Background
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 2004) 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 30% (relative risk [RR] = 0.70; 95% confidence interval [95% CI] 0.64 to 0.76) and TXA by 34% (RR = 0.66; 95%CI 0.54 to 0.81). Aprotinin use saved 1.1 units of red blood cells (RBCs) (95% CI 0.69 to 1.47) in those requiring transfusion, and TXA use saved 1.03 units (95% CI 0.67 to 1.39). There was a non-significant reduction in mortality with both aprotinin (RR = 0.87; 95% CI 0.63 to 1.19) and TXA (RR = 0.43; 95% CI 0.15 to 1.18). Pooled analyses showed that the use of antifibrinolytic agents significantly reduced the risk of undergoing re-operation due to bleeding (RR = 0.45; 95% CI 0.30 to 0.67).
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, the need for transfusion, and mortality following trauma. A simple and widely practicable intervention that reduced blood loss following trauma might prevent hundreds 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).
Why it is important to do this review
To quantify the effect of antifibrinolytic drugs in reducing blood loss, transfusion requirement and mortality after acute traumatic injury we conducted a systematic review of randomised controlled trials.
Objectives
To quantify the effect of antifibrinolytic drugs in reducing blood loss, transfusion requirement and mortality after acute traumatic injury.
Methods
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
- Mortality at the end of the follow up period for each trial.
- Proportion undergoing surgical intervention.
- Proportion receiving blood transfusion.
- Volume of blood transfused (units).
Search methods for identification of studies
Searches were not restricted by language or publication status.
Electronic searches
We searched the following electronic databases:
- Cochrane Injuries Group's Specialised Register (searched March 17, 2004)
- CENTRAL (The Cochrane Library issue 1, 2004)
- MEDLINE (1966-2004 March week 2)
- PubMed (searched March 17, 2004)
- EMBASE (1980-2004 March (week 11)
- 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 included variations of the following terms, adapted as appropritate for each database.
MESH
1. Antifibrinolytic-agents exp
2. Aprotinin exp
4. Tranexamic-Acid exp
5. Aminocaproic Acids exp
6. Antifibrinolytic* or Antifibrinolysin* or Antiplasmin* or Alpha(1) Antiplasmin* or Plasmin Inhibitor*
Textwords
1) Antifibrinolytic* or antifibrinolysin* or antiplasmin* or ((plasmin*) adj3 inhibitor* or inactivator*)
2) Aprotinin* or BPTI or Basic Pancreatic Trypsin Inhibitor* or Bovine Kunitz Pancreatic Trypsin Inhibitor* or Kallikrein-Trypsin Inactivator* or Kunitz Pancreatic Trypsin Inhibitor* or Trypsin Inhibitor* or Antilysin or Bovine Pancreatic Trypsin Inhibitor or Contrical or Contrykal or Dilmintal or Iniprol or Kontrikal or Kontrykal or Pulmin or Traskolan or Trasylol or Zymofren
3) Tranexamic acid* or AMCHA or AMCA or Cyklokapron or KABI 2161 or Transamin or Ugurol or t-AMCHA or trans-4- or Aminomethylcyclohexanecarboxylic Acid
4) Aminocaproic acid* or 6-Aminohexanoic Acid or epsilon-Aminocaproic Acid or Amicar or CY-116 or Caprocid or Epsamon or Epsikapron
Some of the search strategies 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 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, with any disagreements resolved by consensus.
Data extraction and management
Two authors independently extracted information on the following: number of randomised participants, types of participants and types of interventions, method of allocation concealment, loss to follow-up, the use of blinding, and whether an intention-to-treat analysis was carried out. The outcome data sought were: numbers of deaths in each group, numbers requiring surgical intervention, numbers requiring re-operation, and the amount of blood transfused. The authors were not blinded to the authors or journal when doing this. Results were compared and any differences resolved by discussion. 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
Since there is evidence that the quality of allocation concealment particularly affects the results of studies (Schulz 1995), two authors scored this quality on the scale used by Schulz 1995 as shown below, assigning C to poorest quality and A to best quality.
- A = trials deemed to have taken adequate measures to conceal allocation (that is, central randomisation; serially numbered, opaque, sealed envelopes; or other description that contained elements convincing of concealment).
- B = trials in which the authors either did not report an allocation concealment approach at all or reported an approach that did not fall into one of the other categories.
- C = trials in which concealment was inadequate (such as alternation or reference to case record numbers or to dates of birth).
Assessment of heterogeneity
The presence of heterogeneity of the observed treatment effects were assessed using the I
Assessment of reporting biases
Funnel plots were inspected for evidence of publication bias.
Data synthesis
Relative risk (RR) of death and 95% confidence interval (95% CI) were calculated, such that a relative risk of more than 1 indicates a higher risk of death (or surgery or re-operation) in the first group named. Relative risk was chosen because it is more readily applied to the clinical situation. For transfusion volumes, the weighted mean difference in the volume of blood transfused were calculated with 95% CIs.
Subgroup analysis and investigation of heterogeneity
Analysis of subgroups of trials were performed to determine whether effect sizes vary according to the type of antifibrinolytic agent and the dosing regimen.
Results
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies.
Two small randomised controlled trials were identified. See 'table of included studies' for further details.
Risk of bias in included studies
The study by Auer 1979 was described as double blind, suggesting adequate allocation concealment. 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.
The study by McMichan 1982 was a randomised controlled trial, in which 77 patients were randomly allocated to received aprotinin or placebo. 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
The combined search strategy identified a total of 819 records. These were screened by two authors and the full text of nine potentially eligible reports were obtained for closer examination. Of these two studies met the inclusion criteria. 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). Outcome data were reported for death, the proportion undergoing surgical intervention and the volume of blood transfused. Because of the small number of randomised participants in the trial, the estimates for each of these variables were highly imprecise. Data on the proportion undergoing re-operation and the proportion receiving blood transfusion were not reported.
Discussion
There is insufficient evidence from randomised controlled trials of antifibrinolytic agents in trauma to either support or refute a clinically important treatment effect. However, in view of the evidence for the effectiveness of antifibrinolytic agents in reducing blood loss in elective surgery, further randomised controlled trials of antifibrinolytic agents in trauma are required. If such a simple and widely practicable treatment could reduce the risk of death following trauma by even a few percent, then this might affect the treatment of a few hundred thousands of patients each year protecting thousands from premature death.
Any such trial would also need to assess the effect of antifibrinolytic agents on the risks of adverse effects, in particular on the risk of thrombo-embolic events, and would need to examine the use of antifibrinolytic agents in both blunt and penetrating trauma. In surgery, antifibrinolytic agents are given either pre-operatively or peri-operatively. Clinical trials of such agents in trauma would, therefore, need to administer the antifibrinolytic as soon as possible following the injury, while the patient is bleeding.
Authors' conclusions
Implications for practice To date, there is no evidence to support the use of antifibrinolytic agents in trauma. |
Implications for research Further randomised controlled trials of antifibrinolytic agents in trauma are required. |
Acknowledgements
Many thanks to Vasiliy Vlassov for help with translation.
Data and analyses
- Top of page
- Background
- Objectives
- Methods
- Results
- Discussion
- Authors' conclusions
- Acknowledgements
- Data and analyses
- Appendices
- What's new
- History
- Contributions of authors
- Declarations of interest
- Sources of support
- Index terms
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||
Appendices
Appendix 1. Search strategy
Injuries SR (searched 17 March 2004)
((wound* or injur* or trauma* or rupture* or amputat* or perforat* or stab* or lacerat* or mutilat* or crush* or polytrauma* or damag* or lesion* or abrasion* or avulsion* or shoot* or shot* or gun*) AND (aprotinin* or BPTI or antilysin or contrical or contrykal or dilmintal or iniprol or kontrikal or kontrykal or pulmin or trasylol or zymofren or antifibrinolytic* or antifibrinolysin* or antiplasmin* or (plasmin adj inhibitor*))
CENTRAL (The Cochrane Library issue 1, 2004)
1. WOUNDS AND INJURIES exp
2. (injur* or wound* or trauma* or rupture* or amputat* or perforat* or stab* or shot or gunshot* or gun-shot or lacerat* or mutilat* or crush* or polytrauma* or damag* or lesion* or abrasion* or avulsion* or shoot* or shot* or gun*)
3. (#1 or #2)
4. ANTIFIBRINOLYTIC AGENTS exp
5. APROTININ exp
6. TRANEXAMIC ACID exp
7. AMINOCAPROIC ACIDS exp
8. (antifibrinolytic* or antifibrinolysin* or antiplasmin* or (plasmin next inhibitor*))
9. (aprotinin* or antilysin or contrical or contrykal or dilmintal or iniprol or kontrikal or kontrykal or pulmin or traskolan or trasylol or zymofren)
10. (basic next pancreatic)
11. (kunitz next pancreatic)
12. (#10 or #11)
13. (trypsin next inhibitor*)
14. (#12 and #13)
15. (kallikrein-trypsin or (kallikrein next trypsin))
16. inactivator* or inhibitor*
17. (#15 and #16)
18. ((tranexamic next acid) or amcha or amca or cyklokapron or kabi-2161 or transamin or ugurol or t-amcha or (trans-4-aminomethylcyclohexanecarboxylic next acid))
19. (aminocaproic or 6-aminohexanoic or epsilon-aminocaproic)
20. acid*
21. (#19 and #20)
22. (amicar or cy-116 or caprocid or epsamon or epsikapron)
23. (#4 or #5 or #6 or #7 or #8 or #9 or #17 or #18 or #21 or #22)
24. (#3 and #23)
MEDLINE 1966-2004 (March week 2)
- explode "Wounds-and-Injuries" / all SUBHEADINGS in MIME,MJME))
- ((wound* or injur* or trauma* or rupture* or amputat* or perforat* or stab* or lacerat* or mutilat* or crush* or polytrauma* or damag* or lesion* or abrasion* or avulsion* or shoot* or shot* or gun*)
- 1 or 2
- explode "Aprotinin-" / all SUBHEADINGS in MIME,MJME)
- explode "Antifibrinolytic-Agents" / all SUBHEADINGS in MIME,MJME)
- (aminocaproic adj acid*) or (6-aminohexanoic adj acid*)or (epsilon-aminocaproic adj acid*)or amicar or caprocid or epsamon or epsikapron)
- ((tranexamic next acid) or amcha or amca or cyklokapron or kabi-2161 or transamin or ugurol or t-amcha or (trans-4-aminomethylcyclohexanecarboxylic next acid))
- (Basic or bovine or kunitz or kallikrein) adj (trypsin adj (inhibitor* or inactivator*)
- (aprotinin* or BPTI or antilysin or contrical or contrykal or dilmintal or iniprol or kontrikal or kontrykal or pulmin or trasylol or zymofren)
- (antifibrinolytic* or antifibrinolysin* or antiplasmin*) or (plasmin adj inhibitor*))
- explode "Aminocaproic-Acids" / all SUBHEADINGS in MIME,MJME)
- explode "Tranexamic-Acid" / all SUBHEADINGS in MIME,MJME))
- OR/4-12
- 3 and 13
EMBASE 1980-March 2004 (week 11)
1. exp Antifibrinolytic Agent/
2. exp AMINOCAPROIC ACID/
3. exp 4 AMINOMETHYLBENZOIC ACID/
4. exp APROTININ/
5. exp THROMBIN ACTIVATABLE FIBRINOLYSIS INHIBITOR/
6. exp TRANEXAMIC ACID/
7. (antifibrinolysin$ or antifibrinolytic$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]
8. (fibrinolysis adj3 (inhibitor$ or inactivator$)).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]
9. (acikaprin or afibrin or amicar or capracid or capramol or caprocid or caprolest or caprolisine or caprolysin or capromol or eaca or ecapron or ekaprol or epsamon or epsicapron or epsikapron or epsilcapramin or epsilonaminocaproic or ethaaminocaproic or hemocaprol or hepin or ipsilon or neocaprol or tachostyptan).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]
10. ((aminocaproic or aminohexanoic or aminocaproate) adj3 acid$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]
11. ((amino caproic or amino caproate or amino N hexanoic) adj3 acid$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]
12. ((aminomethylbenzoic or amino para toluic or methylbenzoic or aminomethyl) adj3 acid$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]
13. (pamba or styptopur or styptosolut).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]
14. (aprotinin or antagosan or antiysin or antilysine or apronitin$ or apronitrine or aprotinine or aprotonin or contrical or contrycal or contrykal or gordox or iniprol or kontrikal or kontrycal or midran or riker or tracylol or trascolan or trasilol or traskolan or trasylol or trazylol or zymofren or zymophren).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]
15. ((kallikrein or kazal or kunitz or pancrea$) adj3 (trypsin or inhibitor$ or antitrypsin)).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]
16. (thrombin$ adj3 activ$ adj3 fibrinolysis).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]
17. ((Aminomethylcyclohexanecarbonic or tranexamic or Aminomethylcyclohexane or Aminomethylcyclohexanoic or Aminomethylcyclohexanecarboxylic) adj3 acid$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]
18. (amca or amcha or amchafibrin or amikapron or amstat or anvitoff or cyclocapron or cyclokapron or cyklocapron or cyklokapron or exacyl or frenolyse hexacapron or hexakapron or tranex or tranexanic or transamin or ugurol).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]
19. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18
20. exp WOUND/
21. exp INJURY/
22. (wound$ or injur$ or trauma$ or rupture$ or amputat$ or perforat$ or stab$ or lacerat$ or mutilat$ or crush$ or polytrauma$ or damag$ or lesion$ or abrasion$ or avulsion$ or shoot$ or shot$ or gun$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]
23. 20 or 21 or 22
24. 19 and 23
What's new
Last assessed as up-to-date: 3 August 2004.
| |||||||||
History
Protocol first published: Issue 3, 2004
Review first published: Issue 4, 2004
Contributions of authors
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.
Declarations of interest
Tim Coats, Haleema Shakur and Ian Roberts are investigators in the CRASH-2 trial - a large scale multi-centre randomised controlled trial of effect of the antifibrinolytic agent tranexamic acid on mortality and transfusion requirements in trauma patients with significant haemorrhage.
Sources of support
Internal sources
- London School of Hygiene & Tropical Medicine, UK.
External sources
- No sources of support supplied
Index terms
Medical Subject Headings (MeSH)
Antifibrinolytic Agents [*therapeutic use]; Blood Loss, Surgical [prevention & control]; Blood Transfusion [*utilization]; Hemorrhage [*drug therapy; etiology]; Randomized Controlled Trials as Topic; Wounds and Injuries [*complications]
MeSH check words
Humans
* Indicates the major publication for the study