Aortic Stenosis Clinical Trial
Official title:
A sTudy invesTigating the Role of Occult cArdiaC Amyloid in The Elderly With Aortic Stenosis
Aortic stenosis (AS) is the most common valvular heart disease. Once symptomatic with severe
AS, outcome is poor unless the valve is replaced surgically or via transcatheter aortic valve
replacement (TAVR). Transthyretin amyloid (ATTR) deposits are common in the heart muscle in
up to 25% of octogenarians, and after an asymptomatic period of unknown duration, cause overt
heart failure and arrhythmias in a proportion of cases. The prevalence and impact of covert
ATTR amyloidosis in elderly individuals with AS are unknown. Detection would avoid
misdiagnosis, guide treatment and, potentially, improve outcomes. Recent data have shown that
echocardiography, cardiovascular magnetic resonance (CMR), computed tomography (CT), and DPD
scintigraphy, can identify ATTR amyloid deposits, but the clinical performance of these
various tests is unknown.
This study will investigate elderly patients with symptomatic severe AS using imaging to
explore ATTR amyloid in AS and determine its prevalence and impact on outcome.
The investigators aim to recruit a total of 250 patients aged 75 or older being considered
for intervention for severe AS. The prevalence of cardiac amyloid will be assessed in three
arms (sAVR, TAVI and medical therapy, with a likely patient ratio of 50:150:50), using five
investigation modalities - all cohorts (echocardiography and DPD scintigraphy); sAVR cohort
(biopsy and CMR); TAVI cohort (EqCT); medical therapy only cohort (as per work-up/trial prior
to no intervention decision).
The primary outcome measure is patient mortality. Secondary outcomes measures are major
adverse cardiovascular events, length of stay, pacemaker implantation, ECV measured by EqCT
and CMR.
Follow up will be at 1-year with clinical echocardiogram (for sAVR and TAVI patients) and/or
telephone interview for all patients (if not carried out in person at the time of the
echocardiogram).
INTRODUCTION
Calcific aortic stenosis (AS) is the most common valve disease in the West with a prevalence
of 2.8% in patients over 75 years. Once symptomatic with severe AS, outcome is poor, unless
the valve is replaced surgically (sAVR) or via transcatheter aortic valve replacement (TAVR),
which is predominantly used in elderly patients for whom surgery is deemed too high risk.
Systemic amyloidosis is a multisystem disease characterised by extracellular deposition of
abnormally folded protein, which over time results in progressive organ dysfunction. These
protein deposits bind Congo red stain, producing the pathognomonic apple-green birefringence
under polarised light. Cardiac involvement is the leading cause of morbidity and mortality in
these patients. Amyloidosis due to transthyretin deposition (ATTR) can be due to wild-type
transthyretin amyloid deposits, also known as senile systemic amyloidosis, which
predominantly accumulates in the heart. Primary light chain (AL) amyloidosis and hereditary
transthyretin amyloidosis can also affect the heart.
Wild-type ATTR (wtATTR) amyloid deposition is present in up to a 25% of individuals aged over
85 at autopsy. To date, this has been no more than an academic observation, but technology is
changing this: cardiac imaging, particularly cardiovascular magnetic resonance (CMR) and
99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy, can now detect the
disease antemortem, which is generating a major increase in national awareness. There are
also significant advances being made in the treatment of amyloidosis. There are several drugs
in clinical trial including novel antisense and interfering RNA therapeutics that can reduce
production of TTR by up to 80-90%. Also on the horizon are treatments to promote clearance of
established amyloid, notably including monoclonal anti-SAP (serum amyloid P component)
antibodies. Despite the prevalence of wtATTR amyloid deposits at autopsy, their clinical
significance and prognostic impact of in severe AS has not been explored.
Co-existent cardiac amyloid and AS. Given the prevalence of wtATTR in octogenarians at
autopsy, AS and wtATTR are likely to co-exist - the literature has early evidence for this.
In a cohort of 20 patients with AS, who had undergone TAVI and subsequently valve
explantation at autopsy (n=17) or surgery (n=3), cardiac amyloid was found in a third of
these patients and was thought to contribute to death in the majority. Our research also
supports this - the "RELIEF-AS" study. In 146 patients with severe AS undergoing sAVR, we
found cardiac amyloid deposits in 6 patients. All were wtATTR, all calcific AS, with the
youngest patient being aged 69. Comprehensive imaging was performed, which showed a
diagnostic imaging hierarchy: echocardiography was non-contributory, CMR detected a third of
cases, whereas DPD scintigraphy was positive in all four patients scanned (2 died before the
test). Biopsy ATTR deposits were prognostic and the strongest predictor of adverse outcome -
regardless of infiltration degree or its imaging detection: post sAVR 50% with wtATTR died by
1 year vs 9% without (p<0.001). Occult amyloid has also been implicated in the need for
pacemakers in TAVR patients.
The availability of TAVI has extended the range of individuals that can benefit from
intervention for AS, prolonging life. TAVR patients are generally older so more likely to
have wtATTR. One recent abstract found a 16% (23% in men) prevalence of cardiac amyloid in in
patients undergoing TAVR (n=75) using 99mTc-pyrophosphate scintigraphy (PYP, a bone tracer
available in the USA, which is possibly inferior to DPD). WtATTR is also an increasingly
recognized cause of heart failure with preserved ejection fraction (HFpEF). DPD scintigraphy
in 120 hospitalized patients who also had LV wall thickness ≥12 mm and an EF ≥50%, showed
that 16 patients (13.3%) showed moderate to severe myocardial uptake.
Why detect wtTTR amyloid in severe AS? There are two separate aspects of wtATTR in AS. First,
wtATTR in patients with moderate AS may mimic severe AS, (particularly low-flow,
low-gradient) causing misdiagnosis. Second, wtATTR may itself be a disease modifier, leading
to a more severe phenotype with more heart failure, arrhythmia, and higher mortality. We
think there is a large, now detectable, UK population of elderly patients undergoing sAVR or
TAVR with a significant occult amyloid. This could influence therapeutic options (TAVR vs
sAVR vs medical therapy), intervention timing and medications - specific amyloid therapies,
drugs to avoid (e.g. digoxin and diltiazem).
How to detect wtATTR? There are multiple techniques that could detect cardiac wtATTR. Each
has their pros and cons with different evidence bases. Our initial study used three imaging
modalities and biopsy to detect the presence of cardiac amyloid in sAVR. DPD scintigraphy was
the superior imaging modality, with the highest diagnostic sensitivity. There is now a
rapidly growing body of evidence supporting DPD scintigraphy as the non-invasive
investigation of choice for diagnosing cardiac ATTR. A recent multi-centre study of over
1,000 patients showed that bone scintigraphy had a >99% sensitivity for cardiac ATTR deposits
and they proposed it should have a role in diagnosing the condition without the need for
invasive cardiac biopsy, which has previously been considered the gold standard.
The investigators have recently created a new modality: equilibrium contrast computed
tomography (EqCT), which requires a single extra image dataset of the heart to be taken 5
minutes after the routine TAVR work-up CT images are taken. Extracellular volume fraction
(ECV) calculated by EqCT discriminated 100% between cardiac amyloid involvement and patients
with AS in 53 patients.
TRIAL OBJECTIVES
Hypothesis:
In the elderly with severe AS being considered for intervention (TAVR, sAVR), wtATTR is:
- Common.
- Conveys a worse prognosis.
- Can be reliably detected non-invasively.
Aim:
To confirm the prevalence, clinical impact (procedural complications, symptom response to
aortic valve replacement, 1-year mortality) and potential place of imaging (DPD scintigraphy,
ECV by CT, CMR and echocardiography) in occult amyloid in severe AS.
STUDY PLAN
Design: prospective observational cohort with 1 year follow-up.
Population: patients aged 75 or older with severe AS referred to the Barts Heart Centre for
consideration for intervention (sAVR or TAVR) or referred to the John Radcliffe Hospital in
Oxford for consideration for TAVR.
Proposed sample size: two centre study (Barts Heart Centre and the John Radcliffe Hospital),
250 patients.
Recruitment: patients will be recruited from General Cardiology, TAVR and Cardiothoracic
Surgery Outpatient Clinics. A large proportion of these patients are discussed in the Valve
Multidisciplinary Team Meeting, which will provide another source of recruitment. This will
take place over an 18-month period from August 2016 to February 2018.
Baseline assessment: will include clinical history, Quality of Life Questionnaire
(EQ-5D/SF-12), a 6-minute-walk test, blood sampling for haematocrit, renal function,
biomarkers (NT-pro-BNP and troponin), and biobanking (also for AL exclusions if scanning
positive), a urine sample for biobanking (also for AL exclusion if scanning positive), as
well as tests performed as the routine pre-operative work-up (clinical electrocardiogram,
blood pressure to estimate global LV afterload, valvulo-arterial impedance).
Measures of exposure: the prevalence of cardiac amyloid assessed in three arms (sAVR, TAVI
and medical therapy, with a likely patient ratio of 50:150:50), using five investigation
modalities - all cohorts (echocardiography and DPD scintigraphy); sAVR cohort (biopsy and
CMR); TAVR cohort (EqCT); medical therapy only cohort (as per work-up/trial prior to no
intervention decision).
Follow-up: 1-year follow-up with clinical echocardiogram (for sAVR and TAVR patients) and/or
telephone interview for all patients (if not carried out in person at the time of the
echocardiogram). This will include a follow up Quality of Life Questionnaire as per baseline.
If attending clinic or echocardiogram a 6-minute-walk test will also be performed. MACE and
mortality endpoints will also be identified.
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