Publication

• Title: Prehospital Tranexamic Acid for Severe Trauma
• Acronym: PATCH-Trauma
• Year: 2023
• Journal published in: The New England Journal of Medicine
• Citation: PATCH-Trauma Investigators and the ANZICS Clinical Trials Group. Prehospital Tranexamic Acid for Severe Trauma. N Engl J Med. 2023;389(2):127-136.

Context & Rationale

• Background

  Trauma-induced coagulopathy and hyperfibrinolysis contribute to early haemorrhagic death, with major downstream morbidity among survivors.
  Large hospital-based evidence (CRASH-2) suggested tranexamic acid (TXA) reduces mortality when given within 3 hours, but external validity to advanced trauma systems and to systematic prehospital use remained disputed. ¹
  Prehospital RCT evidence before PATCH-Trauma (e.g., STAAMP) did not establish a consistent improvement in patient-important long-term outcomes, and raised continuing questions about phenotyping “who benefits” and the balance of benefit versus thrombosis in modern care. ²
• Research Question/Hypothesis

  In adults with severe trauma at risk of trauma-induced coagulopathy treated by advanced emergency medical services, does prehospital TXA (with in-hospital continuation) increase survival with a favourable functional outcome at 6 months compared with placebo?
• Why This Matters

  TXA is widely embedded in trauma pathways, yet clinicians need high-grade evidence in contemporary systems where rapid haemostatic resuscitation and definitive haemorrhage control may attenuate marginal benefit.
  A disability-sensitive primary endpoint (GOS-E) directly addresses a key concern: survival gains that could be offset by survival with severe neurological disability (especially with concomitant traumatic brain injury). ³

Design & Methods

• Research Question: Among adults with severe trauma at risk of trauma-induced coagulopathy, does prehospital TXA (1 g bolus + 1 g infusion) improve survival with favourable functional outcome at 6 months versus placebo?
• Study Type: Multicentre, randomised, double-blind, placebo-controlled, investigator-initiated pragmatic trial in prehospital emergency care (Australia, New Zealand, Germany), with in-hospital continuation.
• Population:
  • Setting: Participating ambulance services and trauma hospitals within advanced trauma systems (prehospital enrolment; hospital continuation).
  • Inclusion: Adults (≥18 years) with major trauma at risk of trauma-induced coagulopathy, defined by a Coagulopathy of Severe Trauma (COAST) score ≥3, with initiation feasible within 3 hours of injury.
  • COAST score (range 0–7): Entrapment (+1); systolic blood pressure <100 (+1) and <90 (+1 additional); temperature <35°C (+1) and <32°C (+1 additional); suspected pneumothorax (+1); suspected intra-abdominal or pelvic injury (+1).
  • Key exclusions: Suspected pregnancy; nursing home/residential aged care facility residence.
  • Randomisation strata: Australian state/country and initial Glasgow Coma Scale (GCS) <9 versus ≥9 (pre-specified stratification variables).
• Intervention:
  • Tranexamic acid: 1 g IV/IO bolus (10 mL) initiated prehospital (delivered over ~10 minutes), followed by 1 g IV infusion in 100 mL over 8 hours commenced after arrival at the trauma hospital.
• Comparison:
  • Placebo (0.9% sodium chloride) in identical volumes and timings (prehospital bolus + in-hospital infusion), with all other care per local trauma protocols.
• Blinding: Double-blind (prehospital clinicians, in-hospital teams, patients/surrogates, investigators, and outcome assessors); identical study packs and matched placebo.
• Statistics: Power calculation: 1184 patients required to detect a 9% absolute increase in favourable 6-month GOS-E outcome (60% to 69%) with 90% power at two-sided alpha 0.05; target increased to 1316 allowing 10% loss to follow-up; primary analysis by intention-to-treat; pre-specified interim safety monitoring for harm at 25% and 50% enrolment using a Haybittle–Peto approach. ⁴
• Follow-Up Period: Clinical outcomes to 28 days (or hospital discharge/death); functional outcome at 6 months (telephone GOS-E assessment).

Key Results

This trial was not stopped early. Recruitment was stopped after 1310 enrolments (revised target 1316) because the trial agents expired.

• Primary endpoint was neutral: survival with favourable functional outcome at 6 months was identical (53.7% vs 53.7%; RR 1.00; 95% CI 0.90 to 1.12; P=0.95).
• Early mortality signal favoured TXA: death at 24 hours (RR 0.69; 95% CI 0.51 to 0.94) and at 28 days (RR 0.79; 95% CI 0.63 to 0.99) were lower with TXA, while 6-month mortality did not reach conventional statistical certainty (HR 0.81; 95% CI 0.65 to 1.02).
• No clear excess harm was seen: vascular occlusive events were similar (8.5% vs 9.8%; RR 0.87; 95% CI 0.62 to 1.22).
• Subgroup analyses (pre-specified) showed no convincing heterogeneity: time-to-first-dose <1 hour (RR 1.03; 95% CI 0.82 to 1.28), 1 to <2 hours (RR 1.09; 95% CI 0.93 to 1.26), ≥2 hours (RR 0.83; 95% CI 0.66 to 1.03); penetrating/burn injury (RR 1.30; 95% CI 0.92 to 1.83) had wide uncertainty due to small numbers.
• Post hoc (anatomical head/neck injury severity): AIS head/neck >2 showed RR 0.93 (95% CI 0.73 to 1.18), while AIS head/neck ≤2 showed RR 1.06 (95% CI 0.96 to 1.18) for the primary endpoint.

Internal Validity

• Randomisation and allocation concealment: Randomisation used pre-prepared, identical study packs with stratification by jurisdiction and baseline GCS category; allocation concealment and double blinding were robust (prehospital and in-hospital teams remained blinded).
• Post-randomisation exclusions: 1310 underwent randomisation; 3 had unknown allocation due to study packs lost; 7 withdrew consent for any data use (ITT population n=1300; TXA 657 vs placebo 643).
• Missing primary outcome data: 6-month primary endpoint available for 1131/1300 (87.0%): TXA 572 and placebo 559; missingness was similar between groups (TXA: 23 withdrew consent for 6-month follow-up + 61 lost; placebo: 27 withdrew + 58 lost).
• Impact of missingness: Multiple imputation (pre-specified if >5% missing) yielded a primary effect estimate consistent with complete-case analysis (RR 1.00; 95% CI 0.90 to 1.11; P=0.98), reducing concern for differential attrition, but informative missingness remains plausible in major trauma follow-up.
• Protocol adherence and contamination: Full protocol adherence occurred in 442/657 (67.3%) with TXA vs 405/643 (63.0%) with placebo (patients could have multiple deviations).
• Dose delivery (separation of the variable of interest): Both doses administered in 515/657 (78.4%) with TXA vs 480/643 (74.7%) with placebo; “first dose only” in 140/657 (21.3%) vs 163/643 (25.3%).
• Open-label TXA use (crossover/contamination): Open-label TXA was given in 104/657 (15.8%) with TXA vs 106/643 (16.5%) with placebo (in contravention of protocol), which tends to bias towards the null for any causal effect of allocation.
• Baseline characteristics and severity balance: Groups were similar at baseline (e.g., mean age 45.4 vs 44.8 years; median ISS 29 vs 29; blunt trauma 91.8% vs 92.4%; GCS <9: 40.2% vs 38.9%; systolic BP ≤75 mm Hg: 38.4% vs 40.6%).
• Timing fidelity: Time from injury to first dose: <1 hour in 32.6% vs 27.5%; 1 to <2 hours in 45.3% vs 51.3%; ≥2 hours in 22.1% vs 21.2% (TXA vs placebo).
• Outcome assessment: Primary outcome used GOS-E at 6 months via structured telephone interview by trained assessors blinded to allocation; causes of death were clinician-assigned (blinded), which reduces but does not eliminate misclassification risk.
• Statistical rigour: Primary analysis was ITT, with pre-specified imputation and sensitivity analyses; secondary outcomes were not adjusted for multiplicity, and p values were not routinely reported, consistent with an exploratory stance for non-primary endpoints.

Conclusion on Internal Validity: Overall, internal validity is moderate: randomisation and blinding were strong, but a clinically meaningful proportion of missing primary outcomes (13%) plus notable protocol deviations (incomplete dosing and ~16% open-label TXA in both arms) likely diluted separation and complicate causal interpretation for both benefit and harm.

External Validity

• Population representativeness: Enrolled patients were severely injured and physiologically compromised (e.g., ~39–41% with GCS <9; ~38–41% with systolic BP ≤75 mm Hg; median ISS 29), resembling high-acuity major trauma transported by advanced EMS.
• Case-mix considerations: Trauma was predominantly blunt (~92%), with comparatively small penetrating/burn subgroups, limiting inference in penetrating trauma; head injury burden was substantial (important for interpreting disability-centric outcomes).
• System requirements: Implementation assumes EMS capacity for IV/IO access, drug preparation, and a receiving system able to commence an 8-hour infusion; these conditions may not hold in resource-limited or very prolonged-transport environments.
• Exclusions: Pregnancy and residential aged care residents were excluded; paediatric trauma was not studied.

Conclusion on External Validity: Findings are highly applicable to adult severe blunt trauma managed within well-resourced prehospital and trauma-centre systems, but are less generalisable to penetrating-dominant settings, paediatrics, pregnancy, and systems without reliable early IV/infusion delivery.

Strengths & Limitations

• Strengths: Large, pragmatic, multicentre double-blind RCT spanning prehospital to in-hospital care; targeted enrolment of high-risk trauma via a prehospital coagulopathy-risk score; patient-centred primary endpoint (6-month GOS-E); transparent pre-specified statistical analysis plan and sensitivity analyses.
• Limitations: Primary outcome missingness (13%) with reliance on imputation; meaningful non-adherence (only ~75–78% received both doses) and substantial open-label TXA use (~16% in each arm); limited ability to detect treatment-effect heterogeneity in small subgroups (penetrating/burn); uncertain external validity to systems without advanced trauma pathways and without clear screening denominators for non-enrolled patients.

Interpretation & Why It Matters

• What the trial shows

  In severe trauma at risk of coagulopathy, allocating TXA early (prehospital + in-hospital infusion) did not improve survival with favourable functional outcome at 6 months, despite signals of reduced early mortality.
• Clinical practice implications

  If TXA is used, PATCH-Trauma supports a pragmatic view: potential benefit is most plausibly concentrated in preventing early haemorrhagic death rather than shifting long-term disability distribution in an unselected “severe trauma” population (where neurological injury substantially drives disability outcomes).
• Research implications

  Future trials may need tighter biological phenotyping (e.g., hyperfibrinolysis/coagulopathy markers), better contamination control, and endpoints aligned to mechanism (haemorrhage-specific mortality) alongside patient-centred longer-term recovery measures.

Controversies & Subsequent Evidence

• Endpoint selection versus mechanistic plausibility: TXA’s biological target is haemorrhage/hyperfibrinolysis, yet the primary endpoint (favourable 6-month functional survival) is strongly influenced by traumatic brain injury and rehabilitation trajectory; this choice increases patient-centred relevance but may reduce sensitivity to detect haemorrhage-specific benefit (explicitly raised in contemporaneous editorial commentary). ⁵⁶⁷
• Neutral primary outcome with mortality signal: The reduction in 24-hour and 28-day mortality occurred in secondary outcomes without multiplicity correction (and with p values not routinely presented), raising interpretive tension; however, effect estimates were directionally concordant with the broader TXA trauma evidence base (CRASH-2 and subsequent RCTs). ¹²
• Selection/phenotyping debate: Use of a pragmatic COAST score enriched for physiological shock and injury patterns but does not directly measure fibrinolytic state; incomplete biological enrichment can plausibly dilute benefit if only a subset have TXA-responsive hyperfibrinolysis. ⁴⁶
• Contamination and incomplete dosing as a “real-world” signal: ~21–25% received only the bolus without the infusion and ~16% received open-label TXA in both arms; this pragmatic reality may reflect contemporary clinician behaviour but likely biases against detecting an allocation effect (especially for outcomes beyond the first hours).
• Meta-analytic synthesis (post-PATCH): Updated systematic reviews incorporating PATCH-Trauma generally support a modest reduction in early mortality with TXA in traumatic injury, with ongoing uncertainty around long-term functional outcomes and optimal targeting/route/timing in the prehospital environment. ⁸
• Guideline trajectory: Major bleeding/coagulopathy trauma guidelines continue to recommend early TXA in bleeding trauma (typically within 3 hours) while acknowledging evidence limitations and the need for early administration and appropriate patient selection. ⁹¹⁰

Summary

• PATCH-Trauma tested early, protocolised TXA starting prehospital (1 g bolus) with in-hospital continuation (1 g infusion over 8 hours) in adults with severe trauma at risk of coagulopathy.
• The primary outcome (6-month survival with favourable functional status; GOS-E 5–8) was identical between groups (53.7% vs 53.7%; RR 1.00; 95% CI 0.90 to 1.12).
• Secondary outcomes suggested fewer deaths at 24 hours (RR 0.69; 95% CI 0.51 to 0.94) and 28 days (RR 0.79; 95% CI 0.63 to 0.99), with uncertainty at 6 months (HR 0.81; 95% CI 0.65 to 1.02).
• Vascular occlusive events were not increased (8.5% vs 9.8%; RR 0.87; 95% CI 0.62 to 1.22).
• Interpretation is tempered by missing primary outcomes (13%) and pragmatic deviations (incomplete dosing and open-label TXA use in both arms), which likely reduced exposure separation.

Further Reading

Other Trials

• 2010Shakur H, Roberts I, Bautista R, 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(9734):23-32.
• 2019CRASH-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 randomised, placebo-controlled trial. Lancet. 2019;394(10210):1713-1723.
• 2020Rowell 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: The ROC TXA Randomized Clinical Trial. JAMA. 2020;324(10):961-974.
• 2021Guyette 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. 2021;156(1):11-20.
• 2011Roberts I, Shakur H, Afolabi A, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet. 2011;377(9771):1096-1101.

Systematic Review & Meta Analysis

• 2024Fouche PF, Martin MJ, et al. Tranexamic acid for traumatic injury in the emergency setting: a systematic review and bias-adjusted meta-analysis of randomized controlled trials. Ann Emerg Med. 2024.
• 2024Chen Q, Li Y, et al. Effect of tranexamic acid in major trauma patients: an updated systematic review and meta-analysis with trial sequential analysis. BMC Emerg Med. 2024.
• 2023Acharya S, et al. Efficacy and safety of tranexamic acid in prehospital traumatic hemorrhagic shock: a systematic review and meta-analysis. Front Med (Lausanne). 2023;10:1284016.
• 2021Al-Jeabory M, et al. The role of tranexamic acid in traumatic brain injury: a systematic review and meta-analysis. J Clin Med. 2021;10(5):1030.
• 2018Gayet-Ageron A, Prieto-Merino D, Ker K, Shakur H, Afolabi A, Roberts I. Effect of treatment delay on the effectiveness and safety of antifibrinolytics in acute severe haemorrhage: a meta-analysis of individual patient-level data. Lancet. 2018;391(10116):125-132.

Observational Studies

• 2012Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg. 2012;147(2):113-119.
• 2015Cole E, Davenport R, Willett K, Brohi K. Tranexamic acid use in severely injured civilian patients and the effects on outcome: a prospective cohort study. Ann Surg. 2015;261(2):390-394.
• 2017Neeki MM, et al. Efficacy and Safety of Tranexamic Acid in Prehospital Traumatic Hemorrhagic Shock: Outcomes of the Cal-PAT Study. West J Emerg Med. 2017;18(4):673-679.
• 2024Mazzei M, et al. Prehospital tranexamic acid is associated with a survival benefit among patients with traumatic brain injury: a secondary analysis of two trials. J Trauma Acute Care Surg. 2024.
• 2025Bayer J, et al. Prehospital tranexamic acid treatment is associated with reduced mortality in a matched cohort of trauma patients in a national trauma registry. Scand J Trauma Resusc Emerg Med. 2025.

Guidelines

• 2023Rossaint R, et al. The European guideline on management of major bleeding and coagulopathy following trauma: sixth edition. Crit Care. 2023;27:98.
• 2024LaGrone L, et al. The American Association for the Surgery of Trauma/American College of Surgeons Committee on Trauma clinical protocol for damage control resuscitation. J Trauma Acute Care Surg. 2024.
• 2025Dumas RP, et al. The use of tranexamic acid in the management of injured patients at risk of hemorrhage: a systematic review and meta-analysis and an Eastern Association for the Surgery of Trauma Practice Management Guideline. J Trauma Acute Care Surg. 2025.
• 2020Rowell SE, 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(10):961-974.
• 2021Guyette FX, et al. Tranexamic Acid During Prehospital Transport in Patients at Risk for Hemorrhage After Injury. JAMA Surg. 2021;156(1):11-20.

Notes

• Secondary outcomes were analysed without multiplicity adjustment; interpret mortality and transfusion findings as supportive signals rather than definitive effects when the primary outcome is neutral.

Overall Takeaway

PATCH-Trauma is a landmark prehospital RCT because it tested a widely adopted haemostatic intervention (TXA) in modern trauma systems using a disability-sensitive 6-month endpoint. The trial found no improvement in long-term favourable functional survival, while showing consistent signals of reduced early mortality without an excess of thrombotic complications—shifting the debate from “does TXA work?” to “which patients, which outcomes, and what degree of contamination is acceptable in real-world delivery?”.

Bibliography

• 1Shakur H, Roberts I, Bautista R, 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(9734):23-32.
• 2Guyette 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. 2021;156(1):11-20.
• 3CRASH-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 randomised, placebo-controlled trial. Lancet. 2019;394(10210):1713-1723.
• 4Mitra B, Bernard S, Gantner D, et al. Protocol for a multicentre prehospital randomised controlled trial investigating tranexamic acid in severe trauma: the PATCH-Trauma trial. BMJ Open. 2021;11(3):e046522.
• 5Shakur-Still H. Tranexamic Acid for Trauma Patients — More Lives to Save and Less Disability. N Engl J Med. 2023.
• 6Wilhelm K, Toy J. Article commentary: Prehospital Tranexamic Acid for Severe Trauma. Ann Emerg Med. 2023.
• 7Gilbert D, et al. Prehospital tranexamic acid: more than just a PATCH? CJEM. 2024.
• 8Fouche PF, Martin MJ, et al. Tranexamic acid for traumatic injury in the emergency setting: a systematic review and bias-adjusted meta-analysis of randomized controlled trials. Ann Emerg Med. 2024.
• 9Rossaint R, et al. The European guideline on management of major bleeding and coagulopathy following trauma: sixth edition. Crit Care. 2023;27:98.
• 10Dumas RP, et al. The use of tranexamic acid in the management of injured patients at risk of hemorrhage: a systematic review and meta-analysis and an Eastern Association for the Surgery of Trauma Practice Management Guideline. J Trauma Acute Care Surg. 2025.