Circulation - Tranexamic Acid (TXA)

#### TRANEXAMIC ACID (TXA)

Trauma Surg Acute Care Open. 2017 Oct 5;2(1):e000107

# Antifibrinolytics in a rural trauma state: assessing the opprotunities.

Bardes J, Palmer A, Con J, Wilson A, Schaefer G.

Background: Tranexamic acid (TXA) has demonstrated improved mortality among trauma patients. However, recent evidence from urban US trauma centers has failed to show a benefit among the civilian population. TXA in rural states has not been evaluated. This study aimed to evaluate the current use of TXA in the rural trauma population.

Methods: A retrospective observational review at a level 1 trauma center based in a rural environment. Records were reviewed for TXA indications. TXA indication was defined as: systolic blood pressure <90 mm Hg, blood transfusion, or with a clinical concern for ongoing bleeding. Patients were ineligible if the time since injury was >3 hours.

Results: 400 patients were evaluated. 54% of patients met indications for TXA. 14% of these received TXA. 30.4% with an indication for TXA were ineligible due to arrival beyond 3 hours from time of injury. 135 patients arrived as transfers, 265 from the scene. There was no difference in TXA indications between scene and transfers (73 vs 144, p=1). Transfers were more likely to arrive beyond the 3-hour window (59 vs 7, p=0.001). Mortality for patients treated with TXA was 12.5%. This was not significantly different from patients not treated with TXA (19%).

Discussion: In a rural system, long transfers exclude most patients from treatment with TXA. A multicenter rural trauma center study will be needed to better define the optimal use of TXA in rural populations.

Level of evidence: Level IV data: therapeutic/care management.

J Trauma Acute Care Surg. 2018 Jun;84(6S Suppl 1):S54-S62

# Tranexamic acid in severe trauma patients managed in a mature trauma care system.

Boutonnet M(1), Abback P, Le Saché F, Harrois A, Follin A, Imbert N, Cap AP, Trichereau J, Ausset S; Traumabase Group.

BACKGROUND: Tranexamic acid (TXA) use in severe trauma remains controversial notably because of concerns of the applicability of the CRASH-2 study findings in mature trauma systems. The aim of our study was to evaluate the outcomes of TXA administration in severely injured trauma patients managed in a mature trauma care system.

METHODS: We performed a retrospective study of data prospectively collected in the TraumaBase registry (a regional registry collecting the prehospital and hospital data of trauma patients admitted in six Level I trauma centers in Paris Area, France). In hospital mortality was compared between patients having received TXA or not in the early phase of resuscitation among those presenting an unstable hemodynamic state. Propensity score for TXA administration was calculated and results were adjusted for this score. Hemodynamic instability was defined by the need of packed red blood cells (pRBC) transfusion and/or vasopressor administration in the emergency room (ER).

RESULTS: Among patients meeting inclusion criteria (n = 1,476), the propensity score could be calculated in 797, and survival analysis could be achieved in 684 of 797. Four hundred seventy (59%) received TXA, and 327 (41%) did not. The overall hospital mortality rate was 25.7%. There was no effect of TXA use in the whole population but mortality was lowered by the use of TXA in patients requiring pRBC transfusion in the ER (hazard ratio, 0.3; 95% confidence interval, 0.3-0.6).

CONCLUSION: The use of TXA in the management of severely injured trauma patients, in a mature trauma care system, was not associated with reduction in the hospital mortality. An independent association with a better survival was found in a selected population of patients requiring pRBC transfusion in the ER.

LEVEL OF EVIDENCE: Therapeutic study, level III.

Eur J Trauma Emerg Surg. 2018 Jun 19. doi: 10.1007/s00068-018-0974-z. [Epub ahead of print]

# Benefits of the tranexamic acid in head trauma with no extracranial bleeding: a prospective follow-up of 180 patients.

Chakroun-Walha O, Samet A, Jerbi M, Nasri A, Talbi A, Kanoun H, Souissi B, Chtara K, Bouaziz M, Ksibi H, Rekik N

INTRODUCTION: Tranexamic acid (TXA) is one of the debated therapies in the management of traumatic brain injury (TBI). We conducted this study to evaluate the benefits of TXA in TBI on the mortality and its safety in these patients.

METHODS: This was a prospective randomized open-label trial including all patients, aged at 18 years or older, hospitalized in the emergency room during a 13-month period, for TBI. After the realization of the body CT scan, the patients were included if they had intracranial bleeding, and were then randomized according to their medical file number to receive or not the TXA. The eligibility criteria were based on the uncertainty principle, patients with significant extracranial bleeding were excluded since there was evidence that TXA improve their outcome.

RESULTS: We enrolled 180 patients aged at 42 ± 20 years, with an 88% men-proportion. Subarachnoid haemorrhage was the most frequent lesion in the brain CT-scan (67.5%). After randomization, 96 patients were in the TXA group (53%). Demographic data, clinical, biological and radiological features were statistically comparable in the two groups of patients ('TXA' and 'noTXA'). The needs of transfusion or neurosurgery, the mortality rate, the in-hospital length of stay and the dependency at 28-post-traumatic day were similar in the two groups of patients. However, pulmonary embolism was statistically more frequent in 'TXA' group (11.5 versus 2.4%, p = 0.02).

CONCLUSION: TXA is an interesting treatment in haemorrhagic shock. Its efficiency in head trauma is still debated and controversial. Its impact on the mortality and the needs of transfusion or surgery were not demonstrated in this study. Nevertheless, its safety worth to be studied in larger samples as we found a higher rate of pulmonary embolism in the treated group.

Emerg Med J. 2018 Aug;35(8):523-524. doi: 10.1136/emermed-2018-207944.2.

# Intravenous tranexamic acid for the treatment of post-partum haemorrhage.

Coss C, Singh M, Jones J

A short-cut review was carried out to see if administering tranexamic acid reduced mortality in patients with postpartum haemorrhage. The author, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses of these papers are tabulated. Two randomised controlled trials were found, a smaller one suggesting that treatment with tranexamic acid reduced the volume of blood lost and a much larger study that showed a reduction in mortality due to bleeding in this patient group. There were no significant side effects from this treatment found in either study.

J Trauma Acute Care Surg. 2018 Jul;85(1S Suppl 2):S44-S48. doi:10.1097/TA.0000000000001861.

# The effects of hemorrhage on the pharmacokinetics of tranexamic acid in a swine model.

Derickson M, McClellan J, Marko S, Kuckelman J, Phillips C, Barron M, Martin M, Loughren M

BACKGROUND: The early use of tranexamic acid (TXA) is strongly advocated in patients who are likely to require massive transfusion to decrease mortality. This study determines the influence of hemorrhage on the pharmacokinetics of TXA in a porcine model.

METHODS: The investigation was a prospective experimental study in Yucatan minipigs. First, in vitro plasma-cell partitioning of TXA was evaluated by inoculating whole blood with known aliquots, centrifuging, and measuring the supernatant with high-performance liquid chromatography with mass spectrometry (HPLC-MS). Then, using in vivo modeling, normovolemic and hypovolemic (35% reduction in blood volume) swine (n = 4 per group) received 1 g of intravenous TXA and had blood sampled at 14 time points over 4 hours to determine baseline clearance via HPLC-MS. Additional swine (n = 4) were hemorrhaged 35% of their blood volume, and TXA was administered as a 15 mg/kg infusion over 10 minutes followed by infusion of 1.875 mg/kg per hour to simulate massive hemorrhage scenario. During the first hour of TXA administration, one total blood volume was hemorrhaged and simultaneously replaced with TXA free blood. Serial blood samples and the hemorrhaged blood were analyzed by HPLC-MS to determine the percentage of dose lost via hemorrhage.

RESULTS: Clearance of TXA was diminished in the hypovolemic group compared with the normovolemic group (115 ± 4 vs 70 ± 7 mL/min). Percentage of dose lost via hemorrhage averaged 25%. The lowest measured plasma level during the exchange transfusion was 34 μg/mL.

CONCLUSION: Mean 25% of the present 2017 Joint Trauma System Clinical Practice Guideline dosing of TXA can be lost to hemorrhage if a blood volume is transfused within an hour of initiating therapy. In the case of TXA, which has limited distribution and is administered during active hemorrhage and massive blood transfusions, replacement strategies should be developed and tested to find simple methods of adjusting the current dosing guidelines to maintain therapeutic plasma concentrations.

LEVEL OF EVIDENCE: Therapeutic, level II.

Am J Emerg Med. 2018 Jun;36(6):1079-1087

# Efficacy of prehospital administration of tranexamic acid in trauma patients: a meta-analysis of the randomized controlled trials.

El-Menyar A, Sathian B, Asim M, Latifi R, Al-Thani H

OBJECTIVE: Antifibrinolytic agent tranexamic acid (TXA) has a potential clinical benefit for in-hospital patients with severe bleeding but its effectiveness in pre-hospital settings remains unclear. We conducted a systematic review and meta-analysis to evaluate whether pre-hospital administration of TXA compared to placebo improve patients' outcomes?

METHODS: PubMed, MEDLINE, Cochrane Library, WHO International Clinical Trials Registry Platform, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, clinicaltrials.gov and Google scholar databases were searched for a retrospective, prospective and randomized (RCT) or quasi-RCT studies that assessed the effect of prehospital administration of TXA versus placebo on the outcomes of trauma patients with significant hemorrhage. The main outcomes of interest were 24hour 30-day mortality and in-hospital thromboembolic complications. Two authors independently abstracted the data using a data collection form. Results from different studies were pooled for the analysis, when appropriate.

RESULTS: Out of 92 references identified through the search, two analytical studies met the inclusion criteria. The effect of TXA on 24-hour mortality had a pooled odds ratio (OR) of 0.49 (95% CI 0.28-0.85), 30-day mortality OR of 0.86 (95% CI, 0.56-1.32), and thromboembolic events OR of 0.74 (95% CI, 0.27-2.07).

CONCLUSION: Prehospital TXA appears to reduce early mortality in trauma patients. The pooled analysis also shows a trend toward lower 30-day mortality and reduced risk of thromboembolic events. Additional randomized controlled clinical trials are needed to determine the significance of these trends.

J Orthop Surg Res. 2018 Jun 18;13(1):149

# Tranexamic acid is associated with selective increase in inflammatory markers following total knee arthroplasty (TKA): a pilot study.

Grant A, Letson H, Morris J, McEwen P, Hazratwala K, Wilkinson M, Dobson G

BACKGROUND: Tranexamic acid (TXA) is commonly used in orthopedic surgery to reduce excessive bleeding and transfusion requirements. Our aim was to examine if TXA was required in all osteoarthritis patients undergoing TKA surgery, and its possible effects on systemic inflammation and coagulation properties.

METHODS: Twenty-three patients (Oxford Score 22-29) were recruited consecutively; 12 patients received TXA before (IV, 1.2 g/90 kg) and immediately after surgery (intra-articular, 1.4 g/90 kg). Inflammatory mediators and ROTEM parameters were measured in blood at baseline, after the first bone-cut, immediately after surgery, and postoperative days 1 and 2.

RESULTS: After the bone cut and surgery, TXA significantly increased MCP-1, TNF-α, IL-1β and IL-6 levels compared to non-TXA patients, which was further amplified postoperatively. During surgery, TXA significantly prolonged EXTEM clot times, indicating a thrombin-slowing effect, despite little or no change in clot amplitude or fibrinogen. TXA was associated with three- to fivefold increases in FIBTEM maximum lysis (ML), a finding counter to TXA's antifibrinolytic effect. Maximum lysis for extrinsic and intrinsic pathways was < 8%, indicating little or no hyperfibrinolysis. No significant differences were found in postoperative hemoglobin between the two groups.

CONCLUSIONS: TXA was associated with increased systemic inflammation during surgery compared to non-TXA patients, with further amplification on postoperative days 1 and 2. On the basis of little or no change in viscoelastic clot strength, fibrinogen or clot lysis, there appeared to be no clinical justification for TXA in our group of patients. Larger prospective, randomized trials are required to investigate a possible proinflammatory effect in TKA patients.

Anaesthesia. 2018 Jun;73(6):719-729

# Optimisation of the dosage of tranexamic acid in trauma patients with population pharmacokinetic analysis.

Grassin-Delyle S, Theusinger O, Albrecht R, Mueller S, Spahn D, Urien S, Stein P

Tranexamic acid is used both pre-hospital and in-hospital as an antifibrinolytic drug to treat or prevent hyperfibrinolysis in trauma patients; dosing, however, remains empirical. We aimed to measure plasma levels of tranexamic acid in patients receiving pre-hospital anti-hyperfibrinolytic therapy and to build a population pharmacokinetic model to propose an optimised dosing regimen. Seventy-three trauma patients were enrolled and each received tranexamic acid 1 g intravenously pre-hospital. A blood sample was drawn after arrival in the emergency department, and we measured the plasma tranexamic acid concentration using liquid chromatography-mass spectrometry, and modelled the data using non-linear mixed effect modelling. Tranexamic acid was administered at a median (IQR [range]) time of 43 (30-55 [5-135]) min after trauma. Plasma tranexamic acid levels were determined on arrival at hospital, 57 (43-70 [20-148]) min after pre-hospital administration of the drug. The measured concentration was 28.7 (21.5-38.5 [8.7-89.0]) μg.ml-1. Our subjects had sustained severe trauma; injury severity score 20 (16-29 [5-75]), including penetrating injury in 2.8% and isolated traumatic brain injury in 19.7%. The pharmacokinetics were ascribed a two-compartment open model with body-weight as the main covariate. As tranexamic acid concentrations may fall below therapeutic levels during initial hospital treatment, we propose additional dosing schemes to maintain a specific target blood concentration for as long as required. This is the first study to investigate plasma level and pharmacokinetics of tranexamic acid after pre-hospital administration in trauma patients. Our proposed dosing regimen could be used in subsequent clinical trials to better study efficacy and tolerance profiles with controlled blood concentrations.

J Trauma Acute Care Surg. 2018 Jul;85(1):91-100

# Plasma coadministration improves resuscitation with tranexamic acid or prothrombin complex in a porcine hemorrhagic shock model.

Kuckelman J, Barron M, Moe D, Lallemand M, McClellan J, Marko S, Eckert M, Martin MJ.

BACKGROUND: Traumatic coagulopathy has now been well characterized and carries high rates of mortality owing to bleeding. A 'factor-based' resuscitation strategy using procoagulant drugs and factor concentrates in lieu of plasma is being used by some, but with little evidentiary support. We sought to evaluate and compare resuscitation strategies using combinations of tranexamic acid (TXA), prothrombin complex concentrate (PCC), and fresh frozen plasma (FFP).

METHODS: Sixty adult swine underwent 35% blood volume hemorrhage combined with a truncal ischemia-reperfusion injury to produce uniform shock and coagulopathy. Animals were randomized to control (n = 12), a single-agent group (TXA, n = 10; PCC, n = 8; or FFP, n = 6) or combination groups (TXA-FFP, n = 10; PCC-FFP, n = 8; TXA-PCC, n = 6). Resuscitation was continued to 6 hours. Key outcomes included hemodynamics, laboratory values, and rotational thromboelastometry. Results were compared between all groups, with additional comparisons between FFP and non-FFP groups.

RESULTS: All 60 animals survived to 6 hours. Shock was seen in all animals, with hypotension (mean arterial pressure, 44 mm Hg), tachycardia (heart rate, 145), acidosis (pH 7.18; lactate, 11), anemia (hematocrit, 17), and coagulopathy (fibrinogen, 107). There were clear differences between groups for mean pH (p = 0.02), international normalized ratio (p < 0.01), clotting time (CT; p < 0.01), lactate (p = 0.01), creatinine (p < 0.01), and fibrinogen (p = 0.02). Fresh frozen plasma groups had significantly improved resuscitation and clotting parameters (Figures), with lower lactate at 6.5 versus 8.4 (p = 0.04), and increased fibrinogen at 126 versus 95 (p < 0.01). Rotational thromboelastometry also demonstrated shortened CT at 60 seconds in the FFP group vs 65 seconds in the non-FFP group (p = 0.04).

CONCLUSION: When used to correct traumatic coagulopathy, combinations of FFP with TXA or PCC were superior in improving acidosis, coagulopathy, and CT than when these agents are given alone or in combination without plasma. Further validation of pure factor-based strategies is needed.

J Bone Jt Infect. 2018 May 28;3(2):104-107

# The use of tranexamic acid in total elbow replacement to reduce post-operative would infection.

Mannan S, Ali M, Mazur L, Chin M, Fadulelmola A

Background: Incidence of infection following total elbow replacement (TER) is recognised to be higher compared to hip or knee arthroplasty. Extensive swelling following TER can complicate the wound healing which might lead to infection. Tranexamic Acid (TXA) is proven to reduce blood loss peri-operatively which might contribute to better healing outcomes. Our aim is to assess the effect of TXA in wound healing following TER. Methods: A retrospective review of a single surgeon case series. 10 patients had TER mainly for complicated elbow fractures, four of them were relatively immune-supressed. All patients had 2 grams of TXA and antibiotics intra-operatively. All were reviewed at two weeks following surgery for wound check and removal of surgical clips.

Results: Seven females and three males with a mean age of 81.5 had TER and TXA. The mean level of pre-operative haemoglobin was 134.40 g/l and the mean post-operative level was 122.70g/l. No patient in this series required blood transfusion. At two weeks and six weeks follow-up, all wound healed up with no signs of infection. Conclusion: TXA has been proven to be safe an effective way of reducing peri-operative bleeding. TXA maintains haemostasis after releasing the tourniquet and therefore reduces the swelling and wound complications post-operatively.

Am J Emerg Med. 2018 Jun 5. pii: S0735-6757(18)30472-8. doi: 10.1016/j.ajem.2018.06.010. [Epub ahead of print]

# Evaluation of tranexamic acid in trauma patients: a retrospective quantitative analysis.

Ng M, Perrott J, Burgess S

INTRODUCTION: Tranexamic acid (TXA) has been shown to decrease mortality in adult trauma patients with or at significant risk of hemorrhage when administered within 3 h of injury. The use and appropriateness of TXA in adult trauma patients presenting to Royal Columbian Hospital (RCH) was investigated.

METHODS: This retrospective chart review utilized the British Columbia Trauma Registry to identify 100 consecutive trauma patients that presented to the emergency department at RCH between April 2012 to June 2015 and met the following indications for TXA: systolic blood pressure <90 mm Hg and/or heart rate >110 bpm and presentation within 8 h of injury. Primary outcomes included: percentage that met indications for TXA, received TXA according to the CRASH-2 protocol, received a pre-hospital dose, and received TXA ≤1, >1 to ≤3, or >3 h from injury.

RESULTS: During the given time period, 117 subjects (2.7%) met indications for TXA. 67 patients (57%) received TXA in any dose, with 10 subjects (8.5%) receiving TXA according to the CRASH-2 protocol. Of the 67 patients who received any TXA, 76% did so ≤3 h. 22 patients (19%) received TXA as a pre-hospital dose.

CONCLUSIONS: <10% of adult trauma patients that met the indication for TXA received it according to the CRASH-2 protocol. Of those patients that received TXA, 76% did so within 3 h. Further inquiry to identify reasons trauma patients are not receiving TXA as well as quality improvement initiatives in trauma care are required.

LEVEL OF EVIDENCE: III STUDY TYPE: Therapeutic.

Lancet. 2018 May 26;391(10135):2107-2115

# Tranexamic acid for hyperacute primary intracerebral haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial.

Sprigg N, Flaherty K, Appleton J, Al-Shahi Salman R, Bereczki D, Beridze M, Christensen H, Ciccone A, Collins R, Czlonkowska A, Dineen R, Duley L, Egea-Guerrero J, England T, Krishnan K, Laska A, Law Z, Ozturk S, Pocock S, Roberts I, Robinson T, Roffe C, Seiffge D, Scutt P, Thanabalan J, Werring D, Whynes D, Bath P; TICH-2 Investigators.

BACKGROUND: Tranexamic acid can prevent death due to bleeding after trauma and post-partum haemorrhage. We aimed to assess whether tranexamic acid reduces haematoma expansion and improves outcome in adults with stroke due to intracerebral haemorrhage.

METHODS: We did an international, randomised placebo-controlled trial in adults with intracerebral haemorrhage from acute stroke units at 124 hospital sites in 12 countries. Participants were randomly assigned (1:1) to receive 1 g intravenous tranexamic acid bolus followed by an 8 h infusion of 1 g tranexamic acid or a matching placebo, within 8 h of symptom onset. Randomisation was done centrally in real time via a secure website, with stratification by country and minimisation on key prognostic factors. Treatment allocation was concealed from patients, outcome assessors, and all other health-care workers involved in the trial. The primary outcome was functional status at day 90, measured by shift in the modified Rankin Scale, using ordinal logistic regression with adjustment for stratification and minimisation criteria. All analyses were done on an intention-to-treat basis. This trial is registered with the ISRCTN registry, number ISRCTN93732214.

FINDINGS: We recruited 2325 participants between March 1, 2013, and Sept 30, 2017. 1161 patients received tranexamic acid and 1164 received placebo; the treatment groups were well balanced at baseline. The primary outcome was assessed for 2307 (99%) participants. The primary outcome, functional status at day 90, did not differ significantly between the groups (adjusted odds ratio [aOR] 0·88, 95% CI 0·76-1·03, p=0·11). Although there were fewer deaths by day 7 in the tranexamic acid group (101 [9%] deaths in the tranexamic acid group vs 123 [11%] deaths in the placebo group; aOR 0·73, 0·53-0·99, p=0·0406), there was no difference in case fatality at 90 days (250 [22%] vs 249 [21%]; adjusted hazard ratio 0·92, 95% CI 0·77-1·10, p=0·37). Fewer patients had serious adverse events after tranexamic acid than after placebo by days 2 (379 [33%] patients vs 417 [36%] patients), 7 (456 [39%] vs 497 [43%]), and 90 (521 [45%] vs 556 [48%]).

INTERPRETATION: Functional status 90 days after intracerebral haemorrhage did not differ significantly between patients who received tranexamic acid and those who received placebo, despite a reduction in early deaths and serious adverse events. Larger randomised trials are needed to confirm or refute a clinically significant treatment effect.

FUNDING: National Institute of Health Research Health Technology Assessment Programme and Swiss Heart Foundation.

J Spec Oper Med. Spring 2018;18(1):62-68.

# Intramuscular tranexamic acid in tactical and combat settings.

Vu EN, Wan WCY, Yeung TC, Callaway DW.

BACKGROUND: Uncontrolled hemorrhage remains a leading cause of preventable death in tactical and combat settings. Alternate routes of delivery of tranexamic acid (TXA), an adjunct in the management of hemorrhagic shock, are being studied. A working group for the Committee for Tactical Emergency Casualty Care reviewed the available evidence on the potential role for intramuscular (IM) administration of TXA in nonhospital settings as soon as possible from the point of injury.

METHODS: EMBASE and MEDLINE/PubMed databases were sequentially searched by medical librarians for evidence of TXA use in the following contexts and/or using the following keywords: prehospital, trauma, hemorrhagic shock, optimal timing, optimal dose, safe volume, incidence of venous thromboembolism (VTE), IM bioavailability.

RESULTS: A total of 183 studies were reviewed. The strength of the available data was variable, generally weak in quality, and included laboratory research, case reports, retrospective observational reviews, and few prospective studies. Current volume and concentrations of available formulations of TXA make it, in theory, amenable to IM injection. Current best practice guidelines for large-volume injection (i.e., 5mL) support IM administration in four locations in the adult human body. One case series suggests complete bioavailability of IM TXA in healthy patients. Data are lacking on the efficacy and safety of IM TXA in hemorrhagic shock.

CONCLUSION: There is currently insufficient evidence to support a strong recommendation for or against IM administration of TXA in the combat setting; however, there is an abundance of literature demonstrating efficacy and safety of TXA use in a broad range of patient populations. Balancing the available data and risk- benefit ratio, IM TXA should be considered a viable treatment option for tactical and combat applications. Additional studies should focus on the optimal dose and bioavailability of IM dosing of patients in hemorrhagic shock, with assessment of potential downstream sequelae.