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The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial

CRASH-2 trial collaborators Lancet 2011; 377: 1096–101

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Background

CRASH-2 trial collaborators Lancet 2010; 376: 23–32

Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial

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Methods

• Randomised controlled trial• Active vs placebo• Undertaken in 274 hospitals in 40 countries randomised

20,211• Randomisation was balanced by centre, with an

allocation sequence based on a block size of eight, generated with a computer random number generator

• Participants and study staff (site investigators and trial coordinating centre staff) were masked to treatment allocation

• All analyses were by intention to treat• Commenced May 2005 results published June 2010

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Eligibility criteria

• Inclusion criteria– Adult 16+– Trauma

• blunt• penetrating

– Significant bleeding as evidenced by SBP < 90 mmHg and/or heart rate > 110 bpm

• Exclusion criteria– Doctor’s discretion

• TEA clearly indicated• TEA clearly contraindicated

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Were all patients who entered the trial accounted for?

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Were all patients analysed in the groups to which they

were randomised? • All analyses were by intention to treat

minus withdrawn consent, minus no outcome data

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Were measures objective or were the patients and clinicians kept “blind” to which treatment

was being received? • Tranexamic acid and placebo ampoules

were indistinguishable.

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Was the assignment of patients to treatments randomised?

• Randomisation was balanced by centre, with an allocation sequence based on a block size of eight, generated with a computer random number generator.

• In hospitals in which telephone randomisation was not practicable we used a local pack system that selected the lowest numbered treatment pack from a box containing eight numbered packs.

• Hospitals with reliable telephone access used the University of Oxford Clinical Trial Service Unit (CTSU) telephone randomisation service.

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Were the groups similar at the start of the trial?

• Treatment groups were balanced with respect to all baseline patient characteristics (table 1; the webappendix p 1 shows baseline data of patients with follow-up).

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Aside from the allocated treatment, were groups treated equally?

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How large was the treatment effect?

Relative Risk (RR) = risk of the outcome in the treatment group / risk of the outcome in the control group

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How large was the treatment effect?

Relative Risk (RR) = risk of the outcome in the treatment group / risk of the outcome in the control group

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Absolute Risk Reduction (ARR)

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Absolute Risk Reduction (ARR)

ARRAC = 0.16 – 0.145 = 0.015 or 1.5%

ARRB = 0.057 – 0.049 = 0.008 or 0.8%

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Relative Risk Reduction (RRR)

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Relative Risk Reduction (RRR)

RRRAC = 1 – 0.91 = 0.09 or 9%

RRRB = 1 – 0.85 = 0.15 or 15%

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Number Needed to Treat (NNT)

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Number Needed to Treat (NNT)

NNTAC = 1 / (0.16 – 0.145) = 67(40-198)

NNTB = 1 / (0.057 – 0.049) = 125(69-450)

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Background to the exploratory analysis

• The original hypothesis was that TEA exerts its beneficial effect on 28 day mortality by inhibition of fibrinolysis leading to improved effectiveness of homeostasis

• But – no significant difference was recorded in transfusion requirements between TEA and placebo groups, and the CRASH-2 trial did not measure the effect of TEA on fibrinolytic assays

• Also there had been discussion about which trauma patients should be treated with TEA as no strong evidence emerged from the 1st analysis for any subgroup benefit in terms of all cause mortality

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Intial PICO - Research Question

P Adult trauma patients with, or at risk of, significant bleeding, treated within 8h of injury I Tranexamic acid (loading dose 1g over 10min then infusion of 1g over 8h)C Placebo (0.9% saline)O Death in hospital, within 28 days of injury

Research question - Among adult trauma patients with, or at risk of, significant bleeding, treated within 8h of injury is a lower 28 day in-hospital mortality rate achieved using tranexamic acid compared to placebo?

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Initial analysis

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Initial analysis

Post hoc change from <1

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New PICO - Research Question

P Adult trauma patients with, or at risk of, significant bleeding, treated within 8h of injury I Tranexamic acid (loading dose 1g over 10min then infusion of 1g over 8h)C Placebo (0.9% saline)O Death in hospital due to bleeding, within 28 days of injury

Research question - Among adult trauma patients with, or at risk of, significant bleeding, treated within 8h of injury is a lower 28 day in-hospital mortality due to bleeding rate achieved using tranexamic acid compared to placebo?

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Results

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Patient characteristics by time to treatment

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Patient characteristics by time to treatment

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Patient characteristics by time to treatment

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Patient characteristics by time to treatment

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Patient characteristics by time to treatment

• Type of injury?

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Death due to bleeding by subgroup

Death due to all cause by subgroup

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Will the results help me in caring for my patient?

• Is my patient so different to those in the study that the results cannot apply?

• Is the treatment feasible in my setting?

• Will the potential benefits of treatment outweigh the potential harms of treatment for my patient?