Timing Of venous thromboembolism Prophylaxis for adult patients with Traumatic Brain Injury (TOP-TBl): a pragmatic, randomised trial

Research Question

In adult patients admitted to a neuroscience hospital with a traumatic brain injury, does early pharmacological thromboprophylaxis administration (<72 hours from injury) reduce the incidence of clinically relevant venous thromboembolism, compared to late administration (deferred by a minimum of 120 hours)? Background

Every year in the UK, an estimated 1.4 million people suffer a Traumatic Brain Injury (TBI) and 200,000 are admitted to hospital. Following a TBI, patients are at high risk of morbidity and mortality, including the development of venous thromboembolism (VTE). The most common types of VTE are deep vein thrombosis (DVT) and pulmonary embolism (PE). These problems complicate recovery from TBI, lead to long-term reductions in quality of life, and can occasionally be fatal.

A considerable body of evidence suggests that pharmacological thromboprophylaxis (PTP) reduces the incidence of VTE in TBI patients. This can reduce mortality and morbidity, and improve long-term functional outcome and quality of life for TBI patients. However, clinicians are concerned about the risk of PTP exacerbating bleeding and subsequent neurological deterioration in TBI patients.

There is no high-quality evidence defining the optimal time for administration, with wide variation in current management of VTE risk for TBI patients; the timing of PTP initiation being dependent on individual clinicians or locally developed pathways. There is a pressing need to generate new evidence regarding the optimal timing of PTP.

Aim

To perform a multi-centre, parallel-group, pragmatic, randomised superiority trial to determine the clinical- and cost-effectiveness of early PTP administration versus late administration for adult patients with TBI. Primary objective

Recruit 1512 patients in a randomised trial (150 in the internal pilot, 1362 in substantive study) to detect a 5% absolute difference in the proportion of patients developing VTE between the two arms (10% vs 5%, power 90%, 2-sided significance 5%). Secondary objectives • Compare functional neurological outcome and quality of life between the two arms.

• Compare all-cause mortality between the two arms. • Compare intracranial haemorrhage progression and adverse events between the two arms • Undertake a detailed economic evaluation. Methods

This will be a multi-centre, parallel-group, pragmatic, randomised trial based in the UK. Patients will be randomised into one of two study arms: early vs late. The only mandated treatment difference between trial arms will be the timing of PTP initiation, with the rest of medical care continuing as per usual clinical practice. An intention-to-treat analysis of all patients randomised will be performed.

PICO Population: Adult (=16) patients who have sustained an acute TBI managed in a neurosciences unit/MTC Intervention: Early PTP administration (<72 hours) Control: Late PTP administration (deferred by >120 hours or not prescribed if deemed unnecessary by clinical team) Outcome: Clinically relevant VTE within 30 days from randomisation Timelines for delivery

Study duration will be 60 months in total with the pilot due to start in Spring 2024 and end of study planned for late 2028. The study will include a 6 months set-up, 12 months pilot phase, 24 months substantial phase, 12 months follow up and 6 months write up and study close. Anticipated impact and dissemination

Findings will be disseminated through publications in journals, presentations, and social media. Charities related to TBI and VTE will provide regular updates to the public, and aid dissemination of relevant findings at project completion.