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The Role of Occult Cardiac Amyloid in the Elderly With Aortic Stenosis. (ATTRact-AS)

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ClinicalTrials.gov Identifier: NCT03029026
Recruitment Status : Recruiting
First Posted : January 24, 2017
Last Update Posted : April 19, 2018
Sponsor:
Information provided by (Responsible Party):
Queen Mary University of London

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).


Condition or disease Intervention/treatment
Cardiac Amyloidosis Aortic Stenosis 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 Procedure: Cardiac Magnetic Resonance Procedure: Endomyocardial biopsy Other: Follow-up assessment

  Show Detailed Description

Study Type : Observational
Estimated Enrollment : 250 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: A sTudy invesTigating the Role of Occult cArdiaC Amyloid in The Elderly With Aortic Stenosis
Study Start Date : September 2016
Estimated Primary Completion Date : April 2019
Estimated Study Completion Date : April 2019


Group/Cohort Intervention/treatment
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
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).

Procedure: Transthoracic echocardiography

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.

Other Name: Echo

Procedure: 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy
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.
Other Name: DPD scintigraphy

Radiation: CT 3-5-minute post-contrast research sequences
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.
Other Name: ECV by CT

Other: Follow-up assessment
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 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
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).

Procedure: Transthoracic echocardiography

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.

Other Name: Echo

Procedure: 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy
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.
Other Name: DPD scintigraphy

Procedure: Cardiac Magnetic Resonance
CMR will be performed using a 1.5-T Aera for standard late gadolinium enhancement, as well as T1 mapping and ECV.
Other Name: CMR

Procedure: Endomyocardial biopsy
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).

Other: Follow-up assessment
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 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
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).

Procedure: Transthoracic echocardiography

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.

Other Name: Echo

Procedure: 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy
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.
Other Name: DPD scintigraphy

Other: Follow-up assessment
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.




Primary Outcome Measures :
  1. Patient mortality [ Time Frame: 1-year ]
    From patient notes, GP records or Office of National Statistics.


Secondary Outcome Measures :
  1. Major adverse cardiovascular events (MACE) [ Time Frame: 1-year ]
    From patient's medical records. Includes for example: cardiac death, myocardial infarction and emergency cardiac surgery or intervention.

  2. Length of hospital stay [ Time Frame: 1-year ]
    From patient's medical records

  3. Pacemaker implantation [ Time Frame: 1-year ]
    From patient's medical records

  4. Outcome of the various cardiac imaging modalities [ Time Frame: 1-year ]

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).


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Ages Eligible for Study:   75 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients with symptomatic severe AS being considered for intervention.
Criteria

Inclusion Criteria:

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

Exclusion Criteria:

  • Unable to provide informed consent
  • Patient declined or withdrew consent (at any stage)
  • Imaging modality specific contraindications:

    1. 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.
    2. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03029026


Contacts
Contact: Paul R Scully, MBBS MRes 020 3465 6115 paul.scully@bartshealth.nhs.uk
Contact: James C Moon, MD 020 3465 6115 james.moon@bartshealth.nhs.uk

Locations
United Kingdom
Barts Heart Centre Recruiting
London, United Kingdom, EC1A 7BE
Contact: Paul R Scully, MBBS MRes    020 3465 6115    paul.scully@bartshealth.nhs.uk   
Contact: James C Moon, MD    020 3465 6115    james.moon@bartshealth.nhs.uk   
Principal Investigator: Francesca Pugliese, MD PhD         
Sub-Investigator: Paul R Scully, MBBS MRes         
Sub-Investigator: James C Moon, MD         
Sub-Investigator: Philip N Hawkins, FMedSci         
Sub-Investigator: Leon J Menezes, BA BM BCh         
Sub-Investigator: Thomas A Treibel         
Sub-Investigator: Mike Mullen         
Sub-Investigator: Guy Lloyd         
Sub-Investigator: Christopher G McGregor         
The John Radcliffe Hospital Recruiting
Oxford, United Kingdom, OX3 9DU
Contact: Ellie Corps    01865 223349      
Principal Investigator: Andrew Kelion         
Sub-Investigator: Nikant Sabharwal         
Sub-Investigator: Jim Newton         
Sponsors and Collaborators
Queen Mary University of London

Publications:

Responsible Party: Queen Mary University of London
ClinicalTrials.gov Identifier: NCT03029026     History of Changes
Other Study ID Numbers: 006974
First Posted: January 24, 2017    Key Record Dates
Last Update Posted: April 19, 2018
Last Verified: November 2016

Keywords provided by Queen Mary University of London:
Cardiac amyloidosis
Aortic stenosis
DPD scintigraphy

Additional relevant MeSH terms:
Constriction, Pathologic
Amyloidosis
Aortic Valve Stenosis
Pathological Conditions, Anatomical
Proteostasis Deficiencies
Metabolic Diseases
Heart Valve Diseases
Heart Diseases
Cardiovascular Diseases
Ventricular Outflow Obstruction