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Three Part Question

In [patients with neck of femur fractures] is [administration of tranexamic acid in the emergency department] [associated with a reduction in perioperative blood transfusions, perioperative blood loss, length of hospital stay, and mortality]

Clinical Scenario

A 72-year-old woman presents to the emergency department (ED) with hip pain after a fall from standing. She is unable to weight bear. You notice extensive bruising around her left hip and an X-ray confirms a neck of femur fracture. You wonder if giving tranexamic acid (TXA) in the ED would improve her outcome when she later undergoes surgery.

Search Strategy

EMBASE and Ovid MEDLINE(R) (ALL) databases were searched (1974-2024) utilising the Ovid interface and the following keyword strategy:
((tranexamic* OR TXA) AND (femo* OR femu* OR hip fracture OR fractured hip)).ti,ab
No search filters were utilised, including language. A supplementary search of Google Scholar and Cochrane databases was then conducted using the same search terms. Reference lists of relevant papers were screened for any studies missed by our search paradigm.

Search Outcome

610 papers were identified using our search strategy, of which seven were determined to be relevant to our three-part question following title and abstract review. Of the seven studies that proceeded to full-text review, four were excluded because they were incomplete -- i.e. discontinued or unpublished.
Three papers1–3 were retained for final analysis. Two were randomised controlled trials (RCTs)1,3 and one was a cohort study2. The key results of these studies are summarised in Table 1. No statistically significant findings were reported for length of hospital stay or mortality.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Yakel et al, 2023 USA (1)	Adults over 18 with a low energy closed intertrochanteric or subtrochanteric femur fracture. Randomised to 1x IV TXA dose at hospital admission or 1x placebo (saline) dose at hospital admission	Prospective single centre double masked RCT (n = 100	Receipt of perioperative blood transfusion	17.5% of the TXA group received perioperative blood transfusions compared to 36.7% of the control group, RR = 0.48 (p = 0.046).	Only included extracapsular hip fractures and excluded patients on anticoagulants or with multiple injuries. Small sample size, failing to meet authors’ power calculation for detection of the primary outcome of perioperative blood transfusions.
			Peri-operative blood loss	1181ml peri-operative blood loss in TXA group compared to 1548ml in the control group (p = 0.01).
Moran et al, 2022 USA (2)	Patients admitted to a fragility hip fracture service	Prospective cohort study (n = 508)	Receipt of perioperative blood transfusion	9.4% of patients given TXA at hospital admission received blood transfusion, compared to 25.7% of patients who received delayed TXA and 29.4% who received no TXA (p < 0.001).	Non-randomised study design with relatively few patients (n = 32) given TXA on admission
Ma et al, 2021 China (3)	Adults over 65 presenting within 6 hours of an intertrochanteric fracture Randomised to 1x IV TXA dose at hospital admission or 1x placebo (saline) dose at hospital admission	Prospective single centre RCT (n = 125)	Receipt of preoperative blood transfusion	11.1% of the TXA group received pre-op transfusions compared to 22.6% of the control group (p = 0.036). There was 254ml of hidden blood loss in the TXA group compared to 408ml in the control group 3 days post trauma (p < 0.001).	Only included intertrochanteric hip fractures and excluded patients who were on anticoagulants or were unable to access hospital within 6 hours. Only pre-operative but not intra- or -post-operative transfusions recorded. Unclear whether patients, clinicians and outcomes assessors were masked. Unclear whether further doses of TXA were given to patients intra- or post-operatively.
			Serial haematocrit and haemoglobin measurements	Average haemoglobin levels were 100g/L in the TXA group compared to 88g/L in the control group 3 days post trauma (p < 0.001). Average haematocrit levels were 33% in the TXA group compared to 27% in the control group 3 days post trauma (p < 0.001).

Comment(s)

The two RCTs included in our review1,3 indicate that for patients with hip fractures, early TXA administration in ED decreases subsequent perioperative blood loss. All three studies demonstrated a reduction in blood transfusion1–3. None found evidence of increased adverse events, such as venous thromboembolism1–3. The safety of TXA in this population has been supported by a trial currently in press, although the investigators failed to find significant evidence of benefit4. A similar trial is currently underway5. The results of our review should be interpreted cautiously. The two RCTs1,3 restricted their sample to extracapsular hip fractures, limiting the generalisability of results to intracapsular fractures, which make up the majority of hip fractures6. However, extracapsular fractures are associated with greater blood loss7 and may therefore be a more clinically relevant sub-group for a TXA study. The trials in our review variously excluded patients who were taking anticoagulants1,3, multiply injuried1,3, or unable to present to hospital within six hours of injury3. This may limit the generalisability of their findings to our frailer patients, who commonly take anticoagulants, incur multiple injuries from falls, and present to hospital late – either because they cannot self-mobilise after falling, or struggle to access healthcare services in general. Unfortunately, it is this complex sub-group of patients who are likely to be the most vulnerable to the consequences of blood loss after hip fracture. Finally, it is unclear whether any benefits demonstrated by the studies in our review lead to improved outcomes for patients as neither RCT was powered to detect a difference in length of hospital stay or mortality.1,3

Clinical Bottom Line

Early TXA administration in the ED for extracapsular neck of femur fractures appears to be safe and may reduce the need for blood transfusion further down the line. It is unclear whether this is associated with improved patient outcomes, such as length of hospital stay and mortality.

References

1. Yakel S, Than J, Sharp J, et al. The Efficacy of Tranexamic Acid for Reducing Blood Transfusion Rates in Extracapsular Hip Fractures: A Single-Center Randomized Controlled Trial. Orthopedics 2023;46. doi:10.3928/01477447-20230224-03
2. Moran J, Kahan JB, Morris J, et al. Tranexamic Acid Administration at Hospital Admission Decreases Transfusion Rates in Geriatric Hip Fracture Patients Undergoing Surgery. Orthop Surg Rehabil 2022;13:215145932211244.
3. Yaun B. Mayo Clinic. Personal communication by email. 2024 Feb 4.
4. Ascension Health Blood Loss After Early TXA in Hip Fractures. 2021
5. Royal College of Physicians. National Hip Fracture Database (NHFD) Annual report 2017. London: 2017. 2017.
6. Smith GH, Tsang J, Molyneux SG, et al. The hidden blood loss after hip fracture. Injury 2011;42:133–5. doi:10.1016/j.injury.2010.02.015
7. Ma H, Wang H, Long X, et al. Early intravenous tranexamic acid intervention reduces post-traumatic hidden blood loss in elderly patients with intertrochanteric fracture: a randomized controlled trial. J Orthop Surg Res 2021;16:106. doi:10.1186/s13018-020-02166-8