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

Overview

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 2104 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 6 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.

Interventions

• Procedure Aortic valve replacement
  Participants will be assessed by a member of the surgical team performing aortic valve replacement (AVR), and by any other relevant medical professionals identified by the doctors overseeing their care in hospital. When deemed ready for AVR, a member of the surgical team will ask for consent to proceed with the AVR. They will discuss the surgical procedure, covering information on the basic technical procedure, risks and expected recovery time.

Primary outcome measures

• Combined measure of cardiovascular death, hospitalisation for heart failure and Stroke. [Time frame: Through study completion, median 5.5 years]

Secondary outcome measures (7)

• WHO Disability Assessment Schedule (WHODAS 2.0) [Time frame: 6, 12, 24 and 36 months]
• NHS record linkage services [Time frame: Up to 5 years]
• Death (cardiovascular, including sudden cardiac death, and non-cardiovascular), hospitalisation for heart failure, myocardial infarction, stroke [Time frame: Up to 5 years]
• 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 [Time frame: Up to 5 years]
• EuroQol five-level (EQ-5D-5L) questionnaire [Time frame: 6, 12, 24 and 36 months]
• Health Economics Questionnaire [Time frame: 6, 12, 24 and 36 months]
• Edmonton Frail Scale (EFS) (Bedside and Acute Care Version) [Time frame: Baseline]

Eligibility criteria

Inclusion criteria

• 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

Exclusion criteria

• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Prevention

Study locations

United Kingdom · 79 centers

• University Hospital of North Durham — Durham
• Glan Clwyd Hospital — Bodelwyddan
• Dorset County Hospital — Dorchester
• Basingstoke and North Hampshire Hospital — Basingstoke
• University Hospitals Leicester, Glenfield — Leicester
• Royal Liverpool Hospital — Liverpool
• Norfolk and Norwich University Hospital — Norwich
• Scunthorpe General Hospital — Scunthorpe
• … and 71 more centers

Australia · 20 centers

• Canberra Hospital — Garran
• Liverpool Hospital — Liverpool
• Royal North Shore Hospital — St Leonards
• Westmead Hospital — Westmead
• Wollongong Hospital — Wollongong
• Prince Charles Hospital — Chermside
• Townsville Hospital — Douglas
• The Gold Coast Hospital — Southport
• … and 12 more centers

Belgium · 3 centers

• Sint-Jan Hospital — Bruges
• Ziekenhuis Oost-Limburg — Genk
• University Hospital of Brussels — Jette

New Zealand · 3 centers

• Auckland City Hospital — Auckland
• Christchurch Hospital — Christchurch
• Dunedin Hospital — Dunedin

Netherlands · 2 centers

• Frisius Medical Center — Leeuwarden
• Radboud University Medical Center — Nijmegen

Spain · 2 centers

• Hospital Germans Trias — Barcelona
• University Hospital of Navarra — Pamplona

Serbia · 1 center

• Institute of Cardiovascular Diseases — Kamenitz

Publications

• Allmark P, Taylor B, Tod AM, Ryan T, Dweck M, McCann GP, Singh A. Factors influencing the decision to accept or decline aortic valve replacement for asymptomatic aortic stenosis: a nested longitudinal qualitative substudy of the EASY-AS randomised trial. BMJ Open. 2026 Jan 22;16(1):e106485. doi: 10.1136/bmjopen-2025-106485. PMID 41571417
• Richardson C, Gilbert T, Aslam S, Brookes CL, Singh A, Newby DE, Dweck MR, Stewart RAH, Myles PS, Briffa T, Selvanayagam J, Chow CK, Murphy GJ, Akowuah EF, Lord J, Barber S, Paola ASD, McCann GP, Hillis GS. Rationale and design of the early valve replacement in severe asymptomatic aortic stenosis trial. Am Heart J. 2024 Sep;275:119-127. doi: 10.1016/j.ahj.2024.05.013. Epub 2024 May 30. PMID 38821453

Identifiers

NCT: NCT04204915 · 0700 · CS/18/7/33714 · 266292 · 90865 · 0700

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗