Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial

BackgroundTranexamic acid (TXA) reduces death due to bleeding after trauma and post-partum haemorrhage. The aim was to assess if tranexamic acid reduces haematoma expansion and improves outcome in adults with stroke due to intracerebral 6 haemorrhage (ICH). MethodsWe undertook an international, randomised placebo-controlled trial in adults with intracerebral haemorrhage. Participants received 1g intravenous tranexamic acid bolus followed by an 8 hour 1g infusion, or matching placebo, within 8 hours of symptom onset. The primary outcome was functional status at day 90, measured by shift in the modified Rankin Scale (mRS), using ordinal logistic regression, with adjustment for stratification and minimisation criteria. All analyses were performed on an intention to treat basis. This trial is registered as ISRCTN93732214.FindingsWe recruited 2,325 participants (TXA 1161, placebo 1164) from 124 hospitals in 12 countries between 2013 and 2017. Treatment groups were well balanced at baseline. The primary outcome was determined for 2307 (99·2%) participants. There was no statistically significant difference between the groups for the primary outcome of functional status at day 90 (adjusted odds ratio [aOR] 0·88, 95% CI 0·76-1·03, p=0·11). Although there were fewer deaths by day 7 in the TXA group (aOR 0·73, 95% CI 0·53-0·99, p=0·0406), there was no difference in case fatality at 90 days (adjusted hazard ratio 0·92, 95% CI 0·77 to 1·10, p =0·37). There were fewer serious adverse events after TXA vs. placebo by days 2 (p=0·0272), 7 (p=0·0200) and 90 (p=0·0393).InterpretationThere was no significant difference in functional status 90 days after intracerebral haemorrhage with tranexamic acid, despite a reduction in early deaths and serious adverse events. Larger randomised trials are needed to confirm or refute a clinically significant treatment effect

Calibration in the large of the models.

<p>Data are counts (%); <i>p</i> values are derived from a logistic regression model. Figures are given for all patients and separately for those with ischaemic and haemorrhagic strokes.</p

Characteristics of the prognostic models.

<p>Characteristics of the prognostic models.</p

Receiver operating characteristics (ROC) curves for survival and independence, for the total sample.

<p>Optimally, the curve should lie towards the upper left corner of the plot. Survival: assessed at 30 days for the SSVMod and at 100 days for the NIHSSMod. Independence: assessed at 6 months for the SSVMod and at 3 months for the NIHSSMod.</p

C-statistics for survival and independence.

<p>C-statistics for survival and independence.</p

Demographic characteristics of the original and validation samples.

<p>Demographic characteristics of the original and validation samples.</p

Details of the original predictive models [9,11].

<p>Details of the original predictive models [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153527#pone.0153527.ref009" target="_blank">9</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153527#pone.0153527.ref011" target="_blank">11</a>].</p

Characteristics of previous validation studies.

<p>Characteristics of previous validation studies.</p

Calibration plots for survival and independence, for the total sample and based on deciles of patient numbers.

<p>Survival: assessed at 30 days for the SSVMod and at 100 days for the NIHSSMod. Independence: assessed at 6 months for the SSVMod and at 3 months for the NIHSSMod. For illustrative clarity, the origins for the axes vary between plots.</p

Clinical and demographic characteristics of the study sample.

<p>Clinical and demographic characteristics of the study sample.</p