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Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage

  1. Merih I Baharoglu1,
  2. Menno R Germans2,
  3. Gabriel JE Rinkel3,
  4. Ale Algra4,
  5. Marinus Vermeulen1,
  6. Jan van Gijn5,
  7. Yvo BWEM Roos1,*

Editorial Group: Cochrane Stroke Group

Published Online: 30 AUG 2013

Assessed as up-to-date: 4 FEB 2013

DOI: 10.1002/14651858.CD001245.pub2


How to Cite

Baharoglu MI, Germans MR, Rinkel GJE, Algra A, Vermeulen M, van Gijn J, Roos YBWEM. Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD001245. DOI: 10.1002/14651858.CD001245.pub2.

Author Information

  1. 1

    University of Amsterdam, Department of Neurology, Academic Medical Centre, Amsterdam, Netherlands

  2. 2

    University of Amsterdam, Department of Neurosurgery, Academic Medical Centre, Amsterdam, Netherlands

  3. 3

    University Medical Center Utrecht, Department of Neurology and Neurosurgery, Utrecht, Netherlands

  4. 4

    University Medical Center Utrecht, Julius Center for Health Sciences and Primary Care/University Department of Neurology and Neurosurgery, Utrecht, Netherlands

  5. 5

    University Medical Center Utrecht, Department of Neurology, Utrecht, Netherlands

*Yvo BWEM Roos, Department of Neurology, Academic Medical Centre, University of Amsterdam, PO Box 22660, Amsterdam, 1100 DD, Netherlands. y.b.roos@amc.uva.nl.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 30 AUG 2013

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Description of the condition

In people with aneurysmal subarachnoid haemorrhage (SAH) rebleeding is an important cause of death and disability. Without aneurysm treatment approximately 30% of such people experienced a rebleed within one month of the initial haemorrhage (Locksley 1966). The rebleeding rate has now been reduced to about 15% because in most people the aneurysm is occluded early after admission (Roos 2000b). The risk of rebleeding is highest in the first 24 hours after SAH, with a peak in the first six hours (Guo 2011). The prognosis after rebleeding is poor: approximately 60% of people who rebleed die and another 30% remain dependent for activities of daily living (Naidech 2005).

 

 

 

Description of the intervention

Antifibrinolytic drugs were introduced to reduce the occurrence of rebleeding. These drugs are administered orally or intravenously and block endogenous fibrinolytic activity and could help prevent bleeding.

 

How the intervention might work

Dissolution of the blood clot at the site of the ruptured aneurysm is thought to be an important factor in the development of rebleeding. This dissolution probably results from endogenous fibrinolytic activity after SAH. Since antifibrinolytic agents reduce fibrinolytic activity, antifibrinolytic therapy may reduce the occurrence of rebleeding and thereby improve clinical outcome after SAH. However, reducing rebleeding might not automatically improve clinical outcome in all instances. Concerns have been raised that antifibrinolytic therapy might increase the occurrence of cerebral ischaemia. Cerebral ischaemia is a complication of SAH that occurs in about 30% to 40% of people between four and 14 days after SAH. In older trials the beneficial effect of antifibrinolytic treatment (reducing rebleeding) was offset by an increase in cerebral ischaemia, resulting in a neutral effect on outcome (Roos 2003).

 

Why it is important to do this review

In 1967 Gibbs and O'Gorman published the first report on antifibrinolytic treatment in people with SAH (Gibbs 1967). Since then, over 50 studies on antifibrinolytic therapy in aneurysmal SAH have been published. Unfortunately most of these studies are uncontrolled and only a minority of the controlled studies are randomised. Moreover, the results of some of the individual randomised studies contradict each other. Furthermore, as mentioned above, concerns have been raised that antifibrinolytic therapy might increase the occurrence of cerebral ischaemia. In a previous version of this review we found that even in people treated with measures to prevent and reverse cerebral ischaemia (such as administration of nimodipine), clinical outcome was not improved by antifibrinolytic treatment despite a reduction in rebleeding rate. The hypothesis has been posed that, when people with aneurysmal SAH are treated with antifibrinolytic agents, recovery from cerebral ischaemia is impeded by antifibrinolytic treatment. More recently it has been proposed that if antifibrinolytic treatment is discontinued before the period in which cerebral ischaemia typically occurs, the negative effect of antifibrinolytic therapy may be avoided. In this update of a previously published Cochrane review (Roos 2003), we sought to evaluate the effectiveness of short-term antifibrinolytic treatment in people concomitantly treated with measures to prevent or reverse cerebral ischaemia.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

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

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Criteria for considering studies for this review

 

Types of studies

All truly randomised unconfounded trials were eligible in which, after concealed allocation, antifibrinolytic drugs were compared with control treatment (open studies) or placebo (blind studies) in an intention-to-treat analysis. We excluded all trials in which allocation to treatment or control group was not concealed (e.g. trials in which people were allocated by means of an open random number list, alternation, or based on date of birth, days of the week, or hospital-number), since foreknowledge of treatment allocation might lead to biased treatment allocation (i.e. selective enrolment). We also excluded trials in which an intention-to-treat analysis was not performed and could not be reconstructed on the basis of published data without a loss of 20% or more of all randomised participants.

 

Types of participants

Trials in which participants were included with clinical symptoms and signs of SAH from a ruptured aneurysm with confirmation of the diagnosis by the presence of subarachnoid blood on computed tomography (CT) scan or on cerebrospinal fluid (CSF) examination were eligible for this review.

 

Types of interventions

Antifibrinolytic drugs (e.g. tranexamic acid, epsilon amino-caproic acid, or equivalent drugs), oral or intravenous, versus control treatment (open studies) or placebo treatment (blind studies). Since the risk of rebleeding is highest during the first two weeks after the initial bleeding, treatment had to start within two weeks after onset of the SAH. Distinction was made between early and short-term (< 72 hours of onset of symptoms, i.e. before usual timing of onset of cerebral ischaemia) versus long-term (> 72 hours) treatment duration.

 

 

 

Types of outcome measures

 

Primary outcomes

The primary outcome measure was 'poor outcome' (death, vegetative state, or severe disability, as assessed either with the Glasgow Outcome Scale or the Modified Rankin Scale) at the end of follow-up at least three months after SAH. 'Death from all causes' at a minimum of at least three-weeks follow-up was our second primary outcome, since most studies only reported on case fatality.

 

Secondary outcomes

Secondary outcome measures were the effect of antifibrinolytic treatment on both the rates of reported and CT scan or autopsy confirmed (sensitivity analyses) episodes of rebleeding, cerebral ischaemia, and hydrocephalus. In this systematic review, we did not evaluate cerebral vasospasm without clinical signs of cerebral ischaemia.

 

Search methods for identification of studies

See the 'Specialized register' section in the Cochrane Stroke Group module. We searched for trials in all languages and arranged translations of relevant reports published in languages other than English.

 

Electronic searches

We searched the Cochrane Stroke Group Trials Register (last searched February 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 1), MEDLINE (1948 to December 2012) (Appendix 1) and EMBASE (1947 to December 2012) (Appendix 2).

We developed comprehensive search strategies with the help of the Cochrane Stroke Group Trials Search Co-ordinator and adapted the MEDLINE strategy for CENTRAL.

We also searched the following major ongoing trial registers (December 2012): ClinicalTrials.gov (http://www.clinicaltrials.gov/), EU Clinical Trials Register (https://www.clinicaltrialsregister.eu), Stroke Trials Registry (www.strokecenter.org/trials/), Current Controlled Trials (www.controlled-trials.com), and the WHO International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/).

 

Searching other resources

In an effort to identify further published, unpublished, and ongoing studies:

  1. we used Science Citation Index Cited Reference Search for forward tracking of important articles; and
  2. for the first version of this review (1998) we contacted the pharmaceutical company Pharmacia and Upjohn, formerly Kabi, manufacturer and license holder of the antifibrinolytic drug tranexamic acid. We identified no additional (unpublished) studies.

 

Data collection and analysis

 

Selection of studies

Two authors (MIB, MRG) independently screened the titles and abstracts of the records obtained from the electronic searches and excluded obviously irrelevant studies. We obtained the full-text articles for the remaining studies and the same two authors independently selected the trials that met the predefined criteria for inclusion in the review. The authors resolved disagreements by discussion and when necessary in consultation with a third review author (YBWEMR).

 

Data extraction and management

Two authors (MIB, MRG) independently reviewed all eligible studies and extracted details on the number of participants in the treated and the placebo or control group, the randomisation method, blinding method, the definitions for diagnosis and complications, and also ascertained whether an intention-to-treat analyses was done or could be reconstructed from the published data. Whenever consensus could not be reached, the review authors consulted a third review author (YBWEMR).

 

Assessment of risk of bias in included studies

Three authors (MIB, MRG, YBWEMR) independently assessed the risk of bias of each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreements by discussion. We assessed the risk of bias according to the following domains.

  1. Random sequence generation.
  2. Allocation concealment.
  3. Blinding of participants and personnel.
  4. Blinding of outcome assessment.
  5. Incomplete outcome data.
  6. Selective outcome reporting.
  7. Other bias.

We graded each potential source of bias as high, low, or unclear and provided information from each study in the 'Risk of bias' tables.

 

Measures of treatment effect

We processed data in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). 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).

 

Unit of analysis issues

The unit of analysis were individual participants, since we only included individually conducted randomised trials with a parallel design.

 

Dealing with missing data

In trials without intention-to-treat analysis, we tried to reconstruct such an analysis based only on the published data. For two trials (Hillman 2002; Tsementzis 1990) we tried to contact the principal investigator to retrieve data on the number of participants in whom rebleeding or cerebral ischaemia were proven on CT scan or at autopsy. We received a reply from one of the authors. We made no effort to obtain additional information for studies published 15 or more years ago.

 

Assessment of heterogeneity

For each outcome we assessed heterogeneity using the Chi² test and I² index (Higgins 2011). Because we suspected substantial heterogeneity, we used random-effects models for all analyses.

 

Assessment of reporting biases

To investigate possible publication bias in this review, we planned to perform funnel plots when possible.

 

Data synthesis

We used the Review Manager software, RevMan 5.2, for statistical analysis (RevMan 2012), and used Mantel-Haenszel random-effects models for pooled analyses.

 

Subgroup analysis and investigation of heterogeneity

To assess whether masked studies showed different results compared with unmasked studies we divided all analyses into two groups: trials with control treatment (open studies) and trials with placebo treatment (blind studies). We pre-planned an additional subgroup analysis to evaluate the effectiveness of antifibrinolytic therapy in trials with and without additional measures to prevent or reverse cerebral ischaemia and to evaluate the effectiveness of antifibrinolytic therapy according to treatment duration. We divided the included trials into one of three groups: (1) trials without ischaemia prevention and treatment duration > 72 hours, (2) trials with ischaemia prevention and treatment duration > 72 hours, and (3) trials with ischaemia prevention and treatment duration < 72 hours. We did not include a fourth group (trials without ischaemia prevention and treatment duration < 72 hours) as there were no trials that met these criteria.

Additionally we checked whether data were available on aneurysm treatment (i.e. clipping or coiling) according to antifibrinolytic treatment, to evaluate whether a subgroup analysis on clipping versus coiling was possible.

 

Sensitivity analysis

Because our secondary outcome measures were more prone to bias, we carried out sensitivity analyses on confirmed (rather than reported) rebleeding, cerebral ischaemia, and hydrocephalus rates.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Description of studies

 

Results of the search

The updated search of the bibliographic databases yielded a total of 1521 records, from which we removed 476 duplicates, leaving a total of 1045 records. After screening titles and abstracts we excluded 931 records, leaving 114 records for which we obtained the full-text articles. Further assessment resulted in 32 potentially relevant trials. Ten trials met the inclusion criteria for the review and we excluded 21 trials. We identified one ongoing trial from the searches of the trial registers. For an overview of the search results see Figure 1.

 FigureFigure 1. Study flow diagram.

 

Included studies

We included 10 studies (Chandra 1978; Fodstad 1981; Girvin 1973; Hillman 2002; Kaste 1979; Maurice 1978; Roos 2000a; Tsementzis 1990; Van Rossum 1977; Vermeulen 1984), which are described in detail in the Characteristics of included studies table. These 10 studies included 1904 participants of whom 959 were randomised to receive antifibrinolytic drugs, 597 received placebo treatment and 348 received control treatment. The Girvin 1973 study used epsilon-amino-caproic acid (39 participants), in all other studies tranexamic acid was used. In two studies participants were concomitantly treated with measures to prevent or reverse cerebral ischaemia (Hillman 2002; Roos 2000a). The duration of antifibrinolytic treatment differed considerably between studies and ranged from less than 72 hours up to six weeks. Short-term treatment was used in only one study (Hillman 2002). In this study, participants were treated up to 72 hours after SAH. All other studies treated participants for at least 10 days (or until occlusion of the aneurysm) after SAH.

Clinical outcome was reported in four studies (Hillman 2002; Roos 2000a; Tsementzis 1990; Vermeulen 1984) and the number of participants with poor outcomes could be reconstructed. Death from all causes and rebleeding rates were reported in all 10 studies. In six studies, episodes of rebleeding were defined primarily by clinical symptoms.

Two trials (Fodstad 1981; Hillman 2002) reported CT scan or autopsy confirmed episodes of rebleeding. The Dutch-British trial (Vermeulen 1984) and the STAR study (Roos 2000a) defined and reported rebleeding in two ways: as 'probable' if the diagnosis was suspected solely on clinical grounds and as 'definite' when proven by CT (after comparison with an earlier CT) or at autopsy.

Cerebral ischaemia was reported in six studies but defined in only three: in two studies (Roos 2000a; Vermeulen 1984) cerebral ischaemia was defined and reported in the same manner as episodes of rebleeding; as 'probable' and as 'definite' (CT-scan or autopsy confirmed) cerebral ischaemia. Again, as for rebleeding, Fodstad 1981 reported on CT-scan or autopsy confirmed cerebral ischaemia. Hillman 2002 reported percentage of transient and permanent delayed ischaemic neurological deficit. No clear definition was given and CT scans were not routinely used for confirmation of cerebral ischaemia. Because other studies did not make a distinction between permanent or transient cerebral ischaemia, we decided to combine these outcomes. In Hillman 2002, visible infarction on CT scan was reported; however, after contact with the author, we decided not to use this as a measure for cerebral ischaemia since this was not correlated to clinical signs of cerebral ischeamia.The other two studies (Girvin 1973; Tsementzis 1990) made no distinction between participants with episodes clinically suggestive of cerebral ischaemia or participants with confirmed cerebral ischaemia, and reported only an all-inclusive number of participants. One study reported on 'delayed cerebral ischaemia' and 'post operative ischaemia' (Roos 2000a). Since all other studies did not make this distinction and reported an overall number of participants with cerebral ischaemia, we grouped these subgroups of ischaemia together for the analysis on cerebral ischaemia.

Five trials reported on hydrocephalus. Hydrocephalus was defined in only one study by means other than clinical grounds and could therefore be included in the sensitivity analysis concerning 'confirmed hydrocephalus' (Roos 2000a). No trials reported on aneurysm treatment modality (i.e. coiling versus clipping) according to antifibrinolytic or control treatment and thus a subgroup analysis based on modality was not possible.

 

Excluded studies

We excluded 21 studies for various reasons (see Characteristics of excluded studies): some were comparative trials between two or more antifibrinolytic agents, others used unconcealed randomisation methods, and some were not randomised but used historical controls. We excluded Fodstad 1978 as 23% of the participants in the trial were later excluded and an intention-to-treat analysis could not be reconstructed on the basis of the published data.

 

Risk of bias in included studies

For a summary of the risk of bias please see Figure 2 and Figure 3. Five of the 10 included trials used an intention-to-treat analysis; in one of the remaining trials (Maurice 1978) this analysis could be completely reconstructed using the available follow-up data. In the other trials (Fodstad 1981; Hillman 2002; Tsementzis 1990; Van Rossum 1977) there was no follow-up information available for participants who were excluded after randomisation. In three studies only very few participants (Fodstad 1981: n = 1; Tsementzis 1990: n = 4; Van Rossum 1977: n = 3) were excluded from the final analysis and therefore these studies could still be included in our review. In one study (Hillman 2002) 91 (15%) of the 596 participants were excluded after randomisation. Because this was less than the prespecified proportion of 20% we included this study in our analysis. We rated this study as high risk of bias for incomplete outcome data.

 FigureFigure 2. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
 FigureFigure 3. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Six studies used a double-blind method (placebo controlled) and four used a control group with standard treatment without placebo.The control group studies were open label and we rated them as high risk of performance bias (all four studies) and attrition bias (one study).

Girvin 1973 used 'flip-of-a-coin' randomisation as the method of allocation, which is more susceptible to bias compared with, for instance, the sealed envelope method. Nevertheless, we decided to include this study since this is an accepted form of randomisation with allocation concealment according to the Cochrane guidelines. All other studies used a method of concealed allocation that was considered appropriate at time of conducting the trial, although it was not always mentioned whether or not the sealed envelopes that were used were opaque.

 

Effects of interventions

The pooled RR for our primary outcome measure, 'poor outcome', was 1.02 (95% CI 0.91 to 1.15) ( Analysis 1.1). The pooled RR for our second primary outcome measure, 'death from all causes', was 1.00 (95% CI 0.85 to 1.18) ( Analysis 1.2).

In the analysis on rebleeding rates ( Analysis 1.3), antifibrinolytic therapy significantly reduced the risk of rebleeding (RR 0.65, 95% CI 0.44 to 0.97; 78 per 1000 people). Considerable heterogeneity was detected for this comparison (I² = 62%). Similar results were found in the subgroup analysis of the six double-blind and placebo controlled studies (RR 0.64, 95% CI 0.43 to 0.97), the sensitivity analysis including four studies with CT scan or autopsy confirmed rebleeding (RR 0.44, 95% CI 0.26 to 0.75) ( Analysis 1.4), as well as in the subgroup analysis of studies with and without ischaemia prevention according to duration of treatment (< 72 hours > 72 hours) (RR 0.65, 95% CI 0.44 to 0.97) ( Analysis 1.5).

In the six trials that reported cerebral ischaemia rates, antifibrinolytic treatment significantly increased the risk of cerebral ischaemia (RR 1.41, 95% CI 1.04 to 1.91; 83 per 1000 people) ( Analysis 1.6). Similar (though non-significant) results were seen in the subgroup analysis of the three placebo controlled trials (RR 1.38, 95% CI 0.87 to 2.19) as well as in the three trials with CT scan or autopsy confirmed cerebral ischaemia (RR 1.34, 95% CI 0.88 to 2.03) ( Analysis 1.7). In these analyses there was considerable heterogeneity between the results from the four older studies and the results from the most recent studies (Hillman 2002; Roos 2000a), in which specific treatments to prevent cerebral ischaemia were used (I² = 52%).

In five trials hydrocephalus was reported. Antifibrinolytic treatment overall had no effect on the reported rates of hydrocephalus (RR 1.11, 95% CI 0.90 to 1.36) ( Analysis 1.8). In the subgroup analysis on placebo versus open studies the RR of antifibrinolytic treatment for hydrocephalus was 1.19 (95% CI 0.95 to 1.48) in the placebo controlled studies, while it was 0.64 (95% CI 0.34 to 1.18) in the open label trials. The sensitivity analysis on one trial with CT scan or autopsy confirmed hydrocephalus showed no effect of therapy on hydrocephalus rate (RR 1.17, 95% CI 0.87 to 1.55) ( Analysis 1.9). Ischaemia prevention did not appear to have an effect on hydrocephalus in the subgroup analysis of studies with and without ischaemia prevention according to duration of treatment. The RR of hydrocephalus in people receiving antifibrinolytic treatment during > 72 hours with cerebral ischaemia prevention was 1.17 (95% CI 0.87 to 1.55) and for people receiving antifibrinolytic treatment during > 72 hours without ischaemia prevention the RR was 1.03 (95% CI 0.74 to 1.43) ( Analysis 1.10).

In the subgroup analysis of studies with ischaemia prevention according to duration of treatment (< 72 hours versus > 72 hours), the RR for people receiving antifibrinolytic treatment during < 72 hours with cerebral ischaemia prevention was 0.85 (95% CI 0.64 to 1.14) for 'poor outcome' ( Analysis 1.11) and 0.83 (95% CI 0.52 to 1.35) for 'death from all causes' ( Analysis 1.12). Furthermore, cerebral ischaemia did not significantly increase with antifibrinolytic treatment in trials where participants received concomitant ischaemia preventative treatment (Hillman 2002 and Roos 2000a combined: RR 1.09, 95% CI 0.78 to 1.51) ( Analysis 1.13).

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Summary of main results

Although this systematic review shows that antifibrinolytic treatment reduces the rate of rebleeding by approximately 35%, there is no evidence of benefit from antifibrinolytic treatment on case fatality or poor overall outcome. This analysis further shows that the lack of effect on clinical outcome, despite a reduction in rebleeding, may be caused by an increase in cerebral ischaemia with antifibrinolytic treatment, which was also shown in the sensitivity analysis in trials with data on the number of participants with CT or post-mortem proven cerebral ischaemia (two double-blind, one with open control group). Any possible beneficial effect of the reduction in the rebleeding-rate on clinical outcome was offset by an increase in the rate of cerebral ischaemia. This was also seen in the most recent study (Hillman 2002) in which short-term antifibrinolytic therapy was given with ischaemia preventative measures, although permanent delayed neurological deficit was decreased with antifibrinolytic treatment. This finding could suggest that short-term antifibrinolytic treatment (compared to long-term treatment in the study by Roos 2000a) does not influence recovery from initial ischaemia or development of secondary ischaemia and may, therefore, lead to improved clinical outcome. However, confirmatory evidence is needed.

 

Overall completeness and applicability of evidence

Trials in which people were included with symptoms and signs of SAH of suspected or proven aneurysmal cause, with confirmation of the diagnosis by the presence of subarachnoid blood on CT or on CSF examination were eligible for inclusion in the review. We chose this pragmatic approach and did not restrict our review to people with angiographically proven aneurysms, because in contrast to angiography, CT scan or CSF examination can be done instantaneously, independent of the clinical condition of the patient. One could argue that currently people with suspected aneurysmal SAH will undergo CT angiography (CT-A) immediately to confirm the presence of an aneurysm. We chose not to limit our analysis to proven aneurysmal SAH, because CT-A was not available at the time most of the trials were conducted. Moreover, CT-A is not always available in referring hospitals without specialised units. Since antifibrinolytic treatment might be most beneficial when started as soon as possible, it is likely that treatment will start in the referring hospital without CT-A confirmation of the presence of an aneurysm. An analysis on oral versus intravenous treatments or a comparison between treatment dosages could not be performed. Only one study used oral antifibrinolytic treatment, whereas other studies used intravenous therapy alone or a combination of intravenous and oral treatment in varying dosages. Furthermore, in the past decade treatment of cerebral aneurysms has changed considerably: whereas most studies were performed in the era where surgical treatment was the only method of occlusion of the aneurysm, currently endovascular coiling is an accepted alternative to surgical occlusion. Because no data on treatment modality were available from the included trials, an analysis according to aneurysm treatment modality was not possible. Such an analysis could, however, prove worthwhile in the future.

 

Quality of the evidence

In this systematic review we only included true randomised controlled trials and performed a subgroup analysis on masked versus unmasked studies in an attempt to minimise allocation and performance bias. However, many of the included studies were older (1970s and 1980s) and most did not report on many sources of potential bias, such as how the randomisation sequence was generated and if participant outcome was assessed by individuals who were blinded to the intervention given. Therefore, we scored many potential sources of bias as 'unclear risk' as can be seen in Figure 2 and Figure 3. However, most of these studies were small and in total comprised 24% of all included participants. Most included participants originated from three large studies (Hillman 2002; Roos 2000a; Vermeulen 1984). For two of these studies, comprising 50% of all data, we could find no potential sources of bias so we rated them as low risk of bias for each source (Roos 2000a; Vermeulen 1984). For Hillman 2002, however, many potential sources of bias could not be scored and were unclear, such as sequence generation, allocation concealment, and blinded outcome assessment. Moreover, 15% of included participants were later excluded from the analysis and the baseline characteristics and outcome of these participants were not reported. Since this was the only study included in the subgroup analysis for treatment duration of less than 72 hours with ischaemia prevention these results are far from conclusive. We know of only one other case series that evaluated short-term antifibrinolytic treatment (Harrigan 2010). In this study all participants received antifibrinolytic treatment until occlusion of the aneurysm (average 56.5 hours after SAH ictus). Harrigan 2010 reported low rebleeding rates and permanent neurological deficit due to cerebral ischaemia (1.4% and 7.2% respectively). However, no follow-up was done to evaluate the participants' clinical outcomes and no control group was available making it impossible to draw conclusions based on this study.

 

Potential biases in the review process

We searched all major medical electronic databases and other sources, using sensitive and validated search strategies. However, it is possible that we did not find all relevant publications. Furthermore, we only included studies that were published in medical literature and did not search the grey literature, such as government reports and unpublished information. Although all included trials met the predefined inclusion criteria, the studies differed considerably in participant selection, disease severity at baseline, start of treatment after diagnosis, dosage and type of trial medication, classification of events, and outcome and duration of follow-up. This clinical heterogeneity may in part account for the statistical heterogeneity found in the analyses on rebleeding and cerebral ischaemia.

 

Agreements and disagreements with other studies or reviews

Our results are comparable to the results from a recent meta-analysis (Gaberel 2012). However, Gaberel 2012 included all studies in which antifibrinolytic treatment was compared with control treatment, including retrospective analyses and studies with historical control groups. Retrospective analyses are known to be much more susceptible to selection and reporting bias, since the decision to treat a patient is made subjectively. Moreover, the other review did not compare placebo controlled versus open studies, which is another potential source of bias, since all outcomes, except for death, are made on subjective clinical grounds and can be easily biased when the outcome assessor is not blinded to the treatment given. In our review we included only randomised clinical trials and performed several sensitivity analyses, which should yield less biased results. Since most studies did not describe whether outcomes were assessed blinded to treatment, sensitivity analyses are essential. Despite the fact that all authors reported that confirmation of rebleeding was sought, in most instances this was done by examination of the cerebrospinal fluid. Because CSF examination is an unreliable test to confirm rebleeding (Vermeulen 1983) the diagnosis of rebleeding could often not be regarded as proven. The sensitivity analyses we performed on reported versus confirmed (with confirmatory evidence on CT scan or at autopsy) rebleeding, cerebral ischaemia, or hydrocephalus showed similar results to the overall analyses. Lack of confirmatory evidence of these complications thus appears to be of minor importance in our analyses. The analyses we performed on trials with control treatment compared with those given placebo treatment showed similar reducing effects of antifibrinolytic treatment on rebleeding and similar increasing effects on cerebral ischaemia, whereas hydrocephalus trials with control treatment showed a tendency towards a beneficial effect compared with trials with placebo treatment, demonstrating a tendency towards increased hydrocephalus rates.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

 

Implications for practice

Antifibrinolytic treatment does not improve clinical outcome in people after SAH, although it does reduce the risk of rebleeding after SAH. Based on the currently available data, treatment with antifibrinolytic drugs cannot be recommended for people with subarachnoid haemorrhage from a presumed or proven aneurysmal origin.

 
Implications for research

The available data suggest that short-term (less than 72 hours) antifibrinolytic treatment, combined with cerebral ischaemia preventative measures, may reduce rebleeding rates without an increase in the proportion of people with cerebral ischaemia. Thus, short-term treatment with antifibrinolytic therapy may be effective for people with aneurysmal SAH, but confirmatory evidence is lacking and a possible harmful effect can also not be excluded. Based on these findings new randomised trials of short-term antifibrinolytic agents versus control in people with SAH are needed. Recently, a new trial comparing ultra early and short antifibrinolytic treatment (less than 24 hours) with control treatment has been registered and is planned (Verbaan 2012).

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Previous versions of this review were supported by research grants from the Netherlands Heart Foundation (Nederlandse Hart Stichting). We would like to thank Brenda Thomas for her help in developing the new electronic database search. We would like to thank Hazel Fraser for her editorial advice.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
Download statistical data

 
Comparison 1. Antifibrinolytic treatment versus control treatment with or without placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Poor outcome (death, vegetative or severe disability on Glasgow Outcome Scale at end of follow-up): open versus blind studies41546Risk Ratio (M-H, Random, 95% CI)1.02 [0.91, 1.15]

    1.1 Trials with control treatment (open studies)
1505Risk Ratio (M-H, Random, 95% CI)0.85 [0.64, 1.14]

    1.2 Trials with placebo treatment (blind studies)
31041Risk Ratio (M-H, Random, 95% CI)1.06 [0.93, 1.21]

 2 Death from all causes at end of follow up: open versus blind studies101904Risk Ratio (M-H, Random, 95% CI)1.00 [0.85, 1.18]

    2.1 Trials with control treatment (open studies)
4709Risk Ratio (M-H, Random, 95% CI)0.89 [0.56, 1.42]

    2.2 Trials with placebo treatment (blind studies)
61195Risk Ratio (M-H, Random, 95% CI)1.02 [0.87, 1.19]

 3 Rebleeding reported at end of follow up: open versus blind studies101904Risk Ratio (M-H, Random, 95% CI)0.65 [0.44, 0.97]

    3.1 Trials with control treatment (open studies)
4709Risk Ratio (M-H, Random, 95% CI)0.66 [0.25, 1.74]

    3.2 Trials with placebo treatment (blind studies)
61195Risk Ratio (M-H, Random, 95% CI)0.64 [0.43, 0.97]

 4 Confirmed rebleeding at end of follow-up (sensitivity analysis): open versus blind studies41505Risk Ratio (M-H, Random, 95% CI)0.44 [0.26, 0.75]

    4.1 Trials with control treatment (open studies)
2564Risk Ratio (M-H, Random, 95% CI)0.42 [0.11, 1.59]

    4.2 Trials with placebo treatment (blind studies)
2941Risk Ratio (M-H, Random, 95% CI)0.46 [0.25, 0.86]

 5 Rebleeding reported at end of follow-up: trials with and without ischaemia prevention according to treatment duration101904Risk Ratio (M-H, Random, 95% CI)0.65 [0.44, 0.97]

    5.1 Trials without ischaemia prevention, treatment duration > 72 hours
8937Risk Ratio (M-H, Random, 95% CI)0.79 [0.47, 1.31]

    5.2 Trials with ischaemia prevention treatment duration > 72 hours
1462Risk Ratio (M-H, Random, 95% CI)0.58 [0.42, 0.80]

    5.3 Trials with ischaemia prevention, treatment duration < 72 hours
1505Risk Ratio (M-H, Random, 95% CI)0.22 [0.09, 0.52]

 6 Cerebral ischaemia reported at end of follow-up: open versus blind studies61671Risk Ratio (M-H, Random, 95% CI)1.41 [1.04, 1.91]

    6.1 Trials with control treatment (open studies)
3630Risk Ratio (M-H, Random, 95% CI)1.46 [0.99, 2.14]

    6.2 Trials with placebo treatment (blind studies)
31041Risk Ratio (M-H, Random, 95% CI)1.38 [0.87, 2.19]

 7 Confirmed cerebral ischaemia at end of follow-up (sensitivity analysis): open versus blind studies31000Risk Ratio (M-H, Random, 95% CI)1.34 [0.88, 2.03]

    7.1 Trials with control treatment (open studies)
159Risk Ratio (M-H, Random, 95% CI)2.58 [0.76, 8.77]

    7.2 Trials with placebo treatment (blind studies)
2941Risk Ratio (M-H, Random, 95% CI)1.24 [0.82, 1.89]

 8 Hydrocephalus reported at end of follow-up: open versus blind studies51179Risk Ratio (M-H, Random, 95% CI)1.11 [0.90, 1.36]

    8.1 Trials with control treatment (open studies)
2138Risk Ratio (M-H, Random, 95% CI)0.64 [0.34, 1.18]

    8.2 Trials with placebo treatment (blind studies)
31041Risk Ratio (M-H, Random, 95% CI)1.19 [0.95, 1.48]

 9 Confirmed hydrocephalus at end of follow up (sensitivity analysis): open versus blind studies1462Risk Ratio (M-H, Random, 95% CI)1.17 [0.87, 1.55]

   9.1 Trials with control treatment (open studies)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    9.2 Trials with placebo treatment (blind studies)
1462Risk Ratio (M-H, Random, 95% CI)1.17 [0.87, 1.55]

 10 Hydrocephalus reported at end of follow-up: trials with and without ischaemia prevention according to treatment duration51179Risk Ratio (M-H, Random, 95% CI)1.11 [0.90, 1.36]

    10.1 Trials without ischaemia prevention, treatment duration > 72 hours
4717Risk Ratio (M-H, Random, 95% CI)1.03 [0.74, 1.43]

    10.2 Trials with ischaemia prevention, treatment duration > 72 hours
1462Risk Ratio (M-H, Random, 95% CI)1.17 [0.87, 1.55]

   10.3 Trials with ischaemia prevention, treatment duration < 72 hours
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 11 Poor outcome (death, vegetative or severe disability on Glasgow Outcome Scale at end of follow-up): trials with and without ischaemia prevention according to treatment duration41546Risk Ratio (M-H, Random, 95% CI)1.02 [0.91, 1.15]

    11.1 Trials without cerebral ischaemia prevention, treatment duration > 72 hours
2579Risk Ratio (M-H, Random, 95% CI)1.03 [0.86, 1.22]

    11.2 Trials with ischaemia prevention, treatment duration > 72 hours
1462Risk Ratio (M-H, Random, 95% CI)1.10 [0.91, 1.34]

    11.3 Trials with cerebral ischaemia prevention, treatment duration < 72 hours
1505Risk Ratio (M-H, Random, 95% CI)0.85 [0.64, 1.14]

 12 Death from all causes at end of follow-up: trials with and without ischaemia prevention according to treatment duration101904Risk Ratio (M-H, Random, 95% CI)1.00 [0.85, 1.18]

    12.1 Trials without ischaemia prevention, treatment duration > 72 hours
8937Risk Ratio (M-H, Random, 95% CI)1.03 [0.78, 1.35]

    12.2 Trials with ischaemia prevention with treatment duration > 72 hours
1462Risk Ratio (M-H, Random, 95% CI)1.03 [0.79, 1.34]

    12.3 Trials with ischaemia prevention with treatment duration < 72 hours
1505Risk Ratio (M-H, Random, 95% CI)0.83 [0.52, 1.35]

 13 Cerebral ischaemia reported at end of follow-up: trials with and without ischaemia prevention according to treatment duration61671Risk Ratio (M-H, Random, 95% CI)1.41 [1.04, 1.91]

    13.1 Trials without ischaemia prevention, treatment duration > 72 hours
4704Risk Ratio (M-H, Random, 95% CI)1.77 [1.30, 2.40]

    13.2 Trials with ischaemia prevention, treatment duration > 72 hours
1462Risk Ratio (M-H, Random, 95% CI)0.96 [0.75, 1.23]

    13.3 Trials with ischaemia prevention, treatment duration < 72 hours
1505Risk Ratio (M-H, Random, 95% CI)1.35 [0.89, 2.04]

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Appendix 1. MEDLINE search strategy

1. Subarachnoid Hemorrhage/
2. intracranial hemorrhages/ or cerebral hemorrhage/
3. Intracranial Aneurysm/
4. Rupture, Spontaneous/
5. 3 and 4
6. Aneurysm, Ruptured/
7. exp brain/ or exp meninges/
8. 6 and 7
9. ((subarachnoid or arachnoid) adj6 (haemorrhage$ or hemorrhage$ or bleed$ or blood$)).tw.
10. Vasospasm, Intracranial/
11. ((cerebral or intracranial or cerebrovascular) adj6 (vasospasm or spasm)).tw.
12. sah.tw.
13. 1 or 2 or 5 or 8 or 9 or 10 or 11 or 12
14. exp Antifibrinolytic Agents/
15. (anti-fibrinolytic$ or antifibrinolytic$ or antifibrinolysin$ or anti-fibrinolysin$ or antiplasmin$ or anti-plasmin$ or (plasmin adj3 inhibitor$)).tw.
16. (fibrinolysis adj3 (prevent$ or inhib$ or antag$)).tw.
17. tranexamic acid/
18. (4 amino methylcyclohexane carboxylate or 4 aminomethylcyclohexanecarbonic acid or 4 aminomethylcyclohexanecarboxylic acid or amca or AMCHA or amchafibrin or amikapron or aminomethyl cyclohexane carboxylic acid or aminomethyl cyclohexanecarboxylic acid or aminomethylcyclohexane carbonic acid or aminomethylcyclohexane carboxylic acid or aminomethylcyclohexanecarbonic acid or aminomethylcyclohexanecarboxylic acid or aminomethylcyclohexanocarboxylic acid or aminomethylcyclohexanoic acid or amstat or anexan or antivoff or anvitoff orcaprilon or cis 4 aminomethylcyclohexanecarboxylic acid or cis aminomethyl cyclohexanecarboxylic acid or cl 65336 or cl65336 or cyclocapron or cyclokapron or cyklocapron or cyklokapron or exacyl or fibrinon or frenolyse or hemostan or hexacapron or hexakapron or kabi 2161 or kalnex or micranex or para aminomethylcyclohexane carboxylic acid or rikaparin or ronex or spotof or theranex or tramic or tranex or tranexam or tranexamic acid or tranexanic acid or tranexic or trans 1 aminomethylcyclohexane 4 carboxylic acid or trans 4 aminomethylcyclohexane 1 carboxylic acid or trans 4 aminomethylcyclohexane carboxylic acid or trans 4 aminomethylcyclohexanecarboxylic acid or trans achma or trans amcha or trans aminomethyl cyclohexane carboxylic acid or trans aminomethylcyclohexane carboxylic acid or trans aminomethylcyclohexanecarboxylic acid or transamin or transaminomethylcyclohexane carboxylic acid or transexamic acid or traxamic or trenaxin or ugurol).tw,nm.
19. exp Aminocaproic Acids/
20. (acikaprin or afibrin or amicar or amino caproic acid or aminocaproic acid or aminohexanoic acid or capracid or capramol or caproamin or caprocid or caprogel or caprolest or caprolisin or caprolisine or caprolysin orcapromol or cl 10304 or cl10304 or cy 116 or cy116 or e aminocaproic acid or EACA or ecapron or ekaprol or epsamon or epsicaprom or epsicapron or epsikapron or epsilcapramin or epsilon amino caproate or epsilon amino caproic aci or depsilon aminocaproate or epsilon aminocaproic acid or epsilonaminocaproic acid or epsilonaminocapronsav or etha aminocaproic acid or ethaaminocaproic acid or gamma aminocaproic acidor gamma aminohexanoic acidor hemocaprol or hepin or hexalense or ipsilon or jd 177 or jd177 or neocaprol or nsc 26154 or nsc26154 or resplamin or tachostyptan).tw,nm.
21. Aprotinin/
22. (9921 rp or antagosan or antilysin or antilysine or apronitin or apronitine or apronitrine or aprotimbin or aprotinin bovine or aprotinine or aprotonin or bayer a 128 or bayer a128 or bovine pancreatic secretory trypsin inhibitor or contrical or contrycal or contrykal or frey inhibitor or gordox or haemoprot or iniprol or kallikrein trypsin inhibitor or kazal type trypsin inhibitor or kontrikal or kontrycal or Kunitz inhibitor or Kunitz trypsin inhibitor or midran or pancreas antitrypsin or pancreas secretory trypsin inhibitor or pancreas trypsin inhibitor or pancreatic antitrypsin or pancreatic secretory trypsin inhibitor or pancreatic trypsin inhibitor or protinin orriker 52g or rivilina or rp 9921 or rp9921 or tracylol or trascolan or trasilol or traskolan or trasylol or trazylol or tumor associated trypsin inhibitor or zymofren).tw,nm.
23.( 4 aminomethylbenzoic acid or 4 amino methylbenzoic acid or alpha amino para toluic acid or amino methylbenzoic acid or aminomethyl benzoic acid or aminomethylbenzoic acid or PAMBA or para aminomethylbenzoic acid or para amino methylbenzoic acid or styptopur or styptosolut).tw,nm
24. Fibrinolysis/ai, de [Antagonists & Inhibitors, Drug Effects]
25. or/14-24
26. 13 and 25
27. exp animals/ not humans.sh.
28. 26 not 27

 

Appendix 2. EMBASE search strategy

1. Subarachnoid Hemorrhage/
2. brain hemorrhage/ or brain artery aneurysm rupture/
3. Brain Vasospasm/
4. exp Intracranial Aneurysm/
5. exp rupture/
6. 4 and 5
7. Aneurysm Rupture/
8. exp brain/ or exp meninx/
9. 7 and 8
10. ((subarachnoid or arachnoid) adj6 (haemorrhage$ or hemorrhage$ or bleed$ or blood$)).tw.
11. ((cerebral or intracranial or cerebrovascular) adj6 (vasospasm or spasm)).tw.
12. sah.tw.
13. 1 or 2 or 3 or 6 or 9 or 10 or 11 or 12
14. exp antifibrinolytic agent/
15. (anti-fibrinolytic$ or antifibrinolytic$ or antifibrinolysin$ or anti-fibrinolysin$ or antiplasmin$ or anti-plasmin$ or (plasmin adj3 inhibitor$)).tw.
16. (fibrinolysis adj3 (prevent$ or inhib$ or antag$)).tw.
17. tranexamic acid/
18. (4 amino methylcyclohexane carboxylate or 4 aminomethylcyclohexanecarbonic acid or 4 aminomethylcyclohexanecarboxylic acid or amca or AMCHA or amchafibrin or amikapron or aminomethyl cyclohexane carboxylic acid or aminomethyl cyclohexanecarboxylic acid or aminomethylcyclohexane carbonic acid or aminomethylcyclohexane carboxylic acid or aminomethylcyclohexanecarbonic acid or aminomethylcyclohexanecarboxylic acid or aminomethylcyclohexanocarboxylic acid or aminomethylcyclohexanoic acid or amstat or anexan or antivoff or anvitoff orcaprilon or cis 4 aminomethylcyclohexanecarboxylic acid or cis aminomethyl cyclohexanecarboxylic acid or cl 65336 or cl65336 or cyclocapron or cyclokapron or cyklocapron or cyklokapron or exacyl or fibrinon or frenolyse or hemostan or hexacapron or hexakapron or kabi 2161 or kalnex or micranex or para aminomethylcyclohexane carboxylic acid or rikaparin or ronex or spotof or theranex or tramic or tranex or tranexam or tranexamic acid or tranexanic acid or tranexic or trans 1 aminomethylcyclohexane 4 carboxylic acid or trans 4 aminomethylcyclohexane 1 carboxylic acid or trans 4 aminomethylcyclohexane carboxylic acid or trans 4 aminomethylcyclohexanecarboxylic acid or trans achma or trans amcha or trans aminomethyl cyclohexane carboxylic acid or trans aminomethylcyclohexane carboxylic acid or trans aminomethylcyclohexanecarboxylic acid or transamin or transaminomethylcyclohexane carboxylic acid or transexamic acid or traxamic or trenaxin or ugurol).tw.
19. aminocaproic acid/
20. (acikaprin or afibrin or amicar or amino caproic acid or aminocaproic acid or aminohexanoic acid or capracid or capramol or caproamin or caprocid or caprogel or caprolest or caprolisin or caprolisine or caprolysin orcapromol or cl 10304 or cl10304 or cy 116 or cy116 or e aminocaproic acid or EACA or ecapron or ekaprol or epsamon or epsicaprom or epsicapron or epsikapron or epsilcapramin or epsilon amino caproate or epsilon amino caproic aci or depsilon aminocaproate or epsilon aminocaproic acid or epsilonaminocaproic acid or epsilonaminocapronsav or etha aminocaproic acid or ethaaminocaproic acid or gamma aminocaproic acidor gamma aminohexanoic acidor hemocaprol or hepin or hexalense or ipsilon or jd 177 or jd177 or neocaprol or nsc 26154 or nsc26154 or resplamin or tachostyptan).tw.
21. aprotinin/
22. (9921 rp or antagosan or antilysin or antilysine or apronitin or apronitine or apronitrine or aprotimbin or aprotinin bovine or aprotinine or aprotonin or bayer a 128 or bayer a128 or bovine pancreatic secretory trypsin inhibitor or contrical or contrycal or contrykal or frey inhibitor or gordox or haemoprot or iniprol or kallikrein trypsin inhibitor or kazal type trypsin inhibitor or kontrikal or kontrycal or Kunitz inhibitor or Kunitz trypsin inhibitor or midran or pancreas antitrypsin or pancreas secretory trypsin inhibitor or pancreas trypsin inhibitor or pancreatic antitrypsin or pancreatic secretory trypsin inhibitor or pancreatic trypsin inhibitor or protinin orriker 52g or rivilina or rp 9921 or rp9921 or tracylol or trascolan or trasilol or traskolan or trasylol or trazylol or tumor associated trypsin inhibitor or zymofren).tw.
23. 4 aminomethylbenzoic acid/
24. (4 aminomethylbenzoic acid or 4 amino methylbenzoic acid or alpha amino para toluic acid or amino methylbenzoic acid or aminomethyl benzoic acid or aminomethylbenzoic acid or PAMBA or para aminomethylbenzoic acid or para amino methylbenzoic acid or styptopur or styptosolut).tw.
25. fibrinolysis/pc [Prevention]
26. or/14-25
27. 13 and 26
28. limit 27 to human

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Last assessed as up-to-date: 4 February 2013.


DateEventDescription

5 September 2013AmendedMinor layout changes



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Protocol first published: Issue 3, 1998
Review first published: Issue 3, 1998


DateEventDescription

4 February 2013New citation required and conclusions have changedA new subgroup analysis was added and the conclusions changed.

4 February 2013New search has been performedUpdated searches completed and a new study added. We included one new study (Hillman 2002) with 505 participants. This study is different in treatment timing and duration of therapy and contributes 26.5% of all participants. The review now includes 10 trials and 1904 participants in total.

21 July 2008AmendedConverted to new review format.

7 February 2003New search has been performedThe results of the recently published STAR-study, the second largest placebo-controlled randomised trial of antifibrinolytic treatment in subarachnoid haemorrhage, has been added to the review. This study contributes 33% of all included patients in this review and 39% of the patients included in the comparison of antifibrinolytic treatment versus placebo. Furthermore, a Plain language summary of the review has been added.



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Irem Baharoglu: co-ordinated the updated review; collected data; undertook all aspects of the searches; was responsible for data management and entering data into RevMan; analysis of the data; and writing the updated review.

Menno Germans: participated in data collection; reviewed all data and participated in writing this update.

Yvo Roos: co-ordinated and wrote previous versions of this review and oversaw the data collection and writing of the present update.

Gabriel Rinkel: participated in writing the current and previous versions of the review as well as securing funding.

Ale Algra: participated in writing the current and previous versions of the review and has also performed previous work which was the foundation of the current review.

Marinus Vermeulen: secured funding and participated in writing previous versions of the review and has also performed previous work which was the foundation of the current review.

Van Gijn: participated in writing previous versions of the review; and has also performed previous work which was the foundation of the current review.

All the authors participated in conceiving and designing the review; developing the search strategy; interpreting the data; providing methodological, clinical policy and consumer perspectives; and providing general advice on the review.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Some authors (YBWEMR, GJER, MV) participated in one of the two largest trials included in this review (Roos 2000a; Vermeulen 1984), which were co-ordinated by two of the current review authors. MRG has written a protocol for a new trial (Verbaan 2012). None of the review authors have any financial or other commercial conflict of interest to disclose.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Internal sources

  • No sources of support supplied

 

External sources

  • Nederlandse Hartstichting (Netherlands Heart Foundation), Netherlands.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Chandra 1978 {published data only}
Fodstad 1981 {published data only}
  • Fodstad H, Forssell A, Liliequist B, Schannong M. Antifibrinolysis with tranexamic acid in aneurysmal subarachnoid hemorrhage: a consecutive controlled clinical trial. Neurosurgery 1981;8:158-65. [MEDLINE: 1981149180]
Girvin 1973 {published and unpublished data}
  • Girvin JP. The use of antifibrinolytic agents in the preoperative treatment of ruptured intracranial aneurysms. Transactions of the American Neurological Association 1973;98:150-2. [MEDLINE: 1974127393]
Hillman 2002 {published data only}
  • Hillman J, Fridriksson S, Nillson O, Yu Z, Saveland H, Jakobsson KE. Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study. Journal of Neurosurgery 2002;97:771-8. [MEDLINE: 12405362]
Kaste 1979 {published data only}
  • Kaste M, Ramsay M. Tranexamic acid in subarachnoid hemorrhage. A double-blind study. Stroke 1979;10:519-22. [MEDLINE: 1980059548]
Maurice 1978 {published data only}
  • Maurice-Williams RS. Prolonged antifibrinolysis: an effective non-surgical treatment for ruptured intracranial aneurysms?. British Medical Journal 1978;1:945-7. [MEDLINE: 1978145585]
Roos 2000a {published and unpublished data}
  • Roos Y, for the STAR-study group. Antifibrinolytic treatment in aneurysmal subarachnoid haemorrhage: a randomized placebo-controlled trial. Neurology 2000;54:77-82. [MEDLINE: 10636129]
Tsementzis 1990 {published data only}
Van Rossum 1977 {published data only}
  • Van Rossum J, Wintzen AR, Endtz LJ, Schoen JH, de Jonge H. Effect of tranexamic acid on rebleeding after subarachnoid hemorrhage: a double-blind controlled clinical trial. Annals of Neurology 1977;2:238-42. [MEDLINE: 1979081173]
Vermeulen 1984 {published data only}

References to studies excluded from this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Adams 1981 {published data only}
  • Adams HP Jr, Nibbelink DW, Torner JC, Sahs AL. Antifibrinolytic therapy in patients with aneurysmal subarachnoid hemorrhage. A report of the cooperative aneurysm study. Archives of Neurology 1981;38:25-9. [MEDLINE: 1981109034]
Ameen 1981 {published data only}
  • Ameen AA, Illingworth R. Anti-fibrinolytic treatment in the pre-operative management of subarachnoid haemorrhage caused by ruptured intracranial aneurysm. Journal of Neurology, Neurosurgery and Psychiatry 1981;44:220-6. [MEDLINE: 1981193689]
Brzecki 1974 {published data only}
  • Brzecki A, Misztal S. Results of Trasylol treatment of subarachnoid hemorrhage [Wyniki leczenia Trasylolem krwotoku podpajeczynowkowego]. Polski Tygodnik Lekarski 1974;29(2):53-5. [MEDLINE: 4595123]
Buchner 1985 {published data only}
  • Buchner H, Hacke W, Kugel I, Zeumer H, Ferbert A. Antifibrinolytic therapy following an aneurysmal subarachnoid hemorrhage [Antifibrinolytika in der konservativen Therapie der aneurysmatischen Subarachnoidalblutung]. Intensivmed 1985;22:424-7.
Chowdhary 1979 {published data only}
  • Chowdhary UM, Carey PC, Hussein MM. Prevention of early recurrence of spontaneous subarachnoid haemorrhage by epsilon-aminocaproic acid. Lancet 1979;1:741-3. [MEDLINE: 1979155678]
Chowdhary 1981 {published data only}
  • Chowdhary UM, Sayed K. Comparative clinical trial of epsilon amino-caproic acid and tranexamic acid in the prevention of early recurrence of subarachnoid haemorrhage. Journal of Neurology, Neurosurgery and Psychiatry 1981;44:810-3. [MEDLINE: 1982077145]
Chowdhary 1986 {published data only}
  • Chowdhary UM, Sayed K. Prevention of early recurrence of aneurysmal subarachnoid haemorrhage by tranexamic acid: a controlled clinical trial. Vascular Surgery 1986;1:8-13. [EMBASE: 1986195828]
Fodstad 1978 {published data only}
Gelmers 1980 {published data only}
Gibbs 1971 {published data only}
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Kassell 1984 {published data only}
  • Kassell NF, Torner JC, Adams HP. Antifibrinolytic therapy in the acute period following aneurysmal subarachnoid hemorrhage. Preliminary observations from the Cooperative Aneurysm Study. Journal of Neurosurgery 1984;61:225-30. [MEDLINE: 6737046]
Knuckey 1982 {published data only}
Marchel 1992 {published data only}
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Nibbelink 1975 {published data only}
  • Nibbelink DW, Torner JC, Henderson WG. Intracranial aneurysms and subarachnoid hemorrhage. A cooperative study. Antifibrinolytic therapy in recent onset subarachnoid hemorrhage. Stroke 1975;6:622-9. [MEDLINE: 1976082089]
Profeta 1975 {published data only}
  • Profeta G, Castellano F, Guarnieri L, Cigliano A, Amborsio A. Antifibrinolytic therapy in the treatment of subarachnoid haemorrhage caused by arterial aneurysms. Journal of Neurosurgical Sciences 1975;19:77-8. [MEDLINE: 1976145501]
Rosenorn 1988 {published data only}
  • Rosenorn J, Eskesen V, Espersen JO, Haase J, Schmidt K. Antifibrinolytic therapy in patients with aneurysmal subarachnoid haemorrhage. British Journal of Neurosugery 1988;2:447-53. [MEDLINE: 3267328]
Salaschek 1983 {published data only}
  • Salaschek M, Weinrich W. Epsilon aminocaproic acid (FACA) in the treatment of spontaneous subarachnoid haemorrhage [Antifibrinolytische behandlung spontaner subarachnoidalblutungen mit epsilon-aminocapronaure]. Aktuelle Neurologie 1983;10:65-8. [EMBASE: 1983183434]
Sengupta 1976 {published data only}
Shucart 1980 {published data only}
Starke 2008 {published data only}
Wijdicks 1989 {published data only}
  • Wijdicks EF, Hasan D, Lindsay KW, Brouwers PJ, Hatfield R, Murray GD, et al. Short-term tranexamic acid treatment in aneurysmal subarachnoid hemorrhage. Stroke 1989;20:1674-9. [MEDLINE: 2595729]

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Adams 1982
  • Adams HP. Current status of antifibrinolytic therapy for treatment of patients with aneurysmal subarachnoid hemorrhage. Stroke 1982;13:256-9. [MEDLINE: 7039006]
Adams 1987
  • Adams HP. Antifibrinolytics in aneurysmal subarachnoid hemorrhage. Do they have a role? Maybe. Archives of Neurology 1987;44:114-5. [MEDLINE: 3800711]
Biller 1988
  • Biller J, Godersky JC, Adams HP. Management of aneurysmal subarachnoid hemorrhage. Stroke 1988;19:1300-5. [MEDLINE: 3176090]
Carley 2005
Chawjol 2008
Connolly 2012
  • Connolly ES, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2012;43:1711-37. [MEDLINE: 22556195]
Fodstad 1982
Gaberel 2012
  • Gaberel T, Magheru C, Emery E, Derlon J. Antifibrinolytic therapy in the management of aneurismal subarachnoid hemorrhage revisited. A meta-analysis. Acta Neurochirurgica 2012;154:1-9. [MEDLINE: 22002504]
Gibbs 1967
  • Gibbs JR, O'Gorman P. Fibrinolysis in subarachnoid haemorrhage. Postgraduate Medical Journal 1967;43(506):779-84. [MEDLINE: 1968120575]
Guo 2011
Harrigan 2010
  • Harrigan MR, Rajneesh KF, Ardelt AA, Fisher WS. Short-term antifibrinolytic therapy before early aneurysm treatment in subarachnoid hemorrhage: effects on rehemorrhage, cerebral ischemia, and hydrocephalus. Neurosurgery 2010;67:935-9. [MEDLINE: 20881558]
Higgins 2011
  • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Lindsay 1987
Locksley 1966
Maira 2006
Mayberg 1994
  • Mayberg MR, Batjer HH, Dacey R, Diringer M, Haley EC, Heros RC, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage. A statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Circulation 1994;90:2592-605. [MEDLINE: 7955232]
Naidech 2005
  • Naidech AM, Janjua N, Kreiter KT, Ostapkovich ND, Fitzsimmons BF, Parra A, et al. Predictors and impact of aneurysm rebleeding after subarachnoid hemorrhage. Archives of Neurology 2005;62:410-6.
Ramirez 1981
  • Ramirez-Lassepas M. Antifibrinolytic therapy in subarachnoid hemorrhage caused by ruptured intracranial aneurysm. Neurology 1981;31:316-22. [MEDLINE: 1981149246]
RevMan 2012
  • The NordicCochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.2. Copenhagen: The NordicCochrane Centre, The Cochrane Collaboration, 2012.
Rinkel 2008
Roos 2000b
  • Roos YB, de Haan RJ, Beenen LF, Groen RJ, Albrecht KW, Vermeulen M. Complications and outcome in patients with aneurysmal subarachnoid haemorrhage: a prospective hospital based cohort study in the Netherlands. Journal of Neurology, Neurosurgery and Psychiatry 2000;68:337-41. [MEDLINE: 10675216]
Van Gijn 2001
Van Gijn 2007
Vermeulen 1980
Vermeulen 1983
  • Vermeulen M, van Gijn J, Blijenberg BG. Spectrophotometric analysis of CSF after subarachnoid hemorrhage: limitations in the diagnosis of rebleeding. Neurology 1983;33:112-4. [MEDLINE: 1983089354]
Vermeulen 1996
Weaver 1994
Weir 1987
  • Weir B. Antifibrinolytics in subarachnoid hemorrhage. Do they have a role? No. Archives of Neurology 1987;44:116-8. [MEDLINE: 3800712]

References to other published versions of this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Roos 1998
  • Roos YB, Vermeulen M, Rinkel GJ, Algra A, Van Gijn J, Algra A. Systematic review of antifibrinolytic treatment in aneurysmal subarachnoid haemorrhage. Journal of Neurology, Neurosurgery and Psychiatry 1998;65:942-3. [MEDLINE: 9854979]
Roos 2003
  • Roos YB, RinkelGJE, VermeulenM, Algra A, vanGijn J. Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage. Cochrane Database of Systematic Reviews 2003, Issue 2. [DOI: 10.1002/14651858.CD001245]