Clinical trial NCT04204915: The Early Valve Replacement in Severe ASYmptomatic Aortic Stenosis Study
Official title: A Randomised Controlled Trial of Early Valve Replacement in Severe ASYmptomatic Aortic Stenosis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Aortic Stenosis
Keywords: Asymptomatic aortic stenosis
Aortic valve replacement
Randomised controlled trial
Expectant management
Hospitalisation for heart failure
Cardiovascular death
Lead sponsor: University of Leicester
Sponsor class: OTHER
Collaborators: name: University of Auckland, New Zealand
name: University Hospitals, Leicester
name: The University of Western Australia
First posted: 2019-12-19
Enrollment: 2844
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: Inclusion Criteria:

1. Age \>18 years
2. Patient has severe asymptomatic AS, in line with current international guidelines, defined as either:

   1. Peak velocity ≥4m/s OR mean pressure gradient ≥40mmHg WITH aortic valve area ≤1.0cm2 OR ≤0.6cm2/m2 body surface area OR
   2. 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
   3. 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
3. The responsible clinician feels that either ongoing surveillance or early AVR are appropriate.
4. Regarded by the treating cardiologist to be suitable for AVR (surgical or TAVI) with an acceptable risk
5. Willing to provide informed consent and be randomised to early AVR or expectant management
6. 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

   Exclusion Criteria:
7. Symptoms related to AS
8. Additional severe valvular heart disease
9. Other cardiac surgery planned pre-randomisation (eg CABG)
10. Left ventricular systolic dysfunction (LVEF \<50%)
11. Pregnancy
12. Co-morbid condition that, in the opinion of the treating cardiologist, limits life expectancy to \<2 years
13. Patient has previously undergone AVR or TAVI with restenosis

Primary outcomes:
measure: Combined measure of cardiovascular death and hospitalisation for heart failure
timeFrame: Minimum 3 years
Secondary outcomes:
measure: WHO Disability Assessment Schedule (WHODAS 2.0)
timeFrame: 6, 12, 24 and 36 months
measure: NHS record linkage services
timeFrame: Up to 5 years
measure: Death (cardiovascular, including sudden cardiac death, and non-cardiovascular), hospitalisation for heart failure, myocardial infarction, stroke
timeFrame: Up to 5 years
measure: 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
timeFrame: Up to 5 years
measure: EuroQol five-level (EQ-5D-5L) questionnaire
timeFrame: 6, 12, 24 and 36 months
measure: Health Economics Questionnaire
timeFrame: 6, 12, 24 and 36 months
measure: Edmonton Frail Scale (EFS) (Bedside and Acute Care Version)
timeFrame: Baseline
Other outcomes:
Locations:
city: Garran
country: Australia
facility: Canberra Hospital
state: Canberra
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Wollongong
country: Australia
facility: Wollongong Hospital
state: New South Wales
city: Chermside
country: Australia
facility: Prince Charles Hospital
state: Queensland
city: Douglas
country: Australia
facility: Townsville Hospital
state: Queensland
city: Southport
country: Australia
facility: The Gold Coast Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Adelaide
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Clayton
country: Australia
facility: Monash Health
state: Victoria
city: Geelong
country: Australia
facility: University Hospital Geelong
state: Victoria
city: Perth
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Elizabeth Vale
country: Australia
facility: Lyell McEwin Hospital
city: Epping
country: Australia
facility: Northern Hospital
city: Hobart
country: Australia
facility: Royal Hobart Hospital
city: Kingswood
country: Australia
facility: Nepean Hospital
city: New Lambton Heights
country: Australia
facility: John Hunter Hospital
city: Tiwi
country: Australia
facility: Royal Darwin Hospital
city: Brugge
country: Belgium
facility: Sint-Jan Hospital
city: Genk
country: Belgium
facility: Ziekenhuis Oost-Limburg
city: Jette
country: Belgium
facility: University Hospital of Brussels
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Dunedin
country: New Zealand
facility: Dunedin Hospital
city: Sremska Kamenica
country: Serbia
facility: Institute of Cardiovascular Diseases
city: Durham
country: United Kingdom
facility: University Hospital of North Durham
state: County Durham
city: Bodelwyddan
country: United Kingdom
facility: Glan Clwyd Hospital
state: Denbighshire
city: Dorchester
country: United Kingdom
facility: Dorset County Hospital
state: Dorset
city: Basingstoke
country: United Kingdom
facility: Basingstoke and North Hampshire Hospital
state: Hampshire
city: Leicester
country: United Kingdom
facility: University Hospitals Leicester, Glenfield
state: Leicestershire
city: Liverpool
country: United Kingdom
facility: Royal Liverpool Hospital
state: Merseyside
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospital
state: Norfolk
city: Scunthorpe
country: United Kingdom
facility: Scunthorpe General Hospital
state: North Lincolnshire
city: Kettering
country: United Kingdom
facility: Kettering General Hospital
state: Northamptonshire
city: Ashington
country: United Kingdom
facility: Wansbeck General Hospital
state: Northumberland
city: Inverness
country: United Kingdom
facility: Raigmore Hospital
state: Scotland
city: Taunton
country: United Kingdom
facility: Musgrove Park Hospital
state: Somerset
city: Swansea
country: United Kingdom
facility: Morriston Hospital
state: Wales
city: Dudley
country: United Kingdom
facility: Russells Hall Hospital
state: West Midlands
city: Nuneaton
country: United Kingdom
facility: George Eliot Hospital
state: West Midlands
city: Walsall
country: United Kingdom
facility: Walsall Manor Hospital
state: West Midlands
city: West Bromwich
country: United Kingdom
facility: Sandwell General Hospital
state: West Midlands
city: High Wycombe
country: United Kingdom
facility: Wycombe Hospital
state: Wycombe
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Aintree
country: United Kingdom
facility: Aintree University Hospital
city: Ayr
country: United Kingdom
facility: University Hospital Ayr
city: Basildon
country: United Kingdom
facility: Basildon University Hospital
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Blackpool
country: United Kingdom
facility: Blackpool Victoria Hospital
city: Brighton
country: United Kingdom
facility: Royal Sussex County Hospital
city: Carlisle
country: United Kingdom
facility: North Cumbria Integrated Care
city: Chesterfield
country: United Kingdom
facility: Chesterfield Royal Hospital
city: Coventry
country: United Kingdom
facility: University Hospital Coventry &amp; Warwickshire
city: Darlington
country: United Kingdom
facility: County Durham and Darlington NHS Foundation Trust
city: Doncaster
country: United Kingdom
facility: Doncaster Royal Infirmary
city: Edinburgh
country: United Kingdom
facility: The Royal Infirmary of Edinburgh
city: Exeter
country: United Kingdom
facility: Royal Devon & Exeter Hospital
city: Gateshead
country: United Kingdom
facility: Gateshead Health NHS Foundation Trust
city: Glasgow
country: United Kingdom
facility: Golden Jubilee National Hospital
city: Huddersfield
country: United Kingdom
facility: Huddersfield Royal Infirmary
city: Isleworth
country: United Kingdom
facility: West Middlesex University Hospital
city: Keighley
country: United Kingdom
facility: Airedale General Hospital
city: Kilmarnock
country: United Kingdom
facility: University Hospital Crosshouse
city: Leeds
country: United Kingdom
facility: Leeds General Infirmary
city: Lincoln
country: United Kingdom
facility: Lincoln County Hospital
city: Liverpool
country: United Kingdom
facility: Liverpool Heart and Chest Hospital
city: Liverpool
country: United Kingdom
facility: Royal Liverpool Hospital
city: London
country: United Kingdom
facility: St Bartholomew's Hospital
city: London
country: United Kingdom
facility: St Thomas' Hospital
city: London
country: United Kingdom
facility: University Hospital Lewisham
city: London
country: United Kingdom
facility: Chelsea and Westminster Hospital
city: London
country: United Kingdom
facility: St George&#39;s Hospital
city: London
country: United Kingdom
facility: Cleveland Clinic London Hospital
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
city: Maidstone
country: United Kingdom
facility: Maidstone & Tunbridge Wells Hospital
city: Manchester
country: United Kingdom
facility: Wythenshawe Hospital
city: Manchester
country: United Kingdom
facility: North Manchester General Hospital
city: Middlesbrough
country: United Kingdom
facility: The James Cook University Hospital
city: Newcastle upon Tyne
country: United Kingdom
facility: Freeman Hospital
city: Nottingham
country: United Kingdom
facility: Kings Mill Hospital
city: Nottingham
country: United Kingdom
facility: Queens Medical Centre
city: Paisley
country: United Kingdom
facility: Royal Alexandra Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Poole
country: United Kingdom
facility: Poole Hospital
city: Portsmouth
country: United Kingdom
facility: Queen Alexandra Hospital
city: Sheffield
country: United Kingdom
facility: Northern General Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
city: Stirling
country: United Kingdom
facility: Forth Valley Royal Hospital
city: Stockport
country: United Kingdom
facility: Stepping Hill Hospital
city: Stockton-on-Tees
country: United Kingdom
facility: North Tees and Hartlepool NHS Foundation Trust
city: Torquay
country: United Kingdom
facility: Torbay Hospital
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
city: Wakefield
country: United Kingdom
facility: Pinderfields Hospital
city: Warwick
country: United Kingdom
facility: South Warwickshire University NHS Foundation Trust
city: Watford
country: United Kingdom
facility: Watford General Hospital
city: Yeovil
country: United Kingdom
facility: Yeovil District Hospital
Study officials:
affiliation: University of Leicester
name: Gerry McCann, Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: The University of Western Australia
name: Graham Hillis, Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Aukland
name: Ralph Stewart, Prof
role: PRINCIPAL_INVESTIGATOR
References: