Transcript Collecting follow-up data - CRASH-2

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
Tuberculosis
603,522
Self inflicted injury
431,924
Violence
335,202
War injuries
167,329
In-hospital trauma deaths
Exsanguination
CNS injury
41%
45%
4%
Other
10%
Organ failure
Sauaia A et al. Epidemiology of trauma deaths: a reassessment. J Trauma 1995;38:185-193
Fibrinolysis
• 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.
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
Antifibrinolytic agents
in elective surgery
NEED FOR TRANSFUSION
RR (95% CI)
Aprotinin
TXA
0.66 (0.54-0.81)
0
0.4
0.8
Antifibrinolytic better
Henry et al
0.70 (0.64-0.76)
1.2
1.6
2.0
Antifibrinolytic worse
Antifibrinolytic agents
in elective surgery
BLOOD UNITS SAVED
Aprotinin
1.1 (0.7-1.5)
TXA
1.0 (0.7-1.4)
0
Henry et al
0.4
0.8
1.2
1.6
2.0
Blood units
Antifibrinolytic agents
in elective surgery
RE-OPERATION
RR (95% CI)
Aprotinin
TXA
0.72 (0.29-1.79)
0
0.4
0.8
Antifibrinolytic better
Henry et al
0.40 (0.25-0.66)
1.2
1.6
2.0
Antifibrinolytic worse
Antifibrinolytic agents
in elective surgery
MORTALITY
RR (95% CI)
Aprotinin
TXA
0.43 (0.15-1.18)
0
0.4
0.8
Antifibrinolytic better
Henry et al
0.87 (0.63-1.19)
1.2
1.6
2.0
Antifibrinolytic worse
Tranexamic acid for minimising
surgical blood loss
ADVERSE EFFECTS
Non-fatal MI
Stroke
DVT
PE
Any thrombosis
RR
0.69
2.27
0.84
0.32
0.98
95% CI
0.21 - 2.29
0.65 - 7.99
0.30 - 2.30
0.07 - 1.56
0.49 - 1.94
No evidence of increased adverse effects
Henry et al
TXA already being used
in some treatment protocols
Treatment protocol of Israeli Defence Force
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•
•
•
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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
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
Rationale for CRASH-2
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•
•
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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 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
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
TRANEXAMIC ACID
PLACEBO
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
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
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
Patient Entry
PATIENT ENTRY
ALL QUESTIONS BELOW NEED TO BE ANSWERED
BEFORE CALLING THE RANDOMISATION SERVICE
INFORMATION ABOUT YOUR HOSPITAL
Please complete before
randomisation to ensure
patient fulfils eligibility
criteria
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
9.
Type of injury (please circle)
hours
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
14.
Glasgow Coma Score (max 15)
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
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
Treatment
Treatment
Loading
Maintenance
Ampoules
Dose (Tranexamic
Acid or placebo)
Infusion rate
2
1 gram
100 ml over
10 minutes
1 gram
120 mg/hr
[60 ml/hr]
for about 8 hours
2
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/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)
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.
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 [email protected]