Title: Thromboprophylaxis for lower limb immobilisation: An evidence synthesis
Funder: Department of Health and Social Care

Abstract: DESIGN: Systematic review, meta-analysis, decision-analytic modelling and value of information analysis. STRATEGY FOR REVIEWING LITERATURE: Systematic reviews will be used to identify (1) randomised controlled trials (RCTs) and controlled clinical trials (CCTs) that evaluate the efficacy or effectiveness of thromboprophylaxis for lower limb immobilisation, (2) any studies of risk-stratification tools for VTE in lower limb immobilisation and (3) data sources for the decision-analytic model, such as studies that estimate the association between efficacy and effectiveness outcomes and studies that estimate the risk of bleeding-related adverse outcomes. Methodological quality will be assessed using relevant checklists for each included study type. TARGET POPULATION: Adults with isolated lower limb injury requiring temporary immobilisation of any form. HEALTH TECHNOLOGIES BEING ASSESSED: (1) Chemical thromboprophylaxis agents for patients with lower limb immobilisation, compared to placebo, no treatment or alternative treatment; (2) Risk prediction tools that could be used to select patients with lower limb immobilisation for thromboprophylaxis. MEASUREMENT OF COSTS AND OUTCOMES: Meta-analysis will estimate the efficacy (symptomatic or asymptomatic venous thromboembolism (VTE)) and effectiveness (clinically significant VTE, major bleeding or mortality) of thromboprophylaxis. A systematic review and consensus elicitation of expert opinion will identify risk-prediction tools for VTE and estimate the accuracy of these methods. Further literature searches will be used to estimate key parameters for modelling. Decision-analytic modelling will simulate the management of a cohort of people with lower limb immobilisation to estimate (1) the clinical effectiveness of thromboprophylaxis, in terms of clinically significant VTE events, treatment-related adverse events and quality-adjusted life years (QALYs) accrued; (2) the cost-effectiveness of different strategies for selecting patients for thromboprophylaxis (including treating all, treating none and risk-based treatment), in terms of the incremental cost per QALY gained by each strategy compared to the next most effective alternative on the efficiency frontier; and (3) the expected value of information of further primary research. PROJECT TIMETABLE: The project will be completed over 12 months, with the first six months focusing on systematic reviews and meta-analysis, and the second six months focussing on modelling. EXPERTISE IN THE TEAM: The team involves a collaboration between methodological experts at the University of Sheffield who have successfully delivered similar projects in the past and international experts in prevention, diagnosis and treatment of VTE.

Lay abstract: People who have their leg immobilised in a plaster cast or brace are at risk of developing a blood clot in the leg that can travel to their lungs and make them seriously ill. Drugs to thin the blood (anticoagulants) can reduce the risk of this happening but carry a small risk of serious bleeding complications. Previous research has shown that anticoagulant drugs reduce the risk of finding clots in people with an immobilised leg if we look for them with an ultrasound scan of the leg, but we don't know whether this translates into a meaningful reduction in serious clots that make people unwell or whether the reduction in blood clots justifies the risk of bleeding complications. This project will draw upon existing research and use health economic modelling to simulate different approaches to treating the risk of blood clots in people with leg immobilisation. We will collect and analyse all the trials of anticoagulant drugs in people with leg immobilisation to determine how much these drugs reduce the risk of developing blood clots, including those only detected by ultrasound scan screening. We will then collect and analyse studies that measure the risk that people who have a clot in their leg detected on ultrasound screening will develop serious complications. We will also collect and analyse studies that use risk factors, such as previous blood clots or the presence of other diseases, to predict which people are at highest risk of developing a blood clot when they have their leg immobilised. We will use this information and expert opinion to draw up strategies that could be used to select people with leg immobilisation for anticoagulant treatment based on their risk of developing a blood clot. We will then develop a mathematical model that simulates the treatment of people with leg immobilisation using anticoagulant drugs. The model will be used to test different approaches to using anticoagulant drugs, including giving all patients drugs, giving no patients drugs and giving selected patients drugs based on their risk of developing a blood clot. The model will then calculate for each strategy how many patients would develop complications from blood clots or from treatment if each strategy were used. We will then use the model to determine which strategy produces the best health outcomes overall (measured as quality-adjusted life years or QALYs) and which is the most cost-effective in terms of allowing the NHS to "buy" the most QALYs at an acceptable cost. The model will then be used to estimate the cost-effectiveness of future research into this problem, such as a large trial of anticoagulant drugs in people with leg immobilisation or a large study to develop better ways of predicting each patient's risk of developing a blood clot. The project will be undertaken by combining a team of experts in statistics, economics and modelling at the University of Sheffield with international experts in emergency medicine, injuries and blood disorders. Members of two public involvement groups, Thrombosis UK and the Sheffield Emergency Care Forum, will advise the project team and ensure that the project outputs are relevant and comprehensible to patients and the public.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: BLOOD;INJURIES AND ACCIDENTS