樣本數是國家神經異常與中風研究中心試驗的兩倍以上，支持3小時的治療時間視窗。

他表示，藉由蒐集匯整與統合分析大型歐洲登記資料，他們的結果支持前述血栓溶解劑是中風之有效治療的觀念，不過仍有些人有所質疑。哈克博士強調，我們有兩個獨立隨機臨床試驗，初步結果都是正面支持激活劑，所以沒有理由不接受這個科學事實。

歐洲急性卒中合作3的這篇新報告線上登載於10月21日，將於12月的柳葉刀神經學期刊印行。勃林格殷格翰公司支持歐洲急性卒中合作3試驗。

【改變實務】
歐洲急性卒中合作三是對症狀發生後3-4.5小時的821名中風病患比較劑治療和安慰劑的一項隨機試驗。排除電腦斷層掃描確認有腦出血或者嚴重梗塞的病患之後，其他病患被隨機指派接受治療（根據體重，靜脈注射劑量為0.9毫克/千克之劑）（不適用= 418人）或安慰劑（不適用= 403人）。

在此試驗中，給予劑時間的中位數為3小時59分。約有10％是在3-3.5小時內接受治療，50％在3.5-4小時內，40％在4-4.5小時內。

主要終點是90天時的失能，採用二分法，分為可接受的結果（改良式蘭中風等級[黃]）分數為0或1）或不可接受的結果（劉健分數為2 - 6）。作者們報告指出，依此方法檢測，使用劑治療的病患，可接受之結果的人數較使用安慰劑組多;安慰劑組病患有45.2％為適度改善之可接受結果，治療組病患則有52.4％（勝算比為1.34; 95％信心區間[證明書]為1.02 - 1.76，P = .04）。

次級終點之一為四項神經與失能分數的整體分析，也顯示治療組比安慰劑組更有改善（勝算比為1.28; 95％可信區間為1.00 - 1.65，P“0.05）。

作者們報告指出劑的顱內出血和有症狀之顱內出血發生率比安慰劑高，不過，此差異並不代表會增加死亡率（哈克糯等人，ñ英格蘭ĵ雜誌。2008; 359:1317 - 1329）。

根據歐洲急性卒中合作3結果以及其他實證，美國心臟協會/美國中風協會5月28日在中風期刊線上發表科學建議，更新目前的指引且建議在中風症狀發生後3-4.5小時可以考慮使用劑進行治療。

歐洲急性卒中合作3試驗的排除規範和歐洲主管當局的激活劑使用排除規範相同，現在也是美國心臟協會/美國中風協會建議的排除規範。這些排除規範如：80歲以上病患，服用口服抗凝血劑者，國家健康研究中心中風量表（國立衛生研究院卒中量表，NIHSS）之原始分數大於25者，有中風和糖尿病病史者。

【附加分析】
歐洲急性卒中合作研究者目前的這個報告中，發表的附加結果分析包括次組分析與敏感度分析。這些包含90天或30天時的功能性結果，治療反應，以及根據NIHSS原始分數進行的分組反應者分析。

歐洲急性卒中合作- 3研究者報告指出，雖然每一單項分析都不顯著，整體的附加終點分析顯示，鏈激酶至少清楚呈現有利的趨勢。

鏈激酶在各個次組中顯示有效，包括65歲以上和以下的病患性（P = 0.230），且與原本的中風嚴重度無關性（P = 0.631）。

【歐洲急性卒中合作3：各次組在90天時之可接受結果（劉健0 - 1）的勝算比】

次組	勝算比	95% CI
小於 65 歲	1.61	1.05 – 2.48
65 歲 ( 含 ) 以上	1.15	0.80 – 1.64
原始的 NIHSS 分數為 0 – 9	1.28	0.84 – 1.96
原始的 NIHSS 分數為 10 – 19	1.16	0.73 – 1.84
原始的 NIHSS 分數≧20	2.32	0.61 – 8.90

有症狀的顱內出血發生率與原本的抗血小板藥物使用無關(P = .962)、與發生症狀到接受治療的時間也無關(P = .761)，但是與以65歲一分為二進行比較有關(P = .004)（如下表）。
　　
　　【ECASS 3：有症狀的顱內出血】

次組	勝算比	95% CI
原本有使用抗血小板藥物	2.33	0.79 – 6.90
之前沒有使用抗血小板藥物	2.41	1.09 – 5.33
發生症狀到接受治療的時間
181 – 210 分鐘	1.62	0.26 – 10.25
211 – 240 分鐘	1.97	0.82 – 4.76
241 – 270 分鐘	3.15	1.01 – 9.79
年紀
小於 65 歲	0.74	0.28 – 1.96
65 歲 ( 含 ) 以上	5.79	2.18 – 15.39

　　
　　作者們指出，不過，最好還是儘快治療。即使有這些正面結果，急性中風之處置的最主要原則還是掌握時機，越早治療則恢復的機會越大。
　　
　　【無聲的吶喊】
　　加州洛杉磯Cedars-Sinai醫學中心的Patrick Lyden醫師在回應的文章中指出，新文獻中的這些分析顯示出治療是有利的。Lyden醫師寫道，事實是所有的分析都偏向積極治療，認為這些結論是確立的，不同等級的文獻都有類似的證據。
　　
　　他寫道，最重要的是，ECASS 3成功之處在於它的初級終點，雖然勝算比小於原本的「國家神經異常與中風研究中心」試驗，反映出稍後的時間視窗，且確認越晚治療效果越不好。
　　
　　不過，他寫道，次組分析是有風險的，得由細心的研究者謹慎地進行。Lyden醫師指出，舉例來說，有些讀者可能會根據這些分析排除一些治療，但是次組分析不應用於指引個別病患的治療，只能作為未來的試驗設計參考。再者，ECASS 3 試驗未納入的病患組的治療效果未知，極需更多納入這些病患的研究。
　　
　　Lyden醫師結論表示，我對於依舊有人直接反對中風的血栓溶解治療感到訝異，但是本期期刊中發表的ECASS 3試驗後續分析結果，再度令我有信心。
　　
　　【可靠的發現】
　　芝加哥伊利諾大學醫學院的Philip B. Gorelick醫師受邀對這些研究發現發表評論時表示，形容這篇新報告對於附加的終點有一個詳盡的分析，包括了ECASS 3資料的次組分析與敏感度分析，未來可能可以闡述alteplase在3-4.5小時這段時間視窗中的可能利益。
　　
　　Gorelick醫師向Medscape Neurology表示，如果不顯著，這篇分析顯示出這些終點指標至少傾向有利於使用alteplase。這些發現再度使醫師相信，在缺血性中風症狀發生後達4.5小時時，對於多數病患，依舊可以給予alteplase。
　　
　　不過，他指出，重點在遵守這段延遲時間視窗時的建議指引，且將盡速治療病患謹記在心，就會有比較好的結果。
　　
　　Boehringer Ingelheim公司支持本研究。Hacke博士宣告他接受Boehringer Ingelheim公司的諮商與演講費用， 在他擔任指導委員會主席時，Boehringer Ingelheim公司也提供獎金。他也是Medscape Neurology的無給職諮詢委員。共同作者的宣告登載於文章中。 Lyden醫師宣告沒有相關財務關係。
　　
　　Lancet Neurol. 線上發表於2009年10月21日。

New Analyses From ECASS 3 Support Use of tPA Up to 4.5 Hours After Stroke
By Susan Jeffrey
Medscape Medical News
October 20, 2009 — Secondary analyses of data from the third European Cooperative Acute Stroke Study (ECASS 3) trial appear to support the use of recombinant tissue plasminogen activator (rt-PA, alteplase) to treat stroke up to 4.5 hours after symptom onset in patients without exclusions for treatment, but who miss the approved time window of 0 to 3 hours.
"Almost all our additional outcome analyses strongly support the positive primary and secondary trial results of ECASS 3," the investigators, with lead author Werner Hacke, MD, PhD, professor and chairman of the Department of Neurology at Ruprecht-Karls-Universitat, Germany, conclude.
Although not significant in every analysis, all additional efficacy endpoints showed "at least a clear pattern in favor of alteplase," the authors note, in particular confirming that treatment was effective in patients regardless of stroke severity.
Still, the message remains to treat as rapidly as possible, the authors stress. "Even with these encouraging findings, the most important principle of acute stroke intervention should, however, not be lost — ie, time remains critical and fast treatment still provides the greatest chance of recovery."
This new report from ECASS 3 was published online October 21 and will appear in the December issue of Lancet Neurology. ECASS 3 was supported by Boehringer Ingelheim.
Change of Practice
ECASS 3 was a randomized trial comparing tPA treatment with placebo in 821 stroke patients presenting 3 to 4.5 hours after symptom onset. After those patients with evidence of brain hemorrhage or major infarction on computed tomography scan were excluded, the remaining patients were randomly assigned to receive treatment with intravenous tPA in the approved regimen of 0.9 mg/kg body weight (n = 418) or placebo (n = 403).
In this trial, the median time for the administration of tPA was 3 hours and 59 minutes. About 10% were treated between 3 and 3.5 hours, 50% between 3.5 and 4 hours, and 40% between 4.0 and 4.5 hours.
The primary endpoint was disability at 90 days, dichotomized as a favorable outcome (modified Rankin Scale [mRS], 0 or 1) or unfavorable outcome (mRS, 2 – 6). The authors reported that significantly more patients treated with tPA had a favorable outcome by this measure than those who received placebo; 45.2% of placebo patients had a favorable outcome improved "modestly," the authors note, compared with 52.4% for treated patients (odds ratio, 1.34; 95% confidence interval [CI], 1.02 – 1.76; P = .04).
A secondary endpoint, a global analysis combining 4 neurologic and disability scores, also showed an improvement with treatment vs placebo (odds ratio, 1.28; 95% CI, 1.00 – 1.65; P < .05).
The incidence of intracerebral hemorrhage and symptomatic intracerebral hemorrhage was significantly higher with tPA than placebo, the authors reported, although this difference did not translate into an increase in mortality (Hacke W, et al. N Engl J Med. 2008;359:1317–1329).
On the basis of the ECASS 3 results and other corroborating evidence, the American Heart Association/American Stroke Association published a science advisory online May 28 in Stroke, updating current guidelines and recommending tPA be considered in the treatment of stroke between 3 and 4.5 hours after symptom onset.
Exclusion criteria for the ECASS 3 trial, which were the same exclusions mandated by European regulatory authorities for the use of tPA in Europe, are also now exclusions under the American Heart Association/American Stroke Association recommendations. These include, for example, patients older than 80 years, those taking oral anticoagulants, those with a baseline National Institutes of Health Stroke Scale (NIHSS) score greater than 25, and those with a history of stroke and diabetes.
Additional Analyses
In the current report from the ECASS investigators, additional outcome analyses are presented, including subgroup and sensitivity analyses. These included functional endpoints at day 90 or day 30, and treatment response, as well as a stratified responder analysis by baseline NIHSS score.
Although not significant in every case, all additional endpoints showed "at least a clear trend in favour of alteplase," the ECASS-3 investigators report.
Alteplase was effective in various subgroups, including patients older and younger than 65 years (P = .230), and was independent of the severity of stroke at baseline (P = .631).
ECASS 3: Odds of Favorable Outcome (mRS 0 – 1) at 90 Days By Subgroup

Subgroup	Odds Ratio	95% CI
Age < 65 years	1.61	1.05 – 2.48
Age ? 65 Years	1.15	0.80 – 1.64
Baseline NIHSS 0 – 9	1.28	0.84 – 1.96
Baseline NIHSS 10 – 19	1.16	0.73 – 1.84
Baseline NIHSS ? 20	2.32	0.61 – 8.90

The incidence of symptomatic intracranial hemorrhage appeared to be independent of previous antiplatelet drug use (P = .962) and time from onset of symptoms to treatment (P = .761), but not of age dichotomized at 65 years (P = .004).
ECASS 3: Symptomatic Intracranial Hemorrhage

Subgroup	Odds Ratio	95% CI
Previous antiplatelet drug use	2.33	0.79 – 6.90
No previous antiplatelet drug use	2.41	1.09 – 5.33
Time from onset of symptoms to treatment
181 – 210 minutes	1.62	0.26 – 10.25
211 – 240 minutes	1.97	0.82 – 4.76
241 – 270 minutes	3.15	1.01 – 9.79
Age
< 65 years	0.74	0.28 – 1.96
? 65 years	5.79	2.18 – 15.39

Sound and Fury
In a reflection and reaction article accompanying the publication, Patrick Lyden, MD, from Cedars-Sinai Medical Center in Los Angeles, California, points out that all the analyses in the new article show a trend toward benefit for treatment. "The fact that all the analyses favor active treatment suggests that the findings are robust and will manifest similarly on different rating instruments," Dr. Lyden writes.
On the most important analysis, he writes, "ECASS 3 was a clear win as this study succeeded on its primary endpoint, although the odds ratio is less than that of the original [National Institute of Neurological Disorders and Stroke] trial, reflecting the later time window, and confirming that later treatment is less likely to work."
Subgroup analysis is "hazardous," however, and is undertaken with caution by thoughtful investigators, he writes. For example, some readers may try to rule out treatment for some groups on the basis of these analyses, Dr. Lyden notes, but subgroup analysis should not be used to guide therapy for individual patients — only to inform future trial design. Still, the effect of treatment in patient groups that were excluded from ECASS 3 is not known, and more studies including these patients are "sorely needed."
"I continue to be surprised at the sound and fury directed against thrombolytic therapy for stroke by some, but the publication of ECASS 3, with the extended analyses published in this issue of the journal, reassures me," Dr. Lyden concludes.
The study was supported by Boehringer Ingelheim. Dr. Hacke has disclosed that he has received consulting and lecture fees from Boehringer Ingelheim, as well as honoraria from Boehringer Ingelheim in his capacity as chairman of the steering committee. He is also an uncompensated advisory board member for Medscape Neurology. Disclosures for coauthors appear in the article. Dr. Lyden has disclosed no relevant financial relationships.
Lancet Neurol. Published online October 21, 2009.