DIRECT: Delivery and Implementation of a Randomised Cluster Crossover Trial on Thrombosis

NICE RESEARCH PRIORITY

What is the clinical and cost effectiveness of aspirin alone versus other pharmacological strategies for people with fragility fractures of the hip? BACKGROUND

Hip fracture is one of the biggest challenges facing patients and healthcare systems. In the UK, and across the world, hip fracture is the commonest fragility fracture that requires inpatient hospital treatment. There are approximately 70,000 hip fractures in the UK every year, accounting for £1.1 billion in hospital care costs and consuming 2% of the total NHS budget.

Patients sustaining hip fracture are known to be at considerably increased risk of developing a venous thromboembolism (VTE) compared with a matched, uninjured, population. VTE is a major cause of morbidity and mortality. All patients admitted to hospital, including those with a hip fracture, are risk assessed and those at risk are given thromboprophylaxis according to National Institute of Health and Care Excellence (NICE) guidelines.

The existing literature from studies of people with hip fracture, and heterogeneity between effect estimates from randomised trials in elective hip surgery, means that NICE and global opinion leaders have been unable to agree a preferred first-line prophylaxis strategy. Consequently, variation exists in national and international practice for prophylaxis for people with hip fracture.

In 2018 NICE proposed a ‘Top Five’ research recommendation to address this major clinical uncertainty. AIM

To determine whether a first-line thromboprophylaxis management strategy including aspirin is non-inferior in terms of clinical effectiveness and safety, and cost-effective, relative to a first-line VTE thromboprophylaxis management strategy including low molecular weight heparin (LMWH) in adults aged over 60-years with a hip fracture.

DESIGN

A multicentre, pragmatic, standard-of-care controlled, cluster (hospital) randomised, single crossover, registry-enabled noninferiority trial and parallel economic analysis. METHODS

Setting: UK hospitals treating people with acute hip fracture. Population: Adults 60-years and older sustaining fragility hip fracture identified by their entry into UK hip registries. Interventions: First-line thromboprophylaxis management strategy including LMWH (control) versus first-line thromboprophylaxis management strategy including aspirin (test).

Outcomes: Primary-efficacy: hospital associated VTE events within 90 days, Primary-safety: major bleeding events within 28 days; Secondary: all-cause mortality at 90 days, cause-specific mortality: VTE at 90 days, bleeding and cardiovascular at 28 days. Primary within-trial analysis: To present risk differences for each comparison on an intention to treat basis.

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

Study duration will be 45 months in total with the pilot due to start 1/04/2024 and completion on 01/01/2028 (6-month set-up, 12-month pilot phase, 12-month recruitment phase, 9-month data curation (funding freeze), 6-month analysis and study close). ANTICIPATED IMPACT & DISSEMINATION

Our findings will inform national guidance. If aspirin were non-inferior NICE estimate a £27M annual saving. We will publish in medical journals and disseminate our findings via supporting organisations, and provide regular updates to the public throughout the project.