Title: 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
Funder: Department of Health and Social Care

Abstract: 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).

Lay abstract: Individuals attending hospital to undergo operations are at risk of developing blood clots in the legs (deep vein thrombosis or DVT). These blood clots occur for a number of reasons, related to immobility, changes occuring in the blood and any damage to the veins in which the blood travels. The consequences of developing a blood clot in the leg include swelling of the leg, future problems with the skin of that leg including a leg ulcer (which is troublesome and costly to manage and cure), and importantly the possibility of the blood clot dislodging and travelling up to the patient’s lungs (pulmonary embolism or PE). This latter scenario can result in difficulties in oxygen entering the bloodstream from the lungs and also has the potential to place strain on the heart. In a proportion of cases of PE, sudden death may result. DVT and PE are known collectively as venous thromboembolism or VTE. The importance of preventing VTE in patients having surgery is widely recognised and strategies are in place to minimise the development of VTE. The two main ways that have been employed are: thinning the blood with regular injections, and wearing elastic stockings to help stop blood sitting in the leg veins where it can clot. The evidence for using elastic stockings to prevent VTE has recently been challenged. Additionally, there is a lack of evidence for the additional benefit of elastic stockings over and above the benefit of blood thinning. If elastic stockings were to reduce VTE over and above blood thinners, these benefits need to be weighed against a number of risks and disadvantages of elastic stockings, including: discomfort, restricting the blood flow to the leg, blistering, cost, and the requirement for staff to assist patients in wearing. A trial has been designed whereby patients are randomly assigned by a computer program to receive either elastic stockings and blood thinning medicines, or blood thinning medicines alone. The number of cases of VTE occurring up to 90 days following surgery will be determined, as well as potential disadvantages of elastic stockings (as above). It has been calculated that 2236 patients will be required to enroll and participate in the study for sufficient information to confidently answer the scientific question, and these patients will be invited to participate at a number of hospitals. It is hoped that in embarking on this study, we will be able to: • Determine if elastic stockings offer an additional benefit to patients who are receiving blood thinners • Look at the side effects related to elastic stockings and blood thinners • Produce important recommendations for VTE prevention that reduces side effects (without causing a rise in VTE) and improves patients’ quality of life If elastic stockings were found not to reduce the risk of clots in individuals give blood thinning medicines, they would no longer need to be used in these surgical patients. This would reduce the side effects of the stockings, and also save the NHS in England approximately £63.1 million per year. We will ensure that the study findings and updated practice guidelines are shared widely so the results can be acted on.

Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CARDIOVASCULAR