Examining the benefit of graduated compression stockings as an adjunct to low dose low molecular weight heparin in the prevention of venous thromboembolism in elective surgical inpatients identified as moderate or high risk for venous thromboembolism – a multi-centre randomised controlled trial

Introduction The magnitude of the challenge of in hospital venous thromboembolism (VTE) has been well reported and publicised. The evidence base supporting NICE’s recommendations for the use of graduated compression stockings (GCS) for VTE prevention in the UK has recently been challenged (2). Additionally, there is a lack of evidence for the additional benefit of GCS over and above the benefit of low molecular weight heparin (LMWH) alone in this context (1). If GCS were to offer a reduction in VTE risk over and above that afforded by LMWH, these benefits need to be weighed against a number of risks and disadvantages of GCS; including discomfort, ischaemia, blistering, cost, non-compliance, and the need for staff assistance in wearing. Study Design & Setting Seven-centre, UK-wide, open, randomised controlled trial. Non-inferiority, group sequential trial design. Null Hypothesis Under the non-inferiority design, the null hypothesis is that the single therapy (pharmacology) is worse than the combination therapy for VTE at 90 days by at least 3.5% over 6% assumed for the combination therapy. Study Population Elective surgical inpatients assessed as being at moderate or high risk of VTE according to the widely-used UK Department of Health VTE Risk Assessment for Venous Thromboembolism (39) (based upon the NICE recommendations (8)). Exclusions • Contraindications to LMWH/GCS • Documented or known thrombophilia/thrombogenic disorder • Requiring therapeutic anticoagulation • Previous VTE • Having intermittent pneumatic compression beyond theatre & recovery • Pregnancy • Need extended VTE prophylaxis • Cast/brace use • Non-English speakers Endpoints Primary VTE within 90 days {A composite endpoint of duplex ultrasound-proven new lower-limb DVT up to 90 days post-randomisation (symptomatic or asymptomatic) + symptomatic PE (imaging confirmed) up to 90 days post-randomisation} Secondary • Quality of life – EQ5D • Compliance with stockings & LMWH • Overall mortality Safety • GCS-related complications • Bleeding complications • LMWH allergy Sample Size Assuming an event rate of 6% of VTE at 90 days in the combined group and non-inferiority margin of 3.5%, and conservative loss to follow up of 10%, maximum sample size required is total of 2236. Data Monitoring A group sequential design is proposed. The independent Data Monitoring Committee (iDMC) will formally examine data at 25%, 50%, 75% and at a final look at 100% of the information for effectiveness using a Lan-DeMets alpha spending function and at 50% for futility. Follow-Up Telephone, online or SMS (patient preference) at 1 week post-surgery or discharge, and 90 days. Proceeding to imaging at these points if there is clinical suspicion. Routine bilateral full lower limb duplex ultrasound at 14-21 days post-operatively to capture peak VTE incidence (4,5). Expected VTE capture >95% (average DVT time-point 7 days and PE 21 days).