The Early Valve Replacement in Severe ASYmptomatic Aortic Stenosis Study
- Conditions
- Aortic Stenosis
- Interventions
- Procedure: Aortic valve replacement
- Registration Number
- NCT04204915
- Lead Sponsor
- University of Leicester
- Brief Summary
Aortic stenosis (AS) affects approximately 5% of individuals \>65 years old, with \~3% of people \>75 years having moderate to severe disease. The prevalence of AS is rising rapidly due to an ageing population and is projected to double in the next two decades. Increasingly clinicians face the dilemma of how to best manage this growing population of mainly elderly patients, many of whom are asymptomatic but have been identified as having severe AS, often as an incidental finding. Reduced aortic valve opening progresses over decades without any apparent symptoms because the heart compensates for the AS. Ultimately, compensatory mechanisms fail resulting in angina, syncope or heart failure. If these symptomatic patients with severe AS remain untreated, they have a dire prognosis. In this situation the only effective treatment is AVR, either surgically or using TAVI. Conversely, conventional teaching and clinical practice in cardiology has been that, in the absence of symptoms, the prognosis is usually excellent and, except in a few very specific circumstances, conservative management and regular review (expectant management) is recommended. This advice is reflected in current international guidelines but is based largely on historical precedent. There has never been a randomised controlled trial to address the relative benefits of early AVR versus expectant management in patients with severe asymptomatic AS. The relative benefits of a strategy of early AVR/TAVI versus expectant management in patients with asymptomatic severe AS are unclear. There is clinical equipoise but it remains one of the few areas of cardiovascular medicine where no randomised controlled trials (RCT) have been performed. The EASY-AS study will provide crucial data on the relative merits of these differing approaches to management, in terms of important patient orientated outcomes, conventional cardiovascular end-points and cost effectiveness.
- Detailed Description
This is a major pragmatic multi-centre prospective parallel group open RCT. It will be conducted in the UK, Australia and New Zealand, funding is being sought in several countries to expand recruitment internationally. The study is in 2 phases: the vanguard and main phase. Therefore the study will run an internal pilot to prove recruitment of the relevant number of participants during the initial 2 years.
The over-arching aim is to determine whether early AVR results in better clinical outcomes and cost-effectiveness than a strategy of expectant management in asymptomatic patients with severe AS.
The primary hypothesis is that early AVR or TAVI in asymptomatic patients with severe AS will result in a reduction in the composite primary outcome of cardiovascular (CV) death and hospitalisation for heart failure (HHF) when compared to the conventional approach of expectant management.
Potential participants will be identified by a member of the clinical care team following diagnosis with severe AS. Participants will be screened for eligibility using pre-specified inclusion/exclusion criteria. Eligible participants will be provided with a written version of the participant information sheet detailing the exact nature of the study, what it will involve for the participant and any risks involved with taking part. Participants will be given at least 24 hours to consider the information and decide whether or not to take part. The study will randomise up to 2844 patients with severe asymptomatic AS to either allocated expectant management OR aortic valve replacement. Participants randomised to AVR will be placed on a waiting list with the aim that surgery will be performed within 3 months, dependent on local hospitals' waiting lists. Participants randomised to AVR will undergo routine tests/procedures which may include coronary angiography. If the outcome of the coronary angiography reveals coronary heart disease, the decision to perform CABG or PCI will be made by the responsible cardiac surgeon and cardiologist, in consultation with the patient. All analyses will be undertaken using the principles of intention-to-treat with participants analysed in the group they were randomised regardless of treatment received.
EASY-AS is collaborating with the EVoLVeD study (Early Valve Replacement guided by Biomarkers of Left Ventricular Decompensation in Asymptomatic Patients with Severe Aortic Stenosis, Clinical Trials.gov NCT03094143). In centres where both EASY-AS and EVoLVeD are running, participants in EASY-AS will be offered the opportunity to take part in EVoLVeD.
Funding has been granted by the British Heart Foundation (UK), Medical Research Future Fund (Aus) and Heart Foundation (NZ). The UK sponsor is the University of Leicester. Additional support and resources for the study will be provided by the participating Trusts and their corresponding Clinical Research Networks in the UK. The central co-ordination centre is the University of Leicester Clinical Trials Unit.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 2844
-
Age >18 years
-
Patient has severe asymptomatic AS, in line with current international guidelines, defined as either:
- Peak velocity ≥4m/s OR mean pressure gradient ≥40mmHg WITH aortic valve area ≤1.0cm2 OR ≤0.6cm2/m2 body surface area OR
- Peak velocity ≥4m/s OR mean pressure gradient ≥40mmHg WITH aortic valve area >1.0 - ≤1.2cm2 OR >0.6 - ≤0.7cm2/m2 body surface area AND high sex specific calcium score* OR
- Peak Velocity ≥3.5m/s - 3.9m/s AND mean pressure gradient <40 mmHg WITH aortic valve area ≤1.0cm2 OR ≤0.6cm2/m2 body surface area AND high sex specific calcium score* *Sex specific high calcium scores (Agatston units): >1200 females; >2000 males
-
The responsible clinician feels that either ongoing surveillance or early AVR are appropriate.
-
Regarded by the treating cardiologist to be suitable for AVR (surgical or TAVI) with an acceptable risk
-
Willing to provide informed consent and be randomised to early AVR or expectant management
-
An ability to understand one of the written languages that the study has provided written and visual materials in, or the availability of a translator to explain the study documentation
- Symptoms related to AS
- Additional severe valvular heart disease
- Other cardiac surgery planned pre-randomisation (eg CABG)
- Left ventricular systolic dysfunction (LVEF <50%)
- Pregnancy
- Co-morbid condition that, in the opinion of the treating cardiologist, limits life expectancy to <2 years
- Patient has previously undergone AVR or TAVI with restenosis
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Group A: Aortic valve replacement Aortic valve replacement Participants randomised to AVR will be investigated and managed according to local protocols and standard practice. Participants will be placed on the waiting list with the aim that surgery will be performed within 3 months, dependent on local hospitals' waiting lists.
- Primary Outcome Measures
Name Time Method Combined measure of cardiovascular death and hospitalisation for heart failure Minimum 3 years Measured in days from randomisation until end of trial (minimum 3 years).
The primary analysis will be undertaken when 663 events have accrued, which is estimated to be after a median of 5 years follow-up assuming 2844 patients are recruited over 4 years.
- Secondary Outcome Measures
Name Time Method Death (cardiovascular, including sudden cardiac death, and non-cardiovascular), hospitalisation for heart failure, myocardial infarction, stroke Up to 5 years Assessing number of major adverse events.
All participants will be consented for long-term follow-up (10 years) and clinical events will be ascertained through NHS Digital or equivalent.WHO Disability Assessment Schedule (WHODAS 2.0) 6, 12, 24 and 36 months Assessing disability-free survival during the period of active recruitment.
Scores assigned to each of the items - "none" (0), "mild" (1) "moderate" (2), "severe" (3) and "extreme" (4) - are summed. The simple sum of the scores of the items across all domains constitutes a statistic that is sufficient to describe the degree of functional limitations.
Step 1 - Summing of recoded item scores within each domain. Step 2 - Summing of all six domain scores. Step 3 - Converting the summary score into a metric ranging from 0 to 100 (where 0 = no disability; 100 = full disability).Health Economics Questionnaire 6, 12, 24 and 36 months Assessed using self-reported health care resource use and cost effectiveness.
Participants will be asked if they have used any of the following services at a hospital for reasons that may be related to their heart condition or treatment: hospital services, services in the community and specialist equipment.
The data from this questionnaire will be scored by a Health Economist at the end of the study.NHS record linkage services Up to 5 years Assessing number of days alive and out of hospital.
All participants will be consented for long-term follow-up (10 years) and clinical events will be ascertained through NHS Digital or equivalent.Edmonton Frail Scale (EFS) (Bedside and Acute Care Version) Baseline Assessing frailty at baseline using a simple tool to assess frailty in older patients. It consists of nine domains and eleven items, each scoring 0 points (frailty absent or normal health), 1 point (minor errors or mild/moderate impairment), or 2 points (important errors or severely impaired).
EuroQol five-level (EQ-5D-5L) questionnaire 6, 12, 24 and 36 months Assessing quality of life during the period of active recruitment.
EQ-5D-5L has 2 components: health state description and evaluation. In the description part, health status is measured in terms of 5 dimensions (5D); mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Mobility dimension asks about the person's walking ability. Self-care dimension asks about the ability to wash or dress by oneself, and usual activities dimension measures performance in "work, study, housework, family or leisure activities". In pain/discomfort dimension, it asks how much pain or discomfort they have, and in anxiety/depression dimension, it asks how anxious or depressed they are. The respondents self-rate their level of severity for each dimension using a 5-level scale.Number of additional outcomes of special interest: infective endocarditis and major bleeding, resuscitated cardiac arrest, hospitalisation with new onset atrial fibrillation, syncope, revascularization (CABG/PCI), cardiac device implantation Up to 5 years Assessing additional outcomes of special interest.
All participants will be consented for long-term follow-up (10 years) and clinical events will be ascertained through NHS Digital or equivalent.
Trial Locations
- Locations (97)
Sint-Jan Hospital
🇧🇪Brugge, Belgium
Ziekenhuis Oost-Limburg
🇧🇪Genk, Belgium
University Hospital of Brussels
🇧🇪Jette, Belgium
University Hospital Ayr
🇬🇧Ayr, United Kingdom
Chesterfield Royal Hospital
🇬🇧Chesterfield, United Kingdom
Wycombe Hospital
🇬🇧High Wycombe, Wycombe, United Kingdom
University Hospital Coventry & Warwickshire
🇬🇧Coventry, United Kingdom
Golden Jubilee National Hospital
🇬🇧Glasgow, United Kingdom
Gateshead Health NHS Foundation Trust
🇬🇧Gateshead, United Kingdom
West Middlesex University Hospital
🇬🇧Isleworth, United Kingdom
University Hospital Crosshouse
🇬🇧Kilmarnock, United Kingdom
Chelsea and Westminster Hospital
🇬🇧London, United Kingdom
St George's Hospital
🇬🇧London, United Kingdom
Cleveland Clinic London Hospital
🇬🇧London, United Kingdom
Freeman Hospital
🇬🇧Newcastle upon Tyne, United Kingdom
Kings Mill Hospital
🇬🇧Nottingham, United Kingdom
Queens Medical Centre
🇬🇧Nottingham, United Kingdom
Royal Alexandra Hospital
🇬🇧Paisley, United Kingdom
Northern General Hospital
🇬🇧Sheffield, United Kingdom
Stepping Hill Hospital
🇬🇧Stockport, United Kingdom
Forth Valley Royal Hospital
🇬🇧Stirling, United Kingdom
Royal Cornwall Hospital
🇬🇧Truro, United Kingdom
Pinderfields Hospital
🇬🇧Wakefield, United Kingdom
Canberra Hospital
🇦🇺Garran, Canberra, Australia
Watford General Hospital
🇬🇧Watford, United Kingdom
Liverpool Hospital
🇦🇺Liverpool, New South Wales, Australia
Royal North Shore Hospital
🇦🇺St Leonards, New South Wales, Australia
Westmead Hospital
🇦🇺Westmead, New South Wales, Australia
Wollongong Hospital
🇦🇺Wollongong, New South Wales, Australia
Prince Charles Hospital
🇦🇺Chermside, Queensland, Australia
Townsville Hospital
🇦🇺Douglas, Queensland, Australia
The Gold Coast Hospital
🇦🇺Southport, Queensland, Australia
Royal Adelaide Hospital
🇦🇺Adelaide, South Australia, Australia
Flinders Medical Centre
🇦🇺Adelaide, South Australia, Australia
Monash Health
🇦🇺Clayton, Victoria, Australia
University Hospital Geelong
🇦🇺Geelong, Victoria, Australia
Fiona Stanley Hospital
🇦🇺Perth, Western Australia, Australia
Royal Perth Hospital
🇦🇺Perth, Western Australia, Australia
Lyell McEwin Hospital
🇦🇺Elizabeth Vale, Australia
Northern Hospital
🇦🇺Epping, Australia
Royal Hobart Hospital
🇦🇺Hobart, Australia
Nepean Hospital
🇦🇺Kingswood, Australia
John Hunter Hospital
🇦🇺New Lambton Heights, Australia
Royal Darwin Hospital
🇦🇺Tiwi, Australia
Auckland City Hospital
🇳🇿Auckland, New Zealand
Christchurch Hospital
🇳🇿Christchurch, New Zealand
Dunedin Hospital
🇳🇿Dunedin, New Zealand
Institute of Cardiovascular Diseases
🇷🇸Sremska Kamenica, Serbia
University Hospital of North Durham
🇬🇧Durham, County Durham, United Kingdom
Glan Clwyd Hospital
🇬🇧Bodelwyddan, Denbighshire, United Kingdom
Dorset County Hospital
🇬🇧Dorchester, Dorset, United Kingdom
Basingstoke and North Hampshire Hospital
🇬🇧Basingstoke, Hampshire, United Kingdom
University Hospitals Leicester, Glenfield
🇬🇧Leicester, Leicestershire, United Kingdom
Royal Liverpool Hospital
🇬🇧Liverpool, United Kingdom
Norfolk and Norwich University Hospital
🇬🇧Norwich, Norfolk, United Kingdom
Scunthorpe General Hospital
🇬🇧Scunthorpe, North Lincolnshire, United Kingdom
Kettering General Hospital
🇬🇧Kettering, Northamptonshire, United Kingdom
Wansbeck General Hospital
🇬🇧Ashington, Northumberland, United Kingdom
Raigmore Hospital
🇬🇧Inverness, Scotland, United Kingdom
Musgrove Park Hospital
🇬🇧Taunton, Somerset, United Kingdom
Morriston Hospital
🇬🇧Swansea, Wales, United Kingdom
Russells Hall Hospital
🇬🇧Dudley, West Midlands, United Kingdom
George Eliot Hospital
🇬🇧Nuneaton, West Midlands, United Kingdom
Walsall Manor Hospital
🇬🇧Walsall, West Midlands, United Kingdom
Sandwell General Hospital
🇬🇧West Bromwich, West Midlands, United Kingdom
Aberdeen Royal Infirmary
🇬🇧Aberdeen, United Kingdom
Aintree University Hospital
🇬🇧Aintree, United Kingdom
Basildon University Hospital
🇬🇧Basildon, United Kingdom
Queen Elizabeth Hospital
🇬🇧Birmingham, United Kingdom
Blackpool Victoria Hospital
🇬🇧Blackpool, United Kingdom
Royal Sussex County Hospital
🇬🇧Brighton, United Kingdom
North Cumbria Integrated Care
🇬🇧Carlisle, United Kingdom
County Durham and Darlington NHS Foundation Trust
🇬🇧Darlington, United Kingdom
Doncaster Royal Infirmary
🇬🇧Doncaster, United Kingdom
The Royal Infirmary of Edinburgh
🇬🇧Edinburgh, United Kingdom
Royal Devon & Exeter Hospital
🇬🇧Exeter, United Kingdom
Huddersfield Royal Infirmary
🇬🇧Huddersfield, United Kingdom
Airedale General Hospital
🇬🇧Keighley, United Kingdom
St Bartholomew's Hospital
🇬🇧London, United Kingdom
Leeds General Infirmary
🇬🇧Leeds, United Kingdom
Lincoln County Hospital
🇬🇧Lincoln, United Kingdom
Liverpool Heart and Chest Hospital
🇬🇧Liverpool, United Kingdom
St Thomas' Hospital
🇬🇧London, United Kingdom
University Hospital Lewisham
🇬🇧London, United Kingdom
Imperial College Healthcare NHS Trust
🇬🇧London, United Kingdom
Maidstone & Tunbridge Wells Hospital
🇬🇧Maidstone, United Kingdom
Wythenshawe Hospital
🇬🇧Manchester, United Kingdom
North Manchester General Hospital
🇬🇧Manchester, United Kingdom
The James Cook University Hospital
🇬🇧Middlesbrough, United Kingdom
Derriford Hospital
🇬🇧Plymouth, United Kingdom
Poole Hospital
🇬🇧Poole, United Kingdom
Queen Alexandra Hospital
🇬🇧Portsmouth, United Kingdom
Southampton General Hospital
🇬🇧Southampton, United Kingdom
Torbay Hospital
🇬🇧Torquay, United Kingdom
North Tees and Hartlepool NHS Foundation Trust
🇬🇧Stockton-on-Tees, United Kingdom
South Warwickshire University NHS Foundation Trust
🇬🇧Warwick, United Kingdom
Yeovil District Hospital
🇬🇧Yeovil, United Kingdom
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