ED CRASH Course: TXA MATTERS!
Authors: Daniel DeWeert, MD (EM Resident Physician, Advocate Christ Medical Center) and Elise Lovell, MD (EM Associate Program Director, Advocate Christ Medical Center) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) & Justin Bright, MD (@JBright2021)
Your shift starts and all of your patients are bleeding! There is an MVC victim with a tense abdomen and traumatic brain injury, a patient with an upper GI bleed, a woman whose spontaneous vaginal delivery has turned into a post-partum hemorrhage, and a brisk epistaxis in the back hallway. You thank the triage nurse and begin resuscitative measures. What role does tranexamic acid (TXA) play in the treatment of these patients?
Tranexamic acid (TXA; brand names Cyklokapron and Lysteda) is a synthetic derivative of lysine that reversibly attaches to lysine binding sites on plasminogen, preventing its activation to plasmin. Since plasmin breaks down fibrin clots, TXA prevents clot breakdown, which can maintain (not create) clots and reduce bleeding. Also, the coagulation and inflammatory cascades overlap (eg, plasmin activates complement), so TXA may have an anti-inflammatory mechanism as well.
TXA has previously been used to reduce bleeding during elective surgery, particularly for orthopedic and cardiovascular operations. A systematic review of 53 RCTs demonstrated that TXA reduced the need for perioperative blood transfusion by 1/3 (RR 0.62) although there was no significant reduction in mortality.1 There are also multiple chronic indications for TXA, including dysfunctional uterine bleeding2, and disorders where TXA is used for long-term bleeding prophylaxis (eg, preventing epistaxis in hereditary hemorrhagic telangiectasia3).
The focus of this update is the evolving collection of ideas, literature, and guidelines about the use of TXA in acute clinical scenarios in which bleeding can lead to significant morbidity and mortality, with an emphasis on trauma, including traumatic brain injury/intracranial hemorrhage and pediatric trauma. Other emerging indications including post-partum hemorrhage, GI bleeding, epistaxis, and traumatic hyphema will also be discussed, along with upcoming studies.
TXA IN TRAUMA: EVIDENCE
CRASH-24 was a large, randomized, placebo-controlled study (RCT) in 2011 that evaluated the effect of TXA in trauma patients. Over 20,000 adult trauma patients with or at risk of significant bleeding in 274 hospitals in 40 countries were randomly assigned to TXA (loading dose 1 g IV plus another 1 g IV over the next eight hours) or placebo within eight hours of injury. The primary outcome was all-cause mortality at four weeks. Secondary outcomes included vascular occlusive events, surgical interventions, need for blood transfusion, and amount of blood products transfused.
–All-cause mortality was significantly reduced by 1.5% (14.5% for TXA group vs 16.0% for placebo; RR 0.91; NNT 67)
–Mortality from bleeding was significantly reduced by 0.8% (4.9% for TXA vs 5.7% for placebo; RR 0.85; NNT 121)
-Early administration is important! Mortality varied by time TXA given after injury5:
–First hour: 2.4% decrease in mortality (RR 0.68)
–1-3 hours after injury: 1.3% decrease in mortality (RR 0.79)
–3 or more hours after injury: 1.3% increase in mortality (RR 1.44)
-There was no apparent increase in fatal or non-fatal vascular occlusive events, and no significant differences in the other secondary outcomes
NOTE: The criteria for randomization was left up to the treating physician, with recommendation to include those with significant hemorrhage (SBP<90; HR>110) and those whom the treating physician felt substantially uncertain about whether or not to use TXA. Patients with clear indications or contraindications to TXA were treated appropriately and not included in randomization. CRASH-2 was a pragmatic study with broad entrance criteria, large size, a variety of “real world” health care settings, and accepted practice variation.
-Highly generalizable results
-Benefit from TXA was found despite the dilution of effect by the large number of patients that did not receive blood transfusion or surgery.
–External validity: What specific trauma populations will benefit most? Many of the centers involved are in developing countries. Do these results apply in centers with modern trauma practices, safe blood products, and definitive surgical care? A secondary analysis of CRASH-2 found no evidence that TXA’s mortality benefit varied by injury type or geography.6
–Mechanism: How is TXA working in the trauma population? Antifibrinolysis is suspected but coagulation parameters were not measured. Despite the reduction in mortality due to bleeding, TXA did not reduce transfusion requirements. This could be due to practice variation, difficulty recording blood loss in the trauma setting, survivor bias, or perhaps indicates TXA is working by another mechanism.42
The MATTERS7 study found the same trauma mortality benefit in a young, healthy population being treated at a modern trauma center. It also gathered coagulation lab data. This was a retrospective, observational study looking postoperatively at 896 combat-wounded soldiers in an Afghanistan surgical hospital who received at least one unit of pRBCs. Of these, 293 also received TXA with a similar dosing regimen as CRASH-2. The primary outcome was mortality. Secondary outcomes included transfusion requirements/blood product use, coagulopathy, thrombotic complications, and TXA dose. As previously stated, half of patients in CRASH-2 did not receive any blood product transfusion, which may have diluted the treatment effect: MATTERS enrolled a more severely injured cohort.
–Overall mortality was significantly reduced by 6.5% (17.4% for TXA group vs 23.9% for placebo; NNT 15), with mortality differences becoming apparent after 48 hours. Given that early trauma death is most commonly from bleeding, the later mortality benefit again suggests the possibility of another mechanism of action.
-Mortality reduction was greatest, 13.7%, in those receiving massive transfusion (14.4% vs 28.1%; NNT 7)
-Based on PT and aPTT measurements, there was a decrease in the percentage of hypercoagulable patients in the TXA group.
–Transfusion requirements and the rate of PE/DVT was higher in the TXA group. However, since this was a retrospective observational study, it is difficult to interpret these results. Survivor bias may have impacted outcomes, as longer survival time allows for more blood transfusions and thrombotic complications, and there were more survivors in the TXA group.
TXA use has not yet been studied in pediatric trauma, but because of the benefits found in adults and its successful use in pediatric non-trauma surgical settings8, at least one expert has called for the use of TXA in this population, suggesting that protocols should be implemented in adolescents immediately and that further studies are needed for TXA use in young children.9 Potential risk of thromboembolic complications should be lower in children, as their baseline cardiovascular risk is lower. Some literature suggests adults and children have similar coagulopathic responses in trauma. A combined retrospective review and prospective analysis of 102 children presenting with trauma to the ED over 4 years found that 77% were coagulopathic on arrival and that coagulopathy was strongly associated with mortality in pediatric patients ill enough to receive a transfusion.10
TRAUMATIC BRAIN INJURY (TBI)/INTRACRANIAL HEMORRHAGE
Patients with isolated head trauma were excluded from CRASH-2 due to the historic concern of antifibrinolytics causing cerebral ischemia. However, there were still 270 patients who had multi-trauma including both extracranial bleeding and TBI enrolled in CRASH-2. The Intracranial Bleeding Study11 was a randomized, double blind, placebo-controlled trial nested within CRASH-2 that studied the effect of TXA on these patients. Results were not statistically significant, however all clinical trends in this exploratory study favored TXA over placebo. There was less mean total hemorrhage growth at 48 hours as well as a decreased incidence of significant hemorrhage growth, new focal cerebral ischemic lesions, new areas of hemorrhage, signs of mass effect, and all-cause mortality. The authors conclude “neither moderate benefits nor harmful effects.”
A 2014 review of ED patients with TBI pooled results from 2 RCTs to demonstrate statistically significant reduction in ICH progression with TXA as well as a trend of improvement of clinical outcomes. The authors conclude that despite an excellent safety profile, further evidence is required to support the routine use of TXA in patients with TBI.40 The largest RCT for TXA use in isolated TBI, CRASH-3, is ongoing.12
GASTROINTESTINAL BLEEDING (GIB)
A recent systematic review of eight clinical trials of TXA use in upper GIBs (none in lower GIBs) showed a significant reduction in mortality (RR 0.66), however studies were of poor quality and the majority did not report adverse events.20,21 A 2012 Cochrane review of 7 RCTs showed no difference in bleeding, surgery, or transfusion requirements.39 Currently, there are insufficient data on the effectiveness and safety of TXA use in GIBs and it is not routinely used, and was excluded from recent consensus documents on GIB management.22,23 HALT-IT is a large multi-center study in progress that will provide more information for this indication.24
POST PARTUM HEMORRHAGE (PPH)
TXA significantly reduces uterine blood loss in women with menorrhagia, but RCT evidence on the effectiveness of TXA for intractable PPH is lacking. A systematic review of three RCTs of prophylactic TXA use in PPH showed a decreased amount of postpartum blood loss in women receiving TXA (460 total participants; weighted mean blood loss reduction of about 100 mL)26 but the quality of trials was poor and they were too small to assess mortality, hysterectomy, and thrombotic complications. A 2011 RCT including 144 women with PPH of at least 800 mL following vaginal delivery demonstrated that TXA significantly reduced blood loss (median 173 mL in TXA group vs 221 in control), bleeding duration, and transfusion requirements.45 This trial was also too small to assess thromboembolic risk, which is of particular concern in the pregnant population. A 2013 case control study showed that TXA significantly decreases blood loss up to 2 hours peripartum in primiparous C-sections, without any significantly abnormal vital sign changes after administration (TXA group average 42.7 mL blood loss vs placebo control average 80.2 mL).44 The most recently updated PPH treatment guidelines from the World Health Organization (WHO) state that TXA may be used if other measures fail, but that evidence is low quality and more trials are needed. TXA is “recommended for consideration” as a treatment in intractable postpartum hemorrhage in the UK.25 The ongoing WOMAN trial27 will provide more data on TXA’s efficacy and safety for this indication.
A 1999 RCT demonstrated that TXA was significantly more effective than placebo, although not significantly more effective than oral prednisolone, in preventing rebleeding in patients with traumatic hyphema. Rebleeding occurred in 8 patients (10%) in the TXA group, 14 patients (18%) receiving prednisolone, and 21 patients (26%) receiving placebo.13 A 2008 study found no effect when TXA was added to topical steroids in a pediatric population.14 However, a 2013 Cochrane review states that TXA has a significant effect in reducing the rate of secondary hemorrhage (OR 0.25), concluding that other than antifibrinolytics, the decision to use corticosteroids, cycloplegics, binocular patching, bed rest, or head elevation should be individualized for each patient, and that more studies are needed to determine the additive effect of these interventions.15
One small RCT in 1995 found TXA had no effect in the treatment of epistaxis.16 Another 216-patient RTC in 2013 of topical application of TXA in idiopathic anterior epistaxis demonstrated significant benefit of TXA for bleeding, discharge time, and rebleeding rates. Bleeding stopped within 10 minutes in 71% of TXA group compared with 31.2% in the anterior nasal packing group; OR 2.28. Discharge within two hours occurred in 95.3% of the TXA group vs 6.4% in the anterior nasal packing group, and rebleeding rates were 4.7% for TXA vs 11% for anterior packing in first 24 hours17 The quality of the study is disputed, however, due to a substandard control (cotton pledgets soaked in tetracycline). A case report found that topical TXA reduced the need for blood transfusions and iron supplements in a patient with hereditary hemorrhagic telangiectasia with recurrent epistaxis.18 A 2014 review of 33 papers states that there is insufficient evidence to support the use of topical intranasal TXA for spontaneous epistaxis in hemodynamically stable patients in the ED.19 One option used in clinical practice is a Merocel tampon soaked in intravenous TXA, however there is not adequate evidence to support this approach at this time.
DISSEMINATED INTRAVASCULAR COAGULATION (DIC)
Antifibrinolytics are generally contraindicated in DIC since blockade of the fibrinolytic system may increase the risk of thrombotic complications, but may be appropriate in patients who have severe bleeding associated with a hyperfibrinolytic state.46
SUBARACHNOID HEMORRHAGE (SAH)
The 2012 American Stroke Association guidelines state that when definitive treatment of an aneurysm is unavoidably delayed and there are no other contraindications to treatment, short term therapy (<72 hours) with tranexamic acid or aminocaproic acid is reasonable.47 A 2003 Cochrane meta-analysis of nine trials concluded that although antifibrinolytic treatment significantly reduces the risk of rebleeding (OR 0.55), it does not show evidence of reducing mortality or severe disability.48 A 2013 update changed the rebleeding OR to 0.65, and continues to conclude that results on short-term treatment are promising but further RTCs are needed.51
TXA has a long history of use in surgery and adverse effects are uncommon. Increased clotting risk is the primary theoretical concern and was included as a secondary endpoint in CRASH-2. No significant increase in vaso-occlusive events (MI, stroke, PE, DVT) was demonstrated in this study, and there was actually a significant reduction in myocardial infarction with TXA use. There is critique that there may not have been an adequate search for these complications in some of the CRASH-2 settings.28
The hypercoagulable pregnant population is of particular concern. TXA has had a good safety profile for use in menometrorrhagia, and although studies show it decreases bleeding in PPH, these studies have not been powered to address safety. Observed side effects were described as “mild and transient”45. The WOMAN trial will collect information on DVT and PE in patients with PPH who receive TXA.
CRASH-3 and HALT-IT will provide safety data for TXA use in TBI and GIBs, respectively. The 2012 Cochrane review on TXA in GIBs stated that TXA did not increase thrombotic events,39 although studies were not significantly powered for this outcome. It is interesting to note that a 2014 analysis of the use of TXA in hip and knee replacement found no increased risk of vascular occlusive events in this group of patients.49 A 1999 review and meta-analysis of 60 trials concurs that increased risk of thrombosis with TXA thus far has not been demonstrated in clinical trials. Nausea, diarrhea, and orthostatic reactions are the most common side effects reported at the much higher doses used in elective surgery.29
Similarly, a 2011 systematic review of pediatric surgical literature showed that serious adverse events occur very rarely with TXA use in the pediatric population, and are seen at much higher doses (>100 mg/kg) than those used in trauma. Side effects include nausea, diarrhea, hypotension/orthostasis with rapid infusion, dizziness, headache, muscle pain/spasms and postoperative seizure.30,31 There are also reports of rapid infusion hypotension, cerebrovascular infarctions, and a single case of TEN in the pediatric population.9
A 2015 review summarizes that there are few side effects from the use of TXA except post-operative seizures at the high doses used in cardiac surgery (2–10x higher than those used in CRASH-2), possibly from TXA interfering with cerebral GABA and glycine receptors. This review also notes that there is no evidence of increased efficacy at doses higher than 1g in adult patients.41
DOSING AND ADMINISTRATION
The empiric dose of TXA for antiplasmin effect used in CRASH-2 and by most studies since is a 1 g IV bolus, possibly followed by another bolus or infusion. CRASH-2 added another 1 g IV over eight hours; MATTERS utilized a second dose if necessary; STAAMP used only one dose. Dosing is being studied for use in PPH, with the WOMEN trial including an optional second dose. In GIB, HALT-IT follows the initial bolus with an IV infusion of 3 g over 24 hours; TAUGIB follows the initial bolus with 1 g IV over eight hours).
The UK Royal College of Pediatrics and Child Health recommends TXA use in all major pediatric trauma at a dose of 1 g/hr in first three hours post-injury, then 1 g over eight hours. For patients under 12 years of age, the recommendation is 15 mg/kg (maximum 1 g) then 2 mg/kg/hr for at least eight hours or until bleeding stops.33
TXA can also be used topically to reduce bleeding, but there are not significant data about its efficacy or its safety compared to intravenous administration. Topical TXA reduces bleeding and blood transfusion in surgical patients but thromboembolic risk is unknown.43 For epistaxis, a non-evidence-based option is to use a Merocel tampon soaked in 500 mg of the intravenous TXA preparation. Topical application of injectable form (500 mg in 5 mL) has also been successful.17 A case report found that five drops (about 0.25 mL) of 100 mg/mL TXA at onset of bleeding reduced the need for blood transfusions and iron supplements in a patient with hereditary hemorrhagic telangiectasia with recurrent epistaxis.18
TXA is a safe, inexpensive ($100/dose) medication that prevents fibrin breakdown. In traumatic bleeding, it conveys a significant mortality benefit with an impressive NNT for mortality between 7 and 67, depending on injury severity, without apparent serious safety issues. This benefit is associated with early administration. TXA should not be given more than three hours after injury as it may increase mortality after this timeframe. It appears to have equal benefit in a variety of trauma practice environments.
TXA has been included in the WHO’s List of Essential Medicines34 and is included in various trauma protocols worldwide, such as the UK Defense Medical Service’s massive transfusion protocol.50 The UK Royal College of Pediatrics and Child Health’s Nov 2012 evidence statement proposes the use of TXA in all children.33 According to a 2011 review in J Trauma, TXA should be incorporated into trauma clinical practice guidelines and treatment protocols for bleeding trauma patients as it is the only drug with prospective clinical evidence supporting this application.36
Although there is a robust history of using TXA in surgery to reduce perioperative hemorrhage, evidence for its effectiveness in acute conditions is more limited. Large trials evaluating its use in traumatic brain injury, postpartum hemorrhage, and gastrointestinal bleeding are ongoing.
KEEP A LOOK OUT! Summary of FUTURE TRIALS
CRASH-3, WOMAN, and HALT-IT are ongoing large, pragmatic trials studying TXA use in TBI, PPH, and GIB, respectively. There are calls for more trials to study dosing regimens and mechanism of action14 as well as to study its use in pediatric trauma.9
CRASH-3 will assess TXA use in isolated TBI, specifically its effects on mortality, disability, and safety (vasoocclusive events and seizures). The study is still recruiting. As of December 2015, over 6,000 patients were randomized in this large, international, randomised, placebo controlled trial. Estimated completion date is Jan 2017.12
Here is another study on the effect of TXA on patients with isolated TBI. The outcome will be GOS-E scores at 6 months post-TBI. This double-blind, RCT study will include about 1,000 patients and is planned for completion December 2016.
HALT-IT will assess TXA use in GIB. This randomized, double-blind, placebo-controlled trial will study endpoints of mortality, re-bleeding, non-fatal vascular events, thrombotic events, blood transfusion, surgical intervention, and length of hospital stay. Enrollment has been ongoing since July 2013 with plans to recruit 8,000 patients. Recruitment will continue until May 2017.24
TAUGIB is studying TXA use specifically in upper GIB. Enrollment is ongoing, with 414 patients included thus far.
WOMAN will assess TXA use in PPH. Outcomes will include mortality, hysterectomy, other surgical interventions, blood transfusion, non-fatal vascular events, safety for breastfed babies, type of delivery, medical events, and length of hospital stay. This large, randomized, double-blind, placebo-controlled trial is still recruiting with plans to include at least 15,000 women worldwide by May 2016.27
TRAAP will assess if TXA can prevent PPH after vaginal delivery. This multicenter, double-blind RTC is actively recruiting and plans to recruit over 4,000 women for estimated completion Dec 2016.38
STAAMP is studying the effect of TXA given “during air medical transport to a level I trauma center in patients at risk of hemorrhage.” This multicenter, prospective, randomized, double-blind, interventional trial has enrolled approximately 1,000 patients thus far with plans for completion March 2018. Outcome measures will include 24-hour mortality, acute lung injury, multi-organ failure, nosocomial infection, 24-hour blood transfusion, and hyperfibrinolysis.35
Additional FOAMed resources
The Trauma Professional’s Blog: http://regionstraumapro.com/post/17372835122
References / Further Reading
- Henry D.A., Carless P.A., Moxey A.J., O’Connell D., Stokes B.J., Fergusson D.A., Ker K. (2011). Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev, Mar 16 (3). doi: 10.1002/14651858.CD001886.pub4.
- Winkler U.H. (2001). The effect of tranexamic acid on the quality of life of women with heavy menstrual bleeding. Eur J Obstet Gynecol Reprod Biol, Dec 1; 99(2):238-43. PMID: 11788179.
- Gaillard S., Dupuis-Girod S., Boutitie F., Rivière S., Morinière S., Hatron PY., . . . Plauchu H. (2014). Tranexamic acid for epistaxis in hereditary hemorrhagic telangiectasia patients: a European cross-over controlled trial in a rare disease. J Thromb Haemost; Sep;12(9):1494-502. doi: 10.1111/jth.12654.
- The CRASH-2 Collaborators. (2010). Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2). Lancet, 376:23–32.
- CRASH-2 collaborators, Roberts I., Shakur H., Afolabi A., Brohi K., Coats T., Dewan Y., . . .Woolley T. (2011). The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet, Mar 26;377(9771):1096-101, 1101.e1-2. doi: 10.1016/S0140-6736(11)60278-X.
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- Tibbelin A., Aust R., Bende M., Holgersson M., Petruson B., Rundcrantz H., Alander U. (1995). Effect of local tranexamic acid gel in the treatment of epistaxis. ORL J Otorhinolaryngol Relat Spec, Jul-Aug;57(4):207-9.
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- Klepfish A., Berrebi A., Schattner A. (2001). Intranasal tranexamic acid treatment for severe epistaxis in hereditary hemorrhagic telangiectasia. Arch Intern Med, Mar 12;161(5):767.
- Hilton L., Reuben A. (2014). Best evidence topic reports. BET 3: Topical intranasal tranexamic acid for spontaneous epistaxis. Emerg Med J, May; 31(5):436-7. doi: 10.1136/emermed-2014-203763.3.
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- National Collaborating Centre for Womens and Childrens Health (UK). (2007). Intrapartum care of healthy women and their babies during childbirth. In Clinical Guidance RCGO Press, PMID: 21250397
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