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Journal Club: 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







































Slide Text

Journal Club Presentation

Background

     Intracranial bleeding is common after traumatic brain injury (TBI) and increases head injury-related death and disability 
     Intracranial bleeding after traumatic brain injury (TBI) can cause brain herniation and death.
     Tranexamic acid reduces bleeding by inhibiting the enzymatic breakdown of fibrin blood clots (fibrinolysis)  
     This trial aimed to assess the effects of tranexamic acid in patients with TBI.

Evidence before this study

     CRASH-2 trial: administration of tranexamic acid within 3 h of injury reduces death in patients with traumatic extracranial bleeding reduces bleeding deaths by a third 
     This raised the possibility that tranexamic acid might reduce death from traumatic intracranial bleeding
     Before this study, a metanalysis of two small randomised trials of tranexamic acid in traumatic brain injury with a total of 510 patients showed a statistically significant reduction in death with tranexamic acid  (Perel P 2012, Yutthakasemsunt S 2013)

Methods 


Study design and participants 

     international, multi­centre, randomised, placebo ­controlled trial
     Between July 20, 2012, and Jan 31, 2019, recruited patients with TBI from 175 hospitals in 29 countries. 

Inclusion Criteria

     Adults with TBI who were within 3 h of injury
     time window for eligibility was originally within 8 h of injury. However, on Sept 6, 2016, in response to evidence external to the trial indicating that tranexamic acid is unlikely to be effective when initiated beyond 3 h of injury, it was amended to limit recruitment to within 3 h of injury
     Had a Glasgow Coma Scale (GCS) score of 12 or lower
     any intracranial bleeding on CT scan
     no major extracranial bleeding

Exclusion Criteria

     Extracranial bleeding
     >8hrs since injury (limited to >3hrs from Sept 2016)
     Prespecified sensitivity analysis excluding patients with GCS of 3 and those with bilateral non-reactive pupils

Randomisation and masking 

     randomly allocated eligible patients to receive tranexamic acid or matching placebo (0·9% sodium chloride) by intravenous infusion. 
     tranexamic acid was manufactured by Pfizer (Sandwich, UK) 
     Ampoules and packaging were identical in appearance.
     Entry form data were entered into a secure online database by the trial investigators.
     Participants and study staff (site investigators and trial coordinating centre staff) were masked to allocation 

Procedures 

     Patients were randomly allocated to receive a loading dose of 1 g of tranexamic acid infused over 10 min, started immediately after randomisation, followed by an intravenous infusion of 1 g over 8 h  or matching placebo.
     Every patient was assigned a uniquely numbered treatment pack, which contained four ampoules of either tranexamic acid (500 mg) or placebo, one 100 mL bag of 0·9% sodium chloride 

Primary Outcome

Primary outcome was head injury­ related death in hospital within 28 days of injury in patients

Secondary Outcomes

     early head injury ­related death (within 24 h after injury)
     all ­cause and cause ­specific mortality
     vascular occlusive events (myocardial
     infarction, stroke, deep vein thrombosis, and pulmonary embolism)
     Seizures
     Complications
     Neuro­surgery
     Days in intensive care unit
     Adverse events within 28 days of randomisation.

Trial Profile

Statistical analysis 

All analyses were on an intention to­ treat basis.
Reporting the effects of tranexamic acid on the primary outcome stratified by three baseline characteristics:
     severity of head injury: Severity of head injury was assessed using the baseline GCS score—mild to moderate (GCS 9–15) and severe (GCS 3–8)—and by pupil reactivity. 
     time to treatment: treatment (≤1, >1 to ≤3, >3 h) 
     Age : 30 years or younger, 31–60 years, older than 60 years 

Results


Results: Deaths

     reduction in the risk of head injury­ related death with tranexamic acid in patients with mild­ to ­moderate head injury (RR 0·78 [95% CI 0·64–0·95])
     but in patients with severe head injury (0·99 [0·91–1·07]) there was no clear evidence of a reduction (p value for heterogeneity 0·030) 
     Among patients with reactive pupils, head injury ­related deaths were reduced with tranexamic acid (0·87, [0·77–0·98]) 
Effect of tranexamic acid on head injury-related death stratified by baseline severity in patients
randomised within 3 h of injury 

Results: Time to Treatment

RR of head injury ­related death with tranexamic acid was
      0·96 (95% CI 0·79–1·17) in patients randomly assigned within 1 h of injury
     0·93 (0·85–1·02) in more than 1 h and less than 3 h after injury
     0·94 (0·81–1·09) in more than 3 h after injury.
However, as anticipated in the statistical analysis plan, patients who are treated soon after injury often have more severe head injury and so the effect of time to treatment could be confounded by severity. 
Effect of tranexamic acid on head injury-related death by severity and time to treatment in all patients
The models were adjusted for GCS score, age, and systolic blood pressure. 537 patients with mild and moderate GCS scores (9–15) and 918 patients with severe GCS scores (4–8), excluding those with a GCS score of 3 and those with no reactive pupils, died because of head injury 

Results: Deaths in <24 hrs="" span="">

Because early head injury related deaths are more likely to result from intracranial haemorrhage than are late head injury related deaths  
     The RR of head injury­ related death was 0·81 (95% CI 0·69–0·95) within 24 h.
     When patients with a GCS score of 3 and those with bilateral unreactive pupils at baseline were excluded, the RR was 0·72 (0·56–0·92) within 24 h 

Results: Age

no evidence of heterogeneity in the effect of tranexamic acid by patient age (p=0·45) 

Discussion

     tranexamic acid to patients with TBI within 3 h of injury reduces head injury ­related death, with no evidence of adverse effects or complications. 
     substantial reduction in head injury ­related deaths with tranexamic acid in patients with mild and moderate head injuries
     no apparent reduction in those with severe head injury.
     We found no increase in disability among survivors
     Most patients with bilateral unreactive pupils already have extensive intracranial haemorrhage and brain herniation and so tranexamic acid is unlikely to improve the outcome in these patients. 

Discussion

     Because haemorrhage expansion occurs in the hours immediately after injury, treatment delay would reduce the potential for tranexamic acid to prevent intracranial bleeding 
     Patients with severe head injury might have less to gain from tranexamic acid treatment than patients with mild­ to moderate head injury because such patients already have extensive intracranial haemorrhage before treatment or other potentially life ­threatening intracranial pathologies that are not affected by tranexamic acid 
     Limitations
     CRASH-3 is technically a “negative” study, as the primary endpoint falls slightly short of reaching statistical significance (p&gt;0.05)
     The use of 28-day head injury-related mortality as the primary endpoint probably biased the treatment effect towards the null because tranexamic acid is most likely to benefit patients with TBI with intracranial bleeding at risk of early mortality, whereas late deaths are unlikely to be affected by tranexamic acid.
     In CRASH-2 and CRASH-3 trials , the tranexamic acid dosing regimens were very similar. Future study might be warranted to explore the effects of increased tranexamic acid doses in bleeding patients, or possibly alternative routes of administration such as intramuscular administration that might facilitate earlier intervention
     Limitations
     Originally planned for 10,000 patients to have a 90% powered to detect a 15% relative reduction in mortality
     however with the change in time to intervention to within 3h of injury the targeted sample size was increased to 13,000 to have approximately 10,000 patients treated within 3hr of injury which they did not meet (≈9,200 patients)

Conclusion

On the basis of CRASH­2 trial results, tranexamic acid was included in guidelines for the pre­hospital care of patients with trauma.  However, patients with isolated TBI were specifically excluded.
The CRASH­3 trial provides evidence that tranexamic acid is safe in patients with TBI and that treatment will have maximum effects in following:
     Early treatment (less than 3hrs)
     Mild to moderate (GCS 9 – 15)
     ICH on baseline head CT.

Further Reading

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32233-0/fulltext
https://emcrit.org/pulmcrit/crash3/
https://rebelem.com/crash-3-txa-for-ich/

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