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• W4386002405 abstract "Evaluation and management of trauma-induced coagulopathy has seen significant advances in the 21st century. Massive transfusion strategies favoring 1:1:1 ratios of blood components1 or whole blood transfusion2 have increasingly become the standard. Coagulopathy prediction tools3 and viscoelastic hemostatic assays to quantify derangements4,5 are used to anticipate and guide therapies respectively. A focus on treating the hyperfibrinolytic component of trauma-induced coagulopathy has captured clinicians’ attention since the Clinical Randomisation of Antifibrinolytic in Significant Haemorrhage (CRASH-2) study first demonstrated a 28-day mortality benefit in patients who received tranexamic acid (TXA) within three hours of injury.6 Since then, multiple trials of TXA in hemorrhagic shock have yielded mixed results in varied settings, calling into question TXA's role in the acutely unstable trauma patient.7-9 The primary outcome in the CRASH-2 trial was in-hospital death within four weeks of injury. Although the authors demonstrated a significant reduction in all-cause mortality (14.5% TXA group versus 16.0% placebo group; relative risk 0.91, 95% CI 0.85 – 0.97; p = 0.0035), the trial design was criticized over possible selection bias during enrollment in that the trial depended on ‘uncertainty about whether or not to treat with TXA’, meaning patients in whom there was a clear indication for TXA determined by the treatment team were not randomized. The presence of significant hemorrhage in the cohort has also been questioned, since the most common cause of death was traumatic brain injury (TBI), only half of the cohort received blood transfusions, and there was no data related to injury severity scores. As a follow-up, the CRASH-3 trial examined the effects of early (within three hours of injury) in-hospital administration of TXA in trauma patients with a Glasgow Coma Scale (GCS) score of 12 or less, or any intracranial bleeding on computed tomography scan, and no evidence of other major hemorrhage.7 The primary outcome for this randomized, multicenter, placebo-controlled trial was head injury-related in-hospital death within four weeks of injury. The uncertainty principle was again used to determine enrollment; however, since TXA is not a recommended first-line therapy for isolated TBI, the authors reported that virtually all eligible patients were enrolled. There was no significant difference in the primary outcome (risk ratio [RR] 0.94 [95% CI 0.86 – 1.02). In a prespecified sensitivity analysis, when patients with severe head injury (GCS score of 3 or bilateral unreactive pupils) were excluded, there was still no significant difference in group outcomes (RR 0.89 [95% CI 0.80 – 1.00). The only difference was found in a subgroup analysis, where there was a reduction in head injury-related deaths in patients with mild-to-moderate head injury (RR 0.78 [95% CI 0.64 – 0.95]) who received TXA, but not in patients with severe head injury (0.99 [95% CI 0.91 – 1.07]. In 2020, the STAAMP (Study of Tranexamic Acid During Air Medical and Ground Prehospital Transport) trial examined the effects of early (within two hours) pre-hospital administration of TXA in trauma patients at risk or with signs of hemorrhage.8 The primary outcome for this randomized, multi-center, double-blind trial was death within 30 days. Unlike the TXA dosing in the CRASH-2 and CRASH-3 trials (1-gram bolus dose followed by an infusion of 1-gram over 8 hours versus placebo), the STAAMP trial randomized patients to pre-hospital administration of 1-gram of TXA versus placebo along with three different in-hospital dosing regimens involving an additional bolus followed by an infusion. Patients who initially received placebo continued to receive placebo for the second bolus and the infusion, while patients in the TXA group received either a second 1-gram bolus versus placebo, and then either a 1-gram infusion over 8 hours versus placebo, resulting in three potential dosing regimens plus the placebo group. While there was no overall difference in 30-day mortality (8.1% pre-hospital TXA group versus 9.9% in placebo group [difference, –1.8%; 95% CI, –5.6% - 1.9%; p= 0.17]), subgroup analysis revealed multiple positive findings. Mortality was lower in patients receiving TXA within one hour of injury (4.6% versus 7.6%; difference, −3.0%; 95% CI, −5.7% - −0.3%; p < 0.002) as well as in patients with severe shock with systolic blood pressure ≤ 70 mmHg (18.5% versus 35.5%; difference, −17%; 95% CI, −25.8% - −8.1%; p < 0.003). In a prespecified subgroup analysis examining the different dosing regimens compared with placebo, 30-day mortality was lower in the repeat bolus followed by infusion regimen (7.3% versus 10.0%; difference, −2.7%; 95% CI, −5.0% - −0.4%; p = 0.04), indicating a potential benefit for increasing the total administered dose to 3-grams. In 2020, Rowell et all reported a second randomized trial of pre-hospital TXA administration examined the effect of early (within 2 hours) administration in patients with moderate or severe blunt or penetrating TBI who were not in shock.9 Their primary outcome was functional neurologic recovery at six months after injury measured by the Glasgow Outcome Scale-Extended (GOS-E), grouped into favorable and poor outcomes. There were three treatment groups: a 2-gram initial bolus followed by placebo infusion, a 1-gram initial bolus followed by a 1-gram infusion, and a placebo bolus and placebo infusion group. Similar to CRASH-3, there was no difference in the primary outcome (65% TXA versus 62% placebo; p = 0.16) or in secondary outcomes, including 28-day all-cause mortality (14% versus 17%). Unlike the CRASH-3 trial, no subgroups were identified as having potential benefit. The latest trial examining antifibrinolytic use in traumatic injury is the Pre-hospital Anti-fibrinolytics for Traumatic Coagulopathy and Haemorrhage (PATCH-Trauma) trial.10 PATCH-Trauma was an international, multicenter, double-blinded, randomized, placebo-controlled trial in 1,310 severe trauma adult patients who were deemed at high risk for trauma-related coagulopathy by out-of-hospital emergency medical personnel and were able to be administered the first TXA dose (1-gram bolus before hospital admission followed 1-gram infusion over 8 hours after hospital arrival) or placebo dose within three hours from injury. The primary outcome was survival with a favorable functional outcome at 6 months assessed using the same GOS-E scale employed by Rowell et al.9,10 Though the PATCH-Trauma authors found similar rates in the primary outcome between the TXA and placebo groups, there was improved one month survival in the TXA group (17.3% versus 21.8%; (RR 0.79; 95% CI, 0.63 - 0.99). Multiple strengths of the PATCH-Trauma trial methodology deserve highlighting. The investigators had broad inclusion criteria (i.e., severe trauma for any cause in any victim over 18 years being transported to a study-participating facility and able to receive study drug within three hours of injury) with relatively limited exclusion criteria (primarily residence in an elder facility or pregnancy). Statistical analysis strengths included the use of both intention-to-treat (ITT) and per-protocol (PP) population analyses, varying supplementary and subgroup analyses, and the use of multiple imputation analyses to address missing data using a large number (30) of imputed datasets. Based on prior literature, the investigators anticipated a treatment effect of 9% for the fraction of patients who would have a favorable outcome but ultimately powered the trial with a 2-sided alpha of 0.05; hence, this resulted in a slightly larger sample size and greater power if ultimately TXA administration had a positive effect on the primary outcome. Moreover, the validity of their results was further supported by the similar findings in both their ITT (53.7% versus 53.5%, risk ratio 1.00; 95%CI 0.90 - 1.12) and PP (59.6% versus 59.5%, RR 1.02; 95% CI 0.92 - 1.14) analyses for the primary outcome. Interestingly, for the primary outcome, the authors’ Figure 2 (Levels on the GOS-E scale at 6 Months) demonstrates the granularity for GOS-E scores (1 through 8) with an ‘unfavorable’ outcome having a score of 4 or less (score of 1 = death). Excluding a score of 2 (vegetative state) which had less than 0.5% in the placebo group and none in the TXA group, these findings demonstrate a nearly 5% greater number of patients died with placebo or about 20% of the placebo deaths may have lived with TXA administration. This implies that there may be a small percentage of patients with high-acuity injuries who would benefit from TXA. This issue is somewhat elucidated in the subgroup analyses. Despite the investigators demonstrating no significant heterogeneity in TXA's effect on the primary outcome across multiple subgroups, they do acknowledge in their discussion that there is insufficient power for some of these comparisons. Nonetheless, based on their subgroup analyses, TXA may actually be harmful if first administered ≥ 2 hours after injury. Similarly, TXA use may be beneficial in penetrating and/or burn injuries versus blunt trauma and in those with poor initial Glasgow Coma scores. Importantly, GCS is a variable the investigators based their randomization stratification upon, hence, it should not add bias to the results. It is plausible that in TBI patients, a trend towards a benefit with TXA, may in part have constituted the higher death rates in the placebo group. As a prospective randomized controlled trial with negative findings that was not designed as an equivalence trial, the authors appropriately concluded that TXA did not have an impact on the primary outcome. The PATCH-Trauma trial appears to support the findings of the CRASH-2 trial while further teasing out that in mature trauma systems, while TXA reduced early (24 hour and 28 day) mortality, these outcomes did not endure at 6 months. TXA did not favorably impact transfusion rates, fibrinogen, or international normalized ratio values. Importantly, there was no difference in thromboembolic complications between the study groups. When considering the PATCH-trauma trial primary outcome of 6-month survival with a favorable functional outcome, it is categorized as a negative study. While the number needed to treat to save one life was 23, survival was associated with severe disability. However, considering that in the acute trauma cohort, the early reduction of death due to hemorrhage (both extra- or intra-cranial) may be a more clinically meaningful trial endpoint. Within the first 24 hours, more effective hemodynamic stabilization is valuable as the evolution of these injuries are yet to be fully elucidated and innumerable variables exist impacting longer term functional outcomes including long term rehabilitation. Depending on the injury, functional outcomes may continue to improve beyond the 6 month mark evaluated in the PATCH-Trauma trial. Thus, the recently revealed lower GOS-E scores at 6 months should not preclude the many transfusion strategies demonstrated to stabilize critical trauma patients, including TXA administration. As highlighted in the study's accompanying editorial, measures of long-term disability may evolve over time and do not necessarily equate with a patient's perceived quality of life.11 Given the repeatedly confirmed benefits of early mortality reduction from exsanguination or TBI, this low cost intervention with a reasonable side effect profile deserves further study. Current trauma care should still include the continued administration of TXA within two to three hours from injury along with the other interventions known to mitigate life-threatening hemorrhage. Future research related to pre-hospital TXA administration in the trauma context should further focus on varying subgroups (i.e. burns, penetrating trauma, and blunt trauma) individually or in varying combinations as well as relationship to time from injury. 1Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015;313:471-482. DOI: 10.1001/jama.2015.12.2Hanna K, Bible L, Chehab M, et al. Nationwide analysis of whole blood hemostatic resuscitation in civilian trauma. J Trauma Acute Care Surg. 2020;89:329-335. DOI: 10.1097/TA.0000000000002753.3Peltan ID, Rowhani-Rahbar A, Vande Vusse LK, et al. Development and validation of a prehospital prediction model for acute traumatic coagulopathy. Crit Care. 2016;20:371. DOI: 10.1186/s13054-016-1541-9.4Gonzalez E, Moore EE, Moore HB, et al. Goal-directed Hemostatic Resuscitation of Trauma-induced Coagulopathy: A Pragmatic Randomized Clinical Trial Comparing a Viscoelastic Assay to Conventional Coagulation Assays. Ann Surg. 2016;263:1051-1059. DOI: 10.1097/SLA.0000000000001608.5Baksaas-Aasen K, Gall LS, Stensballe J, et al. Viscoelastic haemostatic assay augmented protocols for major trauma haemorrhage (ITACTIC): a randomized, controlled trial. Intensive Care Med. 2021;47:49-59. DOI: 10.1007/s00134-020-06266-1.6CRASH-2 trial collaborators, Shakur H, Roberts I, et al. 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. DOI: 10.1016/S0140-6736(10)60835-5.7CRASH-3 trial collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomized, placebo-controlled trial: CRASH-3 trial collaborators. Lancet. 2019;394:1713-1723. DOI: 10.1016/S0140-6736(19)32233-0.8Guyette FX, Brown JB, Zenati MS, et al. Tranexamic Acid During Prehospital Transport in Patients at Risk for Hemorrhage After Injury: A Double-blind, Placebo-Controlled, Randomized Clinical Trial. JAMA Surg. 2020;156:11-20. DOI: 10.1001/jamasurg.2020.4350.9Rowell SE, Meier EN, McKnight B, et al. Effect of Out-of-Hospital Tranexamic Acid vs Placebo on 6-Month Functional Neurologic Outcomes in Patients With Moderate or Severe Traumatic Brain Injury. JAMA. 2020;324:961-974. DOI: 10.1001/jama.2020.8958.10PATCH-Trauma Investigators and the ANZICS Clinical Trials Group, Gruen RL, Biswadev M, et al. Prehospital Tranexamic Acid for Severe Trauma. N Engl J Med. 2023;389:127-136. DOI: 10.1056/NEJMoa2215457.11Shakur-Still H, Roberts I. Tranexamic Acid for Trauma Patients - More Lives to Save and Outcomes to Consider. N Engl J Med. 2023;389:181-183. DOI: 10.1056/NEJMe2305075. none None of the 3 authors have any conflicts of interest." @default.
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• W4386002405 date "2023-08-01" @default.
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• W4386002405 title "The PATCH-Trauma Trial: Antifibrinolytics and Stanching the Blood Meridian in Trauma" @default.
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