PATCH-Trauma Investigators and the ANZICS Clinical Trials Group; Gruen RL, Mitra B, Bernard SA, et al. Prehospital Tranexamic Acid for Severe Trauma. N Engl J Med. 2023 Jun 14. doi: 10.1056/NEJMoa2215457. Epub ahead of print. PMID: 37314244.
Introduction
Continued hemorrhage is a leading cause of preventable deaths in patients with severe trauma. Exacerbation of the fibrinolytic process in trauma due to tissue injury and hemorrhagic shock often triggers failure to achieve hemostasis. Tranexamic acid, a fibrinolytic agent, has the potential to attenuate the fibrinolytic process and reduce bleeding in severe trauma.
The CRASH-2 trial had shown improved survival at 4 weeks in bleeding trauma patients with tranexamic acid use (1); the CRASH-3 trial revealed reduced 28-day mortality associated with traumatic brain injury (TBI) among tranexamic acid-treated patients (2). Many countries that participated in these trials may not have organized trauma response systems. Subsequent trials have also failed to reproduce the previously observed favorable results in isolated TBI (3) or in trauma patients with suspected bleeding (4). Furthermore, a dose-dependent increase in thromboembolism was observed in another trial (5).
The ready availability of critical care services, blood products, damage-control surgery, and interventional radiology hold the key to saving lives in trauma. Does tranexamic acid make a difference among bleeding trauma patients in advanced trauma systems with efficient and timely access to such life-saving interventions? Besides, long-term functional outcomes had not previously been reported with tranexamic acid use in trauma.
The PATCH investigators conceptualized a randomized controlled trial (RCT) to evaluate the safety and efficacy of tranexamic acid in patients with severe trauma with a high risk of trauma-induced coagulopathy. The authors hypothesized that pre-hospital administration of tranexamic acid would result in survival with a favorable functional outcome at 6 months.
Setting and design
The PATCH RCT was conducted over a 7-year period between July 2014 to September 2021 by 15 emergency medical services across 21 hospitals in Australia, New Zealand, and Germany.
Adult patients with severe traumatic injury, treated at the scene and transferred to trauma centers were eligible. Patients were at a high risk of coagulopathy based on a COAST score of ≥3 points. The first dose of tranexamic acid could be administered within 3 hours of injury and before hospital admission.
Randomization was to either tranexamic acid or placebo was carried out in a 1:1 ratio.
Exclusion
Pregnant patients and those who resided in elder care facilities were excluded.
Intervention
Tranexamic acid, 1g was administered intravenously over 10 minutes at the scene or en route to the hospital. A further dose of 1g was administered as an 8-hour infusion.
Control
Patients in the control group received an identical placebo bolus and 8-hour infusion.
Common management
Both groups of patients received the usual pre-hospital, in-hospital, and post-hospital care. The study drug could be discontinued if allergy was suspected or a reason for exclusion was identified later. Doppler ultrasonography was performed to screen for deep vein thrombosis around day 7.
Sample size
The study was designed to detect a difference of 9 percentage points between groups in survival with a good functional outcome at 6 months. The authors calculated a sample size of 1184 patients aimed to provide 90% power to the study with a two-sided alpha level of 0.05.
Results
A total of 1310 patients with severe trauma were enrolled and randomized. Fifty patients declined participation in the follow-up; 119 could not be contacted. This left 572 patients in the tranexamic acid group and 559 patients in the placebo group for the primary outcome analysis. Patients were well-matched at baseline. Most were blunt injuries (tranexamic acid: placebo: 92.8% vs. 91.4%); the systolic BP was less than 90 mm Hg in 72.6% of patients in the tranexamic acid group and 71.1% in the placebo group. The median Injury Severity Score (scale of 0–75) was 29 in both groups. Most patients received tranexamic acid or placebo between 1–2 hours. Protocol violations occurred in 32.7% of patients in the tranexamic acid group and 37% of patients in the placebo group. Open-label tranexamic acid was administered in the hospital in 16.5% of patients in the placebo group.
Outcomes
The primary outcome: survival with favorable functional outcome at 6 months.
A score of 5 or above on the Glasgow Outcome Scale – Extended (GOS-E) was considered a favorable functional outcome; a score between 1–4 was considered an unfavorable outcome (Table 1). On intention-to-treat analysis, there was no significant difference between the tranexamic acid and the placebo groups in survival with a favorable functional outcome at 6 months (53.7% vs. 53.5%; risk ratio, 1.0, 95% CI, 0.90 to 1.12; p = 0.95). There was no significant difference in the primary outcome among predefined subgroups of patients based on age, mechanism of injury (blunt vs. penetrating), time to intervention, the initial systolic BP, initial GCS, or the abbreviated injury score for head or neck.
Table 1. The Glasgow Outcome Scale – extended (GOS-E). A score of 5 or higher was considered a favorable functional outcome (marked in green)
| Score | Clinical state |
|
1 |
Dead |
|
2 = Vegetative state |
Lack of awareness of self and environment |
|
3 = Lower severe disability |
Needs full assistance in ADL |
|
4 = Upper severe disability |
Needs partial assistance in ADL |
|
5 = Lower moderate disability |
Independent, but unable for work/schooling or all previous social activities |
|
6 = Upper moderate disability |
Some disability present, but can partly resume work or previous activities |
|
7 = Lower good recovery |
Minor physical or mental deficits that affects daily life |
|
8 = Upper good recovery |
Full recovery or minor symptoms that do not affect daily life |
Secondary outcomes
Mortality at 24 hours (9.7% vs. 14.1%) and 28 days (17.3% vs. 21.8%) were lower in the tranexamic acid group. Mortality at 6 months after the injury, although lower with tranexamic acid (19% vs. 22.9%), was not significantly different between groups. However, mortality attributable to bleeding was lower (29.3% vs. 36.1%) in the tranexamic acid group. Vascular occlusive events occurred at a similar rate – 23.6% in the tranexamic acid group and 19.7% in the placebo group. The incidence of different types of vascular events, including deep vein thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke, and other arterial events, were also similar in both groups. The main study outcomes are summarized in Table 2.
Table 2. Main study outcomes
| Outcome | Tranexamic acid (657 patients) | Placebo (643 patients) | Risk Ratio / Hazard ratio with 95% CI |
| Survival with favorable outcome |
307/572 (53.7%) |
299/559 (53.5%) |
1.00 (0.90–1.12) |
|
24-h mortality |
64/657 (9.7%) |
90/640 (14.1%) |
0.69 (0.51–0.94) |
|
28-d mortality |
113/653 (17.3%) |
139/637 (21.8%) |
0.79 (0.63–0.99) |
|
6-month mortality |
123/648 (19.0%) |
144/629 (22.9%) |
0.83 (0.67–1.03) |
|
Mortality attributable to bleeding |
36/123 deaths (29.3%) |
52/244 deaths (36.1%) | |
|
Vascular occlusive events |
155/657 (23.6%) |
126/641 (19.7%) |
1.2 (0.97–1.48) |
Strengths
This large, adequately powered RCT evaluated long-term outcomes at 6 months in patients with severe trauma who were treated with tranexamic acid. A lower 28-day mortality was observed with tranexamic acid use in the CRASH-2 trial. The study was adequately blinded, with a low possibility of bias. The investigators performed intention-to-treat and per-protocol analyses, adding robustness to the trial. The trial evaluated the efficacy of tranexamic acid in advanced trauma systems with ready access to blood products, emergency surgery, and interventional radiology. The study evaluated patients who sustained severe trauma based on an objective scoring system – a selected population likely to benefit from tranexamic acid administration.
Limitations
Data on the primary outcome were not available in a sizeable number (13%) of patients, largely owing to loss to follow-up. Protocol violations occurred in 35% of patients, with some receiving open-label administration of tranexamic acid while others did not receive the full dose. The investigators administered the same dose of tranexamic acid that was used in the CRASH-2 trial. It is unclear if this may be the optimal dose of tranexamic acid. Information was not available on patients who were screened but not enrolled. The study was not powered to identify possible benefit in subgroups of patients, particularly in penetrating injury. Although 6 months is a reasonable time frame to assess neurological outcomes, a longer duration of follow-up (1year) may shed more light on patients who may continue to make late improvement.
Key points
- Tranexamic acid administration in severe trauma did not result in survival with a favorable functional outcome at 6 months (the primary outcome).
- Improved early survival (at 24 hours and at 28 days) was noted with tranexamic acid, similar to the findings of the CRASH-2 trial.
- Bleeding-related mortality was also lower with tranexamic acid compared with placebo.
- The findings of the study suggest that tranexamic acid may reduce hemorrhage and improve survival, albeit with a higher level of disability at 6 months among survivors
- There was no significant increase in vascular-occlusive events with tranexamic acid use
References
1. CRASH-2 trial collaborators, Shakur H, Roberts I, Bautista R, Caballero J, Coats T, 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 Lond Engl. 2010 Jul 3;376(9734):23–32.
2. CRASH-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 Lond Engl. 2019 Nov 9;394(10210):1713–23.
3. Rowell SE, Meier EN, McKnight B, Kannas D, May S, Sheehan K, 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 Sep 8;324(10):961–74.
4. Guyette FX, Brown JB, Zenati MS, Early-Young BJ, Adams PW, Eastridge BJ, 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 Oct 5;156(1):11–20.
5. Spinella PC, Bochicchio K, Thomas KA, Staudt A, Shea SM, Pusateri AE, et al. The risk of thromboembolic events with early intravenous 2- and 4-g bolus dosing of tranexamic acid compared to placebo in patients with severe traumatic bleeding: A secondary analysis of a randomized, double-blind, placebo-controlled, single-center trial. Transfusion (Paris). 2022 Aug;62 Suppl 1:S139–50.
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