Patient Care, Trauma

An Interdisciplinary Literature Review of Prehospital Use of Tranexamic Acid (TXA) in Major Bleeding

Issue 1 and Volume 43.

An interdisciplinary literature review

Discovered in the 1950s, tranexamic acid (TXA) is an antifibrinolytic medication that, over the last decade, has drawn considerable attention from researchers, clinicians and mainstream media.1

TXA is a synthetic chemical that’s a competitive antagonist to the lysine binding site of plasminogen.2 When a fibrin clot forms in the body in response to bleeding, it’s naturally degraded over time. In major trauma and hemorrhage, it’s thought that the body’s fibrin degradation process is accelerated due to high levels of fibrinolytic factors in circulation.3

This contributes to a lethal downward spiral causing severe dysregulation, annihilation of the body’s clotting process, and ultimately death due to hemorrhage. This is termed hyperfibrinolysis (HF).4,5

Enter TXA, the inhibitor of fibrin-degradation. By blocking the activation of plasminogen to plasmin, the body’s normal process of fibrin degradation is hindered. This is favorable in the setting of massive hemorrhage due to trauma—clots will remain viable and abate hemorrhage as originally intended.

This drug is routinely used around the world in various settings of major hemorrhage. It can be purchased over the counter in Japan for heavy menses. TXA is typically given in major bleeding prehospitally. Other implications of its use which have been identified and validated include postpartum hemorrhage, gastrointestinal bleeding, knee arthroplasty, coronary artery bypass, and several other applications.6–9

Before her death in April 2016, TXA’s co-creator, Utako Okamoto, lived to see its induction into the World Health Organization’s Essential Medicines and Health Products Report, as well as its clinical validation in several studies, including the Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage (CRASH-2) trial and the Military Application of Tranexamic Acid in Trauma Emergency Resuscitation study (MATTERs).10–12

It’s crucial to review the major clinical trials that assess TXA’s safety and efficacy and to analyze the interdisciplinary literature to fully appreciate its diversified application within multiple clinical scenarios. The primary objective of this literature review is to thoroughly evaluate the viability of TXA’s routine use in the prehospital setting.

All available data drawn from studies that utilize TXA in the manner suggested to EMS (i.e., 1 gram over 10 minutes within the first hour after injury) show significant benefit in all-cause mortality. This is a drug that belongs in the EMS community. TXA saves lives and needs to be given as soon as possible after severe traumatic hemorrhagic injury.

Photo Courtesy Mark Voyles and David Howerton

Major Studies of TXA Use

The CRASH-2 trial is conceivably one of the most referenced studies with regard to hemostasis and TXA. It was a randomized, placebo- controlled, double-blinded study with over 20,200 patients.

The 274 clinical centers participating in the study were from 40 countries throughout the world, mainly Western Europe, Sub-Saharan Africa and Western India.11

The primary outcome was death in hospital within four weeks of injury described based on bleeding, myocardial infarction (MI), stroke, pulmonary embolism (PE), multiorgan failure, head injury and other injuries. CRASH-2 collaborators found that all-cause mortality was significantly reduced in the TXA treatment arm (14.5%) vs. the placebo (16%). That’s a number needed to treat (NNT) of 67.11

The risk of death due to bleeding was significantly reduced (4.9% in the TXA group vs. 5.7% in the placebo group). There was no significant increase in mortality due to vascular occlusive events (e.g., PE, deep vein thrombosis [DVT], stroke or MI).11

The MATTERs study is a retrospective observational trial that was carried out in a United States military hospital based in Afghanistan. Looking back over a period of approximately two years, researchers compared a group of patients receiving TXA following combat injury to those who didn’t receive it.12

With a primary outcome of mortality at 24 hours, 48 hours, and 30 days, the trial found that the TXA group had a lower 48-hour mortality than the no-TXA group (11.3% vs. 18.9%, respectively; p = 0.004) as well as lower unadjusted mortality than the no-TXA group (17.4% vs 23.9%, respectively; p = 0.03).

The benefit was greatest in those who received a massive transfusion where TXA was independently associated with survival (odds ratio = 7.23) and less coagulopathy.12

A similar, single-center retrospective observational study, MATTERS-II compared multiple treatments: TXA-only, cryoprecipitate- only, TXA and cryoprecipitate, and neither. Over 1,300 patients were enrolled in the study. Analogous to the original MATTERS, participants required one unit or more of blood to participate.

The primary outcome was in-hospital mortality. Despite greater injury severity scores and packed red blood cells (PRBC) requirements, mortality was significantly lower in the TXA and cryoprecipitate group (11.6%) and TXA-only group (18.2%) than it was in the cryoprecipitate-only (21.4%) and neither (23.6%) groups.13

All available data drawn from studies that utilize TXA in the manner suggested to EMS show significant benefit in all-cause mortality. Photo courtesy Ed Pepin/Fairhaven Fire Department

All available data drawn from studies that utilize TXA in the manner suggested to EMS show significant benefit in all-cause mortality. Photo courtesy Ed Pepin/Fairhaven Fire Department

Study Criticisms

A common criticism of the CRASH-2 trial is that there were no defined inclusion criteria—it was the clinical impression of the treating physician that decided enrollment in the study.14 The CRASH-2 trial was designed to be a pragmatic, effectiveness trial where the authors sought to test TXA in a real clinical setting.

Therefore, clinicians decided when a patient needed adjunct interventions to blood transfusion.11,14 If there were defined, restricting inclusion criteria, it would have severely limited the number of patients who were tested with TXA, thus narrowing the population to whom TXA can be given.

There are also objections that most of the clinical centers in CRASH-2 weren’t providing the same care as in the U.S., since less than 2% of the enrolled clinical centers were U.S. trauma- level equivalent.15

Subgroup analysis of the CRASH-2 study shows that TXA must be given within three hours of injury for the mortality reduction and is most beneficial if given within one hour of injury. In fact, if given more than three hours after injury, mortality was slightly increased. Some feel this is a major limitation of the routine use of TXA.11,14

The reality is that patients involved in major trauma or who sustain serious injury in the U.S. may not present to a trauma center. In rural areas, patients are transferred from non- tertiary hospitals that provide initial trauma care to a trauma center. One study found that 43% of patients meeting criteria for major trauma were transferred from the initial hospital to a tertiary trauma center.16

Another study looking at the variability of trauma transfer practices in the U.S. detected that 37% of qualifying trauma patients were transferred to a tertiary care hospital from the primary hospital.17 That means there’s a need for administration of TXA in patients with prolonged pre-trauma center care—whether by EMS or at a non-trauma medical center.

Similarly, most clinical centers included in the CRASH-2 study, such as those in Sub- Saharan Africa, had fewer resources than most U.S. ALS units. This reinforces the concept that TXA is a prehospital drug to be given when an operating room isn’t immediately available.

The primary criticism of MATTERs is that it was a retrospective trial, and therefore carries inherent selection and information bias—chiefly because studies can’t control exposure to outcome and they rely heavily on accurate record keeping. Another issue people take with the MATTERS study is that the TXA group had a higher occurrence of DVT and PE.14,15

The authors of MATTERs state that this can be explained by the fact that the group receiving TXA was more severely injured based on the injury severity score that was used; increased injury burden has been associated with more thrombotic events.12

These findings of association—not causation—are a result of the retrospective nature of the study. TXA is fundamentally antifibrinolytic, not pro-thrombotic, therefore it can’t cause fibrin clot formation; it merely stabilizes existing clots.

Some argue that TXA should only be used in patients with HF. As previously stated, HF is a condition wherein the body’s fibrin degradation process is enhanced and unopposed.3

One current method for HF diagnosis is thromboelastography (TEG)—that is, a measurement of the coagulability of a patient’s blood.5 Some feel that TXA should only be given to patients when HF is diagnosed via TEG in a hospital.15

There have been several studies evaluating the utility of TEG in the diagnosis of acute traumatic bleeding, including one meta- analysis which concluded that there isn’t enough research available on the accuracy of TEG to validate its use for diagnosing HF in adult trauma patients.18

Currently, the gold standard for diagnosing trauma-related coagulopathy lies in universally available coagulation studies, including prothrombin time/international normalized ratio (INR) and activated partial thromboplastin time. At this time, TEG doesn’t play an essential role in the routine diagnosis of HF.

Arguments Against the Use of TXA

Finally, there are a few studies that recommend against the routine use of TXA. Those that are opposed to its use include a retrospective study of 1,032 patients from the American College of Surgeons database who met their criteria for trauma and had evidence of HF. The study compared TXA to no-TXA and it was determined that the TXA group had an increased 24-hour mortality.19

There were colossal differences in the injury severity score (ISS) and the mean measured physiology between the two groups. The use of a logistic regression formula seemingly failed to correct for the differences. This study’s conclusions are based on retrospective data prone to selection bias.

As in the MATTERs study, the TXA group was more severely injured, with a mean ISS difference of 15 (p < 0.001). The two groups weren’t representative of the same patient population receiving the same treatment.

Moreover, the conclusions of this study, which suggest against the use of TXA in trauma, are partly based on the use of TEG, which isn’t validated in the literature for diagnosis of HF in the clinical setting.18

Another retrospective study cautioning the use of TXA reported increased mortality in the TXA group. This study used a single center dataset with propensity scoring to shorten the gap between a much sicker TXA group (n = 150) and a non-TXA group.

Critically reviewing the article reveals a clear explanation for why mortality was increased. Consecutive trauma patients (n = 1,217) who required emergency surgery and/or transfusions from August 2009 to January 2013 were reviewed. At surgeon discretion, TXA was administered at a median of 97 minutes (1 g bolus, then 1 g over 8 hours) to 150 patients deemed high risk for hemorrhagic death.

Mortality associated with TXA was influenced by the timing of administration (p < 0.05), but any benefit was eliminated in those who required more than 2,000 mL packed red blood cells (PRBCs), who presented with systolic blood pressure of less than 120 mmHg, or who required emergency surgery (all p < 0.05).

In patients who didn’t need emergency surgery, mortality was reduced by 40% with TXA, but didn’t reach statistical significance. Additionally, in patients who received less than 2,000 mL of PRBCs (6.67 units), the mortality was 5.7% with TXA vs. 12.7% with no TXA.

However, once again the study was underpowered and the p-value was only 0.0959. Most telling was when and how their fatalities happened. The authors write, “The fact is that, in our hands, most of the time, TXA was administered in the operating room after the patient had already received a transfusion.”20

TXA was usually administered at the end of surgery—an average time of 97 minutes after admission (not injury)—to patients in the operating room (OR) who required more than six units of blood and had systolic blood pressure (SBP) less than 120 on presentation.

They selected 150 patients from a much larger cohort (n = 1,067) who didn’t receive TXA.28 It’s clear that TXA wasn’t used as indicated; it shouldn’t be given in this setting. TXA has been validated in early use and shouldn’t be given to patients after they sustain injury, are transported to the OR, given multiple units of PRBCs and are continuing to bleed.

This study shouldn’t be used as a basis for argument to not administer TXA in a prehospital setting.

Other Indications for TXA

It’s essential to review interdisciplinary literature to fully appreciate the value of TXA as a safe and effective antifibrinolytic in various clinical settings. The injectable form of TXA was originally approved by the U.S. Food and Drug Administration (FDA) for hemorrhage in hemophilia patients who receive tooth extraction.21 It was quickly identified as having various clinical benefits and since then, its off-label use has been expanded to include a seemingly endless list of applications.

Recently, a randomized, double-blind, placebo- controlled trial with over 20,000 patients confirmed TXA’s safety and efficacy in postpartum hemorrhage. Women 16 years of age and older were enrolled with a clinical diagnosis of postpartum hemorrhage after vaginal or cesarean delivery.

Over a period of six years, the trial found that death due to bleeding was significantly reduced in women given TXA (1.5%) vs. the placebo group (1.9%; p = 0.045). All-cause mortality didn’t differ significantly between the groups. There was also no difference in occurrence of adverse events (including thromboembolic events such as PE, DVT, MI,or stroke) between the two groups.6

TXA has also been reported as advantageous for decades in the orthopedic surgical community. A retrospective analysis of TXA administration perioperatively in patients undergoing total joint arthroplasty revealed a decrease in transfusion rates from 22.7% in the non-TXA cohort to 11.9% in those who received TXA (p < 0.05).

There was a significant actual cost savings for discharge-to-inpatient facilities and direct hospital costs (p < 0.001).22 Another meta-analysis reviewed 16 randomized controlled trials—1,308 cases in all—and found no significant difference between intra- articular and IV administration of TXA (p < 0.05). There was also no increase in complications of DVT or PE (p < 0.05).9

Finally, TXA significantly reduced estimated blood loss and calculated blood loss in adult patients having elective posterior thoracic/lumbar spinal fusion surgery; there was a 5% reduction in blood loss between the group receiving TXA and the placebo group (p = 0.017).23

A more recent meta-analysis in October 2017 reviewed orthopedic trauma patients from twelve different studies (1,333 patients). The risk for blood transfusion was evaluated as the primary outcome in patients who received TXA vs. control. There was significantly less risk for blood transfusion in the TXA group (odds ratio: 0.407, p < 0.001). There was significantly less blood loss in patients who received TXA (average difference 304 mL, p < 0.001). Additionally, there was no significant difference in the risk for symptomatic thromboembolic events (odds ratio: 0.968, p = 0.684).24

TXA has been used for many years in open heart and coronary artery surgery. A recent trial endorses its use in patients undergoing cardiac surgery.25 The study found that, among patients undergoing coronary artery surgery, TXA was associated with a lower risk of bleeding than placebo (4,331 units of blood were transfused in the TXA group; 7,994 units of blood were transfused in the placebo group; p < 0.001). Additionally, major hemorrhage or cardiac tamponade leading to re-operation occurred in 1.4% of the TXA group and 2.8% of patients in the placebo group (p = 0.001).

A clinical conundrum for many is whether to use TXA in patients with massive gastrointestinal (GI) bleeding. Though the supporting literature is currently limited, there’s a notable recent literature review of human and animal-based randomized controlled trials, meta-analyses, and case studies revealing a potential benefit of TXA administration in upper GI bleeding.7

The results of the Hemorrhage Alleviation with Tranexamic Acid—Intestinal system (HALT-IT) trial are expected in 2018. With approximately 40 countries and more than 200 hospitals participating the study will evaluate whether early administration of TXA in people with acute GI bleeding can reduce their risk of dying in the hospital. This will be the largest trial ever performed assessing TXA performance in acute GI bleeding with an expected excess of 8,000 patients.25

TXA is also safe to give in pediatric patients. In the Pediatric Trauma and Tranexamic Acid study (PED-TRAX), TXA was independently associated with decreased mortality among all 766 patients studied who were 18 years or younger (Odds Ratio: 0.3; p = 0.03). There was no significant difference in thromboembolic complications or other cardiovascular events reported in this retrospective study.27

An inclusive literature review of TXA must include mention of a common application of TXA in the acute care setting. TXA can be applied topically uncontrollable bleeding— particularly those with uncontrollable epistaxis. Patients with epistaxis may benefit from saturating nasal packing or gauze with 500 to 1,000 mg of TXA and inserting into the affected nares.28

One of the most recent randomized controlled clinical trials out of Iran included 124 participants with epistaxis on antiplatelet medication from two EDs. Topical TXA (intranasal [IN], 500 mg saturated in a cotton pledget) was compared to anterior nasal packing (ANP) alone and the proportion of patients with bleeding control at 10 minutes was recorded as the primary outcome. Topical TXA application resulted in significantly faster bleeding cessation (73% cessation in the TXA group vs. 29% in the ANP group, p < 0.001). Secondary outcomes included significantly less re-bleeding at one week, shorter ED LOS, and higher patient satisfaction as compared with ANP.28

If healthcare providers adhere to current recommendations that TXA is given within three hours (preferably within one hour) of injury, the prehospital period is the optimal window for administration. Photo courtesy Mark Voyles and David Howerton

If healthcare providers adhere to current recommendations that TXA is given within three hours (preferably within one hour) of injury, the prehospital period is the optimal window for administration. Photo courtesy Mark Voyles and David Howerton

Benefits of TXA

The cost of TXA in the U.S. ranges from $27.60 to $50.40 per 10 mL vial (1,000 mg/10 mL). Current off-label dosing recommendations are 10 mg/kg up to 1,000 mg over 15 minutes within 3 hours of bleeding, followed by a 1 mg/kg/hr infusion for 8 hours (based on CRASH-2 data).29

For reference, in the MATTERs trial, a one-time dose of 1,000mg was given.12 At most, using the CRASH-2 protocol, that’s $100.80 per patient treated. If we extrapolate based on the NNT from the CRASH-2 data, it costs $6,753.60 to save one life (that’s $100.80 per patient multiplied by a NNT of 67).

If healthcare providers adhere to current recommendations that TXA is given within three hours (preferably within one hour) of injury, the prehospital period is the optimal window for administration. Is it safe to administer outside of a hospital setting?

A retrospective cohort study isolated two statistically identical cohorts: A group that received TXA prehospitally, and a control group that didn’t receive it. They found that early mortality was significantly lower in the TXA group (24-hour mortality of 5.8% in the TXA cohort and 12.4% in the control; p = 0.01). Mean time to death in the TXA and control groups was 13.4 days vs. 4.9 days, respectively (p = 0.001).30

There are other prehospital studies evaluating the dynamics of clot formation and degradation using thromboelastometry (TEM, similar to TEG). It was found that a patient’s ability to maintain coagulation significantly improved after administration of TXA in the prehospital setting.31 This may be limited, by the deficiency that TEG shouldn’t be used in an everyday clinical setting as it isn’t sufficiently validated.18

A combined study involving the Israel Defense Forces (IDF) and Magen David Adom (MDA, the Israeli civilian emergency medical service) established feasibility in civilian and military settings for giving TXA outside of the hospital. The study established fully-functioning civilian protocol based on lessons learned in military casualties.32

Similarly, the Royal Flying Doctor Service of Queensland has been using a functional prehospital protocol since 2012, where one gram of TXA is loaded over 10 minutes followed by an additional 1 g over about eight hours.33

In Ohio, a safe and feasible TXA protocol was established with inclusion criteria based on the outcomes of CRASH-2.

Patients with life-threatening hemorrhage that required blood transfusion or massive transfusion protocol where the time of injury was less than three hours received 1 g of TXA before reaching the hospital. A maintenance dose of an additional 1 g over eight hours was then ordered by the receiving physician.11,34

Several major professional associations recommend the use of TXA. In their updated 2017 guidelines, the Eastern Association for the Surgery of Trauma (EAST) conditionally recommends its routine in-hospital use. 35

In Europe, the multidisciplinary Task Force for Advanced Bleeding Care in Trauma (ABC-T) guidelines from 2013 recommend that TXA be administered as early as possible to trauma patients who are bleeding or at risk of significant hemorrhage. Additionally, they recommend that TXA be administered within three hours after injury, including the first dose en route to the hospital.36,37

The British National Health System (NHS) has been using TXA in their trauma protocol since 2012. To date, no significant post- implementation issues have been identified or published.38

A recent, large meta-analysis published in November 2017 evaluated data of over 40,000 patients—the largest meta-analysis comparing TXA and control to date.39 The primary goal of the study was to examine the effect of treatment delay on the effectiveness of TXA.

The two major randomized clinical trial data sets included were from the CRASH-2 trial (20,127 trauma patients)11 and the recent WOMAN trial (20,011 postpartum hemorrhage patients).6 Logistic regression models demonstrated that 40% of deaths were due to bleeding, and 63% of those deaths due to bleeding occurred within 12 hours of injury.39

As expected, overall survival was significantly increased in the group who received TXA (odds ratio 1.2, p = 0.001). Immediate treatment with TXA improved survival by more than 70% (odds ratio: 1.72, p < 0.0001). The study determined that for every 15 minutes of treatment delay, survival benefit decreased by 10% until three hours (at which time there was no survival benefit). Additionally, there was no increase in vascular occlusive events with TXA in this large meta-analysis.39

Conclusion

Based on all available evidence in major clinical trials as well as literature of multiple disciplines, TXA is safe, economical, and effective for prehospital use. This is consistent with a recent review which suggests that TXA can reduce mortality in bleeding trauma patients without increasing risk of adverse reaction.40 Perhaps more importantly, a recent study demonstrated that for every 15 minute delay in treatment, survivability decreases by 10%.39

The bottom line: use TXA as soon as possible in the setting of massive hemorrhage. Traditionally, it’s given in the setting of hemorrhage due to trauma, but it has also been readily used in bleeding associated with postpartum hemorrhage, orthopedic surgery and coronary artery surgery. It appears to be safe to use in patients with acute GI bleeding, which will likely be confirmed with the release of the HALT-IT trial in 2018. TXA is safe and reasonable to use in pediatrics, and equally in the prehospital setting.

TXA has been endorsed by reputable trauma associations and is included in recent EAST and ABC-T guidelines. It’s been used for years in England as part of the NHS trauma protocol without evidence of unfavorable adverse effects or outcomes.

TXA should be given to patients with major hemorrhage as soon as possible. This is supported by a plethora of clinical trials, retrospective reviews and meta-analyses that reveal its safety and efficacy. Its use in the prehospital setting and upon arrival to most emergency departments is, therefore, well justified.

References

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33. Weingart S. (Feb. 19, 2012.) Tranexamic acid (TXA), Crash 2, & pragmatism with Tim Coats. EMCrit. Retrieved Nov. 28, 2017, from www.emcrit.org/podcasts/tranexamic-acid-trauma/.

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