Does the Administration of Antifibrinolytic Drugs in Acute Trauma Reduce Mortality?
Article Outline
Take-Home Message
The use of tranexamic acid may reduce the risk of death in bleeding trauma patients.
Methods
Data Sources
In July 2010, the authors searched the Cochrane Injuries Group's specialized register, Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Science Citation Index, National Research Register, Zetoc, SGILE, Global Health, LILACS, and Current Controlled Trials.
Study Selection
All randomized controlled trials of the administration of antifibrinolytic agents (aprotinin, tranexamic acid, and ε-aminocaproic acid) to patients of any age with acute traumatic injury.
Data Extraction and Synthesis
Two independent authors reviewed all titles and abstracts and identified those that met a specific set of inclusion criteria. Data were pooled from randomized controlled trials comparing tranexamic acid, aprotinin, or ε-aminocaproic acid with placebo, with the primary outcome of mortality. Two authors assessed the quality of the individual trials, and disagreements were resolved by consensus. Information on loss to follow-up, the use of blinding, and intention to treat was extracted.
Results
Outcomes in patients treated with tranexamic acid versus placebo.1
| Outcome | Relative Risk (95% CI) | Number Needed to Treat |
|---|---|---|
| All-cause mortality | 0.90 (0.85–0.97) | 68 |
| Death caused by bleeding⁎ | 0.85(0.76–0.96) | NA |
| Vascular occlusive events⁎ | 0.84(0.68–1.02) | NA |
⁎ Based on data only from the CRASH-2 trial. |
Only 2 trials (N=20,451) were included that compared tranexamic acid with placebo. The Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage 2 (CRASH-2) trial comprised the majority of the patients (N=20,211) and was responsible for 99% of the weighted effect estimate. In this large multinational study, trauma patients older than 16 years and presenting within 8 hours of injury with significant hemorrhage (systolic blood pressure <90 mm Hg, pulse rate >110 beats/min, or both) or considered to be at risk of significant hemorrhage were eligible for the trial. Tranexamic acid was administered intravenously as a loading dose of 1 g over 10 minutes, followed by an intravenous infusion of 1 g over 8 hours.1 The risk of bias was graded as low for the large CRASH-2 trial, but the risk of bias in the smaller trial by Yutthakasemsunt et al2 (N=240) was unclear because data were available only from an abstract when the Cochrane review was conducted.
The authors estimated a 10% relative risk reduction for mortality without an increased risk of vascular occlusive events or increased need for blood products or surgical intervention; the absolute risk reduction in the large CRASH-2 trail was approximately 1.5%, with an estimated number needed to treat of 68.
Only 2 older trials compared the effects of aprotinin versus placebo. Auer et al3 randomized 20 subjects and then enrolled an additional 5 patients to the aprotinin group; it was not possible to separate the nonrandomized patient data from the randomized data. McMichan et al4 performed a randomized controlled trial including 77 patients that demonstrated no difference in mortality between aprotinin and placebo. Aprotinin was removed from the US market in 2007 because of safety concerns.5
Commentary
Trauma is a leading cause of death worldwide, with approximately 4 million deaths annually.6 Tranexamic acid is inexpensive and easy to use and, when given early, may reduce mortality. According to the British National Formulary in 2009, a gram of tranexamic acid costs $5.70. The CRASH-2 collaborators published a cost-effectiveness analysis showing that the administration of tranexamic acid is cost-effective across low-, middle-, and high-income countries.7 A recent Lancet article from the CRASH-2 collaborators concludes that the benefits of tranexamic acid are observed only when the drug is administered in the first 3 hours after trauma.8 Although the results from these 2 trials are promising, most of the data come from 1 large study that enrolled most of the subjects in developing countries, so the applicability to North America is uncertain; tranexamic acid has not been approved by the Food and Drug Administration (FDA) for treatment of traumatic injury (Figure).9 The authors of the Cochrane review were also the authors of the CRASH-2 study, so there may exist some intellectual conflict of interest.
References
- 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
- Tranexamic Acid for preventing progressive intracranial hemorrage in adults with traumatic brain injury; a preliminary report . National Neurotrauma Symposium . July 14-17, 2010;
- Proteolytic enzyme activity in patients with severe head injury and the effect of a proteinase inhibitor . Acta Neurochir (Wien) . 1979;49:207–217
- . Prophylaxis of post-traumatic pulmonary insufficiency by protease-inhibitor therapy with aprotinin: a clinical study . Circ Shock . 1982;9:107–116
- . Bayer withdraws heart surgery drug . [New York Times Web site.] http://www.nytimes.com/2007/11/05/health/05cnd-bayer.html?hp Accessed July 14, 2011
- . Deaths by age, sex and cause for the year 2008 . World Health Organization Global Health Observatory Data Repository Web site http://apps.who.int/ghodata/ Accessed April 25, 2011
- Cost-effectiveness analysis of administering tranexamic acid to bleeding trauma patients using evidence from the CRASH-2 Trial . [PLoS One Web site.] http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.0018987 Accessed July 25, 2011
- The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial . Lancet . 2011;377:1096–1101 1101.e1-2
- . Cyklokapron (tranexamic acid) injection label . (action date January 25, 2011). [Food and Drug Administration Web site.] http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist Accessed July 25, 2011
This is a clinical synopsis, a regular feature of the Annals' Systematic Review Snapshot (SRS) series. The source for this systematic review snapshot is: Roberts I, Shakur H, Ker K, et al, on behalf of the CRASH-2 Trial Collaborators. Antifibrinolytic drugs for acute traumatic injury. Cochrane Database Syst Rev. 2011;(1):CD004896. Doi:10.1002/14651858.CD004896.pub3. (Assessed as up to date: July 2010.)
Systematic Review Author Contact
Ian Roberts, MD, PhD
Cochrane Injuries Group
London School of Hygiene & Tropical Medicine
London, UK
E-mail: Ian.Roberts@Lshtm.ac.uk
PII: S0196-0644(11)01757-4
doi:10.1016/j.annemergmed.2011.10.019
© 2012 Published by Elsevier Inc.
