The Early Valve Replacement in Severe ASYmptomatic Aortic Stenosis Study

A Randomised Controlled Trial of Early Valve Replacement in Severe ASYmptomatic Aortic Stenosis

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.

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.

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