TOP-TBI

Background

Annually, an estimated 69 million people suffer a traumatic brain injury (TBI) with about 200,000 TBI patients admitted to hospitals in the UK. Following a TBI, patients are at high risk of morbidity and mortality, including the development of venous thromboembolism (VTE), deep vein thrombosis (DVT) and pulmonary emboli (PE) being the 2 most common VTEs. VTEs complicate recovery and can be fatal. A considerable body of evidence suggests that administration of pharmacological thromboprophylaxis (PTP) administration can reduce the incidence of VTEs in TBI patients. This, in turn, can reduce mortality and morbidity, and improve long-term functional outcome and quality of life for TBI patients. However, there is a lack of high-quality evidence defining the optimal time for administration. This results in heterogeneous management of VTE risk in TBI patients with PTP timing being dependent on individual surgeons, hospitals, or service practices. Standard practice for many neuroscience units in the UK involves waiting for at least 72 hours to give PTP, because of theoretical concerns involving further bleeding after TBI. There is a need to generate high-quality new knowledge regarding the optimal timing of PTP, which this study has the capacity to do

Aims of trial 

The aim of this trial is to perform a multi-centre, parallel-group, pragmatic, randomised trial to determine the clinical- and costeffectiveness of early (within 72 hours of injury) PTP administration versus late PTP administration (at least 120 hours following injury) for adult patients with acute TBI. Patients will be randomised into one of two study arms (early vs late arm). The only mandated treatment difference between trial arms will be the time of PTP commencement, with the rest of medical care remaining as usual clinical practice. Intention-to-treat analysis will take place

A total of 1512 patients in a randomised trial (150 in the internal pilot, 1362 in substantive study) will be recruited.  Overall aim of trial is to define best practice in the timing of venous thromboembolism prophylaxis following TBI and to estimate the absolute difference in the proportion of patients developing VTE between the two arms. Primary outcome measure will be clinically relevant VTE within 30 days from randomisation to include any confirmed diagnosis of symptomatic DVT, pulmonary embolism, death related to VTE. 

Secondary objectives will include comparison of the consequences of early versus standard PTP administration on function, neurological outcome, and quality of life; comparison of mortality between the two arms, adverse events and intracranial haemorrhage progression between the two arms. There will also be a detailed economic evaluation. 

Intervention

Trial participants randomised into either the early or late arm will receive standard of care agents available for VTE prophylaxis (Heparin, Low molecular weight heparins (LMWH), Heparinoids, Fondaparinux sodium, oral anticoagulants). Standard hospital stocks will be used and administered according to local hospital policy and at the discretion of the treating doctor. Participants will receive the drug while they are in hospital. Following discharge, patient will be followed up for up to 12 months for occurrence of VTE, mortality, quality of life.

Findings will be disseminated through publications in journals and presentations at academic meetings. Charities related to TBI and VTE will provide regular updates to the public.