Drugs for preventing blood clot dissolution (antifibrinolytic therapy) to reduce the occurrence of rebleeding in aneurysmal subarachnoid haemorrhage

A subarachnoid haemorrhage (SAH) is a bleed into the small space between the brain and skull that contains blood vessels that supply the brain (the subarachnoid space). The cause of a bleeding here is usually a rupture of a weak spot in one of these vessels. A SAH is a relatively uncommon type of stroke, but it often occurs at a young age (half the patients are younger than 50 years). The outcome of SAH is often poor: one-third of people die after the haemorrhage and of those who survive, one-fifth will require help for everyday activities. An important cause of poor recovery after SAH is a second bleed from the weakened vessel (rebleeding). This is thought to be caused by the dissolving of the blood clot at the original bleeding site that results from natural blood clot dissolving (fibrinolytic) activity. Antifibrinolytic therapy that reduces this activity was introduced as a treatment for reducing rebleeding and therefore for improving recovery after SAH. This review included 10 trials, totaling 1904 participants that investigated the effect of these drugs in people with SAH. Antifibrinolytic treatment does indeed reduce the risk of rebleeding, but does not improve survival or the chance of being independent in everyday activities. This may be due to an increase in one of the other common complications of SAH. We conclude that antifibrinolytic treatment should not routinely be given to people with SAH, but new randomised trials are needed to establish if short-term treatment might be beneficial.

Authors' conclusions: 

The current evidence does not support the use of antifibrinolytic drugs in the treatment of people with aneurysmal subarachnoid haemorrhage, even in those who have concomitant treatment strategies to prevent cerebral ischaemia. Results on short-term treatment are promising, but not conclusive. Further randomised trials evaluating short-term antifibrinolytic treatment are needed to evaluate its effectiveness.

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Background: 

Rebleeding is an important cause of death and disability in people with aneurysmal subarachnoid haemorrhage. Rebleeding is probably related to dissolution of the blood clot at the site of aneurysm rupture by natural fibrinolytic activity. This review is an update of a previously published Cochrane review.

Objectives: 

To assess the effects of antifibrinolytic treatment in people with aneurysmal subarachnoid haemorrhage.

Search strategy: 

We searched the Cochrane Stroke Group Trials Register (February 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 1), MEDLINE (1948 to December 2012), and EMBASE (1947 to December 2012). In an effort to identify further published, unpublished, and ongoing studies we searched reference lists and trial registers, performed forward tracking of relevant references and contacted drug companies.

Selection criteria: 

Randomised trials comparing oral or intravenous antifibrinolytic drugs (tranexamic acid, epsilon amino-caproic acid, or an equivalent) with control in people with subarachnoid haemorrhage of suspected or proven aneurysmal cause.

Data collection and analysis: 

Two review authors independently selected trials for inclusion and extracted the data. Three review authors assessed trial quality. For the primary outcome we converted the outcome scales between good and poor outcome for the analysis. We scored death from any cause and rates of rebleeding, cerebral ischaemia, and hydrocephalus per treatment group. We expressed effects as risk ratios (RR) with 95% confidence intervals (CI). We used random-effects models for all analyses.

Main results: 

We included 10 trials involving 1904 participants. The risk of bias was low in six studies. Four studies were open label and were rated as high risk of performance bias. One of these studies was also rated as high risk for attrition bias. Four trials reported on poor outcome (death, vegetative state, or severe disability) with a pooled risk ratio (RR) of 1.02 (95% confidence interval (CI) 0.91 to 1.15). All trials reported on death from all causes with a pooled RR of 1.00 (95% CI 0.85 to 1.18). In a trial that combined short-term antifibrinolytic treatment (< 72 hours) with preventative measures for cerebral ischaemia the RR for poor outcome was 0.85 (95% CI 0.64 to 1.14). Antifibrinolytic treatment reduced the risk of re-bleeding reported at the end of follow-up (RR 0.65, 95% CI 0.44 to 0.97; 78 per 1000 participants), but there was heterogeneity (I² = 62%) between the trials. The pooled RR for reported cerebral ischaemia was 1.41 (95% CI 1.04 to 1.91, 83 per 1000 participants), again with heterogeneity between the trials (I² = 52%). Antifibrinolytic treatment showed no effect on the reported rate of hydrocephalus in five trials (RR 1.11, 95% CI 0.90 to 1.36).

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