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…
ID
Source
Brief title
Condition
- Cardiac valve disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
A combined measure of CV death and HHF, 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
• Disability-free survival (WHODAS)
• Number of days alive and out of hospital
• Number of major adverse events including: death (cardiovascular, including
sudden cardiac death, and non-cardiovascular), hospitalisation for heart
failure, myocardial infarction, stroke
• 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 (permanent pacemaker or implantable cardioverter defibrillator)
• Quality of life measured by the EQ-5D-5L questionnaire
Background summary
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 aging 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. Approximately 50% of patients with
severe AS are asymptomatic at the time of diagnosis and the management of this
growing population is among the most contentious issues in modern cardiology.
Existing data have evident limitations, and it is impossible to be certain
whether early AVR improves prognosis or results in worse outcomes. However,
there is an increasing trend for clinicians to refer patients for early
AVR(28). There is a widespread consensus that randomized trials comparing
conventional expectant management to early AVR are required. Prior to EASY-AS
commencing there were no randomized controlled trials to address the relative
benefits of early AVR versus expectant management in patients with severe
asymptomatic AS.
Study objective
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.
The key secondary hypotheses are that early intervention results in:
• Improved disability free survival
• Improved quality of life
• Reduced total mortality, CV mortality and HHF
• Increased days alive and out of hospital
• A more cost-effective strategy than expectant management
Study design
This is a major pragmatic multi-centre prospective parallel group open
randomised controlled study. The study will be conducted in the UK, Australia
and New Zealand, funding is being sought in several countries to expand
recruitment internationally. Each country will be responsible for its own
sponsorship of the study. There will be an agreed master protocol to be
approved by each countries respective ethics and regulatory bodies.
The proposed study is in two 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 two years.
Agreed Stop-go criteria:
The funder in the UK (BHF) has stipulated that a vanguard phase is undertaken
to prove that randomisation is feasible and 200 patients should be recruited
during the first 16 months of recruitment. The following criteria have been
agreed with the BHF in the UK:
Go: >= 90% of target (180) recruited by 21 months
Discuss options with BHF: 60-90% of target (120-179)
Stop: < 60% of target (<120).
A second criterion in the BHF award was that additional funding for the study
should be obtained in another country outside the UK and this was achieved in
2019 with a Medical Research Future Fund (MRFF) award in Australia.
Aims of the study
The over-arching aim of the study 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.
Intervention
The study will compare two clinical strategies: either early AVR (surgical or
TAVI) or initial expectant management (with prompt AVR recommended if symptoms
of AS develop).
Study burden and risks
E2. What is the burden of the research (and any prior inspection) for the test
subjects? - follow-up:
The total duration of the study for the individual subject is 24 months for the
Netherlands, 60 months for the other countries.
University Road Maurice Shock Building
Leicester LE1 7RH, UK
AF
University Road Maurice Shock Building
Leicester LE1 7RH, UK
AF
Listed location countries
Age
Inclusion criteria
1. Age >18 years
2. Patient has severe asymptomatic AS, in line with current international
guidelines, defined as either:
a) Peak velocity >=4m/s OR mean pressure gradient >=40mmHg WITH aortic valve area
<=1.0cm2 OR <=0.6cm2/m2 body surface area
OR
b) 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
c) 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
1. Symptoms related to AS
2. Additional severe valvular heart disease
3. Other cardiac surgery planned pre-randomisation (eg CABG)
4. Left ventricular systolic dysfunction (LVEF <50%)
5. Pregnancy
6. Co-morbid condition that, in the opinion of the treating cardiologist,
limits life expectancy to <2 years
7. Patient has previously undergone AVR or TAVI with restenosis
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL86593.099.24 |