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

Baseline characteristics by treatment groups.

<p>Data are shown as mean (standard deviation) and number (%).</p

Recruitment flow chart.

<p>Recruitment flow chart.</p

Serious Adverse Events, by group and time to event in days; includes all SAEs up to day 90, and any fatal SAEs post day 90.

<p>Serious Adverse Events, by group and time to event in days; includes all SAEs up to day 90, and any fatal SAEs post day 90.</p

Recovery outcome measures by treatment group (bars represent the standard error).

<p>a) Rivermead Motor Assessment (RMA) by G-CSF vs. placebo. b) Quality of life (EQ-5D) by G-CSF vs. placebo. c) Rivermead Motor Assessment (RMA) by physiotherapy vs. control. d) Quality of life (EQ-5D) by physiotherapy vs. control.</p

Additional file 1: of Baseline characteristics, analysis plan and report on feasibility for the Prevention Of Decline in Cognition After Stroke Trial (PODCAST)

Trial protocol. (PDF 2304 kb

Changes in Addenbrooke’s Cognitive Examination-Revised score during follow-up for intensive vs guideline groups.

<p><b>Data are mean and standard error of mean</b>. (A) Intensive vs guideline blood pressure lowering. (B) Intensive vs guideline lipid lowering.</p

CONSORT flow diagram of patient randomisation, follow up, outcome, and withdrawals.

<p>Screening for eligibility was not collected routinely. Data are number/Number (%).</p

Clinical characteristics at randomisation, by intensive vs guideline blood pressure and lipid lowering.

<p>Clinical characteristics at randomisation, by intensive vs guideline blood pressure and lipid lowering.</p

Primary and secondary cognition and other functional measures by treatment group: intensive vs guideline blood pressure lowering.

<p>Comparison by multiple regression of mean on-treatment score with adjustment for baseline value and age, systolic blood pressure, total cholesterol, time since stroke, treatment assignment (intensive vs lipid guideline lowering vs none).</p