Haemostatic drug therapies for acute spontaneous intracerebral haemorrhage

 

Abstract

Background

Because spontaneous (non-traumatic) intracerebral haemorrhage (ICH) volume influences its outcome and a third of ICHs enlarge by a third within 24 hours of onset, early haemostatic drug therapy might improve outcome. This is an update of a Cochrane review first published in 2006.

Objectives

To examine the clinical effectiveness and safety of haemostatic drug therapies for acute ICH in a randomised controlled trial (RCT) design.

Search methods

I searched the Cochrane Stroke Group Trials Register (last searched 26 June 2009), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2009), MEDLINE (1966 to June 2009) and EMBASE (1980 to June 2009). In an effort to identify further published, ongoing and unpublished studies I scanned bibliographies of relevant articles, searched international registers of clinical trials and research, and contacted authors and pharmaceutical companies.

Selection criteria

I sought RCTs of any haemostatic drug therapy for acute ICH, compared against placebo or open control, with relevant clinical outcome measures.

Data collection and analysis

Two authors independently applied the inclusion criteria, reviewed the relevant studies, and extracted data.

Main results

I found five phase II RCTs and one phase III RCT, involving 1398 adults aged 18 years or over, within four hours of ICH onset: 423 participants received placebo and 975 participants received haemostatic drugs (two received epsilon-aminocaproic acid (EACA) and 973 received recombinant activated factor VII (rFVIIa)). Haemostatic drugs did not significantly reduce 90-day case fatality after ICH (risk ratio (RR) 0.85, 95% confidence interval (CI) 0.58 to 1.25), and rFVIIa did not significantly reduce death or dependence on the modified Rankin Scale (grades 4 to 6) within 90 days of ICH (RR 0.91, 95% CI 0.72 to 1.15). There was a trend towards more participants on rFVIIa experiencing thromboembolic serious adverse events (RR 1.37, 95% CI 0.74 to 2.55)

Authors' conclusions

Haemostatic drugs cannot be recommended for the treatment of acute spontaneous ICH in clinical practice, but a large RCT would be justified.

 

Plain language summary

Haemostatic drug therapies for acute spontaneous intracerebral haemorrhage

More than one tenth of all strokes are caused by bleeding in the brain (known as intracerebral haemorrhage). Most of these intracerebral haemorrhages do not have an identifiable cause. The bigger the haemorrhage, the more likely it is to be fatal. Roughly one third of these haemorrhages enlarge significantly within the first 24 hours. Therefore, drugs that promote clotting - known as haemostatic drugs - might reduce the risk of death or being disabled after an intracerebral haemorrhage by limiting its growth, if given soon after the bleeding starts. But haemostatic drugs can cause unwanted clotting, such as heart attacks and clots in leg veins. I reviewed the evidence in 1398 adults from five phase II randomised controlled trials and one phase III randomised controlled trial. Recombinant activated factor VII (rFVIIa) was the most widely tested drug. rFVIIa did not significantly reduce the risk of a bad outcome (death or dependence) within 90 days of intracerebral haemorrhage, when compared against placebo. I found no evidence of benefit from haemostatic drug treatments for people with spontaneous intracerebral haemorrhage, though further trials appear justified.

 

摘要

背景

促凝血用藥在急性自發性腦出血的使用

因急性自發性腦出血的血量，影響病人的預後甚巨，且有三分之一的病人在發作的24小時內其出血量增加了三分之一，故及早使用促凝血藥物可能可以改善預後

目標

使用隨機分配控制試驗，來檢驗臨床上促凝血用藥治療，在自發性腦出血病患的有效性及安全性。

搜尋策略

我們搜尋了Cochrane stroke group Trial(最後一次搜尋2006年5月)、The Cochrane central register of controlled trials　(CENTRAL) (The Cochrane Library Issue 2, 2006)、MEDLINE (1966 to August 2005)、及EMBASE (1980 to August 2005)。 為了找到更多已發表、正在進行中和尚未發表的研究，我們搜尋了相關重要研究的參考文獻、臨床試驗的國際登錄資料，並聯繫相關作者及藥廠。

選擇標準

對於自發性腦出血病患的治療，我們搜尋了使用任何促凝血藥物，和使用安慰劑做比較，並測量適當的臨床預後指標的隨機分配控制試驗。

資料收集與分析

兩位評論者獨立運用納入標準搜尋文獻，評讀重要的相關研究，並從中摘錄資料。

主要結論

我們找到了四個第二期(phase II)的隨機分配控制試驗，受試者為發生自發性腦出血4小時之內的18歲以上成年人。有116位接受安慰劑，有373位接受促疑血藥物(2位接受了epsilonaminocaproic acid，另外371位接受重組的活化第七凝血因子(rFVIIa))。使用修訂Rankin scale(4到6分)分級病人時，促凝血藥物似乎降低了自發性腦出血病患90天內的死亡率及殘障程度(相對風險0.79，95%信賴區間0.67 to 0.93)；但若使用 extended Glasgow Outcome Scale時，其相對風險僅降低至0.90(95%信賴區間0.81 to 1.01)。另外，使用160微克/公斤的rFVIIa會顯著增加動脈血栓栓塞發生的機率。

作者結論

目前並無足夠的證據指引我們，在自發性腦出血病患身上使用促凝血藥物。重組的活化第七凝血因子對自發性腦出血的成人病患，似乎有所幫助，但其證據既不健全也不精確。故需要大規模第三期隨機分配控制試驗，以驗證重組的活化第七凝血因子，和其它較不昂貴藥物的療效。

翻譯人

本摘要由臺北榮民總醫院邱苓瑜翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

此回顧在評估促進凝血藥物用在成人自發性腦出血的早期治療。腦出血佔了中風病患的五分之一。大部分都是無確定原因的自發性腦出血。一些自發性腦出血會在發病初期的24小時擴大，而當出血越大，其死亡率隨之越高。因此，已知的促凝血藥物可以在促進凝血之後，也許可以降低出血量，進而減少成人自發性腦出血的死亡率及降低後遺症。但是促凝血藥物可能帶來有害的血液凝集(如心臟病發或靜脈栓塞)。我們回溯整理了四篇受試者為成人的第二期(phase II)隨機分配控制試驗。重組的活化第七凝血因子是最常用來試驗的藥物。雖然它改善了預後(死亡或殘障)降低了90天內的成人自發性腦出血的風險，但高劑量的第七凝血因子卻會導致有害的動脈栓塞。整體而言，這些試驗的結果並不精確，治療的好處需要更大、更嚴謹的試驗才能證實。目前，平均每八個自發性腦出血的病人中，僅有一個適合施打重組的活化第七凝血因子，所以如何將這些藥物應用在發病四個小時後的病患，以及那些本身有凝血病史的病患，值得進一步的研究。最後，其他比重組的活化第七凝血因子便宜的藥物，也許和第七凝血因子一樣有效，這些藥物值得未來進一步的大型試驗。