Introduction
The aim of the Health Technology Assessment (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
What is the clinical and cost-effectiveness of thromboprophylaxis in patients with lower limb immobilisation?
- Patient group: Adults with temporary lower limb immobilisation and assessed for risk of venous thromboembolism (VTE) using an appropriate risk assessment tool, defined and justified by the applicants (applicants also to define and justify types of injuries, treatments and methods of immobilisation to be included/excluded).
Applications are encouraged which include recruitment from geographic populations with high disease burden which have been historically underserved by research activity in this field. - Interventions/control:
Trial 1) For patients deemed at low risk of VTE:
A) Prophylaxis with direct oral anticoagulants (DOAC) vs B) Prophylaxis with parenteral anticoagulant vs C) No prophylaxis.
Trial 2) For patients deemed at high risk of VTE:
A) Prophylaxis with DOAC vs B) Prophylaxis with parenteral anticoagulant.
Drugs and dosing regimens to be defined and justified by applicants.
- Setting: Any appropriate setting.
- Study design: A study comprising two linked randomised controlled trials depending on VTE risk, with each powered separately, and with internal pilot phase to test key trial processes such as recruitment and adherence. Clear stop/go criteria should be provided to inform progression from pilot to full trial.
- Important outcomes:A composite of measures of effectiveness and measures of harm including for example, but not necessarily limited to cause-specific mortality; symptomatic pulmonary embolism and/or DVT; quality of life; post-thrombotic syndrome severity; major bleeding; clinically relevant non-major bleeding (to include surgical site bleeding); hospital admissions; medication use; cost-effectiveness.
- Other outcomes: Acceptability; adherence. 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).
- Minimum duration of follow-up: Applicants to define and justify.
Rationale
Patients requiring temporary immobilisation (e.g. hard cast) of their lower limbs due to some kind of injury (e.g. ankle fracture) are at increased risk of developing a venous thromboembolism (VTE), in particular a deep vein thrombosis (DVT) or pulmonary embolism (PE). Such VTEs are a significant cause of morbidity and mortality.
Although the overall risk of developing a VTE in this population is relatively small, the number of patients with such injuries each year makes this a significant concern and financial burden to the health service. A number of factors, in particular age, increases the risk of developing a VTE.
Whether or not chemical thromboprophylaxis for prevention of VTE in this population should be used generates much international debate. It is routine in many European countries, including the UK, but is actively discouraged in North American guidelines. But even in the UK where the guidelines recommend such practice for those at higher risk, there remains considerable uncertainty about who to treat, and with what, and therefore practice varies considerably.
The available, but not strong, evidence comes from studies of parenteral anticoagulation (daily injections with low molecular weight heparin (LMWH) or fondaparinux), and with an indication that this should potentially be restricted to patients at higher risk of VTE, as assessed using a risk assessment tool/model, of which there are several, based on a range of risk factors.
Direct oral anticoagulants (DOACs), of which there are a number of specific drugs, have been shown to be as or even more effective then LMWHs for a range of indications but may also have an increased risk of bleeding. There is therefore much interest to determine the place of DOACs for chemical thromboprophylaxis in lower limb immobilisation, not least because taken orally, there is likely to be better patient acceptability and adherence to treatment compared to daily injections. DOACs do not currently have a licence for this indication and despite the lack of evidence their use is already expanding.
Two significant uncertainties remain in this population which will only be able to be answered with an adequately powered randomised trial. In patients deemed at low(er) risk of VTE is doing nothing appropriate or is there a still a role for prophylaxis with either parenteral anticoagulation or DOACs. For those assessed at high(er) risk, where doing nothing is already not recommended, is there any difference in outcomes between parenteral anticoagulation or DOACs. Both effectiveness (prevention of VTE) and safety (bleeding) outcomes will need to be considered, together with cost-effectiveness.
Applications should be co-produced, demonstrating an equal partnership with service commissioners, providers and service users (or their advocates) in order to provide evidence and actionable findings of immediate utility to decision-makers and service users. Applicants may wish to consult the NIHR Learning for Involvement guidance on co-producing research.
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 htaresearchers@nihr.ac.uk.
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 online no later than 1pm on the 27 July 2022. Applications will be considered by the HTA Funding Committee at its meeting in September 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 January 2023.
Applications received electronically after 13:00 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 e.g. 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.
Should you have any queries please contact us by email: htacommissioning@nihr.ac.uk