The Role of Occult Cardiac Amyloid in the Elderly With Aortic Stenosis.

NCT03029026 | Completed

• 1 other identifier: 006974
• Study Type: observational
• Target: 581
• Locations: 1 country
• Sites: 2

Brief Summary

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).

Conditions

Cardiac Amyloidosis; Aortic Stenosis

Keywords

Cardiac amyloidosis; Aortic stenosis; DPD scintigraphy

Outcome Measures

Primary Outcomes (1)

• Patient mortality

  From patient notes, GP records or Office of National Statistics.

  Through study completion, an average of 1 year

Secondary Outcomes (4)

• Major adverse cardiovascular events (MACE)

  Post-TAVI investigation - 1-year

• Length of hospital stay

  Post-TAVI investigation - 1-year

• Pacemaker implantation

  Post-TAVI investigation - 1-year

• Outcome of the various cardiac imaging modalities

  1-year

Study Arms (3)

Those patients for TAVR

Those patients who are undergoing TAVR (clinical decision) who are recruited at the Barts Heart Centre will undergo clinical echocardiography, research DPD scintigraphy and clinical TAVR work-up CT (with research post contrast acquisitions at 3-5 minutes), unless already performed prior to recruitment. Those patients undergoing TAVR (clinical decision) who are recruited at the John Radcliffe Hospital will undergo clinical echocardiography and research DPD scintigraphy only. N=150.

Other: Baseline assessment; Procedure: Transthoracic echocardiography; Procedure: 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy; Radiation: CT 3-5-minute post-contrast research sequences; Other: Follow-up assessment

Those patients for sAVR

Those patients who are undergoing sAVR (clinical decision) will undergo clinical echocardiography, research DPD scintigraphy, research CMR and endomyocardial biopsy at the time of surgery. N=50.

Other: Baseline assessment; Procedure: Transthoracic echocardiography; Procedure: 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy; Procedure: Cardiac Magnetic Resonance; Procedure: Endomyocardial biopsy; Other: Follow-up assessment

Those patients for medical management

Those patients who are decided for medical management (clinical decision) will undergo clinical echocardiography, research DPD scintigraphy and any other imaging as per work-up/trial prior to no intervention decision. N=50.

Other: Baseline assessment; Procedure: Transthoracic echocardiography; Procedure: 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy; Other: Follow-up assessment

Interventions

Baseline assessment OTHER

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 exclusions 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).

Those patients for TAVR; Those patients for medical management; Those patients for sAVR

Transthoracic echocardiography PROCEDURE

Patients will undergo a clinical transthoracic echocardiogram for the assessment of AS severity and diastolic function in line with the British Society of Echocardiography guidance. Simultaneous, optimised 2-chamber, 3-chamber and 4-chamber views will need to be recorded (over 3 cycles) for strain analysis. Severe AS will be defined using standard echocardiography guidelines in conjunction with MDT consensus.

Also known as: Echo

Those patients for TAVR; Those patients for medical management; Those patients for sAVR

99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy PROCEDURE

Scanning will use a hybrid SPECT-CT gamma camera after intravenous injection of 700 MBq of DPD (effective dose 4mSv). Acquisition technique: 5-minute (early) and then 3-hour (late) whole body planar scans, followed by SPECT-CT of the heart. Qualitative visual (Perugini) scoring of the cardiac uptake is performed from the 3-hour whole body planar images and the SPECT-CT images.

Also known as: DPD scintigraphy

Those patients for TAVR; Those patients for medical management; Those patients for sAVR

CT 3-5-minute post-contrast research sequences RADIATION

Cardiac CT for ECV will use the dedicated cardiac CT scanner (Somatom FORCE; Siemens Medical Solutions, Germany). 3-5-minute post contrast research images will be taken at the end of the clinically indicated TAVR work-up CT.

Also known as: ECV by CT

Those patients for TAVR

Cardiac Magnetic Resonance PROCEDURE

CMR will be performed using a 1.5-T Aera for standard late gadolinium enhancement, as well as T1 mapping and ECV.

Also known as: CMR

Those patients for sAVR

Endomyocardial biopsy PROCEDURE

Septal tissue specimens will be taken under direct vision by the surgical team using a 14-gauge coaxial needle system. Biopsies will be screened for amyloid by Congo red staining; if positive, tissue will be fully sub-typed (immunohistochemistry, mass spectrometry).

Those patients for sAVR

Follow-up assessment OTHER

1-year follow-up 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). 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.

Those patients for TAVR; Those patients for medical management; Those patients for sAVR

Eligibility Criteria

• Age: 75 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients with symptomatic severe AS being considered for intervention.

You may qualify if:

• Aged 75 or above
• Severe aortic stenosis being considered for intervention
• Patient informed consent

You may not qualify if:

• Unable to provide informed consent
• Patient declined or withdrew consent (at any stage)
• Imaging modality specific contraindications:
• Being considered for sAVR, however unsuitable for study CMR due to contraindications such as a device in situ, severe claustrophobia, renal impairment (eGFR \<30) or previous severe gadolinium contrast allergy.
• Being considered for TAVR work-up CT, however unsuitable for contrast due to previous severe iodinated contrast allergy. NB patients with significant renal impairment are given pre-hydration routinely by the managing clinicians.

Sponsors & Collaborators

• Queen Mary University of London: lead

Study Sites (2)

Barts Heart Centre

London, EC1A 7BE, United Kingdom

Location

The John Radcliffe Hospital

Oxford, OX3 9DU, United Kingdom

Location

Related Publications (19)

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Biospecimen

Retention: SAMPLES WITH DNA

Blood and urine samples will be biobanked for all patients (n=250). Endomyocardial biopsy specimens will be snap frozen and biobanked for those patients undergoing sAVR (n=50).

MeSH Terms

Conditions

Amyloid Neuropathies, Familial; Aortic Valve Stenosis

Interventions

Caves

Condition Hierarchy (Ancestors)

Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Nervous System Diseases; Amyloid Neuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Amyloidosis, Familial; Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases; Amyloidosis; Proteostasis Deficiencies; Aortic Valve Disease; Heart Valve Diseases; Heart Diseases; Cardiovascular Diseases; Ventricular Outflow Obstruction

Intervention Hierarchy (Ancestors)

Geological Phenomena; Physical Phenomena; Environment; Ecological and Environmental Phenomena; Biological Phenomena; Environment and Public Health

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 9, 2017
• First Posted: January 24, 2017
• Study Start: February 22, 2011
• Primary Completion: March 1, 2021
• Study Completion: March 1, 2021
• Last Updated: March 11, 2025

Record last verified: 2025-03

Locations

GB (2)