Title: RCT of clinical and cost-effectiveness of drug coated balloons, drug eluting stents and balloon angioplasty with bail-out bare metal stent revascularisation strategies for severe limb ischaemia due to femoro-popliteal disease: BASIL-3 (Balloon vs Stenting in Severe Ischaemia of the Leg)
Funder: Department of Health and Social Care

Abstract: Design: Individually randomised multi-centre pragmatic 3-arm open trial of 861 patients comparing drug coated balloon (DCB), drug eluting stent (DES) with plain balloon angioplasty and ‘bail-out’ bare metal stent (PBA+/-BMS) first revascularisation strategies for severe limb ischemia (SLI) due to femoro-popliteal (FP) atherosclerotic arterial disease; incorporating an internal pilot phase and within-trial health economic analysis. Randomisation will be undertaken by minimisation, stratifying for age, gender, DM, CKD and severity of clinical disease (ischaemic rest/night pain only, tissue loss, both). Setting: Approximately 60 sites throughout the UK using vascular and endovascular surgical services located within NHS Hospitals. Target Population: Patients admitted to hospital with SLI requiring early endovascular FP intervention in the opinion of a vascular multi-disciplinary team (MDT). Inclusion Criteria: Patients with SLI due to FP atherosclerotic arterial disease; who are judged by the responsible clinicians (consultant vascular surgeons, interventional radiologists, diabetologists) in an MDT to require early endovascular FP intervention; who have supra-inguinal ‘inflow’ adequate to support all 3 possible trial revascularisation strategies (this can be achieved by a prior successful inflow [aorto-iliac] procedure if required); and who are judged suitable for all 3 possible trial revascularisation strategies following diagnostic imaging and a formal discussion by the MDT. Exclusion criteria: Patients with life expectancy <6 months; who are unable to provide consent due to incapacity; who are non-English speakers and where translation facilities are insufficient; who are unsuitable for the 3 treatments being evaluated. Health Technologies Being Assessed: 3 FP revascularisation strategies of the FP arteries, with the initial procedure being a drug eluting stent (DES), plain balloon angioplasty (PBA) and ‘bail-out’ bare metal stent (BMS) or a drug coated balloon (DCB) also with or without a BMS. The trial will also monitor new technologies using the “tracker trial” methodology and working with the NIHR Horizon Scanning Centre at the University of Birmingham to incorporate relevant new technologies into the trial. Measurement of Costs and Outcomes: 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 randomisation. Secondary outcomes: Overall survival (OS), re- and cross-over intervention rates, the composite major adverse limb events (MALE) outcome; in-hospital and 30-day procedure related morbidity and mortality; major cardiovascular events (SLI affecting the contralateral limb, acute coronary syndrome, stroke); relief of ischaemic pain (VAS, medication usage); QoL assessed using generic (EQ-5D-5L, SF-12) and disease specific (VascuQoL) tools; healing of tissue loss (ulcers, gangrene) using the PEDIS and WiFi instruments; extent and healing of minor (toe and forefoot) amputations; haemodynamic changes; absolute ankle and toe pressures; and ankle and toe to brachial pressure indices (ABPI, TBPI) Measurement of outcomes: Research nurses will review participants at baseline, 1 month post-intervention and 6, 12, 24 and 36 months after randomisation.

Lay abstract: As a result of diabetes, smoking, 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 whilst 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. 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, increases in diabetes, and continuing high rates of smoking. As well as 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, and endovascular treatment which involves opening up the diseased arteries with balloons and/or the use of little metal tubes called stents. Based on the results of the HTA-funded BASIL-1 trial, SLI patients with more limited disease affecting the arteries in their thigh (the so-called femoro-popliteal arteries) are usually offered endovascular treatment first because it is associated with a lower risk of death and major complications than surgery, and appears to work as well as, bypass surgery up to 2 years. For many years the ‘standard of care’ endovascular treatment for such patients has been plain balloon angioplasty (PBA) with the use of so-called ‘bail-out’ (bare metal) stenting (BMS) when PBA alone has been unsuccessful in satisfactorily opening up the artery. More recently, drug coated balloons (DCB) and drug eluting stents (DES) have entered the market and are widely used around the world. These DCB and DES release various drugs which act on the vessel wall and are believed to reduce the risks of the artery narrowing down or blocking off again. However, the evidence base underpinning the use of DCB and DES is weak and they are much more expensive than PBA+/-BMS. For that reason, both the NICE and the HTA have recommended randomised controlled trials to determine whether DCB and DES are better than PBA+/-BMS and should, therefore, be used by the NHS as first-line treatment. In the proposed study, we will invite people affected by SLI due to atherosclerosis in their thigh (femoro-popliteal) arteries, and who are considered suitable for DCB, DES and PBA+/-BMS, to be randomly allocated to one of these endovascular treatments in the first instance. If the allocated treatment doesn't work, then patients can go on to have one of the other treatments; or go on to have surgery as clinically appropriate. We will follow-up patients for an average of 3 years, during which time 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: 6.1 PHARMACEUTICALS;6.3 MEDICAL DEVICES
Health categories: CARDIOVASCULAR