Tranexamic acid to improve functional status in adults with spontaneous intracerebral haemorrhage: the TICH-2 RCT.

BACKGROUND

Tranexamic acid reduces death due to bleeding after trauma and postpartum haemorrhage.

OBJECTIVE

The aim of the study was to assess if tranexamic acid is safe, reduces haematoma expansion and improves outcomes in adults with spontaneous intracerebral haemorrhage (ICH).

DESIGN

The TICH-2 (Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage) study was a pragmatic, Phase III, prospective, double-blind, randomised placebo-controlled trial.

SETTING

Acute stroke services at 124 hospitals in 12 countries (Denmark, Georgia, Hungary, Ireland, Italy, Malaysia, Poland, Spain, Sweden, Switzerland, Turkey and the UK).

PARTICIPANTS

Adult patients (aged ≥ 18 years) with ICH within 8 hours of onset.

EXCLUSION CRITERIA

Exclusion criteria were ICH secondary to anticoagulation, thrombolysis, trauma or a known underlying structural abnormality; patients for whom tranexamic acid was thought to be contraindicated; prestroke dependence (i.e. patients with a modified Rankin Scale [mRS] score > 4); life expectancy < 3 months; and a Glasgow Coma Scale score of < 5.

INTERVENTIONS

Participants, allocated by randomisation, received 1 g of an intravenous tranexamic acid bolus followed by an 8-hour 1-g infusion or matching placebo (i.e. 0.9% saline).

MAIN OUTCOME MEASURE

The primary outcome was functional status (death or dependency) at day 90, which was measured by the shift in the mRS score, using ordinal logistic regression, with adjustment for stratification and minimisation criteria.

RESULTS

A total of 2325 participants (tranexamic acid,

LIMITATIONS

Despite attempts to enrol patients rapidly, the majority of participants were enrolled and treated > 4.5 hours after stroke onset. Pragmatic inclusion criteria led to a heterogeneous population of participants, some of whom had very large strokes. Although 12 countries enrolled participants, the majority (82.1%) were from the UK.

CONCLUSIONS

Tranexamic acid did not affect a patient's functional status at 90 days after ICH, despite there being significant modest reductions in early death (by 7 days), haematoma expansion and SAEs, which is consistent with an antifibrinolytic effect. Tranexamic acid was safe, with no increase in thromboembolic events.

FUTURE WORK

Future work should focus on enrolling and treating patients early after stroke and identify which participants are most likely to benefit from haemostatic therapy. Large randomised trials are needed.

TRIAL REGISTRATION

Current Controlled Trials ISRCTN93732214.

FUNDING

This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in

BACKGROUND

Stroke caused by bleeding in the brain [i.e. an intracerebral haemorrhage (ICH)] is a medical emergency. Around one-third of such strokes are complicated by continuing bleeding, which usually occurs within the first few hours after trauma and childbirth, and is associated with death or severe disability. Tranexamic acid is a drug that is seen to reduce death from bleeding after trauma and childbirth.

METHODS

The study enrolled adults within 8 hours of an ICH into this large randomised trial. Half of the participants were given an injection of tranexamic acid and the other half placebo (in the form of salt water). The main aim of the trial was to measure changes in recovery by a telephone questionnaire on how much the person was able to do or needed help with 90 days after the stroke (i.e. functional status). Other measures included amount of brain bleeding, complications after stroke (serious adverse events), drug side effects and death within 7 days of stroke.

RESULTS

A total of 2325 participants from 124 hospitals in 12 countries were enrolled between 2013 and 2017. Participants treated with tranexamic acid had no significant difference in functional status 90 days after stroke. There were small but significant reductions in brain bleeding, death in the first 7 days and complications after stroke, and tranexamic acid was safe with no increased side effects.

CONCLUSION

Treatment with tranexamic acid did not result in a significant improvement in recovery at 90 days (i.e. functional status), despite small reductions in the number of early deaths, amount of brain bleeding and the number of complications. Larger trials are needed to confirm if these small benefits observed after treatment with tranexamic acid can significantly improve functional status after stroke due to bleeding in the brain (ICH).

Déclaration de conflit d'intérêts

Rustam Al-Shahi Salman is a member of the Efficacy and Mechanism Evaluation Funding Board panel. Lelia Duley reports grants from the Nottingham Clinical Trials Unit during the conduct of the study. Christian Ovesen reports grants from the Velux Foundation (Søborg, Denmark), the Hojmosegaard Grant/Danish Medical Association (Copenhagen, Denmark), the Axel Muusfeldt’s Foundation (Albertslund, Denmark), the University of Copenhagen (Copenhagen Denmark) and non-financial support from Merck Sharp & Dohme (MSD; Kenilworth, NJ, USA) outside the submitted work. Robert A Dineen reports grants from the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (project number 11/129/109) during the conduct of the study. Timothy J England reports grants from the NIHR HTA programme during the conduct of the study. Thompson G Robinson reports grants from the University of Leicester. Christine Roffe has been a member of the HTA General Board since 2017. David Werring reports personal fees from Bayer AG (Leverkusen, Germany) outside the submitted work. Philip M Bath reports grants from the British Heart Foundation and the NIHR HTA programme during the conduct of the study, others from Platelet Solutions Ltd (Nottingham, UK) and personal fees from Diamedica (UK) Ltd (Bratton Fleming, UK), Nestlé SA (Vevey, Switzerland), Phagenesis Ltd (Manchester, UK), ReNeuron Group plc (Bridgend, UK), Athersys Inc. (Cleveland, OH, USA) and Covidien (Dublin, Ireland) outside the submitted work.