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21/588 Timing of pharmacological thromboprophylaxis in traumatic brain injury commissioning brief



The aim of the HTA Programme is to ensure that high quality research information on the clinical effectiveness, cost-effectiveness and broader impact of healthcare treatments and tests are produced in the most efficient way for those who plan, provide or receive care from NHS and social care services. The commissioned workstream invites applications in response to calls for research on specific questions which have been identified and prioritised for their importance to the NHS, patients and social care.

Research question

In adult patients with a traumatic brain injury (TBI), is early administration of pharmacological thromboprophylaxis (PTP) superior with regards to clinical effectiveness when compared to late PTP administration?

  1. Intervention: Early (to be defined and justified by applicants) pharmacological thromboprophylaxis with low molecular weight heparin (LMWH), until discharge or until no longer indicated. Dose based on measured or estimated weight of the patient according to standard prescribing practice and local policy.
  2. Patient group: Patients = 16 years of age presenting with an acute TBI (applicants to define and justify) – confirmed on cranial imaging.  Applications are encouraged which include recruitment from geographic populations with high disease burden which have been historically underserved by research activity in this field.
  3. Setting: Any appropriate hospital setting, to be justified by applicants.
  4. Control: Late (to be defined and justified by applicants) pharmacological thromboprophylaxis with LMWH, until discharge or until no longer indicated. Dose based on measured or estimated weight of the patient according to standard prescribing practice and local policy. Applicants should also account for the potential use of graduated compression stockings or intermittent pneumatic compression across control and intervention arms.
  5. Study design: A randomised controlled trial with an internal pilot phase to test key trial processes such as recruitment, adherence and to demonstrate clear differentiation of timing between treatment groups. Clear stop/go criteria should be provided to inform progression from pilot to full trial.
  6. Important outcomes: Clinically important venous thromboembolism (VTE; clinically detected and radiologically confirmed pulmonary embolism (PE or proximal leg deep vein thrombosis (DVT)) within 30 days from randomisation; clinically important intracranial haemorrhage (ICH) within 14 days after randomisation; objectively confirmed new or progressing ICH on radiology; mortality.
  7. Other outcomes: Quality of life; functional outcome as measured by the Extended Glasgow Outcome Scale (GOS-E); other clinically significant bleeding; healthcare resource use. Existing Core Outcomes should be included amongst the list of outcomes unless a good rationale is provided to do otherwise. Applicants are encouraged to report recruitment and findings disaggregated by sex (and other demographic factors where relevant).
  8. Minimum duration of follow-up: Applicants to define and justify.


Traumatic brain injury (TBI) is a traumatically induced structural injury and/or physiological disruption of brain function as a result of an external force that can cause death, impairment in consciousness, cognition, physical function and/or psychological function.

Following a TBI, patients are at a significant risk of developing blood clots, called venous thromboembolism (VTE), often in the legs, a deep vein thrombosis (DVT), or the lungs, a pulmonary embolism (PE).

This is thought to be secondary to prolonged periods of immobilisation and the systemic response to trauma. The risk of VTE following TBI is associated with older age, increasing number of comorbidities, craniotomy or craniectomy and more severe injuries. Such VTE episodes complicating recovery, adversely affecting long-term functional outcome, prolonging hospitalisation and increasing inpatient costs.

Evidence suggests that administration of pharmacological thromboprophylaxis can reduce the incidence of VTEs in patients with TBI which in turn can reduce mortality and morbidity and improve long-term functional outcome and quality of life of patients with TBI. There is however often a reluctance to initiate such prophylaxis early due to the lack of high-quality evidence demonstrating superior clinical effectiveness and the potential that such early treatment could increase the risk of clinically important intracranial haemorrhage (ICH) incidence or progression, and as such there is substantial variation in practice.

There is a growing evidence base that early prophylaxis (i.e. within 72 hours of injury) reduces VTE events in TBI without an increased with ICH progression but this is almost entirely from retrospective analyses and until and unless this question is answered with an adequately powered randomised trial this will remain a clinically important uncertainty.

Additional commissioning brief background information

A background document is available that provides further information to support applicants for this call. It is intended to summarise what prompted the call and the existing evidence base, including relevant work from the HTA and wider NIHR research portfolio. It was researched and written on the basis of information from a search of relevant sources and databases, and in consultation with a number of experts in the field. If you would like a copy, please email

Making an application

If you wish to submit a Stage 1 application for this call, the online application form can be found on the funding opportunities page. To select this call, use the filters on the right of the screen or search using the call name and/or number.

Your application must be submitted on-line no later than 1pm on the 30 March 2022. Applications will be considered by the HTA Funding Committee at its meeting in May 2022.

Guidance notes and supporting information for HTA Programme applications are available.

Important: Shortlisted Stage 1 applicants will be given eight weeks to submit a Stage 2 application. The Stage 2 application will be considered at the Funding Committee in September 2022.

Applications received electronically after 1300 hours on the due date will not be considered.

For commissioned topics, the Programme strongly discourages the practice of the same co-applicant joining more than one competing team. There may be unusual circumstances where the same person could be included on more than on application eg a lead from a named charity or a unique national expert in a condition.

For such exceptions (i) each application needs to state the case as to why the same person is included (ii) the shared co-applicant should not divulge application details between teams and (iii) both teams should acknowledge in their application that they are aware that one of their co-applicants is part of a competing application and that study details have not been shared.

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