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Antifibrinolytic drugs for acute traumatic injury

  1. Ian Roberts1,*,
  2. Haleema Shakur2,
  3. Katharine Ker1,
  4. Tim Coats3,
  5. on behalf of the CRASH-2 Trial collaborators2

Editorial Group: Cochrane Injuries Group

Published Online: 12 DEC 2012

Assessed as up-to-date: 14 JUL 2010

DOI: 10.1002/14651858.CD004896.pub3


How to Cite

Roberts I, Shakur H, Ker K, Coats T, on behalf of the CRASH-2 Trial collaborators. Antifibrinolytic drugs for acute traumatic injury. Cochrane Database of Systematic Reviews 2012, Issue 12. Art. No.: CD004896. DOI: 10.1002/14651858.CD004896.pub3.

Author Information

  1. 1

    London School of Hygiene & Tropical Medicine, Cochrane Injuries Group, London, UK

  2. 2

    London School of Hygiene & Tropical Medicine, Clinical Trials Unit, London, UK

  3. 3

    Leicester Royal Infirmary, Department of Emergency Medicine, Leicester, UK

*Ian Roberts, Cochrane Injuries Group, London School of Hygiene & Tropical Medicine, North Courtyard, Keppel Street, London, WC1E 7HT, UK. Ian.Roberts@Lshtm.ac.uk.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 12 DEC 2012

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. Differences between protocol and review
  17. Index terms
 

Description of the condition

For people aged five to 45 years, trauma is second only to HIV/AIDS as a cause of death. Each year, worldwide, about three million people die as a result of trauma (Murray 1996), many after reaching hospital. Among trauma patients who do survive to reach hospital, exsanguination is a common cause of death, accounting for nearly half of in-hospital trauma deaths in some settings (Sauaia 1995). Central nervous system injury and multi-organ failure account for most of the remainder, both of which can be exacerbated by severe bleeding (BTF 2000).

Clotting helps to maintain the integrity of the circulatory system after vascular injury, whether traumatic or surgical in origin (Lawson 2004). Major surgery and trauma trigger similar haemostatic responses and the consequent massive blood loss presents an extreme challenge to the coagulation system. Part of the response to surgery and trauma in any patient, is stimulation of clot breakdown (fibrinolysis) which may become pathological (hyper-fibrinolysis) in some cases. Antifibrinolytic agents have been shown to reduce blood loss in patients with both normal and exaggerated fibrinolytic responses to surgery, without apparently increasing the risk of post-operative complications.

 

Description of the intervention

Antifibrinolytic agents are widely used in major surgery to prevent fibrinolysis and reduce surgical blood loss. A recent systematic review (Henry 2011) of randomised controlled trials of antifibrinolytics (mainly aprotinin or tranexamic acid [TXA]) in elective surgical patients showed that antifibrinolytics reduced the numbers needing transfusion by one third, reduced the volume needed per transfusion by one unit, and halved the need for further surgery to control bleeding. These differences were all statistically significant at the P<0.01 level. Specifically, aprotinin reduced the rate of blood transfusion by 34% (relative risk [RR]=0.66; 95% confidence interval [CI] 0.60 to 0.72) and TXA by 39% (RR=0.61; 95% CI 0.53 to 0.70). Aprotinin use saved 1.02 units of red blood cells (RBCs) (95% CI 0.79 to 1.26) in those requiring transfusion, and TXA use saved 0.87 units (95% CI 0.53 to 1.20). There was a non-significant reduction in mortality with both aprotinin (RR=0.81; 95% CI 0.63 to 1.06) and TXA (RR=0.60; 95% CI 0.33 to 1.10).

 

How the intervention might work

Because the coagulation abnormalities that occur after injury are similar to those after surgery, it is possible that antifibrinolytic agents might also reduce blood loss and mortality following trauma. A simple and widely practicable intervention that reduced blood loss following trauma might prevent tens of thousands of premature deaths. A reduction in the need for transfusion would also have important public health implications. Blood is a scarce and expensive resource and major concerns remain about the risk of transfusion-transmitted infection. Trauma is particularly common in parts of the world where the safety of blood transfusion cannot be assured. A recent study in Uganda estimated the population-attributable fraction of HIV acquisition as a result of blood transfusion to be around two percent (Kiwanuka 2004) although some estimates are much higher (Heymann 1992).

 

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. Differences between protocol and review
  17. Index terms

To quantify the effect of antifibrinolytic drugs on mortality, vascular occlusive events, surgical intervention and receipt of blood transfusion after acute traumatic injury.

 

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. Differences between protocol and review
  17. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomised controlled trials (RCT), as per the following definition.

RCT: A study involving at least one intervention and one control treatment, concurrent enrolment and follow-up of the intervention and control groups, and in which the interventions to be tested are selected by a random process, such as the use of a random numbers table (coin flips are also acceptable). If the study author(s) state explicitly (usually by using some variant of the term 'random' to describe the allocation procedure used) that the groups compared in the trial were established by random allocation, then the trial is classified as an 'RCT'.

 

Types of participants

People of any age following acute traumatic injury.

 

Types of interventions

The interventions considered are the antifibrinolytic agents: aprotinin, tranexamic acid (TXA) and epsilon-aminocaproic acid (EACA).

 

Types of outcome measures

 

Primary outcomes

  • Mortality at the end of the follow up.

 

Secondary outcomes

  • Number of patients experiencing an adverse event, specifically vascular occlusive events (myocardial infarction, stroke, deep vein thrombosis or pulmonary embolism).
  • Number of patients undergoing surgical intervention.
  • Number of patients receiving blood transfusion.
  • Volume of blood transfused (units).

 

Search methods for identification of studies

Searches were not restricted by date, language or publication status.

 

Electronic searches

We searched the following electronic databases:

  • Cochrane Injuries Group's Specialised Register (searched July 2010)
  • Cochrane Central Register of Controlled Trials Issue 3, 2010 (The Cochrane Library)
  • MEDLINE (1966 to July week 2, 2010)
  • PubMed (searched March 17, 2004)
  • EMBASE (1980 to week 28, July 2010)
  • Science Citation Index (searched March 17, 2004)
  • National Research Register (issue 1, 2004)
  • Zetoc (searched March 17, 2004)
  • SIGLE (searched March 17, 2004)
  • Global Health (searched March 17, 2004)
  • LILACS (searched March 17, 2004)
  • Current Controlled Trials (searched March 17, 2004)

The search strategies used in the latest update are listed in full in Appendix 1.

 

Searching other resources

All references in the identified trials and background papers were checked and study authors contacted to identify relevant published and unpublished data. Pharmaceutical companies were contacted in 2004 to obtain information on ongoing trials.

 

Data collection and analysis

 

Selection of studies

The titles and abstracts identified in the electronic searches were screened by two independent authors to identify studies that had the potential to meet the inclusion criteria. The full reports of all such studies were obtained. From the results of the screened electronic searches, bibliographic searches and contacts with experts, two authors independently selected trials meeting the inclusion criteria. There were no disagreements on study inclusion.

 

Data extraction and management

Two authors independently extracted information on the following: number of randomised participants, types of participants and types of interventions. The outcome data sought were: numbers of deaths in each group, numbers with vascular occlusive events, numbers requiring surgical intervention, and the amount of blood transfused. Information on loss to follow-up, blinding, and whether an intention-to-treat analysis was performed was also extracted. The authors were not blinded to the authors or journal when doing this. Results were compared and differences would have been resolved by discussion had there been any. Where there was insufficient information in the published report, we attempted to contact the authors for clarification.

 

Assessment of risk of bias in included studies

Two authors assessed the risk of bias for allocation concealment. Each trial was assessed as being at high, low or unclear risk of bias according to the criteria presented in Higgins 2008.

 

Assessment of heterogeneity

The presence of heterogeneity of the observed treatment effects were assessed using the I2 statistic, which describes the percentage of total variation across studies due to heterogeneity rather than chance. A value of 0% indicates no observed heterogeneity, and larger values show increasing heterogeneity; substantial heterogeneity is considered to exist when I2 >50% (Higgins 2008). The following were specified a-priori as factors that could explain any observed heterogeneity: adequacy of allocation concealment; injury severity based on the injury severity score (an ISS of greater than or equal to 16 defines the severely injured strata); and according to whether the study population included predominantly blunt or penetrating trauma.

 

Assessment of reporting biases

We planned to investigate the presence of reporting (publication) bias using funnel plots, however there were too few included studies to enable meaningful analysis.

 

Data synthesis

Risk ratios (RR) and 95% confidence intervals (95% CI) were calculated. The risk ratio was chosen because it is more readily applied to the clinical situation. For transfusion volumes, the mean difference (MD) in the units of blood transfused were calculated with 95% CI.

 

Subgroup analysis and investigation of heterogeneity

We planned to conduct subgroup analyses to explore whether effect sizes vary according to the type of antifibrinolytic agent and the dosing regimen. However there were too few trials for such analyses.

 

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. Differences between protocol and review
  17. Index terms
 

Description of studies

Searches conducted in April 2004 identified a total of 819 records. These were screened by two authors and the full texts of nine potentially eligible reports were obtained for closer examination. Of the nine potentially eligible reports, two trials met the inclusion criteria. Two further trials were identified in an updated search conducted in July 2010. In summary, four randomised controlled trials including 20,548 randomised patients have been identified as meeting the inclusion criteria and are included in this review.

 

Tranexamic acid

Two trials compared TXA with placebo in trauma patients. The CRASH-2 2010 recruited 20,211 trauma patients with, or at risk of, significant haemorrhage. A trial in Thailand (Yutthakasemsunt 2010) recruited 240 trauma patients with moderate to severe traumatic brain injury. As of November 2012, the Thai trial Yutthakasemsunt 2010 was only available as an abstract with publication of the full trial report pending. The trial has been included based on the data reported in the abstract. The full trial data will be incorporated into this systematic review once the full trial report is available.

 

Aprotinin

Two trials compared the effects of aprotinin with placebo in trauma patients. One trial (Auer 1979) involved 20 patients with severe head injury, and one (McMichan 1982) involved 77 patients with a combination of hypovolaemic shock and major fractures of either the lower limb, pelvis or both.

See 'Characteristics of included studies' for further details.

 

Risk of bias in included studies

The CRASH-2 2010 trial was judged to be at low risk of bias. It was a large randomised controlled trial involving 20,211 adult trauma patients who were randomly allocated to receive TXA or placebo. TXA and placebo were packaged in identical ampoules. Hospitals with reliable telephone access used a telephone randomisation service, hospitals without used a local pack system; allocation concealment was adequate. Participants and trial staff were blinded to treatment allocation. Over 99% of patients were followed up.

There was insufficient information presented in the abstract to assess the risk of bias of the trial by Yutthakasemsunt 2010.

The trial by Auer 1979 was described as double blind. The adequacy of allocation concealment was unclear. However, after randomly allocating the first 20 patients, five patients were added to the aprotinin group. Because it was not possible to separate the outcome data for the 20 randomised and the five non-randomised patients, this study provided no useable outcome data.

In the randomised controlled trial by McMichan 1982 the aprotinin and placebo were prepared in "similar ampoules". All ampoules were in boxes of 50, with a code number assigned to each box. The nature of the content of the ampoules was not known to any of the investigators nor to the attending physicians. The codes were not broken until the end of the study. There were seven post-randomisation exclusions from the study in which there were three deaths. These three deaths were excluded because they occurred within the first 24 hours (it is not clear whether or not this was specified in the study protocol). Three patients refused the trial investigations, and one patient was transferred to another hospital for specialist treatment of quadriplegia and later died.

 

Effects of interventions

 

Tranexamic acid versus placebo

 

Mortality

Both the CRASH-2 2010 trial and the trial by Yutthakasemsunt 2010 reported mortality data.

All-cause mortality was significantly reduced with tranexamic acid (pooled risk ratio (RR) 0.90, 95% CI 0.85 to 0.97; P=0.003:  Analysis 1.1). There was no evidence of statistical heterogeneity (Chi²=0.77, df=1 (P=0.38); I²=0%).

The CRASH-2 2010 also presented mortality data by cause. The risk of death due to bleeding and myocardial infarction were significantly reduced with TXA. There were no statistically significant differences in the risk of death from other causes:

  • Bleeding: RR 0.85, 95% CI 0.76 to 0.96; P=0.0077
  • Myocardial infarction: RR 0.32, 95% CI 0.14 to 0.75; P=0.0053
  • Vascular occlusion: RR 0.69, 95% CI 0.44 to 1.07; P=0.096
  • Stroke: RR 1.60, 95% CI 0.52 to 4.89; P=0.40
  • Pulmonary embolism: RR 0.86, 95% CI 0.46 to 1.61; P=0.63
  • Multi-organ failure: RR 0.90, 95% CI 0.75 to 1.08; P=0.25
  • Head injury: RR 0.97, 95% CI 0.87 to 1.08; P=0.60
  • 'Other’ causes: RR 0.94, 95% CI 0.74 to 1.20; P=0.63

Although not prespecified subgroup analyses of this review, the effects of TXA on death due to bleeding by time to treatment, severity of haemorrhage, Glasgow coma score, and type of injury were assessed in the CRASH-2 trial (CRASH-2 2011). The results are presented below.

Analysis of the risk of death due to bleeding indicated that the effect of TXA varied by time to treatment. Treatment within one hour of injury was associated with a 32% relative reduction in risk of death due to bleeding (RR 0.68, 95% CI 0.57 to 0.82; P<0.0001) and treatment between 1 and 3 hours after injury was associated with a 21% reduction (RR 0.79, 95% CI 0.64 to 0.97; P=0.03). Treatment with TXA after three hours of injury was associated with a 44% relative increase in risk of death due to bleeding (RR 1.44, 95% CI 1.12 to 1.84; P=0.004). Test for subgroup differences: Chi²=23.51, P<0.00001.

There was no evidence that the effect of TXA on death due to bleeding varied by the severity of haemorrhage, Glasgow coma score, or type of injury:

  • Severity of haemorrhage (as assessed by systolic blood pressure): >89 mm Hg (RR 0.88, 95% CI 0.71 to 1.10); 76-89 (RR 1.01, 95% CI 0.79 to 1.30); ≤75 (RR 0.81, 95% CI 0.69 to 0.95). Test for subgroup differences: Chi²=2.24, P=0.33.
  • Glasgow coma score: severe (RR 0.92, 95% CI 0.76 to 1.13); moderate (RR 0.77, 95% CI 0.59 to 0.99); mild (RR 0.86, 95% CI 0.72 to 1.02). Test for subgroup differences: Chi²=1.28, P=0.53.
  • Type of injury: blunt (RR 0.89, 95% CI 0.77 to 1.04); penetrating (RR 0.79, 95% CI 0.66 to 0.96). Test for subgroup differences: Chi²=0.92, P=0.34.

 

Vascular occlusive events

The CRASH-2 2010 trial reported data on vascular occlusive events. There was no difference in the risk of experiencing one or more vascular occlusive events (fatal or non-fatal; myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis) between the TXA and placebo groups (RR 0.84, 95% CI 0.68 to 1.02; P=0·084). TXA reduced the risk of myocardial infarction (RR 0.64, 95% CI 0.42 to 0.97; P=0.035). There was no difference in the risk of stroke (RR 0.86, 95% CI 0.61 to 1.23; P=0.42), pulmonary embolism (RR 1.01, 95% CI 0.73 to 1.41; P=0.93) or deep vein thrombosis (RR 0.98, 95% CI 0.63 to 1.51; P=0.91).

 

Surgical intervention

Data from the CRASH-2 2010 trial suggest that there is no statistically significant difference in the risk of receiving one or more surgical interventions (neurosurgery, chest, abdominal or pelvic surgery) (RR 1.00, 95% CI 0.97 to 1.03; P=0.79)  Analysis 1.2.

 

Receipt of blood transfusion

Of the patients allocated to TXA in the CRASH-2 2010 trial, 5067 (50.4%) received a blood product transfusion versus 5160 (51.3%) of the patients allocated to placebo (RR 0.98, 95% CI 0.96 to 1.01; P=0.21)  Analysis 1.3. There was no difference in the average number of blood units transfused (MD -0.17; 95% CI -0.39 to 0.05; P=0.13)  Analysis 1.4.

 

Aprotinin versus placebo

The study by Auer 1979, with 20 randomised patients, provided no useable outcome data for the reasons outlined above. The study by McMichan 1982, with 77 randomised patients (seven post-randomisation exclusions), was reported in four separate reports (Rosengarten 1977; Rosengarten 1979 and McMichan 1977 in 'included studies' reference McMichan 1982).

 

Mortality

McMichan 1982 reported mortality data; there was no difference in the risk of death between the aprotinin or placebo groups (RR 0.14, 95% CI 0.01 to 2.67; P=0.19)  Analysis 2.1.

 

Vascular occlusive events

Data on vascular occlusive events were not reported.

 

Surgical intervention

McMichan 1982 reported data on the number of patients undergoing a surgical intervention; there was no difference between the aprotinin or placebo groups (RR 1.07, 95% CI 0.87 to 1.33; P=0.53)  Analysis 2.2.

 

Receipt of blood transfusion

Data on the number of patients receiving a blood transfusion were not reported. The volume of blood transfused was reported, there was no difference between groups (MD -0.40 units; 95% CI -0.91, 0.11; P=0.12)  Analysis 2.3.

 

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. Differences between protocol and review
  17. Index terms
 

Summary of main results

Tranexamic acid reduces all-cause mortality in bleeding trauma patients, with no apparent increase in the risk of vascular occlusive events. This conclusion is based on the results of the CRASH-2 2010 trial which recruited 20,211 bleeding trauma patients from 274 hospitals in 40 countries.

 

Overall completeness and applicability of evidence

The large numbers of patients in a wide range of different health care settings around the world studied in the CRASH-2 2010 trial help the result to be widely generalised. The treatment is effective in patients with blunt and penetrating trauma. Because TXA is inexpensive and easy to administer, it could readily be added to the normal medical and surgical management of bleeding trauma patients in hospitals around the world.

Each year, worldwide, about four million people die as a result of traumatic injuries and violence.  Approximately 1.6 million of these deaths occur in hospital and about one third of these deaths (480,000) are from haemorrhage. The CRASH-2 2010 trial has shown that TXA reduces mortality from haemorrhage by about one sixth. If this widely practicable intervention was used worldwide in the treatment of bleeding trauma patients, it could prevent over 70,000 deaths each year (see  Table 1).

Many trauma patients suffer a brain injury. Traumatic brain injury (TBI) is commonly accompanied by intracranial bleeding which can develop or worsen after hospital admission. Traumatic intracranial haemorrhage is associated with an increased risk of death and disability, and regardless of location, haemorrhage size is strongly correlated with outcome. If TXA reduced intracranial bleeding after isolated TBI then this could improve patient outcomes. Although, many of the bleeding trauma patients included in the CRASH-2 2010 trial also suffered a brain injury, it is possible that the effects of TXA may differ in patients with isolated TBI. The trial by Yutthakasemsunt 2010 provides some promising evidence for the beneficial effect of TXA on mortality in patients with isolated TBI; however, further evidence is required from larger trials which also assess the effect on disability.   

There is no evidence for the effect of aprotinin for trauma. 

 

Quality of the evidence

The quality of the evidence supporting the use of tranexamic acid for trauma is high. The findings of this review are based primarily on the results of the CRASH-2 2010 trial. This was a large, high quality randomised trial with low risk of bias. Sequence generation was appropriately randomised, allocation was concealed and participants, trial personnel and outcome assessors were all blinded. Furthermore, there were minimal missing data with over 99% of patients followed up. 

 

Potential biases in the review process

This systematic review addresses a focused research question and uses pre-defined inclusion criteria and methodology to select and appraise eligible trials.

As with all systematic reviews, the possibility of publication bias should be considered as a potential threat to validity. However, in light of our extensive and sensitive searching we believe that the risk of such a bias affecting the results is minimal.

 

Agreements and disagreements with other studies or reviews

A systematic review of randomised trials assessing the effects of TXA in patients undergoing elective surgery has been conducted (Henry 2011). This review found that compared to control, TXA reduced the need for blood transfusion without any apparent increase in the risk of adverse events. Unlike the Henry 2011 review, we found no evidence of any substantial reduction in the receipt of a blood transfusion or the amount of blood transfused in trauma patients. One possible explanation is that in the CRASH-2 2010 trial, following the loading dose, TXA was infused over a period of eight hours, whereas decisions about transfusion are made very soon after hospital admission. The absence of any large effect on blood transfusion may also reflect the difficulty of accurately estimating blood loss in trauma patients when assessing the need for transfusion. Finally, the absence of any substantial reduction in transfusion requirements in patients treated with TXA acid may reflect the fact that there were fewer deaths in patients allocated to TXA acid than to placebo and patients who survive as a result of TXA administration would have had a greater opportunity to receive a blood transfusion (competing risks).

 

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. Differences between protocol and review
  17. Index terms

 

Implications for practice

Tranexamic acid (TXA) safely reduces mortality in bleeding trauma patients. As there is evidence that the effect on death due to bleeding depends on the time interval between the injury and treatment, TXA should be given as early as possible and within three hours of the injury as treatment later than this is unlikely to be effective.

 
Implications for research

The knowledge that TXA safely reduces the risk of death from traumatic bleeding raises the possibility that it might also be effective in other situations where bleeding can be life threatening or disabling and further research is warranted to explore this potential. Randomised trials involving patients with isolated traumatic brain injury that assess both mortality and disability outcomes are required before TXA can be recommended for use in these patients. The ongoing CRASH-3 trial with a planned sample size of 10,000 patients with traumatic brain injury, will contribute to resolving the uncertainty about the effects of TXA in this group.

 

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. Differences between protocol and review
  17. Index terms

Many thanks to Vasiliy Vlassov for help with translation.

We also thank Karen Blackhall for designing and conducting the electronic searches.

 

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. Differences between protocol and review
  17. Index terms
Download statistical data

 
Comparison 1. Tranexamic acid versus placebo

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

 1 All-cause mortality220367Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.85, 0.97]

 2 Proportion undergoing surgical intervention1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 3 Proportion receiving blood transfusion1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 4 Volume of blood transfused1Mean Difference (IV, Fixed, 95% CI)Subtotals only

 
Comparison 2. Aprotinin versus placebo

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

 1 Death1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 2 Proportion undergoing surgical intervention1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 3 Volume of blood transfused1Mean Difference (IV, Fixed, 95% CI)Subtotals only

 

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. Differences between protocol and review
  17. Index terms
 

Appendix 1. Search strategy

Cochrane Injuries Group Specialised Register (searched July 2010)

(Aprotinin* or kallikrein-trypsin inactivator* or bovine kunitz pancreatic trypsin inhibitor* or bovine pancreatic trypsin inhibitor* or basic pancreatic trypsin inhibitor* or BPTI or contrykal or kontrykal or kontrikal or contrical or dilmintal or iniprol or zymofren or traskolan or antilysin or pulmin or amicar or caprocid or epsamon or epsikapron or antilysin or iniprol or kontrikal or kontrykal or pulmin* or Trasylol or Antilysin Spofa or rp?9921 or antagosan or antilysin or antilysine or apronitin* or apronitrine or bayer a?128 or bovine pancreatic secretory trypsin inhibitor* or contrycal or frey inhibitor* or gordox or kallikrein trypsin inhibitor* or kazal type trypsin inhibitor* or (Kunitz adj3 inhibitor*) or midran or (pancrea* adj2 antitrypsin) or (pancrea* adj2 trypsin inhibitor*) or riker?52g or rp?9921or tracylol or trascolan or trasilol or traskolan or trazylol or zymofren or zymophren) or (tranexamic or Cyclohexanecarboxylic Acid* or Methylamine* or amcha or trans-4-aminomethyl-cyclohexanecarboxylic acid* or t-amcha or amca or kabi 2161 or transamin* or exacyl or amchafibrin or anvitoff or spotof or cyklokapron or ugurol oramino methylcyclohexane carboxylate or aminomethylcyclohexanecarbonic acid or aminomethylcyclohexanecarboxylic acid 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 anvitoff or cl?65336 or cl65336 or cyclocapron or cyclokapron or cyklocapron or exacyl or frenolyse or hexacapron or hexakapron or tranex or TXA) or (aminocaproic or amino?caproic or aminohexanoic or amino?hexanoic or epsilon-aminocaproic or E-aminocaproic) adj2 acid*) or epsikapron or cy-116 or cy116 or epsamon or amicar or caprocid or lederle or Aminocaproic or aminohexanoic or amino caproic or amino n hexanoic or acikaprin or afibrin or capracid or capramol or caprogel or caprolest or caprolisine or caprolysin or capromol or cl 10304 or EACA or eaca roche or ecapron or ekaprol or epsamon or epsicapron or epsilcapramin or epsilon amino caproate or epsilon aminocaproate or epsilonaminocaproic or etha?aminocaproic or ethaaminocaproich or emocaprol or hepin or ipsilon or jd?177or neocaprol or nsc?26154 or tachostyptan)

Cochrane Central Register of Controlled Trials 2010, Issue 3 (The Cochrane Library)

#1 MeSH descriptor Antifibrinolytic Agents explode all trees
#2 (anti-fibrinolytic* or antifibrinolytic* or antifibrinolysin* or anti-fibrinolysin* or antiplasmin* or anti-plasmin* ):ab,ti or ((plasmin or fibrinolysis) near3 inhibitor*):ab,ti
#3 MeSH descriptor Aprotinin explode all trees
#4 (Aprotinin* or kallikrein-trypsin inactivator* or bovine kunitz pancreatic trypsin inhibitor* or bovine pancreatic trypsin inhibitor* or basic pancreatic trypsin inhibitor* or BPTI or contrykal or kontrykal or kontrikal or contrical or dilmintal or iniprol or zymofren or traskolan or antilysin or pulmin or amicar or caprocid or epsamon or epsikapron or antilysin or iniprol or kontrikal or kontrykal or pulmin* or Trasylol or Antilysin Spofa or rp?9921 or antagosan or antilysin or antilysine or apronitin* or apronitrine or bayer a?128 or bovine pancreatic secretory trypsin inhibitor* or contrycal or frey inhibitor* or gordox or kallikrein trypsin inhibitor* or kazal type trypsin inhibitor or riker?52g or rp?9921or tracylol or trascolan or trasilol or traskolan or trazylol or zymofren or zymophren or midran):ab,ti or ((Kunitz near3 inhibitor*) or (pancrea* near3 antitrypsin) or (pancrea* near3 trypsin next inhibitor*)):ab,ti
#5 MeSH descriptor Tranexamic Acid explode all trees
#6 (tranexamic or Cyclohexanecarboxylic Acid* or Methylamine* or amcha or trans-4-aminomethyl-cyclohexanecarboxylic acid* or t-amcha or amca or kabi 2161 or transamin* or exacyl or amchafibrin or anvitoff or spotof or cyklokapron or ugurol oramino methylcyclohexane carboxylate or aminomethylcyclohexanecarbonic acid or aminomethylcyclohexanecarboxylic acid 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 anvitoff or cl?65336 or cl65336 or cyclocapron or cyclokapron or cyklocapron or exacyl or frenolyse or hexacapron or hexakapron or tranex or TXA):ab,ti
#7 MeSH descriptor Aminocaproic Acids explode all trees
#8 MeSH descriptor 6-Aminocaproic Acid explode all trees
#9 (epsikapron or cy-116 or cy116 or epsamon or amicar or caprocid or lederle or Aminocaproic or aminohexanoic or amino caproic or amino n hexanoic or acikaprin or afibrin or capracid or capramol or caprogel or caprolest or caprolisine or caprolysin or capromol or cl 10304 or EACA or eaca roche or ecapron or ekaprol or epsamon or epsicapron or epsilcapramin or epsilon amino caproate or epsilon aminocaproate or epsilonaminocaproic or etha?aminocaproic or ethaaminocaproich or emocaprol or hepin or ipsilon or jd?177or neocaprol or nsc?26154 or tachostyptan):ab,ti
#10 (aminocaproic or amino?caproic or aminohexanoic or amino?hexanoic or epsilon-aminocaproic or E-aminocaproic):ab,ti
#11 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10)

MEDLINE(Ovid) 1950 to July Week 2 2010
1.exp Antifibrinolytic Agents/
2.(anti-fibrinolytic* or antifibrinolytic* or antifibrinolysin* or anti-fibrinolysin* or antiplasmin* or anti-plasmin* or ((plasmin or fibrinolysis) adj3 inhibitor*)).ab,ti.
3.exp Aprotinin/
4.(Aprotinin* or kallikrein-trypsin inactivator* or bovine kunitz pancreatic trypsin inhibitor* or bovine pancreatic trypsin inhibitor* or basic pancreatic trypsin inhibitor* or BPTI or contrykal or kontrykal or kontrikal or contrical or dilmintal or iniprol or zymofren or traskolan or antilysin or pulmin or amicar or caprocid or epsamon or epsikapron or antilysin or iniprol or kontrikal or kontrykal or pulmin* or Trasylol or Antilysin Spofa or rp?9921 or antagosan or antilysin or antilysine or apronitin* or apronitrine or bayer a?128 or bovine pancreatic secretory trypsin inhibitor* or contrycal or frey inhibitor* or gordox or kallikrein trypsin inhibitor* or kazal type trypsin inhibitor* or (Kunitz adj3 inhibitor*) or midran or (pancrea* adj2 antitrypsin) or (pancrea* adj2 trypsin inhibitor*) or riker?52g or rp?9921or tracylol or trascolan or trasilol or traskolan or trazylol or zymofren or zymophren).ab,ti.
5.exp Tranexamic Acid/
6.(tranexamic or Cyclohexanecarboxylic Acid* or Methylamine* or amcha or trans-4-aminomethyl-cyclohexanecarboxylic acid* or t-amcha or amca or kabi 2161 or transamin* or exacyl or amchafibrin or anvitoff or spotof or cyklokapron or ugurol oramino methylcyclohexane carboxylate or aminomethylcyclohexanecarbonic acid or aminomethylcyclohexanecarboxylic acid 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 anvitoff or cl?65336 or cl65336 or cyclocapron or cyclokapron or cyklocapron or exacyl or frenolyse or hexacapron or hexakapron or tranex or TXA).ab,ti.
7.exp Aminocaproic Acids/ or exp 6-Aminocaproic Acid/
8.(((aminocaproic or amino?caproic or aminohexanoic or amino?hexanoic or epsilon-aminocaproic or E-aminocaproic) adj2 acid*) or epsikapron or cy-116 or cy116 or epsamon or amicar or caprocid or lederle or Aminocaproic or aminohexanoic or amino caproic or amino n hexanoic or acikaprin or afibrin or capracid or capramol or caprogel or caprolest or caprolisine or caprolysin or capromol or cl 10304 or EACA or eaca roche or ecapron or ekaprol or epsamon or epsicapron or epsilcapramin or epsilon amino caproate or epsilon aminocaproate or epsilonaminocaproic or etha?aminocaproic or ethaaminocaproich or emocaprol or hepin or ipsilon or jd?177or neocaprol or nsc?26154 or tachostyptan).ab,ti.
9.1 or 2 or 3 or 4 or 5 or 6 or 7 or 8
10.randomi?ed.ab,ti.
11.randomized controlled trial.pt.
12.controlled clinical trial.pt.
13.placebo.ab.
14.clinical trials as topic.sh.
15.randomly.ab.
16.trial.ti.
17.10 or 11 or 12 or 13 or 14 or 15 or 16
18.(animals not (humans and animals)).sh.
19.17 not 18
20.9 and 19

EMBASE (Ovid) 1980 to 2010 (Week 28)
1.exp Antifibrinolytic Agent/
2.(anti-fibrinolytic* or antifibrinolytic* or antifibrinolysin* or anti-fibrinolysin* or antiplasmin* or anti-plasmin* or ((plasmin or fibrinolysis) adj3 inhibitor*)).ab,ti.
3.exp Aprotinin/
4.(Aprotinin* or kallikrein-trypsin inactivator* or bovine kunitz pancreatic trypsin inhibitor* or bovine pancreatic trypsin inhibitor* or basic pancreatic trypsin inhibitor* or BPTI or contrykal or kontrykal or kontrikal or contrical or dilmintal or iniprol or zymofren or traskolan or antilysin or pulmin or amicar or caprocid or epsamon or epsikapron or antilysin or iniprol or kontrikal or kontrykal or pulmin* or Trasylol or Antilysin Spofa or rp?9921 or antagosan or antilysin or antilysine or apronitin* or apronitrine or bayer a?128 or bovine pancreatic secretory trypsin inhibitor* or contrycal or frey inhibitor* or gordox or kallikrein trypsin inhibitor* or kazal type trypsin inhibitor* or (Kunitz adj3 inhibitor*) or midran or (pancrea* adj2 antitrypsin) or (pancrea* adj2 trypsin inhibitor*) or riker?52g or rp?9921or tracylol or trascolan or trasilol or traskolan or trazylol or zymofren or zymophren).ab,ti.
5.exp Tranexamic Acid/
6.(tranexamic or Cyclohexanecarboxylic Acid* or Methylamine* or amcha or trans-4-aminomethyl-cyclohexanecarboxylic acid* or t-amcha or amca or kabi 2161 or transamin* or exacyl or amchafibrin or anvitoff or spotof or cyklokapron or ugurol oramino methylcyclohexane carboxylate or aminomethylcyclohexanecarbonic acid or aminomethylcyclohexanecarboxylic acid 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 anvitoff or cl?65336 or cl65336 or cyclocapron or cyclokapron or cyklocapron or exacyl or frenolyse or hexacapron or hexakapron or tranex or TXA).ab,ti.
7.exp Aminocaproic Acid/
8.(((aminocaproic or amino?caproic or aminohexanoic or amino?hexanoic or epsilon-aminocaproic or E-aminocaproic) adj2 acid*) or epsikapron or cy-116 or cy116 or epsamon or amicar or caprocid or lederle or Aminocaproic or aminohexanoic or amino caproic or amino n hexanoic or acikaprin or afibrin or capracid or capramol or caprogel or caprolest or caprolisine or caprolysin or capromol or cl 10304 or EACA or eaca roche or ecapron or ekaprol or epsamon or epsicapron or epsilcapramin or epsilon amino caproate or epsilon aminocaproate or epsilonaminocaproic or etha?aminocaproic or ethaaminocaproich or emocaprol or hepin or ipsilon or jd?177or neocaprol or nsc?26154 or tachostyptan).ab,ti.
9.1 or 2 or 3 or 4 or 5 or 6 or 7 or 8
10.exp Randomized Controlled Trial/
11.exp controlled clinical trial/
12.randomi?ed.ab,ti.
13.placebo.ab.
14.*Clinical Trial/
15.randomly.ab.
16.trial.ti.
17.10 or 11 or 12 or 13 or 14 or 15 or 16
18.exp animal/ not (exp human/ and exp animal/)
19.17 not 18
20.9 and 19

 

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. Differences between protocol and review
  17. Index terms

Last assessed as up-to-date: 14 July 2010.


DateEventDescription

5 November 2012New search has been performedAdditional data from the CRASH-2 trial of the effects of tranexamic acid on death due to bleeding according to time to treatment, severity of haemorrhage, Glasgow coma scale and type of injury, have been incorporated.

The conclusions have been edited to emphasise the importance of early administration (≤3 hours of injury) of tranexamic acid.



 

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. Differences between protocol and review
  17. Index terms

Protocol first published: Issue 3, 2004
Review first published: Issue 4, 2004


DateEventDescription

22 November 2010New citation required and conclusions have changedTwo new trials (CRASH-2 2010 - 20,211 bleeding trauma patients) and Yutthakasemsunt 2010 2010 - 240 patients with traumatic brain injury) have been included.

The objectives of the review have been amended. The Results, Discussion and Conclusions sections have been amended accordingly.



 

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. Differences between protocol and review
  17. Index terms

TC helped design the protocol, identified the included trials, extracted data and drafted the final version of the review.

IR helped design the protocol, identified the included trials, extracted data and drafted the final version of the review.

HS helped design the protocol and draft the final version of the review.

KK helped identify the included trials, extract data and revised the text of the review for the November 2010 and 2012 updates.

 

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. Differences between protocol and review
  17. Index terms

Tim Coats, Haleema Shakur and Ian Roberts were investigators in the CRASH-2 trial.

Haleema Shakur and Ian Roberts are investigators in the ongoing CRASH-3 trial.

Ian Roberts: LSHTM has received funds from pharmaceutical companies to pay for the drug and placebo used in RCTs of tranexamic acid in acute severe bleeding. These funds are delared in the relevant publications.

Haleema Shakur: I am an investigator and grant holder for the WOMAN Trial of tranexamic acid for the treatment of postpartum hemorrhage, the CRASH-3 trial of tranexamic acid for the treatment of traumatic brain injury and the Halt-it trial of tranexamic acid for the treatment of gastrointestinal bleeding.

Katharine Ker: none known.

 

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. Differences between protocol and review
  17. Index terms
 

Internal sources

  • London School of Hygiene & Tropical Medicine, UK.

 

External sources

  • No sources of support supplied

 

Differences between protocol and review

  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. Differences between protocol and review
  17. Index terms

The objectives of the review have changed. Reducing blood loss has been removed, and vascular occlusive events and surgical intervention have been added as outcomes.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  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. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
Auer 1979 {published data only}
CRASH-2 2010 {published data only}
  • CRASH-2 trial collaborators, Roberts I, Shakur H, Afolabi A, Brohi K, Coats T, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet 2011;377(9771):1096-101.
  • CRASH-2 trial collaborators, Shakur H, Roberts I, Bautista R, Caballero J, Coats T, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet 2010;376:23-32.
McMichan 1982 {published data only}
  • McMichan JC, Rosengarten DS, McNeur JC, Philipp E. Posttraumatic lung syndrome. Definition, diagnosis, and therapy [Das Posttraumatische Lungen-Syndrom Defintion, Diagnose und Therapie]. Med Welt 1976;76(48):2331-9.
  • McMichan JC, Rosengarten DS, McNeur JC, Philipp E. Pulmonary failure after major trauma and shock. Intensive Care Medicine 1977;3:Abstract no. 37.
  • McMichan JC, Rosengarten DS, Philipp E. Prophylaxis of post-traumatic pulmonary insufficiency by protease-inhibitor therapy with aprotinin: a clinical study. Circulatory Shock 1982;9(2):107-16.
  • Rosengarten DS, McMichan JC, McNeur JC, Philipp E. Platelet and pulmonary insufficiency after bony trauma. Intensive Care Medicine 1977;3:Abstract no. 327.
  • Rosengarten DS, McMichan JC, Philipp E. The effect of prophylactic proteinase inhibitor therapy on post-traumatic pulmonary insufficiency and platelet counts. Advances in Experimental Medicine and Biology 1979;120B:349-60.
Yutthakasemsunt 2010 {published data only}
  • Yutthakasemsunt S, Kittiwattanagul W, Piyavechvirat P, Thinkhamrop B, Phuenpathom N, Lumbiganon P. Tranexamic Acid for preventing progressive intracranial hemorrhage in adults with traumatic brain injury; a preliminary report. National Neurotrauma Symposium. 14-17 July 2010.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  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. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
Gierhake 1971 {published data only}
  • Gierhake FW, Grabow L, Spitzer G, Muller C, Braun R, Hessler C, Orth HD, Skibbe G, Zimmerman K. Protease inhibitors and wound healing. Results of a double blind study. Der Chirurg 1979;42(8):360-3.
Husted 2003 {published data only}
  • Husted H, Blond L, Sonne Holm S, Holm G, Jacobsen TW, Gebuhr P. Tranexamic acid reduces blood loss and blood transfusions in primary hip arthroplasty: a prospective randomized double blind study in 40 patients. Acta Orthopaedica Scandinavica 2003;74(6):665-9.
Klobow 1977a {published data only}
  • Klobow H, Barthels M, Oestern HJ, Sturm J, Wannske M, Schaps D. Early changes of the coagulation system in multiple injuries and their modification with heparin and Trasyolol. Chirurgisches forum fur experimentelle und klinishe forschung 1977;April:119-23.
Klobow 1977b {published data only}
  • Klobow H, Barthels M, Oestern HJ, Sturm J, Trentz O, Wannske M. Early changes in the coagulation and fibrinolytic system in patients receiving heparin or trasylol after massive trauma. Intensive Care Medicine 1977;3:Abstract no 324.
Kuiian 1999 {published data only}
  • Kuiian SM, Pogosov VS, Kokliaeva NV, Tiukov VL, Riazanov VB, Gur'ianov VA, Akopian RG, Daikhes N, Davudov KhSh, Nazhmudinov I. The use of tranexamic acid as an anesthetic component in ENT surgeries in patients with high surgical-anesthetic risk and in hemorrhagic shock intensive therapy. Vestnik Otorinolaringologii 1999;1:47-51.
Loew 1970 {published data only}
  • Loew D. Pathophysiologic importance of kinins in traumatic shock. Langenbecks Archiv Fur Chirurgie 1970;327:1042-6.
Nissen 1989 {published data only}
  • Nissen R, Loeschke S, Peters A. Pharmacological treatment of post-traumatic oedema to allow early functional exercise. Langenbecks Archiv fur Chirurgie 1989;Supplement II:475-8.
Schneider 1976 {published data only}
  • Schneider B. Results of a field study on the therapeutic value of aprotinin in traumatic shock. Arzneimittel Forshung 1976;26:1606-10.

References to ongoing studies

  1. Top of page
  2. AbstractRésumé
  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. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
CRASH-3 {published data only}
  • Dewan Y, Komolafe EO, Mejía-Mantilla JH, Perel P, Roberts I, Shakur H, on behalf CRASH-3 Collaborators. CRASH-3 - tranexamic acid for the treatment of significant traumatic brain injury: study protocol for an international randomized, double-blind, placebo-controlled trial. Trials 2012;13:87.

Additional references

  1. Top of page
  2. AbstractRésumé
  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. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
BTF 2000
  • The Brain Trauma Foundation. The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care. Hypotension. Journal of Neurotrauma 2000;17(6-7):591-5.
CRASH-2 2011
  • CRASH-2 collaborators, Roberts I, Shakur H, Afolabi A, Brohi K, Coats T, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet 2011;377(9771):1096-101.
Henry 2011
  • Henry DA, Moxey AJ, Carless PA, O'Connell D, Henderson KM, Fergusson D, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database of Systematic Reviews 2011, Issue 1. [DOI: 10.1002/14651858.CD001886.pub2]
Heymann 1992
Higgins 2008
  • Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.0. The Cochrane Collaboration. Available from www.cochrane-handbook.org, 2008.
Kiwanuka 2004
  • Kiwanuka N, Gray RH, Serwadda D, et al. The incidence of HIV-1 associated with injections and transfusions in a prospective cohort, Raki, Uganda. AIDS 2004;18:343-3.
Lawson 2004
Murray 1996
  • Murray CJL, Lopez AD. Global health statistics: a compendium of incidence, prevalence and mortality estimates for over 200 conditions. Harvard School of Public Health, 1996.
Sauaia 1995