The PATCH-Trauma Trial. Antifibrinolytics and Stanching the Blood Meridian in Trauma

Evaluation and management of trauma-induced coagulopathy has seen significant advances in the 21st century. Massive transfusion strategies favoring 1:1:1 ratios blood components1 or whole transfusion2 have increasingly become standard. Coagulopathy prediction tools3 viscoelastic hemostatic assays to quantify derangements4,5 are used anticipate guide therapies respectively. A focus on treating hyperfibrinolytic component captured clinicians’ attention since Clinical Randomisation Antifibrinolytic Significant Haemorrhage (CRASH-2) study first demonstrated a 28-day mortality benefit patients who received tranexamic acid (TXA) within three hours injury.6 Since then, multiple trials TXA hemorrhagic shock yielded mixed results varied settings, calling into question TXA's role acutely unstable trauma patient.7-9 The primary outcome CRASH-2 trial was in-hospital death four weeks injury. Although authors reduction all-cause (14.5% group versus 16.0% placebo group; relative risk 0.91, 95% CI 0.85 – 0.97; p = 0.0035), design criticized over possible selection bias during enrollment that depended ‘uncertainty about whether not treat with TXA’, meaning whom there clear indication for determined by treatment team were randomized. presence hemorrhage cohort also been questioned, most common cause traumatic brain injury (TBI), only half transfusions, no data related severity scores. As follow-up, CRASH-3 examined effects early (within injury) administration Glasgow Coma Scale (GCS) score 12 less, any intracranial bleeding computed tomography scan, evidence other major hemorrhage.7 this randomized, multicenter, placebo-controlled head injury-related uncertainty principle again determine enrollment; however, is recommended first-line therapy isolated TBI, reported virtually all eligible enrolled. There difference (risk ratio [RR] 0.94 [95% 0.86 1.02). In prespecified sensitivity analysis, when severe (GCS 3 bilateral unreactive pupils) excluded, still outcomes (RR 0.89 0.80 1.00). found subgroup where deaths mild-to-moderate 0.78 0.64 0.95]) TXA, but (0.99 0.91 1.07]. 2020, STAAMP (Study Tranexamic Acid During Air Medical Ground Prehospital Transport) two hours) pre-hospital at signs hemorrhage.8 multi-center, double-blind 30 days. Unlike dosing (1-gram bolus dose followed an infusion 1-gram 8 placebo), randomized along different regimens involving additional infusion. Patients initially continued receive second infusion, while either placebo, then resulting potential plus group. While overall 30-day (8.1% 9.9% [difference, –1.8%; CI, –5.6% - 1.9%; p= 0.17]), analysis revealed positive findings. Mortality lower receiving one hour (4.6% 7.6%; difference, −3.0%; −5.7% −0.3%; < 0.002) as well systolic pressure ≤ 70 mmHg (18.5% 35.5%; −17%; −25.8% −8.1%; 0.003). examining compared repeat regimen (7.3% 10.0%; −2.7%; −5.0% −0.4%; 0.04), indicating increasing total administered 3-grams. Rowell et effect 2 moderate blunt penetrating TBI shock.9 Their functional neurologic recovery six months after measured Outcome Scale-Extended (GOS-E), grouped favorable poor outcomes. groups: 2-gram initial Similar CRASH-3, (65% 62% placebo; 0.16) secondary outcomes, including (14% 17%). trial, subgroups identified having benefit. latest antifibrinolytic use Pre-hospital Anti-fibrinolytics Traumatic (PATCH-Trauma) trial.10 PATCH-Trauma international, double-blinded, 1,310 adult deemed high trauma-related out-of-hospital emergency medical personnel able be before hospital admission arrival) from survival 6 assessed using same GOS-E scale employed al.9,10 Though similar rates between groups, improved month (17.3% 21.8%; 0.79; 0.63 0.99). Multiple strengths methodology deserve highlighting. investigators had broad inclusion criteria (i.e., victim 18 years being transported study-participating facility drug relatively limited exclusion (primarily residence elder pregnancy). Statistical included both intention-to-treat (ITT) per-protocol (PP) population analyses, varying supplementary imputation analyses address missing large number (30) imputed datasets. Based prior literature, anticipated 9% fraction would ultimately powered 2-sided alpha 0.05; hence, resulted slightly larger sample size greater power if outcome. Moreover, validity their further supported findings ITT (53.7% 53.5%, 1.00; 95%CI 0.90 1.12) PP (59.6% 59.5%, RR 1.02; 0.92 1.14) Interestingly, outcome, authors’ Figure (Levels Months) demonstrates granularity scores (1 through 8) ‘unfavorable’ 4 less (score 1 death). Excluding (vegetative state) which than 0.5% none group, these demonstrate nearly 5% died 20% may lived administration. This implies small percentage high-acuity injuries TXA. issue somewhat elucidated analyses. Despite demonstrating heterogeneity across subgroups, they do acknowledge discussion insufficient some comparisons. Nonetheless, based actually harmful ≥ Similarly, beneficial and/or burn those Importantly, GCS variable randomization stratification upon, it should add results. It plausible patients, trend towards part constituted higher prospective controlled negative designed equivalence appropriately concluded did impact appears support teasing out mature systems, reduced (24 28 day) mortality, endure months. favorably rates, fibrinogen, international normalized values. thromboembolic complications groups. When considering PATCH-trauma 6-month categorized study. needed save life 23, associated disability. However, acute cohort, due (both extra- intra-cranial) more clinically meaningful endpoint. Within 24 hours, effective hemodynamic stabilization valuable evolution yet fully innumerable variables exist impacting longer term long rehabilitation. Depending injury, continue improve beyond mark evaluated trial. Thus, recently preclude many stabilize critical highlighted study's accompanying editorial, measures long-term disability evolve time necessarily equate patient's perceived quality life.11 Given repeatedly confirmed benefits exsanguination low cost intervention reasonable side profile deserves Current care include interventions known mitigate life-threatening hemorrhage. Future research context (i.e. burns, trauma, trauma) individually combinations relationship 1Holcomb JB, Tilley BC, Baraniuk S, al. Transfusion plasma, platelets, red cells vs 1:1:2 trauma: PROPPR clinical JAMA. 2015;313:471-482. DOI: 10.1001/jama.2015.12.2Hanna K, Bible L, Chehab M, Nationwide resuscitation civilian trauma. J Trauma Acute Care Surg. 2020;89:329-335. 10.1097/TA.0000000000002753.3Peltan ID, Rowhani-Rahbar A, Vande Vusse LK, Development validation prehospital model coagulopathy. Crit Care. 2016;20:371. 10.1186/s13054-016-1541-9.4Gonzalez E, Moore EE, HB, Goal-directed Hemostatic Resuscitation Trauma-induced Coagulopathy: Pragmatic Randomized Trial Comparing Viscoelastic Assay Conventional Coagulation Assays. Ann 2016;263:1051-1059. 10.1097/SLA.0000000000001608.5Baksaas-Aasen Gall LS, Stensballe J, haemostatic assay augmented protocols haemorrhage (ITACTIC): Intensive Med. 2021;47:49-59. 10.1007/s00134-020-06266-1.6CRASH-2 collaborators, Shakur H, Roberts I, Effects death, vascular occlusive events, (CRASH-2): randomised, Lancet. 2010;376:23-32. 10.1016/S0140-6736(10)60835-5.7CRASH-3 collaborators. disability, events morbidities (CRASH-3): trial: 2019;394:1713-1723. 10.1016/S0140-6736(19)32233-0.8Guyette FX, Brown Zenati MS, Transport Risk Hemorrhage After Injury: Double-blind, Placebo-Controlled, Trial. JAMA 2020;156:11-20. 10.1001/jamasurg.2020.4350.9Rowell SE, Meier EN, McKnight B, Effect Out-of-Hospital Placebo 6-Month Functional Neurologic Outcomes With Moderate Severe Brain Injury. 2020;324:961-974. 10.1001/jama.2020.8958.10PATCH-Trauma Investigators ANZICS Trials Group, Gruen RL, Biswadev Trauma. N Engl 2023;389:127-136. 10.1056/NEJMoa2215457.11Shakur-Still I. More Lives Save Consider. 2023;389:181-183. 10.1056/NEJMe2305075. None conflicts interest.