Restart tICrH: A Randomised Trial of Timing to Restart Direct Oral Anticoagulants after Traumatic Intracranial Haemorrhage

Research question In adults with a traumatic intracranial haemorrhage (tICrH) who are taking oral anticoagulants (OAC) when is the safest time to restart a direct oral anticoagulant (DOAC): early (1 week) or late (4 weeks)? Background Head injury in older people falling from a standing height affects ~25000 per year in the UK. Approximately 17-35% are taking OACs. OACs are stopped when CT scan confirms tICrH. The decision to restart balances the risk of worsening tICrH versus stroke/thromboembolism. OAC prescribing has changed from warfarin to direct OACs (DOACs). There are no studies assessing the safest time to restart DOAC in this setting. Many patients are unaware of the importance of restarting to prevent future stroke/thromboembolism. Aims & objectives Primary objective: •Determine the proportion of patients who meet the composite end-point of critical haemorrhagic and thrombotic events at 12 weeks Primary economic objective: •Estimate cost effectiveness of restarting DOAC Secondary objectives: Determine: •Patient function & quality of life •Time to death & mortality rate •Patient/carer attitudes to restarting DOAC Methods Health technologies being assessed: 1:1 randomisation of DOAC at: •1 week after tICrH •4 weeks after tICrH Design: multi-centre, randomised controlled trial Setting: neurosurgery, emergency, medical departments Population: adults on OAC/DOAC who sustain tICrH Eligibility criteria: Inclusion: •tICrH whilst on OAC where starting a DOAC is indicated •On pre-injury OAC for AF or VTE •At high risk for thromboembolic complications (CHA2DS2-VASc score >3) Exclusion: •Mechanical heart valve •Plan for anti-platelet therapy •Abbreviated Injury Scale other than head of >3 •Pregnancy •DOAC hypersensitivity/contraindication •Bleeding where it is unsafe to restart DOAC at 1 week •Clinical reason to restart DOAC before 4 weeks or complete within 12 weeks •Concomitant p-gp and CYP3A4 inducers/inhibitors •Indication to stay on OAC Internal pilot (assess at 9 months): Establish feasibility of site opening & recruitment. Corroborate assumptions about primary outcome. Embedded qualitative sub-study to explore patient/carer attitudes to restart DOAC (10-20 participants and 10 who decline) using semi-structured interviews and thematic analysis. Samples size/recruitment: The time to critical haemorrhagic/thrombotic event is the primary outcome based on a composite event rate of 12% in the group restarting at 4 weeks. When the sample size in each group is 483, with 80 events required, a 0.05 level two-sided log-rank test for equality of survival curves has 90% power to detect the difference between a proportion at 12 weeks of 0.88 and a proportion of 0.94 (constant hazard ratio of 2.066). Allowing 10% attrition we will recruit 1074. 10-20 patients with tICrH on DOAC are referred to neurosurgery units/ month. Assuming each unit screens 5 patients/month and 33% of eligible patients are recruited, this totals a conservative estimate of 20/unit/year. A recruitment period of 42 months is sufficient to reach the target. Timelines for delivery (60 months) •Set-up: 6 months •Pilot: 9 months •Recruitment: 42 months (includes pilot) •Follow-up: 6 months •Data cleaning/analysis: 6 months Anticipated impact & dissemination Study set up, promotion, recruitment and results by study team and charities. Traumatic brain injury is common, and the study will inform guidelines for starting DOAC that will inform neurosurgery practice.