作者：Susan Jeffrey
出處：WebMD醫學新聞
【24drs.com】May 14, 2010 — 採用組織胞漿素原活化劑(tPA)治療急性缺血性中風的隨機試驗統合分析，納入一些最近研究的新分析確認了發生後4.5小時治療的效果，也首次顯示這段時間之後的風險大於利益。
這篇新分析資料來自最近的「European Cooperative Acute Stroke Study 3 (ECASS 3)」和「Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET)」這2個研究，使彙整的研究總數達8個。
第一作者、蘇格蘭Glasgow大學Western Infirmary的Kennedy R. Lees醫師結論表示，更新版的分析顯示，中風發生之後4.5小時使用血栓溶解治療仍有不錯的結果。
有趣的是，器質性出血率和治療時間無關，但是，4.5小時之後才使用血栓溶解劑治療則死亡率增加，這表示有其他因素影響死亡率。
他們寫道，不過，這整個研究的時間視窗中，我們的分析顯示，及早治療可以有最大的利益，因為在我們的樣本中，4.5小時之後才治療則好處減少，甚至無法察覺。
此篇分析發表於5月15日的The Lancet期刊。
【依照計畫分析】
作者們指出，自從第一篇tPA中風試驗設計進行之後，即針對共通資料條件進行蒐集彙整分析，彙整的分析包括了「National Institute of Neurological Disorders and Stroke (NINDS)試驗」第1部分和第2部分，最初的2個 ECASS試驗，2次「Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS)」試驗等資料，以及最近的ECASS 3和EPITHET。
研究作者寫道，最初，我們傾向不納入EPITHET，但是，當我們準備發表我們的發現時，我們得知EPITHET試驗的研究者已經蒐集了分析所需的所有變項。EPITHET試驗根據影像檢查結果納入，而其他試驗是根據中風發生後一定時間之臨床診斷與電腦斷層掃描有明顯出血。
新增的這2篇試驗，ECASS 3共有821名隨機分組的病患，EPITHET有100名病患，使全部彙整的病患數達3670人，有1850人使用tPA治療，1820人使用安慰劑。他們使用多變項邏輯回歸評估從中風發生時到開始治療之時間和3個月時結果的關係，包括修改版Rankin氏量表分數為0-1分、死亡率、臨床相關器質性出血的發生率與結果，病患治療360分鐘(6小時)內檢視結果。
他們發現，當「從中風發生時到開始治療之時間」減少時，可接受的結果比率增加(P = .0269)，270分鐘(4.5小時)之後才治療則無更多利益。
表1.根據「從中風發生時到開始治療之時間(OTT)」，3個月時可接受結果之校正勝算比
| OTT, 分鐘 | OR (95% CI) |
| 0 – 90 | 2.55 (1.44 – 4.52) |
| 91 – 180 | 1.64 (1.12 – 2.40) |
| 181 – 270 | 1.34 (1.06 – 1.68) |
| 271 – 360 | 1.22 (0.92 – 1.61) |
CI =信心區間；OR =勝算比
死亡風險隨著時間增加，在4.5小時之後則是風險大於利益。
表2. 根據「從中風發生時到開始治療之時間(OTT)」，死亡率之校正勝算比
| OTT, 分鐘 | OR (95% CI) |
| 0 – 90 | 0.78 (0.41 – 1.48) |
| 91 – 180 | 1.13 (0.70 – 1.82) |
| 181 – 270 | 1.22 (0.87 – 1.71) |
| 271 – 360 | 1.49 (1.00 – 2.21) |
CI =信心區間；OR =勝算比
tPA用於中風治療時最令人擔心的併發症、大規模器質性出血的發生比率，治療組有96人(5.2%)，對照組有18人(1.0%)，但是，中風發生時間和治療之間並無明顯關係(P = .4140)。
研究作者寫道，死亡率和器質性出血之間的明顯差異還需要探討，因為以前認為，延後治療的死亡率風險是因為出血風險增加。
【一定有其他機轉和死亡率增加有關】
他們推測，這個發現可能是因為研究強度偏低，因為案例數相對較少，不過，雖然發生器質性出血與死亡風險較高有關，但是案例數相當低，多數死亡案例可能不是因為這類型出血所致：一定有其他機轉和死亡率增加有關。
他們指出，雖然血栓溶解治療的效果是無疑的，但是對多數病患依舊沒有幫助，他們的分析顯示，在症狀發生之後0-90分鐘時，每治療5個病患才有1人獲得好結果，91-180分鐘時，則需治療9個病患、181-270分鐘時，則需治療15個病患，才有1人獲得好結果。
需要更多資料，以便更清楚瞭解影響個別病患之治療效果的因素。
他們結論表示，中風學界在改善中風治療方面有許多研究方向，例如研究更有效劑量的alteplase、減少血栓溶解劑引起顱內出血的傾向、測試新的血栓溶解劑、運用新的且更快的影像檢查方式來引導治療、增加使用超音波、抗血栓劑、動脈內血塊處理等方式，加上可以在救護車上開始使用神經保護劑治療，且進行臨床試驗檢視認知功能，以便掌握所有的治療利益或風險。
【更新的命令】
對Lees等人彙整分析的編輯評論中，加州大學洛杉磯分校Geffen醫學院的Jeffrey L. Saver醫師以及紐約市西奈山醫學院的Steven R. Levine醫師寫道，這是首次清楚地描繪出一般病患使用alteplase之時機利益與風險的分析，急性中風治療之初次疏通血管治療的論述已有清楚結論。
他們寫道，如同在2004年時的前一次彙整分析，這些結果顯示，治療利益隨著時間下降。一個重要的新發現是，越慢開始治療(離發生時間超過4.5小時)則與死亡率增加有關，和Cochrane研究等級的26篇探討各種血栓溶解劑的試驗(7152名病患)之統合分析發現一致(Wardlaw等人，Cochrane Database Syst Rev. 2009;4:CD000213)。
他們指出，死亡率增加的機轉還有爭議，因為器質性出血並沒有在相同時間有相關性的增加。
此外，從這些資料中，更重要的一個訊息是，在症狀初期，治療助益隨時間急速下降，症狀發生後每90分鐘，以2倍的係數下降。
Saver醫師和Levine醫師結論表示，這些發現令醫師和政策制定者更新現有的命令，以促進及早介入，呼籲納入更佳的症狀認知公共教育、到院前照護者的及時處理訓練政策、救護車通往中風中心的路線，以及減少中風中心內所謂的「到院時間與接受治療之時間差」。
他們結論表示，在血栓溶解中風治療中，越快開始治療越好。
此篇分析未接受商業資助。Lees醫師報告接受來自Boehringer Ingelheim的獎助金，因其主持ECASS試驗，資金也來自Lundbeck和Thrombogenics。共同作者的宣告登載於報告中。Saver 醫師指出，他是加州大學的員工，擁有中風恢復裝置的專利；是Concentric Medical、Talecris與Ev3的試驗設計與執行科學顧問；接受Boehringer Ingelheim的演講獎金；在Vernalis、Paion、Lundbeck及 Neurobiological Technologies等贊助的多中心試驗中擔任研究評估者 ，而加州大學董事會根據臨床試驗合約納入的研究對象數量給付；也是國家健康研究中心(NIH)IRIS、CLEAR、IMS 3、SAMMPRIS和VERITAS多中心試驗的研究人員，加州大學董事會根據臨床試驗合約納入的研究對象數量給付；是NIH MR RESCUE這項多中心試驗的第一研究者；由NIH-NINDS Awards資助。Levine醫師報告擔任NIH資助的tenecteplase(Genentec藥廠製造)試驗的研究員；接受國家中風協會網路廣播獎助金；接受NIH-NINDS Awards資助，他也是NIH臨床試驗 IMS 3、CLEAR-ER、FAST-MAG和INSTINCT的獨立監測者。
Pooled Analysis of tPA Stroke Trials Underlines Need for Rapid Treatment
By Susan Jeffrey
Medscape Medical News
Stroke TrialsMay 14, 2010 — A new pooled analysis of randomized trials of tissue plasminogen activator (tPA) in the treatment of acute ischemic stroke, now expanded to include more recent trials, confirms the benefit of treatment to 4.5 hours but shows for the first time that risk may outweigh benefit after that time.
The new analysis adds data from the recent European Cooperative Acute Stroke Study 3 (ECASS 3) and the Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET), bringing the total number of pooled studies to 8.
The updated analysis "shows that treatment with thrombolysis until 4.5 [hours] from stroke onset enhances the chance of favorable outcome," the researchers, with lead study author Kennedy R. Lees, FRCP, from the Western Infirmary at the University of Glasgow, Scotland, conclude.
Interestingly, parenchymal hemorrhage rates were independent of time to treatment, but mortality increased with thrombolytic therapy after 4.5 hours, suggesting other mechanisms of mortality may be involved.
"However, across the time window studied, our analysis showed that the greatest benefit comes from earlier treatment, since net benefit is diminishing and is undetectable in our sample beyond 4.5 [hours]," they write.
The analysis is published in the May 15 issue of The Lancet.
Planned Analysis
Since the first trials of tPA in stroke were designed, common data elements have been collected with an eye to pooling the datasets, the study authors note. This pooled analysis includes data from the National Institute of Neurological Disorders and Stroke (NINDS) trial parts 1 and 2, the first 2 ECASS trials, 2 Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) trials, and the more recently reported ECASS 3, as well as EPITHET.
"Initially, we intended not to include [EPITHET], but while preparing to publish our findings we learned that all variables needed for the analysis had been gathered by the EPITHET investigators," the study authors write. EPITHET based inclusion on imaging findings, whereas enrollment in all the other trials was based on clinical diagnosis of a clearly defined time of stroke onset and a computed tomographic scan clear of bleeding.
The 2 additional trials, ECASS 3 with a total of 821 randomized patients and EPITHET with 100 patients, brought the pooled patient total to 3670, with 1850 treated with tPA and 1820 receiving placebo. They used multivariate logistic regression to assess the relationship between the time from stroke onset to the start of treatment and favorable 3-month outcome, defined as a modified Rankin scale score of 0 to 1, mortality, and the occurrence and outcome of clinically relevant parenchymal hemorrhage. Outcomes were examined for patients treated within 360 minutes (6 hours).
They found that the odds of a favorable outcome increased as the time from stroke onset to treatment decreased (P = .0269), with no further benefit seen after 270 minutes (4.5 hours).
Table 1. Adjusted Odds of a Favorable 3-Month Outcome by Time From Stroke Onset to Start of Treatment (OTT)
| OTT, min | OR (95% CI) |
| 0 – 90 | 2.55 (1.44 – 4.52) |
| 91 – 180 | 1.64 (1.12 – 2.40) |
| 181 – 270 | 1.34 (1.06 – 1.68) |
| 271 – 360 | 1.22 (0.92 – 1.61) |
CI = confidence interval; OR = odds ratio
Mortality risk also increased with time and appeared to outweigh benefit after 4.5 hours.
Table 2. Adjusted Odds of Mortality by Time From Stroke Onset to Start of Treatment (OTT)
| OTT, min | OR (95% CI) |
| 0 – 90 | 0.78 (0.41 – 1.48) |
| 91 – 180 | 1.13 (0.70 – 1.82) |
| 181 – 270 | 1.22 (0.87 – 1.71) |
| 271 – 360 | 1.49 (1.00 – 2.21) |
CI = confidence interval; OR = odds ratio
Large parenchymal hemorrhage, perhaps the most feared complication of tPA therapy in stroke, occurred in 96 (5.2%) of treated patients and 18 (1.0%) of controls, but with no clear relationship between time of stroke onset and treatment (P = .4140).
"The apparent discrepancy between mortality and parenchymal bleeding deserves comment," the study authors write, because it had been thought previously that the risk of mortality with later treatment lies with increased hemorrhage risk.
....there must be another mechanism underlying the increase in mortality...
The finding might be caused by low power, they speculate, due to a relatively small number of cases. "However, although parenchymal hemorrhage, when it occurs, is associated with a high risk of death, the number of cases is so low that mortality is evidently not a result of such bleeds in most cases: there must be another mechanism underlying the increase in mortality."
Although the effectiveness of thrombolytic therapy is "beyond dispute," they note, treatment still does not help a large proportion of patients. Their analysis shows that about 5 patients need to be treated within 0 to 90 minutes, 9 patients within 91 to 180 minutes, or 15 patients between 181 and 270 minutes after symptom onset for one of them to have a good outcome.
More information is needed to understand better the factors that may prevent treatment from being effective in individual patients.
"The stroke community has many lines of research to improve stroke treatment, such as looking for a possible more effective dose of alteplase, reducing the tendency of thrombolytic drugs to cause intracerebral hemorrhage, testing new thrombolytic agents, exploiting new and faster imaging methods to guide treatment, increasing the extent of lysis with ultrasound, antithrombotic agents, intra-arterial clot manipulation, adding neuroprotective therapies that could be started in the ambulance, and examining cognitive function in clinical trials so that important benefits or risks of treatment are not missed," they conclude.
Renewed Mandate
In a commentary accompanying the publication, Jeffrey L. Saver, MD, from the Geffen School of Medicine at the University of California, Los Angeles, and Steven R. Levine, MD, from Mount Sinai School of Medicine in New York City, write that with this new pooled analysis by Lees et al, "the time profile of benefit and harm for alteplase in broadly selected patients is for the first time well delineated, and the first age of recanalization therapy development in acute stroke therapy draws to a close."
As seen in the previous pooled analysis in 2004, these results showed that benefit decreased substantially over time, they write. "An important new finding is that later onset to start of treatment (more than 4.5 hours from onset) was associated with increased mortality, consonant with findings of a Cochrane study–level meta-analysis of a larger group of 26 trials (7152 patients) that investigated a wider variety of thrombolytics" (Wardlaw et al. Cochrane Database Syst Rev. 2009;4:CD000213).
The mechanism of this increased mortality, though, may be of some debate, they note, because there was no parallel time-related increase in parenchymal hemorrhage.
Still, an "even more important message" from these data is the steep decrease in benefit at the earlier periods, with odds of a favorable outcome appearing to decrease by a factor of 2 for each 90-minute period after symptom onset.
"These findings mandate a renewed commitment by clinicians and policymakers to foster very early intervention," Dr. Saver and Dr. Levine conclude, advocating strategies that include better education of the public of symptom recognition, training prehospital personnel in a policy of "scoop and go," routing ambulances to stroke centers, and decreasing so-called door to needle times within stroke centers.
"In thrombolytic stroke therapy, sooner is better than later, much better," they conclude.
The analysis received no commercial funding. Dr. Lees reports he has received honoraria from Boehringer Ingelheim for his role in conduct of the ECASS trials, as well as from Lundbeck and Thrombogenics. Disclosures for coauthors appear in the paper. Dr. Saver reports he is an employee of the University of California, which holds a patent on retriever devices for stroke; is a scientific consultant regarding trial design and conduct to Concentric Medical, Talecris, and Ev3; has received lecture honoraria from Boehringer Ingelheim; has been a site investigator in multicenter trials sponsored by Vernalis, Paion, Lundbeck, and Neurobiological Technologies, for which the University of California Regents received payments based on the clinical trial contracts for the number of subjects enrolled; is a site investigator in the National Institutes of Health (NIH) IRIS, CLEAR, IMS 3, SAMMPRIS, and VERITAS multicenter clinical trials, for which the University of California Regents receive payments based on the clinical trial contracts for the number of subjects enrolled; is a lead investigator in the NIH MR RESCUE multicentre trial; and is funded by NIH-NINDS Awards. Dr. Levine reports he has been an investigator for an NIH-funded trial of tenecteplase, manufactured by Genentec; has received an honorarium from the National Stroke Association for a Webcast; and is funded by NIH-NINDS Awards. He is the independent medical monitor for NIH clinical trials IMS 3, CLEAR-ER, FAST-MAG, and INSTINCT.
Lancet. 2010;375:1695-1703, 1667-1668.
