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)

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

Exsanguination CNS injury

Organ failureOther

45% 41%

10%4%

In-hospital trauma deathsIn-hospital trauma deaths

Sauaia A et al. Epidemiology of trauma deaths: a reassessment. J Trauma 1995;38:185-193

FibrinolysisFibrinolysis

• During fibrinolysis, plasminogen is converted into plasmin by tissue plasminogen activator

• Plasmin binds to fibrin via its lysine binding sites to cause fibrinolysis.

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.

SYSTEMATIC REVIEWS

APROTININ61 Randomised controlled trials including 7,027 participants

TRANEXAMIC ACID (TXA)18 Randomised controlled trials including 1342 participants

Antifibrinolytic agents in elective surgery

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

NEED FOR TRANSFUSION

TXA

Aprotinin

Antifibrinolytic better Antifibrinolytic worse

0.70 (0.64-0.76)

0.66 (0.54-0.81)

RR (95% CI)

0 0.4 0.8 1.2 1.6 2.0

Antifibrinolytic agents in elective surgery

Henry et al

BLOOD UNITS SAVEDBLOOD UNITS SAVED

0 0.4 0.8 1.2 1.6 2.0

Blood units

1.1 (0.7-1.5)

1.0 (0.7-1.4)TXA

Aprotinin

Antifibrinolytic agents in elective surgery

Henry et al

RE-OPERATIONRE-OPERATION

RR (95% CI)

Antifibrinolytic better Antifibrinolytic worse0 0.4 0.8 1.2 1.6 2.0

TXA

Aprotinin 0.40 (0.25-0.66)

0.72 (0.29-1.79)

Antifibrinolytic agents in elective surgery

Henry et al

MORTALITYMORTALITY

TXA

Aprotinin

RR (95% CI)

Antifibrinolytic better Antifibrinolytic worse0 0.4 0.8 1.2 1.6 2.0

0.87 (0.63-1.19)

0.43 (0.15-1.18)

Antifibrinolytic agents in elective surgery

Henry et al

Tranexamic acid for minimising surgical blood loss

Henry et al

ADVERSE EFFECTS

RR 95% CINon-fatal MI 0.69 0.21 - 2.29Stroke 2.27 0.65 - 7.99DVT 0.84 0.30 - 2.30PE 0.32 0.07 - 1.56Any thrombosis 0.98 0.49 - 1.94

No evidence of increased adverse effects

TXA already being used in some treatment protocols

• 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

Treatment protocol of Israeli Defence Force

1 randomised controlled trial including 70 patients

Drug versus Placebo: 0 vs. 3 deaths

Roberts IG, Coates T, Shakur H Antifibrinolytic drugs for acute traumatic injury. Cochrane Database Syst Rev. 2004 Oct 18(4):CD004896

Antifibrinolytic agents in trauma

Systematic review

• Insufficient evidence to support clinical use in trauma

• Need for RCT – CRASH-2

• Insufficient evidence to support clinical use in trauma

• Need for RCT – 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

Rationale for CRASH-2

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

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

DOCTOR IS “REASONABLY CERTAIN” THAT ANTI-FIBRINOLYTIC AGENTS

ARE INDICATED.

INELIGIBLEGIVE ANTI-FIBRINOLYTIC AGENTS;

DO NOT RANDOMISE.

DOCTOR IS “REASONABLY CERTAIN” THAT ANTI-FIBRINOLYTIC AGENTS ARE CONTRA-INDICATED.

INELIGIBLEDON’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

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

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

Randomisation

• Give brief patient details

• Computer determines treatment allocation

• Treatments ‘balanced’ on prognostic factors

• Select lowest numbered treatment pack

• Patient details sent by via secure website, email or fax

Central (by telephone)Central (by telephone)

Non-centralNon-central

• 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

Consent

Patient Entry

PATI ENT ENTRY ALL QUESTIONS BELOW NEED TO BE ANSWERED BEFORE CALLING THE RANDOMISATION SERVICE

INFORMATION ABOUT YOUR HOSPITAL

1. Country

2. Name of hospital (or your hospital code)

3. Name of caller

INFORMATION ABOUT THE PATIENT

4. Patient sex (please circle) Male Female 5. Patient initials

6. Patient hospital identification number

7. Do you know patient’s date of birth?

a. YES – date of birth / / b. NO – approximate age

INFORMATION ABOUT THE INJURY

8. Estimated number of hours since injury hours

9. Type of injury (please circle) 1 Blunt 2 Penetrating 3 Both

FIRST MEASUREMENT IN HOSPITAL OF THE FOLLOWING ( IF UNKNOWN GIVE VALUE AT RANDOMISATION)

10. Systolic BP (mmHg) 11. Respiratory rate (per min)

12. Central capillary refill time (sec) 13. Heart rate (per min)

EYE OPENING MOTOR RESPONSE VERBAL RESPONSE 4 Spontaneous 6 Obeys commands 5 Orientated

3 To sound 5 Localising 4 Confused speech

2 To pain 4 Normal flexion 3 Words

1 None 3 Abnormal flexion 2 Sounds

2 Extending 1 None

14. Glasgow Coma Score (max 15)

1 None

Now call Randomisation Service with these answers and write down the treatment pack number given at the end of the phone call

Box Pack Get this pack and follow the instructions on it carefully

Or paper randomise as per instructions in site file

Please complete before randomisation to ensure patient fulfils eligibility criteria

Please complete before randomisation to ensure patient fulfils eligibility criteria

TreatmentAmpoule

s

Dose (Tranexamic Acid

or placebo)Infusion rate

Loading 2 1 gram100 ml over 10 minutes

Maintenance

2 1 gram

120 mg/hr [60 ml/hr] for about 8 hours

Treatment

Fixed dose more practicable in emergency situation

Dose within range shown to inhibit fibrinolysis and provide haemostatic benefit

Fixed dose more practicable in emergency situation

Dose within range shown to inhibit fibrinolysis and provide haemostatic benefit

Treatment

EACH BOX WILL CONTAIN 8 PATIENT TREATMENT PACKS

Each pack contains:4 ampoules of tranexamic acid/placebo100 mL bag sodium chloride1x 10 mL syringe1x green needle

Plus:Adhesive labels for medical notes and data formsConsent forms (if needed)Patient information sheetData forms (Entry & Outcome)

Outcome data

OUTCOME FORM COMPLETE AT DISCHARGE FROM THE RANDOMISING HOSPITAL,

DEATH IN HOSPITAL OR 28 DAYS AFTER INJURY, WHICHEVER OCCURS FIRST

1. HOSPITAL

2. PATIENT Patient Initials Hospital I D Number Sex M F

Date of Birth DAY / MONTH / YEAR .

3. OUTCOME 3.2 PATIENT ALIVE

…. Discharged – Date of discharge DAY / MONTH/ YEAR.

…. Still in this hospital now (28 days after inj ury) – Date DAY / MONTH/ YEAR..

3.3 IF ALIVE TICK ONE BOX THAT BEST DESCRIBES THE PATIENT’S CONDITION ( at 28 days or prior discharge)

3.1 DEATH IN HOSPITAL

Date of death DAY / MONTH/ YEAR.

Cause of death

…. Bleeding

…. Head injury

…. Myocardial Infarction

…. Stroke

…. Pulmonary Embolism

…. Multi organ failure

…. Other – describe

…………………………………

…. No symptoms

…. Minor symptoms

…. Some restriction in lifestyle but

independent

…. Dependent, but not requiring constant

attention

…. Fully dependent, requiring attention

day and night

4. MANAGEMENT 7. TRANSFUSION

a) Days in I ntensive Care Unit (if not admitted to I CU, write ‘0 ’ here)

a) Blood products transfusion YES NO

b) Significant Head I njury YES NO b) Units transfused in 28 days

c) Operation site - Tick one box on every line Red cell products units

Neurosurgical YES NO Fresh frozen plasma units

Chest YES NO Platelets units

Abdomen YES NO Cryoprecipitate units

Pelvis YES NO

Recombinant Factor VI Ia YES NO

5. COMPLICATIONS 8. PERSON COMPLETING FORM

Tick one box on every line NAME

Pulmonary Embolism YES NO POSITION

Deep Vein Thrombosis YES NO DATE

Stroke YES NO

Operation for bleeding YES NO

NOW SEND THIS FORM TO THE CO-ORDINATING

CENTRE IN ONE OF THE FOLLOWING WAYS:

Myocardial Infarction YES NO SECURE WEBSITE

Gastrointestinal bleeding YES NO

ELECTRONIC DATA FORMS / EMAI L

6. TRIAL TREATMENT FAX +44 (0)20 7299 4663

a) Complete loading dose given YES NO

b) Complete maintenance dose given YES NO

(Hospital name or code)

Attach treatment

pack sticker here

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.

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.

CRASH Trials Co-ordinating CentreLondon School of Hygiene & Tropical Medicine

Keppel Street, London WC1E 7HT

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

WWW.CRASH2.LSHTM.AC.UK WWW.CRASH2.LSHTM.AC.UK