Title: Effective Treatments for Thoracic Aortic Aneurysms (ETTAA study): A prospective cohort study
Funder: Department of Health and Social Care

Abstract: The effective treatments for thoracic aortic aneurysm (ETTAA) study will observe a cohort of patients with chronic thoracic aortic aneurysm (CTAA) for up to 5 years, documenting changes in health status and describing their quality of life before, during and after any intervention. We will determine how treatment options [best medical therapy (BMT), endovascular stent-grafting (ESG) and open surgical repair (OSR)] are chosen. We will evaluate the clinical- and cost-effectiveness of these strategies. This will be achieved by prospective data collection for consecutive patients referred to specialist multidisciplinary teams (MDTs), followed by statistical and economic analysis. The study will generate an evidence base to inform policy-makers about which treatments the NHS should provide for specific patient groups. DESIGN: A prospective, multi-centre, observational, cohort study with statistical and economic modelling of patients with CTAA. SETTING: Participating MDTs that assess patients with CTAA > 4cm will invite consecutive patients into the study. Management options are watchful waiting [WW] if the risk of aneurysm rupture is low and BMT, ESG or OSR when the risk of aneurysm rupture is moderate-high. Patients will be allocated to BMT when risk of ESG/OSR is considered prohibitive, the general health of the patient precludes ESG/OSR, or the patient refuses ESG/OSR. Treatment options will be discussed in the MDT, then agreed with the patient but will not be influenced by participation this observational study. Patients enrolled in the study will be observed from referral until the study concludes at 5 years (median follow up 3 years). TARGET POPULATION: Patients will be enrolled from UK centres with expertise in managing CTAA. Current collaborators include Birmingham, Cambridge, Liverpool, Manchester and London. Further UK aortic centres will be invited to participate to secure the broadest possible sample of practice. HEALTH TECHNOLOGIES BEING ASSESSED: WW: patients with aneurysms considered to be at low risk of rupture will remain under surveillance with annual CT/MR scan and MDT review. These patients’ data will contribute to the natural history component of our study. BMT: Patients who are considered unsuitable for, or who refuse ESG/OSR. Both WW and BMT groups will be assigned to prophylactic measures: control of hypertension (BP<140/90 or 130/80 for patients with diabetes or renal impairment), lipid profile optimisation (target cholesterol <70mg/dL), smoking cessation. ESG: Endovascular repair of the aneurysm via transluminal introduction of a stent-graft under X-ray guidance. Hybrid procedures that comprise a combination of a conventional surgical component and a transluminal repair are also included in this group since the aim of such techniques is to minimise the overall invasive nature of repair. OSR: replacement of the aneurysmal aorta with prosthetic conduit via a sternotomy or thoracotomy with circulatory support. MEASUREMENT OF COST AND OUTCOMES: Primary outcome measures are: Aneurysm growth; Quality of life (QoL); Freedom from re-intervention; Freedom from death or permanent neurological injury; Incremental cost per quality adjusted life year gained. Procedure-related complications, clinical outcome data and EQ-5D-5L QoL scores will be collected prospectively. Clinical outcomes and EQ-5D-5L scores will be recorded at initial review, 3, 6, 12, 18, 24 months, then annually until the follow-up concludes at 5 years. Technical outcomes and aneurysm size will be assessed less frequently since they require interval CT/MR scans. These will be performed in line with current practice guidelines (minimum once per year, with further scans as clinically indicated), supported by morphological analysis at the Corelab to reduce reporting bias. Data will be collated using an internet-based secure electronic case record form. In the early phase of the project we will analyse the retrospective Yale database of CTAA patients. This will provide prior estimates of the comparability of patients undergoing BMT, ESG and OSR and the factors affecting treatment choice, thereby allowing us to select the most appropriate statistical methods for analysis of the prospectively collected UK data. SAMPLE SIZE: 360 elective operations and stents are performed each year in the UK for arch and descending aneurysms (from UK registry data). Clinical collaborators estimate that 3 patients undergo WW and 1 patient is given BMT for every 1 that undergoes ESG/ OSR. According to these estimates, there are 1800 patients per year potentially eligible for this study. Of these we hope to capture 40% in this study and we will recruit patients for 4 years. We expect that 75% of eligible patients will consent to data collection and therefore our estimated total sample size is 2200. PROJECT TIMETABLE: 6 year project (4 years recruitment and 1 year further follow up). Month 1: HTA contract starts; invitations to MDTs at other aortic centres; advertise out for study staff; submission of REC and R&D applications. Months 2 - 4: Final dataset decided and submitted for database construction; development of database & website; central staff training; arrange 'kick-off' meeting; REC approval in place; participating centres finalised; R&D approvals underway; subcontracts signed; database training and site initiations for external research staff (ongoing). Months 3 - 5: Image-bank and Corelab opened; Months 2 - 61: Patient recruitment and follow up; data collected and entered onto OpenClinica database; anonymised CT/MRI images sent to Corelab for analysis. Months 7 - 61: Analysis of retrospective Yale data, finalisation of statistical methods of comparison. Months 62 - 69: Delphi consensus to formulate recommendations for UK practice and policy. Completion of analyses and report submission. EXPERTISE IN THE TEAM: The ETTAA team brings together academic and clinical leaders in aortic interventions (ESG/ OSR), specialists in biomedical statistics and health economics, experienced R&D personnel and patients' representatives. The academic team has a track record of risk- and health economic- modelling that includes previous HTA-funded work on abdominal aortic aneurysm. The team has experience in publishing guidelines based on clinical- and cost-effectiveness studies, and writing HTA monographs

Lay abstract: What is Chronic Thoracic Aortic Aneurysm and why is it important? The aorta is the main artery that leaves the left side of the heart and carries oxygen-rich blood to the body. An aortic aneurysm is an enlargement (or bulge) of any part of the aorta that results from weakening of the artery wall. Over time, the pressure of the blood flowing in the aorta stretches the weakened area of the wall creating a risk of rupture or tearing, which can be fatal. Chronic thoracic aortic aneurysm (CTAA) is an enlargement of the thoracic aorta (the part of the aorta that sits inside the chest cavity), that has not yet ruptured, but is beyond 50% of normal size. CTAA is a potentially fatal disease and unfortunately the incidence is increasing in western populations. There are estimated to be 3000-8000 new cases of CTAA in the UK each year. The natural history of CTAA is not clearly understood because patients usually remain undiagnosed until they suffer rupture, tearing or death. However, CTAA can be detected prior to such events on imaging investigations, such as CT scans or MRI scans, which have been performed for other conditions. What treatments are available? When a potential aneurysm is detected patients are usually referred to a multidisciplinary medical team (MDT) consisting of heart surgeons, vascular surgeons and interventional radiologists. This team will discuss each individual case, taking into account the patient’s particular medical condition and the exact nature of their aneurysm, and decide on the best treatment to recommend. While aneurysms remain small, the risks posed by surgical intervention are often greater than the risk of rupture, dissection or death from the aneurysm. Therefore in such cases, patients undergo a watchful waiting (WW) approach whereby they have regular CT or MRI scans to assess growth of the aneurysm. When aneurysms are identified early (as in WW); or are found in patients unsuitable or unwilling to have surgery; the best medical therapy (BMT) recommended is to control blood pressure, reduce cholesterol, lose weight and stop smoking. Modifying these risk factors can help to slow the rate of aneurysm growth. Above a certain size (usually 5.5cm for CTAA), treatment either by open surgical repair (OSR) or endovascular stent grafting (ESG) is usually recommended. Treatment may be considered sooner (4.5cm) in patients with connective tissue disorders, as the aortic wall is weaker and dilates more easily. Open surgery (OSR) is the traditional way to repair aortic aneurysms and it is the method with the longest reported patient follow-up (approximately 30 years). The operation is invasive, challenging for the patient and associated with considerable risk of death and post operative complications. ESG is a newer technique which can be performed by ‘keyhole’ surgery. In this technique, a pre-fabricated tube or ‘stent’ is delivered into the aneurysm via arteries in the leg under x-ray guidance. The stent re-lines the aorta from the inside and prevents blood from flowing into the aneurysm, causing further dilation and rupture. However, ESG appears to be a more expensive intervention due to the costs of the devices required for the procedure. Why is research needed? Both OSR and ESG come with a risk of complications, such as organ failure, heart attack, stroke, spinal injury and death. It is probable that some patients will be best treated by OSR and others by ESG. OSR tends to be offered to younger patients with less coexisting illness and ESG tends to be offered to older patients who may have several other medical disorders. The best research data available to date suggests that ESG may result in fewer early deaths, less spinal cord injury and fewer short-term complications but there is much less data on long-term survival compared to OSR. Thus, there is no conclusive research evidence available on the best way to treat CTAA in the UK in terms of both clinical and cost effectiveness. We do not yet have enough information available to provide evidence based guidelines on which treatment should be recommended for which particular groups of patients. What research is planned? The research proposed in this grant application aims to collect data on patients referred to aortic aneurysm clinics across the UK, with a thoracic aortic aneurysm of greater than 4cm. Following a detailed consent process and adequate time to make an informed decision, patients who are willing to take part in the study will be followed up over a period of 1-5 years after their referral. No additional tests will be undertaken as part of the study, but participants will be asked to provide information on their quality of life and use of NHS and social care services throughout the course of the study and before and after any surgical intervention they might have. Participants will also be asked to give permission for their medical records to be examined in detail, in order to collected information about their health status and any treatments that they have throughout the follow up period. This will include both hospital and general practice records. We aim to analyse all the information collected in order to: 1. Understand the growth rate of aneurysms of CTAA and identify which factors influence the growth rate. 2. Clarify the outcomes (procedure success rates and post operative complications) of ESG and OSR for CTAA in the current era. 3. Estimate the cost-effectiveness of BMT, ESG and OSR by measuring changes in survival and quality of life of patients compared to the cost of treatment and post operative patient care. 4. Create a risk score that will help specialists determine which intervention (stenting or surgery) is best suited to a given patient. Our collaborators’ wide catchment area (currently Cambridge, Liverpool, Papworth, Birmingham, London and Manchester) should allow rapid recruitment into the study. Our relatively large sample size (2,200 patients) will allow for a better understanding of good outcomes and the risk factors associated with poor outcomes, as well as helping us create valid risk prediction tools. Another unique feature of this application is the far-reaching scope of the proposed health economic analysis. The methodology we plan to use will, for the first time, achieve an assessment of costs not only to the NHS but also the patient and the wider society.

Research activity codes: 5.4 SURGERY;7.3 MANAGEMENT AND DECISION MAKING
Health categories: CARDIOVASCULAR