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Global deaths at ages 5-45 years (both sexes)

A large randomised controlled trial among trauma patients with significant haemorrhage, of the effects of antifibrinolytic treatment on death and transfusion requirement. Global deaths at ages 5-45 years (both sexes). Deaths (2000 projected) HIV/AIDS 2,104,454 Road traffic injury 657,614

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Global deaths at ages 5-45 years (both sexes)

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  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. Exsanguination CNS injury 41% 45% 10% 4% Other Organ failure In-hospital trauma deaths Sauaia A et al. Epidemiology of trauma deaths: a reassessment. J Trauma 1995;38:185-193

  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, 2004. Chichester, UK: John Wiley & Sons, Ltd

  7. Antifibrinolytic agents in elective surgery NEED FOR TRANSFUSION RR (95% CI) Aprotinin 0.70 (0.64-0.76) TXA 0.66 (0.54-0.81) 0 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 (0.7-1.5) TXA 1.0 (0.7-1.4) 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 (0.25-0.66) TXA 0.72 (0.29-1.79) 0 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 (0.63-1.19) TXA 0.43 (0.15-1.18) 0 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 0.69 0.21 - 2.29 Stroke 2.27 0.65 - 7.99 DVT 0.84 0.30 - 2.30 PE 0.32 0.07 - 1.56 Any thrombosis 0.98 0.49 - 1.94 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. 2004 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. 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 DOCTOR IS “REASONABLY CERTAIN” THAT ANTI-FIBRINOLYTIC AGENTS ARE INDICATED. INELIGIBLE GIVE ANTI-FIBRINOLYTIC AGENTS; DO NOT RANDOMISE. DOCTOR IS “REASONABLY CERTAIN” THAT ANTI-FIBRINOLYTIC AGENTS ARE CONTRA-INDICATED. INELIGIBLE DON’T GIVE ANTI-FIBRINOLYTIC AGENTS; DO NOT RANDOMISE. Doctor is “SUBSTANTIALLY UNCERTAIN” as to the appropriateness of anti-fibrinolytic agents in this patient TELEPHONE FOR RANDOMISATION OR PAPER RANDOMISE PLACEBO TRANEXAMIC ACID

  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) • 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, email 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. Treatment 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)20 7299 4684, Fax +44(0)20 7299 4663 Email CRASH@Lshtm.ac.uk

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