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Prehospital Tranexamic Acid for Acute Traumatic Hemorrhage
Transcript of Prehospital Tranexamic Acid for Acute Traumatic Hemorrhage
for Acute Traumatic Hemorrhage
An evidence based analysis
Derek P Sifford, FP-C, CCP-C, NREMT-P
"Road traffic injuries are the
leading cause of death globally, and such injuries are predicted to become the
leading cause of death and disability by 2020."
Tranexamic Acid (TXA) is a synthetic derivative of lysine that inhibits fibrinolysis by binding with lysine sites on plasminogen and plasmin.
Why is this significant?
Pathophysiologic Response to Hemorrhage
Plasminogen activators from injured blood vessles convert plasminogen into plasmin.
The plasmin then binds to the fibrin clot and breaks it down (AKA fibrinolysis).
This process is often fatal to the patient with uncontrolled internal hemorrhage as these "primary" fibrin clots are often the only source of bleeding control until the patient reaches definitive surgical intervention.
Response with Tranexamic Acid
TXA competitively binds to the lysine sites on plasminogen, blocking the activation of plasminogen into plasmin, and does not allow breakdown of existing clots to occur.
How does it work?
Randomised controlled trial
20,211 adult trauma patients
with, or at risk of, signiﬁcant bleeding were randomly assigned
within 8 h of injury
to either tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo.
The primary outcome was death in hospital within 4 weeks of injury, and was described with the following categories:
Vascular Occlusion (myocardial infarction, stroke and pulmonary embolism).
All-cause mortality was signiﬁcantly reduced with tranexamic acid (1463 [14·5%] tranexamic acid group vs 1613 [16·0%] placebo group; RR 0·91, 95% CI 0·85–0·97; p=0·0035).
The risk of death due to bleeding was signiﬁcantly reduced (489 [4·9%] vs 574 [5·7%]; RR 0·85, 95% CI 0·76–0·96; p=0·0077).
10,096 patients in TXA group (10,060 analysed).
10,115 patients in placebo group (10,067 analysed).
"Tranexamic acid safely reduced the risk of death in bleeding trauma patients in this study. On the basis of these results, tranexamic acid should be considered for use in bleeding trauma patients."
signiﬁcantly reduced all-cause mortality.
(1 h from injury) signiﬁcantly reduced the risk of death due to bleeding (198/3747 [5·3%] events in tranexamic acid group vs 286/3704 [7·7%] in placebo group; relative risk [RR] 0·68, 95% CI 0·57–0·82; p<0·0001)." (2)
should be given as early as possible
to bleeding trauma patients." (2)
"The estimated OR of tranexamic acid on death due to bleeding when given immediately after injury was 0·61(95% CI 0·50–0·74). We estimated that this OR is
multiplied by 1·15 (95% CI 1·08–1·23) for every hour that passes since the injury.
Our results strongly endorse the importance of early administration of tranexamic acid in bleeding trauma patients and suggest that trauma systems should be conﬁgured to facilitate this recommendation.
"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." (6)
The best place for tranexamic acid in developed trauma systems might actually be in the prehospital environment
. Helicopter and road transport direct to major trauma centres has reduced overall injury mortality, but has extended the time before patients reach hospital. Prehospital administration of blood products, especially plasma, is uncommon in civilian settings, resulting in little directed management of coagulopathy. By contrast,
tranexamic acid can be safely stored in vehicles and simply administered.
Evidence Based Q&A
What about the adverse effects that come with inhibiting clot breakdown? Surely there must be an increase in morbidity and mortality by vasoocclusive events, right?
"Harms in Percentage - 0% were harmed" (10)
"There were 33 (0·3%) deaths in the tranexamic acid group versus 48 (0·5%) in the placebo group from vascular occlusion, including seven versus 22 deaths from myocardial infarction, eight versus ﬁve from stroke, and 18 versus 21 from pulmonary embolism, respectively. Deaths from multiorgan failure, from head injury, or due to other causes did not dier signiﬁcantly in the tranexamic acid group versus the placebo group." (1)
"Vascular occlusive events (fatal or non-fatal) did not differ significantly, with 168 (1·7%) patients with one or more vascular occlusive events (myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis) in patients allocated to tranexamic acid versus 201 (2·0%) in those allocated to placebo." (1)
"Tranexamic acid reduced the odds of death from bleeding by about 30% in each of the baseline risk strata studied and reduced the odds of thrombotic events by about 30%." (5)
"Use of tranexamic acid should not be limited to high risk patients" (5)
"There were fewer thrombotic events with tranexamic acid with no evidence of heterogeneity by baseline risk" (5)
"The beneficial effect of tranexamic acid on all cause mortality or deaths from bleeding is not affected by baseline risk of death" (5)
"these data suggest that tranexamic acid can be administered safely to a wide spectrum of patients with traumatic bleeding and that its use should not be restricted to those with the most severe haemorrhage." (5)
How can supporting your use in the prehospital setting benefit us in the hospital?
"Blood product transfusions were given to 5067 (50·4%) patients allocated to tranexamic acid versus 5160 (51·3%) allocated to placebo (table 3). Those allocated to tranexamic acid and transfused received a mean of 6·06 (SD 9·98) blood units, compared with a mean of 6·29 (10·31) for placebo." (1)
"patients who survived as a result of tranexamic acid administration would have had a greater opportunity to receive a blood transfusion (competing risks)." (1)
"TXA is not only life saving, as shown by the CRASH-2 trial, but also that it is a highly cost effective intervention if administered routinely to bleeding trauma patients in high, middle and low income countries." (9)
"Early administration (within three hours) of TXA would cost $48, $66 and $64 per LY saved in Tanzania, India and the UK respectively. According to the WHO Commission on Macroeconomics, healthcare interventions costing less than GDP per capita per Disability-Adjusted Life Year (DALY) averted should be considered "very cost effective". According to the World Bank classification, GDP per capita in low income countries ranges from $380 to $975, in lower middle income countries between $976 and $3855, upper middle income between $3,856 and $11,905 and high income countries GDP above $11,906 . Thus, if the life years saved by TXA are spent in perfect health (one LY saved is equal to one DALY averted) TXA is a highly cost effective intervention in all the countries considered. The sensitivity analyses presented reinforce this conclusion." (9)
"This study suggests that TXA is a highly cost effective intervention in three very different settings. Given that TXA is effective and it is of relatively low cost it is not surprising that it is cost-effective in high income settings." (9)
How many lives are we really saving? Is it REALLY worth the hassle?
"When ranked by the number of premature deaths potentially averted, nine of the top ten countries are low or middle income, the exception being the USA where approximately 4,000 and 3,500 deaths would be averted by TXA given within one hour and three hours of injury, respectively." (7)
"TXA is a practicable treatment suitable for use in a range of health-care settings, including pre-hospital. If TXA was used in the pre-hospital setting then many more premature deaths might be averted." (7)
Most of these papers are drawn from one data set (CRASH-2). If there is an error in the data, all are invalid. How, on that basis, can we be sure of ourselves enough to implement TXA in the field?
The MATTERS trial was a completely separate study with very similar results. (8)
The British NHS has been widespread using the drug for more than a year without any new reports of harm.
Has EMS use ever been studied?
No. However, NATO military (including US forces) has been using TXA in the prehospital setting without any reports of harm.
Who has adopted TXA into their prehospital protocols thus far?
Well, to name a few.......
Royal Flying Doctor Service (Australia)
Mayo Clinic Helicopters
British Columbia Ambulance Service
South Western Ambulance Service (UK)
In summary, here are some key points as to why Tranexamic Acid should be implemented into prehospital EMS protocols.
It saves lives.
It saves hospitals money and blood products.
Easy to administer.
Easy to store.
Easy to dose.
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 - The Lancet 3 July 2010 (Volume 376 Issue 9734 Pages 23-32 DOI: 10.1016/S0140-6736(10)60835-5)
The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial
- The Lancet 26 March 2011 (Volume 377 Issue 9771 Pages 1096-1101.e2 DOI: 10.1016/S0140-6736(11)60278-X)
Tranexamic acid for trauma
Russell L Gruen, Biswadev Mitra
- The Lancet 26 March 2011 (Volume 377 Issue 9771 Pages 1052-1054 DOI: 10.1016/S0140-6736(11)60396-6)
CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage) intracranial bleeding study: the effect of tranexamic acid in traumatic brain injury - a nested randomised, placebo-controlled trial - (Perel) 52 pages, Volume 16, number 13
Roberts I ,Perel P ,Prieto-Merino D ,Shakur H ,Coats T ,Hunt BJ ,et al. Effect of tranexamic acid on mortality in patients with traumatic bleeding: prespecified analysis of data from randomised controlled trial.
- BMJ 2012;345:e5839
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 2011, Issue 1. Art. No.: CD004896. DOI: 10.1002/14651858.CD004896.pub3.
Ker K, Kiriya J, Perel P, Edwards P, Shakur H, Roberts I. Avoidable mortality from giving tranexamic acid to bleeding trauma patients: an estimation based on WHO mortality data, a systematic literature review and data from the CRASH-2 trial. - BMC Emerg Med 2012;12(1):3.
Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study.
- Arch Surg. 2012;147(2):113-119. doi:10.1001/archsurg.2011.287.
Guerriero C, Cairns J, Perel P, Shakur H, Roberts I (2011) Cost-Effectiveness Analysis of Administering Tranexamic Acid to Bleeding Trauma Patients Using Evidence from the CRASH-2 Trial.
- PLoS ONE 6(5): e18987. doi:10.1371/journal.pone.0018987
The NNT - Trauma interventions that work: Tranexamic Acid for Severe Trauma http://www.thennt.com/nnt/tranexamic-acid-for-severe-trauma/
Special Thanks to...
Howard K. Mell, MD, MPH, FACEP
Chair Elect - ACEP EMS Section
EMS Medical Director
Lake West Medical Center
Alexei Wagner MD, MBA
Chief Flight Physician
University of Chicago Aeromedical Network
Large therapeutic range - in adults, 1 dose fits all!
1g bolus over 10 min, followed by 1g infusion over 8 hours
Store at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F)
Mayo Clinic HEMS currently utilizes TXA for trauma with no reports of harm. It is important to note also that they auto-launch to every serious motor vehicle crash in their county so they are often the first ALS unit on scene.