1. A large randomised controlled trial among trauma patients with significant haemorrhage, of the effects of antifibrinolytic treatment on death and transfusion requirement

2. Global deaths at ages 5-45 years (both sexes)
Deaths (2000 projected)
HIV/AIDS 2,104,454
Road traffic injury 657,614
Tuberculosis 603,522
Self inflicted injury 431,924
Violence 335,202
War injuries 167,329

3. In-hospital trauma deaths
Exsanguination
CNS injury
Organ failure
Other
45%
41%
10% 4%
Sauaia A et al. Epidemiology of trauma deaths: a reassessment. J Trauma 1995;38:

4. Fibrinolysis
During fibrinolysis, plasminogen is converted into plasmin by tissue plasminogen activator
Plasmin binds to fibrin via its lysine binding sites to cause fibrinolysis.

5. Pharmacologic inhibition of fibrinolysis
Tranexamic Acid (TXA) is a synthetic derivative of the amino acid lysine.
It has a very high affinity for the lysine binding sites of plasminogen.
It blocks these sites and prevents binding of activated plasminogen to the fibrin surface, thus exerting its antifibrinolytic effect.

6. Antifibrinolytic agents
in elective surgery
SYSTEMATIC REVIEWS
APROTININ
61 Randomised controlled trials including 7,027 participants
TRANEXAMIC ACID (TXA)
18 Randomised controlled trials including 1342 participants
Henry DA et al. Antifibrinolytic use for minimising perioperative allogeneic blood transfusion (Cochrane Review). In: The Cochrane Library, Issue 3, Chichester, UK: John Wiley & Sons, Ltd

7. Antifibrinolytic agents
in elective surgery
NEED FOR TRANSFUSION
RR (95% CI)
Aprotinin
0.70 ( )
TXA
0.66 ( )
0.4
0.8
1.2
1.6
2.0
Antifibrinolytic better Antifibrinolytic worse
Henry et al

8. Antifibrinolytic agents
in elective surgery
BLOOD UNITS SAVED
Aprotinin
1.1 ( )
TXA
1.0 ( )
0.4
0.8
1.2
1.6
2.0
Blood units
Henry et al

9. Antifibrinolytic agents
in elective surgery
RE-OPERATION
RR (95% CI)
Aprotinin
0.40 ( )
TXA
0.72 ( )
0.4
0.8
1.2
1.6
2.0
Antifibrinolytic better Antifibrinolytic worse
Henry et al

10. Antifibrinolytic agents
in elective surgery
MORTALITY
RR (95% CI)
Aprotinin
0.87 ( )
TXA
0.43 ( )
0.4
0.8
1.2
1.6
2.0
Antifibrinolytic better Antifibrinolytic worse
Henry et al

11. Tranexamic acid for minimising surgical blood loss
ADVERSE EFFECTS
RR 95% CI
Non-fatal MI
Stroke
DVT PE
Any thrombosis
No evidence of increased adverse effects
Henry et al

12. TXA already being used in some treatment protocols
Treatment protocol of Israeli Defence Force
Crystalloids (warm) 1L (250X4)
Blood -2 units + Tranexamic acid IV 2gr
rFVIIa 9.6 mg
Blood -2 units, consider BTB transfusion
Fibrinogen + bicarbonate+ rFVIIa 9.6mg
Cont. fluids + blood according patient’s condition
Repeat rFVIIa in case of re-bleeding

13. Antifibrinolytic agents in trauma
Systematic review
1 randomised controlled trial including 70 patients
Drug versus Placebo: 0 vs. 3 deaths
Insufficient evidence to support clinical use in trauma
Need for RCT – CRASH-2
Roberts IG, Coates T, Shakur H Antifibrinolytic drugs for acute traumatic injury. Cochrane Database Syst Rev Oct 18(4):CD004896

14. Rationale for CRASH-2 Bleeding is a leading cause of trauma death
Blood transfusion can be dangerous
Antifibrinolytics reduce blood loss after surgery
Surgery and trauma produce similar haemostatic responses
Trials in trauma too small to confirm or refute a moderate effects
A simple intervention like TXA could prevent thousands of trauma deaths and transfusion associated infections
MRC CRASH trial showed that large numbers of patients can be enrolled in the emergency setting

15. Rationale for TXA TXA may be as effective as aprotinin*
Lower cost of TXA
Need for a test dose of aprotinin to assess for potential allergic reactions (not practical in emergencies)
In some settings TXA more acceptable than aprotinin which is derived from bovine lung
* Henry et al

16. Aims
To quantify the effect of tranexamic acid (TXA) on death and transfusion requirement in adult trauma patients with significant ongoing haemorrhage, or who are considered to be at risk of significant haemorrhage
To quantify the effect of such treatment on the risk of non-fatal vascular events

17. TELEPHONE FOR RANDOMISATION
DOCTOR IS “REASONABLY CERTAIN”
THAT ANTI-FIBRINOLYTIC AGENTS
ARE INDICATED.
INELIGIBLE
GIVE ANTI-FIBRINOLYTIC AGENTS;
DO NOT RANDOMISE.
ARE CONTRA-INDICATED.
DON’T GIVE ANTI-FIBRINOLYTIC AGENTS;
Doctor is “SUBSTANTIALLY UNCERTAIN”
as to the appropriateness of
anti-fibrinolytic agents in this patient
TELEPHONE FOR RANDOMISATION
OR PAPER RANDOMISE
TRANEXAMIC ACID
PLACEBO
POTENTIALLY ELIGIBLE
Trauma patients judged to be 16 years or older,
with significant haemorrhage (systolic blood pressure less than 90 mmHg and/or heart rate more than 110 beats per minute), or considered to be at risk of significant haemorrhage, within 8 hours of the injury

18. What is meant by ‘risk of significant haemorrhage’
Patients with major trauma who are likely to need an early blood transfusion in the view of the attending doctor after taking into account mechanism of injury, findings from secondary survey, physiology and response to fluid infusion

19. Randomisation Central (by telephone) Non-central
Give brief patient details
Computer determines treatment allocation
Treatments ‘balanced’ on prognostic factors
Non-central
Select lowest numbered treatment pack
Patient details sent by via secure website, or fax

20. Consent
CRASH-2: involve patients who have suffered serious injuries and are at risk of life threatening haemorrhage
Most patients will have some impairment in their level of consciousness caused either by blood loss or coexisting head-injury
Patients may not be able to provide written informed consent
Trial treatment has to be administered as soon as possible after injury
Need to comply with local approved consent process

21. Patient Entry
Please complete before randomisation to ensure patient fulfils eligibility criteria

22. Dose (Tranexamic Acid or placebo)
Treatment
Treatment
Ampoules
Dose (Tranexamic Acid or placebo)
Infusion rate
Loading 2
1 gram
100 ml over
10 minutes
Maintenance
120 mg/hr
[60 ml/hr]
for about 8 hours
Fixed dose more practicable in emergency situation
Dose within range shown to inhibit fibrinolysis and provide haemostatic benefit

23. Treatment EACH BOX WILL CONTAIN 8 PATIENT TREATMENT PACKS
Each pack contains:
4 ampoules of tranexamic acid/placebo
100 mL bag sodium chloride
1x 10 mL syringe
1x green needle
Plus:
Adhesive labels for medical notes and data forms
Consent forms (if needed)
Patient information sheet
Data forms (Entry & Outcome)

24. Outcome data Primary outcome measure:
death in hospital within four weeks of injury
Cause of death is described to assess whether due to haemorrhage or vascular occlusion.

25. WWW.CRASH2.LSHTM.AC.UK CRASH Trials Co-ordinating Centre
London School of Hygiene & Tropical Medicine
Keppel Street, London WC1E 7HT
Tel +44(0) , Fax +44(0)