Thromboprophylaxis in Lower Limb Immobilisation (TiLLI): a multicentre study comprising two linked open label phase III randomised controlled trials evaluating the effectiveness and cost effectiveness of different methods of pharmacological prophylaxis for patients with temporary lower limb immobilisation

BACKGROUND

Venous thromboembolism (VTE) is a major global health burden. Many people who survive VTE suffer from longer term physical complications or psychological sequelae. Temporary lower limb immobilisation (plaster cast, walking boot or rigid splint) and injury are combined risk factors for VTE.

Approximately 70,000 people are immobilised after injury every year in the UK. VTE in this setting is potentially preventable through early prophylaxis with anticoagulant medication. However, baseline VTE risk varies widely across the population and there are multiple drugs for prophylaxis, including Direct Oral AntiCoagulants (DOACs) and parenteral therapies.

There is no high-quality evidence comparing different methods of pharmacological thromboprophylaxis for patients at high risk of VTE and limited evidence of the benefits and risks of any prophylaxis for patients at low risk of VTE. AIM

What is the comparative clinical and cost effectiveness of different methods of pharmacological thromboprophylaxis for patients with temporary lower limb immobilisation after injury? DESIGN

A pragmatic, open-label, linked pair of randomised controlled trials with common outcomes and parallel economic analysis:

• TiLLI-High: a non-inferiority trial in 4354 people with temporary lower limb immobilisation at high risk of VTE comparing DOACs (intervention) to parenteral prophylaxis (routine care).

• TiLLI-Low: a superiority trial in in 5689 people with temporary lower limb immobilisation at low risk of VTE comparing parenteral prophylaxis (intervention), DOACs (intervention) and no pharmacological prophylaxis (routine care). METHODS Setting: UK hospitals with type 1 emergency departments. Population: Patients aged =16-years, prescribed rigid lower limb immobilisation for a recent injury.

Risk stratification: We will dichotomise VTE risk into high or low, using the TRiP(cast) VTE risk assessment tool at a threshold at greater than or equal to 6, or subjective clinical decision by local team/treating clinician, to determine high risk. Interventions: (1) Usual care (2) Usual care and direct oral anticoagulant (3) Usual care and parenteral anticoagulant.

Outcomes: Primary: A composite primary outcome of net clinical benefit, including symptomatic VTE events, major bleeding and cause-specific mortality within 90 days from randomisation; Secondary: individual components of the composite, complications, adherence, quality of life, acceptability, resource use (including hospital admissions/reattendance) and relative cost effectiveness.

Primary within-trial analysis: To present adjusted risk ratios (95% CI) for each principal comparison on an intention to treat basis.

Modelling: use existing Markov model, informed by the trial effect estimates, to model long term outcomes such as post thrombotic syndrome, pulmonary hypertension and bleeding. TIMELINES FOR DELIVERY

Study duration will be 60 months in total (9-month set-up, 12-month pilot phase, 30-month substantial phase, 3 months follow up and 6 months write up and study close). ANTICIPATED IMPACT AND DISSEMINATION

We will publish in medical journals and disseminate our findings via supporting organisations, who will also provide regular updates to the public throughout the project. Our findings will inform national guidance on this issue.