Title: The United Kingdom Transcatheter Aortic Valve Implantation (UK TAVI) Trial
Funder: Department of Health and Social Care

Abstract: DESIGN: The study comprises a prospective, multi-centre, open-label, parallel group, pragmatic, randomised controlled trial (RCT), comparing TAVI and AVR in patients with severe symptomatic aortic stenosis, who are at intermediate or high operative risk from AVR but considered suitable for either AVR or TAVI. SETTING: Specialist hospitals with active cardiac surgical and TAVI programmes, and at least 30 prior TAVI cases performed, to minimise learning curve effects. TARGET POPULATION: Patients with severe symptomatic aortic stenosis, referred for surgical intervention, aged 80 years or over, or aged 70 years or over with one or more factors associated with increased operative risk. The latter group is likely to comprise patients with STS risk scores of between 4% and 12% but these are not strict thresholds for inclusion and patients with higher or lower scores may be included if the MDT believes that there is clinical equipoise regarding the choice of intervention. HEALTH TECHNOLOGIES BEING ASSESSED: TAVI will be assessed as a generic intervention using any CE-marked device and any approach in current use, subject to satisfactory and sufficient global and local user experience, as adjudicated by the Trial Steering Committee. In the comparator group, any form of conventional surgical AVR will be accepted. MEASUREMENT OF COSTS AND OUTCOMES: The RCT will primarily assess non-inferiority of TAVI in respect of all-cause mortality at one year and then annually out to 5 years. Mortality is the primary consideration in considering operability and operative risk. The RCT will also assess the immediate impact of TAVI on quality of life. Long-term follow-up, out to 5 years, will include an assessment of the durabilty of any quality of life gains and the need for re-intervention. Cost-utility will be assessed using an NHS perspective over the duration of the trial and extrapolated over a lifetime using modelling techniques. Incremental cost-effectiveness will be calculated. SAMPLE SIZE: Assuming that there is truly no difference in one-year mortality between surgical AVR and TAVI, and that it is 15% for surgical AVR, allowing for 2% dropout in both arms, then 808 patients will be required to ensure 90% power that the upper limit of a one-sided 95% confidence interval will exclude a difference in favour of surgical AVR of more than 7.5%. The sample size will be reviewed by the Data Monitoring Committee in the light of the observed event rate in the surgical arm, and any treatment difference, and amended if necessary. PROJECT TIMETABLES: Planned study duration is 9 years, comprising 6 months set-up, 3 years recruitment, 5 years minimum follow-up and 6 months close-out. There are currently 20 experienced centres that have indicated their intention to participate. If 6 high-volume centres enrol 2 patients per month and 14 lower volume centres enrol 1 patient per month, full recruitment will be achievable within 3 years. Additional centres will further underwrite these conservative assumptions.

Lay abstract: Aortic stenosis, narrowing of the valve through which blood flows as it leaves the heart, affects almost 3% of people over the age of 75 years. It is usually due to age-related degeneration. If the narrowing becomes severe, chest pain, breathlessness, fluid retention and fainting are common, and the outlook is poor with a high risk of death within 2-3 years. The only effective conventional treatment is surgical replacement of the valve, which involves open chest surgery and temporarily stopping the heart, with use of a heart-lung machine. Surgical results are generally excellent but the elderly often have other medical problems that may result in an increased risk of death and complications and in some cases surgery is not possible due to technical factors or unacceptably high risk. Transcatheter Aortic Valve Implantation (TAVI) is a recently developed technique to implant an artificial aortic valve without major surgery, using a catheter to deliver the valve to the heart through the arteries, which are usually accessed by puncturing the skin in the groin. In some cases, the valve is delivered directly through a small incision in the chest wall. The short-term results of TAVI appear to be good with immediate relief of symptoms, improved quality of life and better heart function. However, little is known about long-term outcomes and whether they are as good as the excellent long-term results from conventional surgery in patients for whom that is an option albeit at increased risk. The proposed trial will compare TAVI with conventional surgery in a group of patients, aged 70 years or over, for whom either treatment is an option but in whom the risks of surgery are considered by an expert local medical team to be moderately increased or high. Each patient who consents to take part will be randomly assigned to receive either TAVI or surgery. Outcomes in each group will then be assessed and compared to see whether TAVI offers advantages in the short-term and whether the long-term results, over 5 years, are as good as with surgery. One recent trial with a similar design compared TAVI and conventional surgery in patients at very high operative risk and found the main outcomes (mortality and quality of life) to be similar at one year. There was a higher incidence of stroke and vascular complications with TAVI and a higher incidence of major bleeding with conventional surgery. Importantly, that trial included only the highest risk surgical candidates, used only an early model of one type of TAVI device from a single manufacturer, and had numerous exclusion criteria that limit the generalisability of the findings to many of the patients who are seen in routine clinical practice. The proposed trial will include patients at somewhat lower operative risk and will permit the use of more recent devices of any type from any manufacturer. It is likely that complication rates may be lower with the more modern devices, as the delivery systems through which they are introduced to the vascular system and heart are smaller in profile. The trial will also include a wider range of patients, including those with coronary artery disease requiring revascularisation, which is often present in the eligible population but was excluded from the previous study. The cost implications for the NHS will be assessed to see if TAVI offers value for money. The basic costs of TAVI are similar to surgery but in surgical patients at high-risk, the hospital stay is often prolonged, with a longer stay on the intensive care unit, incurring substantial additional costs. The results of the study will inform future NHS policy and practice for the use of TAVI and guide treatment decisions for individual patients. The research team brings together interventional cardiologists and cardiac surgeons, who are international leaders in the field. It also includes patient representatives and experts in research design, clinical trials, medical statistics, health economics, cardiac imaging and geriatric medicine. In addition, the team is working in close collaboration with the Department of Health Heart Team, the National Specialised Commissioning groups, NICE, and the national societies for interventional cardiology and cardiac surgery.

Research activity codes: 6.4 SURGERY
Health categories: CARDIOVASCULAR