Title: Multicentre randomised controlled trial to compare the clinical and cost-effectiveness of a ‘vein bypass first’ with an ‘endovascular first’ revascularisation strategy for severe limb ischaemia due to infrageniculate arterial disease (Bypass v Angioplasty in Severe Ischaemia of the Leg, BASIL-2)
Funder: Department of Health and Social Care

Abstract: DESIGN: An individually randomised multi-centre pragmatic two-arm open trial of two alternative revascularisation strategies (vein bypass first vs. best endovascular first) for the management of severe limb ischaemia (SLI) due to below the knee (BTK) infra-geniculate (IG), with or without at or above the knee (AATK) femoro-popliteal (FP) disease, incorporating an internal pilot phase and within-trial health economic analysis. SETTING: Eleven UK regions comprising networks of vascular and endovascular surgical services located within NHS Hospital Trusts. TARGET POPULATION: Patients admitted to hospital with SLI due to BTK (IG), with or without AATK (FP), disease and who in the opinion of the responsible clinicians (vascular surgeons, interventional radiologists, diabetologists) require early BTK (IG) +/- AATK (FP) revascularisation in addition to evidence-based best medical therapy (BMT) and foot and wound care. HEALTH TECHNOLOGIES BEING ASSESSED: Participants will be allocated to either a ‘vein bypass first’ or a ‘best endovascular first’ (angioplasty +/- stent) revascularisation strategy. All patients will receive treatment to BTK (IG) arteries and, where clinically indicated, also to (FP) disease AATK. MEASUREMENT OF COSTS AND OUTCOMES: As recommended by NICE (CG 147) the primary outcome will be amputation free survival (AFS), defined as the time to major limb (above the ankle) amputation of the index (trial) limb or death from any cause. Follow-up will be between 2 and 5 years post intervention (median 3.3 years). Secondary end-points will include: • Overall survival (OS) • In-hospital and 30-day procedure related morbidity and mortality • Major adverse limb events (MALE) • Major cardiovascular events (SLI affecting the contralateral limb, acute coronary syndrome (ACS), stroke) • Relief of ischaemic pain (VAS, medication usage) • Psychological morbidity (HADS) • QoL assessed using generic (EQ-5D-5L, SF-12, ICECAP-O) and disease specific (VascuQoL) tools. • Re- and cross-over intervention rates • Healing of tissue loss (ulcers, gangrene) using SINBAD and PEDIS (International Working Group on the Diabetic Foot) classifications and the 2012 Infectious Diseases Society of America Clinical Practice Guideline for the Diagnosis and Treatment of Diabetic Foot Infections • Extent and healing of minor (toe and forefoot) amputations • Haemodynamic changes; absolute ankle and toe pressures as well as ankle and toe to brachial indices (ABI, TBI). Costs incurred to the NHS will be derived by measuring and valuing health care resource use. Relevant resource use will include using patient case notes and hospital record systems to obtain details of initial and subsequent procedures (bypass and/or interventional revascularisation) provided to patients; inpatient stay, length of hospital stay and use of resources during the stay. Information on consultations with general practitioners and practice-based nurses will be collected through patient-reported questionnaires. Cost to the individual patients and carers, due to out-of-pocket payments and travel expenses, will be collected through patient reported questionnaires. As in BASIL-1, outcomes will be measured by dedicated research nurses at baseline and months 1, 3, 6, 9, 12, 18, 24, 30 and 36 after randomisation. The primary AFS outcome will also be assessed at the end of the study follow-up period. SAMPLE SIZE: The trial will have a sample size of 600, equally randomised between the two groups, providing 90% power to detect a hazard ratio of 0.66 for the primary outcome of AFS at the 5% significance (equivalent to a difference in AFS at 3 years of 12% between 53% and 65%). The sample size calculation is based on a time-to-event analysis across the duration of trial, conservatively allowing for 10% loss-to-follow up (it was less than 1% in BASIL-1). PROJECT TIMETABLE INCLUDING RECRUITMENT RATES: Study duration of 69 months: 0-6: setup; 7-18 recruitment commences in all sites (internal pilot); 19-42: complete recruitment; 43-66: complete follow-up; 67-69: analysis and reporting. The internal pilot study will comprise the first year of recruitment and assess whether recruitment rates are adequate for the full study to be judged feasible. The trial will recruit in 11 regions across the UK (South and South West, South London, North London, Oxford, West Midlands, East Midlands, Hull and East of England, Leeds and West Yorkshire, Sheffield, North East, East and West Scotland). Some centres comprise a single large unit (e.g. Sheffield) while others represent a network of vascular units across several NHS Trusts (e.g. West Midlands, North and South London, Scotland). The PIs in each centre have reviewed the proposal; analysed their clinical activity; and have attested to the fact that they believe the proposed recruitment target of 2 patients per region per month is feasible and achievable (letters of support appended). Many of the PIs successfully recruited patients into BASIL-1. ECONOMIC EVALUATION: A within-trial economic evaluation will be carried out from the perspective of NHS and personal social services (PSS), based on the prospective collection of resource use and effectiveness data. The analysis will be based on a number of outcomes including cost per year AFS and QoL measures. In addition, a cost-utility analysis will be undertaken to calculate the cost per additional quality-adjusted life year (QALY) gained.

Lay abstract: As a result of smoking, diabetes, high blood pressure, high cholesterol and kidney failure, some people develop atherosclerosis (aka ‘hardening of the arteries') in their legs. This atherosclerosis blocks their arteries so reducing the blood supply to their legs and feet. In the early stages, such disease often causes pain in the leg only when walking, but as the disease progresses, the blood supply to the leg can become so poor that people get severe pain (requiring morphine) all the time, especially at night (preventing sleep). At this stage, even minor injuries to the foot can fail to heal, allowing infection to enter the tissues, resulting in the development of ulceration, even gangrene. Unless the blood supply to the leg and foot is improved, many affected people will lose the limb and/or die within 12 months as a result of this so-called “severe limb ischaemia” (SLI). One in every 1000-2000 people in the UK will be diagnosed with SLI each year; and this rate is rising as a result of the ageing population, the large increase in the numbers of people with diabetes, and continuing high rates of smoking. As well causing great suffering, SLI places a very large economic burden upon health (NHS) and social care services. The two main treatments available are bypass surgery, where a vein is used to bypass the blockage in the arteries, and endovascular treatment which involves opening up the diseased arteries with balloons and sometimes the use of little metal tubes called stents. Both treatments have pros and cons and the purpose of the trial is to determine which treatment is best at preventing amputation and death, getting the ulcers and gangrene to heal, and relieving pain. We aim to specifically study people with SLI due to disease of the arteries below the knee (BTK) (also termed infrageniculate, IG, arteries) which is now the commonest site of severe disease and the hardest area to treat. We will invite people affected by SLI due to IG BTK disease, and who are suitable for both bypass surgery and endovascular treatment, to be randomly allocated to one or other of the treatments. Each person will receive the allocated treatment first; if it doesn't work, then they can go on and have the other treatment. We will follow-up patients for an average of 3 years, during which they will be offered further medical, surgical, and endovascular treatment as required. We will also study the costs of the treatments to see which offers best ‘value for money’ for the NHS.

Research activity codes: 6.4 SURGERY
Health categories: CARDIOVASCULAR