<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03029026</url>
  </required_header>
  <id_info>
    <org_study_id>006974</org_study_id>
    <nct_id>NCT03029026</nct_id>
  </id_info>
  <brief_title>The Role of Occult Cardiac Amyloid in the Elderly With Aortic Stenosis.</brief_title>
  <acronym>ATTRact-AS</acronym>
  <official_title>A sTudy invesTigating the Role of Occult cArdiaC Amyloid in The Elderly With Aortic Stenosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Queen Mary University of London</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Queen Mary University of London</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Aortic stenosis (AS) is the most common valvular heart disease. Once symptomatic with severe&#xD;
      AS, outcome is poor unless the valve is replaced surgically or via transcatheter aortic valve&#xD;
      replacement (TAVR). Transthyretin amyloid (ATTR) deposits are common in the heart muscle in&#xD;
      up to 25% of octogenarians, and after an asymptomatic period of unknown duration, cause overt&#xD;
      heart failure and arrhythmias in a proportion of cases. The prevalence and impact of covert&#xD;
      ATTR amyloidosis in elderly individuals with AS are unknown. Detection would avoid&#xD;
      misdiagnosis, guide treatment and, potentially, improve outcomes. Recent data have shown that&#xD;
      echocardiography, cardiovascular magnetic resonance (CMR), computed tomography (CT), and DPD&#xD;
      scintigraphy, can identify ATTR amyloid deposits, but the clinical performance of these&#xD;
      various tests is unknown.&#xD;
&#xD;
      This study will investigate elderly patients with symptomatic severe AS using imaging to&#xD;
      explore ATTR amyloid in AS and determine its prevalence and impact on outcome.&#xD;
&#xD;
      The investigators aim to recruit a total of 250 patients aged 75 or older being considered&#xD;
      for intervention for severe AS. The prevalence of cardiac amyloid will be assessed in three&#xD;
      arms (sAVR, TAVI and medical therapy, with a likely patient ratio of 50:150:50), using five&#xD;
      investigation modalities - all cohorts (echocardiography and DPD scintigraphy); sAVR cohort&#xD;
      (biopsy and CMR); TAVI cohort (EqCT); medical therapy only cohort (as per work-up/trial prior&#xD;
      to no intervention decision).&#xD;
&#xD;
      The primary outcome measure is patient mortality. Secondary outcomes measures are major&#xD;
      adverse cardiovascular events, length of stay, pacemaker implantation, ECV measured by EqCT&#xD;
      and CMR.&#xD;
&#xD;
      Follow up will be at 1-year with clinical echocardiogram (for sAVR and TAVI patients) and/or&#xD;
      telephone interview for all patients (if not carried out in person at the time of the&#xD;
      echocardiogram).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      INTRODUCTION&#xD;
&#xD;
      Calcific aortic stenosis (AS) is the most common valve disease in the West with a prevalence&#xD;
      of 2.8% in patients over 75 years. Once symptomatic with severe AS, outcome is poor, unless&#xD;
      the valve is replaced surgically (sAVR) or via transcatheter aortic valve replacement (TAVR),&#xD;
      which is predominantly used in elderly patients for whom surgery is deemed too high risk.&#xD;
&#xD;
      Systemic amyloidosis is a multisystem disease characterised by extracellular deposition of&#xD;
      abnormally folded protein, which over time results in progressive organ dysfunction. These&#xD;
      protein deposits bind Congo red stain, producing the pathognomonic apple-green birefringence&#xD;
      under polarised light. Cardiac involvement is the leading cause of morbidity and mortality in&#xD;
      these patients. Amyloidosis due to transthyretin deposition (ATTR) can be due to wild-type&#xD;
      transthyretin amyloid deposits, also known as senile systemic amyloidosis, which&#xD;
      predominantly accumulates in the heart. Primary light chain (AL) amyloidosis and hereditary&#xD;
      transthyretin amyloidosis can also affect the heart.&#xD;
&#xD;
      Wild-type ATTR (wtATTR) amyloid deposition is present in up to a 25% of individuals aged over&#xD;
      85 at autopsy. To date, this has been no more than an academic observation, but technology is&#xD;
      changing this: cardiac imaging, particularly cardiovascular magnetic resonance (CMR) and&#xD;
      99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy, can now detect the&#xD;
      disease antemortem, which is generating a major increase in national awareness. There are&#xD;
      also significant advances being made in the treatment of amyloidosis. There are several drugs&#xD;
      in clinical trial including novel antisense and interfering RNA therapeutics that can reduce&#xD;
      production of TTR by up to 80-90%. Also on the horizon are treatments to promote clearance of&#xD;
      established amyloid, notably including monoclonal anti-SAP (serum amyloid P component)&#xD;
      antibodies. Despite the prevalence of wtATTR amyloid deposits at autopsy, their clinical&#xD;
      significance and prognostic impact of in severe AS has not been explored.&#xD;
&#xD;
      Co-existent cardiac amyloid and AS. Given the prevalence of wtATTR in octogenarians at&#xD;
      autopsy, AS and wtATTR are likely to co-exist - the literature has early evidence for this.&#xD;
      In a cohort of 20 patients with AS, who had undergone TAVI and subsequently valve&#xD;
      explantation at autopsy (n=17) or surgery (n=3), cardiac amyloid was found in a third of&#xD;
      these patients and was thought to contribute to death in the majority. Our research also&#xD;
      supports this - the &quot;RELIEF-AS&quot; study. In 146 patients with severe AS undergoing sAVR, we&#xD;
      found cardiac amyloid deposits in 6 patients. All were wtATTR, all calcific AS, with the&#xD;
      youngest patient being aged 69. Comprehensive imaging was performed, which showed a&#xD;
      diagnostic imaging hierarchy: echocardiography was non-contributory, CMR detected a third of&#xD;
      cases, whereas DPD scintigraphy was positive in all four patients scanned (2 died before the&#xD;
      test). Biopsy ATTR deposits were prognostic and the strongest predictor of adverse outcome -&#xD;
      regardless of infiltration degree or its imaging detection: post sAVR 50% with wtATTR died by&#xD;
      1 year vs 9% without (p&lt;0.001). Occult amyloid has also been implicated in the need for&#xD;
      pacemakers in TAVR patients.&#xD;
&#xD;
      The availability of TAVI has extended the range of individuals that can benefit from&#xD;
      intervention for AS, prolonging life. TAVR patients are generally older so more likely to&#xD;
      have wtATTR. One recent abstract found a 16% (23% in men) prevalence of cardiac amyloid in in&#xD;
      patients undergoing TAVR (n=75) using 99mTc-pyrophosphate scintigraphy (PYP, a bone tracer&#xD;
      available in the USA, which is possibly inferior to DPD). WtATTR is also an increasingly&#xD;
      recognized cause of heart failure with preserved ejection fraction (HFpEF). DPD scintigraphy&#xD;
      in 120 hospitalized patients who also had LV wall thickness ≥12 mm and an EF ≥50%, showed&#xD;
      that 16 patients (13.3%) showed moderate to severe myocardial uptake.&#xD;
&#xD;
      Why detect wtTTR amyloid in severe AS? There are two separate aspects of wtATTR in AS. First,&#xD;
      wtATTR in patients with moderate AS may mimic severe AS, (particularly low-flow,&#xD;
      low-gradient) causing misdiagnosis. Second, wtATTR may itself be a disease modifier, leading&#xD;
      to a more severe phenotype with more heart failure, arrhythmia, and higher mortality. We&#xD;
      think there is a large, now detectable, UK population of elderly patients undergoing sAVR or&#xD;
      TAVR with a significant occult amyloid. This could influence therapeutic options (TAVR vs&#xD;
      sAVR vs medical therapy), intervention timing and medications - specific amyloid therapies,&#xD;
      drugs to avoid (e.g. digoxin and diltiazem).&#xD;
&#xD;
      How to detect wtATTR? There are multiple techniques that could detect cardiac wtATTR. Each&#xD;
      has their pros and cons with different evidence bases. Our initial study used three imaging&#xD;
      modalities and biopsy to detect the presence of cardiac amyloid in sAVR. DPD scintigraphy was&#xD;
      the superior imaging modality, with the highest diagnostic sensitivity. There is now a&#xD;
      rapidly growing body of evidence supporting DPD scintigraphy as the non-invasive&#xD;
      investigation of choice for diagnosing cardiac ATTR. A recent multi-centre study of over&#xD;
      1,000 patients showed that bone scintigraphy had a &gt;99% sensitivity for cardiac ATTR deposits&#xD;
      and they proposed it should have a role in diagnosing the condition without the need for&#xD;
      invasive cardiac biopsy, which has previously been considered the gold standard.&#xD;
&#xD;
      The investigators have recently created a new modality: equilibrium contrast computed&#xD;
      tomography (EqCT), which requires a single extra image dataset of the heart to be taken 5&#xD;
      minutes after the routine TAVR work-up CT images are taken. Extracellular volume fraction&#xD;
      (ECV) calculated by EqCT discriminated 100% between cardiac amyloid involvement and patients&#xD;
      with AS in 53 patients.&#xD;
&#xD;
      TRIAL OBJECTIVES&#xD;
&#xD;
      Hypothesis:&#xD;
&#xD;
      In the elderly with severe AS being considered for intervention (TAVR, sAVR), wtATTR is:&#xD;
&#xD;
        -  Common.&#xD;
&#xD;
        -  Conveys a worse prognosis.&#xD;
&#xD;
        -  Can be reliably detected non-invasively.&#xD;
&#xD;
      Aim:&#xD;
&#xD;
      To confirm the prevalence, clinical impact (procedural complications, symptom response to&#xD;
      aortic valve replacement, 1-year mortality) and potential place of imaging (DPD scintigraphy,&#xD;
      ECV by CT, CMR and echocardiography) in occult amyloid in severe AS.&#xD;
&#xD;
      STUDY PLAN&#xD;
&#xD;
      Design: prospective observational cohort with 1 year follow-up.&#xD;
&#xD;
      Population: patients aged 75 or older with severe AS referred to the Barts Heart Centre for&#xD;
      consideration for intervention (sAVR or TAVR) or referred to the John Radcliffe Hospital in&#xD;
      Oxford for consideration for TAVR.&#xD;
&#xD;
      Proposed sample size: two centre study (Barts Heart Centre and the John Radcliffe Hospital),&#xD;
      250 patients.&#xD;
&#xD;
      Recruitment: patients will be recruited from General Cardiology, TAVR and Cardiothoracic&#xD;
      Surgery Outpatient Clinics. A large proportion of these patients are discussed in the Valve&#xD;
      Multidisciplinary Team Meeting, which will provide another source of recruitment. This will&#xD;
      take place over an 18-month period from August 2016 to February 2018.&#xD;
&#xD;
      Baseline assessment: will include clinical history, Quality of Life Questionnaire&#xD;
      (EQ-5D/SF-12), a 6-minute-walk test, blood sampling for haematocrit, renal function,&#xD;
      biomarkers (NT-pro-BNP and troponin), and biobanking (also for AL exclusions if scanning&#xD;
      positive), a urine sample for biobanking (also for AL exclusion if scanning positive), as&#xD;
      well as tests performed as the routine pre-operative work-up (clinical electrocardiogram,&#xD;
      blood pressure to estimate global LV afterload, valvulo-arterial impedance).&#xD;
&#xD;
      Measures of exposure: the prevalence of cardiac amyloid assessed in three arms (sAVR, TAVI&#xD;
      and medical therapy, with a likely patient ratio of 50:150:50), using five investigation&#xD;
      modalities - all cohorts (echocardiography and DPD scintigraphy); sAVR cohort (biopsy and&#xD;
      CMR); TAVR cohort (EqCT); medical therapy only cohort (as per work-up/trial prior to no&#xD;
      intervention decision).&#xD;
&#xD;
      Follow-up: 1-year follow-up with clinical echocardiogram (for sAVR and TAVR patients) and/or&#xD;
      telephone interview for all patients (if not carried out in person at the time of the&#xD;
      echocardiogram). This will include a follow up Quality of Life Questionnaire as per baseline.&#xD;
      If attending clinic or echocardiogram a 6-minute-walk test will also be performed. MACE and&#xD;
      mortality endpoints will also be identified.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>September 2016</start_date>
  <completion_date type="Anticipated">April 2019</completion_date>
  <primary_completion_date type="Anticipated">April 2019</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Patient mortality</measure>
    <time_frame>1-year</time_frame>
    <description>From patient notes, GP records or Office of National Statistics.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Major adverse cardiovascular events (MACE)</measure>
    <time_frame>1-year</time_frame>
    <description>From patient's medical records. Includes for example: cardiac death, myocardial infarction and emergency cardiac surgery or intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of hospital stay</measure>
    <time_frame>1-year</time_frame>
    <description>From patient's medical records</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pacemaker implantation</measure>
    <time_frame>1-year</time_frame>
    <description>From patient's medical records</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Outcome of the various cardiac imaging modalities</measure>
    <time_frame>1-year</time_frame>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Anticipated">250</enrollment>
  <condition>Cardiac Amyloidosis</condition>
  <condition>Aortic Stenosis</condition>
  <arm_group>
    <arm_group_label>Those patients for TAVR</arm_group_label>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Those patients for sAVR</arm_group_label>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Those patients for medical management</arm_group_label>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Baseline assessment</intervention_name>
    <description>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).</description>
    <arm_group_label>Those patients for TAVR</arm_group_label>
    <arm_group_label>Those patients for medical management</arm_group_label>
    <arm_group_label>Those patients for sAVR</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Transthoracic echocardiography</intervention_name>
    <description>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.&#xD;
Severe AS will be defined using standard echocardiography guidelines in conjunction with MDT consensus.</description>
    <arm_group_label>Those patients for TAVR</arm_group_label>
    <arm_group_label>Those patients for medical management</arm_group_label>
    <arm_group_label>Those patients for sAVR</arm_group_label>
    <other_name>Echo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy</intervention_name>
    <description>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.</description>
    <arm_group_label>Those patients for TAVR</arm_group_label>
    <arm_group_label>Those patients for medical management</arm_group_label>
    <arm_group_label>Those patients for sAVR</arm_group_label>
    <other_name>DPD scintigraphy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>CT 3-5-minute post-contrast research sequences</intervention_name>
    <description>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.</description>
    <arm_group_label>Those patients for TAVR</arm_group_label>
    <other_name>ECV by CT</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Cardiac Magnetic Resonance</intervention_name>
    <description>CMR will be performed using a 1.5-T Aera for standard late gadolinium enhancement, as well as T1 mapping and ECV.</description>
    <arm_group_label>Those patients for sAVR</arm_group_label>
    <other_name>CMR</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Endomyocardial biopsy</intervention_name>
    <description>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).</description>
    <arm_group_label>Those patients for sAVR</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Follow-up assessment</intervention_name>
    <description>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.</description>
    <arm_group_label>Those patients for TAVR</arm_group_label>
    <arm_group_label>Those patients for medical management</arm_group_label>
    <arm_group_label>Those patients for sAVR</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood and urine samples will be biobanked for all patients (n=250). Endomyocardial biopsy&#xD;
      specimens will be snap frozen and biobanked for those patients undergoing sAVR (n=50).&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients with symptomatic severe AS being considered for intervention.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Aged 75 or above&#xD;
&#xD;
          -  Severe aortic stenosis being considered for intervention&#xD;
&#xD;
          -  Patient informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Unable to provide informed consent&#xD;
&#xD;
          -  Patient declined or withdrew consent (at any stage)&#xD;
&#xD;
          -  Imaging modality specific contraindications:&#xD;
&#xD;
               1. Being considered for sAVR, however unsuitable for study CMR due to&#xD;
                  contraindications such as a device in situ, severe claustrophobia, renal&#xD;
                  impairment (eGFR &lt;30) or previous severe gadolinium contrast allergy.&#xD;
&#xD;
               2. Being considered for TAVR work-up CT, however unsuitable for contrast due to&#xD;
                  previous severe iodinated contrast allergy. NB patients with significant renal&#xD;
                  impairment are given pre-hydration routinely by the managing clinicians.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>75 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Paul R Scully, MBBS MRes</last_name>
    <phone>020 3465 6115</phone>
    <email>paul.scully@bartshealth.nhs.uk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>James C Moon, MD</last_name>
    <phone>020 3465 6115</phone>
    <email>james.moon@bartshealth.nhs.uk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Barts Heart Centre</name>
      <address>
        <city>London</city>
        <zip>EC1A 7BE</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Paul R Scully, MBBS MRes</last_name>
      <phone>020 3465 6115</phone>
      <email>paul.scully@bartshealth.nhs.uk</email>
    </contact>
    <contact_backup>
      <last_name>James C Moon, MD</last_name>
      <phone>020 3465 6115</phone>
      <email>james.moon@bartshealth.nhs.uk</email>
    </contact_backup>
    <investigator>
      <last_name>Francesca Pugliese, MD PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Paul R Scully, MBBS MRes</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>James C Moon, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Philip N Hawkins, FMedSci</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Leon J Menezes, BA BM BCh</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Thomas A Treibel</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Mike Mullen</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Guy Lloyd</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Christopher G McGregor</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>The John Radcliffe Hospital</name>
      <address>
        <city>Oxford</city>
        <zip>OX3 9DU</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ellie Corps</last_name>
      <phone>01865 223349</phone>
    </contact>
    <investigator>
      <last_name>Andrew Kelion</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Nikant Sabharwal</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Jim Newton</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <reference>
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    <PMID>8459080</PMID>
  </reference>
  <reference>
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    <PMID>10716479</PMID>
  </reference>
  <reference>
    <citation>Banypersad SM, Moon JC, Whelan C, Hawkins PN, Wechalekar AD. Updates in cardiac amyloidosis: a review. J Am Heart Assoc. 2012 Apr;1(2):e000364. doi: 10.1161/JAHA.111.000364. Epub 2012 Apr 24. No abstract available.</citation>
    <PMID>23130126</PMID>
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  <reference>
    <citation>Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation. 2005 Sep 27;112(13):2047-60. doi: 10.1161/CIRCULATIONAHA.104.489187. No abstract available.</citation>
    <PMID>16186440</PMID>
  </reference>
  <reference>
    <citation>Tanskanen M, Peuralinna T, Polvikoski T, Notkola IL, Sulkava R, Hardy J, Singleton A, Kiuru-Enari S, Paetau A, Tienari PJ, Myllykangas L. Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study. Ann Med. 2008;40(3):232-9. doi: 10.1080/07853890701842988.</citation>
    <PMID>18382889</PMID>
  </reference>
  <reference>
    <citation>Coelho T, Adams D, Silva A, Lozeron P, Hawkins PN, Mant T, Perez J, Chiesa J, Warrington S, Tranter E, Munisamy M, Falzone R, Harrop J, Cehelsky J, Bettencourt BR, Geissler M, Butler JS, Sehgal A, Meyers RE, Chen Q, Borland T, Hutabarat RM, Clausen VA, Alvarez R, Fitzgerald K, Gamba-Vitalo C, Nochur SV, Vaishnaw AK, Sah DW, Gollob JA, Suhr OB. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013 Aug 29;369(9):819-29. doi: 10.1056/NEJMoa1208760.</citation>
    <PMID>23984729</PMID>
  </reference>
  <reference>
    <citation>Ackermann EJ, Guo S, Booten S, Alvarado L, Benson M, Hughes S, Monia BP. Clinical development of an antisense therapy for the treatment of transthyretin-associated polyneuropathy. Amyloid. 2012 Jun;19 Suppl 1:43-4. doi: 10.3109/13506129.2012.673140. Epub 2012 Apr 12.</citation>
    <PMID>22494066</PMID>
  </reference>
  <reference>
    <citation>Richards DB, Cookson LM, Berges AC, Barton SV, Lane T, Ritter JM, Fontana M, Moon JC, Pinzani M, Gillmore JD, Hawkins PN, Pepys MB. Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component. N Engl J Med. 2015 Sep 17;373(12):1106-14. doi: 10.1056/NEJMoa1504942. Epub 2015 Jul 15.</citation>
    <PMID>26176329</PMID>
  </reference>
  <reference>
    <citation>Nietlispach F, Webb JG, Ye J, Cheung A, Lichtenstein SV, Carere RG, Gurvitch R, Thompson CR, Ostry AJ, Matzke L, Allard MF. Pathology of transcatheter valve therapy. JACC Cardiovasc Interv. 2012 May;5(5):582-590. doi: 10.1016/j.jcin.2012.03.012.</citation>
    <PMID>22625199</PMID>
  </reference>
  <reference>
    <citation>Kim WK, Rolf A, Liebetrau C, Van Linden A, Blumenstein J, Kempfert J, Bachmann G, Nef H, Hamm C, Walther T, Mollmann H. Detection of myocardial injury by CMR after transcatheter aortic valve replacement. J Am Coll Cardiol. 2014 Jul 29;64(4):349-57. doi: 10.1016/j.jacc.2014.03.052.</citation>
    <PMID>25060368</PMID>
  </reference>
  <reference>
    <citation>Castano A, Bokhari S, Maurer MS. Could late enhancement and need for permanent pacemaker implantation in patients undergoing TAVR be explained by undiagnosed transthyretin cardiac amyloidosis? J Am Coll Cardiol. 2015 Jan 27;65(3):311-2. doi: 10.1016/j.jacc.2014.09.084. No abstract available.</citation>
    <PMID>25614433</PMID>
  </reference>
  <reference>
    <citation>Gonzalez-Lopez E, Gallego-Delgado M, Guzzo-Merello G, de Haro-Del Moral FJ, Cobo-Marcos M, Robles C, Bornstein B, Salas C, Lara-Pezzi E, Alonso-Pulpon L, Garcia-Pavia P. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J. 2015 Oct 7;36(38):2585-94. doi: 10.1093/eurheartj/ehv338. Epub 2015 Jul 28.</citation>
    <PMID>26224076</PMID>
  </reference>
  <reference>
    <citation>Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, Wechalekar AD, Berk JL, Quarta CC, Grogan M, Lachmann HJ, Bokhari S, Castano A, Dorbala S, Johnson GB, Glaudemans AW, Rezk T, Fontana M, Palladini G, Milani P, Guidalotti PL, Flatman K, Lane T, Vonberg FW, Whelan CJ, Moon JC, Ruberg FL, Miller EJ, Hutt DF, Hazenberg BP, Rapezzi C, Hawkins PN. Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. Circulation. 2016 Jun 14;133(24):2404-12. doi: 10.1161/CIRCULATIONAHA.116.021612. Epub 2016 Apr 22.</citation>
    <PMID>27143678</PMID>
  </reference>
  <reference>
    <citation>Treibel TA, Bandula S, Fontana M, White SK, Gilbertson JA, Herrey AS, Gillmore JD, Punwani S, Hawkins PN, Taylor SA, Moon JC. Extracellular volume quantification by dynamic equilibrium cardiac computed tomography in cardiac amyloidosis. J Cardiovasc Comput Tomogr. 2015 Nov-Dec;9(6):585-92. doi: 10.1016/j.jcct.2015.07.001. Epub 2015 Jul 10.</citation>
    <PMID>26209459</PMID>
  </reference>
  <reference>
    <citation>Perugini E, Guidalotti PL, Salvi F, Cooke RM, Pettinato C, Riva L, Leone O, Farsad M, Ciliberti P, Bacchi-Reggiani L, Fallani F, Branzi A, Rapezzi C. Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. J Am Coll Cardiol. 2005 Sep 20;46(6):1076-84. doi: 10.1016/j.jacc.2005.05.073.</citation>
    <PMID>16168294</PMID>
  </reference>
  <verification_date>November 2016</verification_date>
  <study_first_submitted>January 9, 2017</study_first_submitted>
  <study_first_submitted_qc>January 19, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 24, 2017</study_first_posted>
  <last_update_submitted>April 17, 2018</last_update_submitted>
  <last_update_submitted_qc>April 17, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">April 19, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Cardiac amyloidosis</keyword>
  <keyword>Aortic stenosis</keyword>
  <keyword>DPD scintigraphy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aortic Valve Stenosis</mesh_term>
    <mesh_term>Amyloidosis</mesh_term>
    <mesh_term>Constriction, Pathologic</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03029026
org study id: 006974
nct id: NCT03029026
lead sponsor: 
has dmc: No
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.
observational model: Cohort
time perspective: Prospective
measure: Patient mortality
time frame: 1-year
description: From patient notes, GP records or Office of National Statistics.
measure: Major adverse cardiovascular events (MACE)
time frame: 1-year
description: From patient's medical records. Includes for example: cardiac death, myocardial infarction and emergency cardiac surgery or intervention.
measure: Length of hospital stay
time frame: 1-year
description: From patient's medical records
measure: Pacemaker implantation
time frame: 1-year
description: From patient's medical records
measure: Outcome of the various cardiac imaging modalities
time frame: 1-year
arm group label: Those patients for TAVR
description: 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.
arm group label: Those patients for sAVR
description: 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.
arm group label: Those patients for medical management
description: 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.
intervention type: Other
intervention name: Baseline assessment
description: 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).
arm group label: Those patients for TAVR
arm group label: Those patients for medical management
arm group label: Those patients for sAVR
intervention type: Procedure
intervention name: Transthoracic echocardiography
description: 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.
arm group label: Those patients for TAVR
arm group label: Those patients for medical management
arm group label: Those patients for sAVR
other name: Echo
intervention type: Procedure
intervention name: 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy
description: 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.
arm group label: Those patients for TAVR
arm group label: Those patients for medical management
arm group label: Those patients for sAVR
other name: DPD scintigraphy
intervention type: Radiation
intervention name: CT 3-5-minute post-contrast research sequences
description: 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.
arm group label: Those patients for TAVR
other name: ECV by CT
intervention type: Procedure
intervention name: Cardiac Magnetic Resonance
description: CMR will be performed using a 1.5-T Aera for standard late gadolinium enhancement, as well as T1 mapping and ECV.
arm group label: Those patients for sAVR
other name: CMR
intervention type: Procedure
intervention name: Endomyocardial biopsy
description: 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).
arm group label: Those patients for sAVR
intervention type: Other
intervention name: Follow-up assessment
description: 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.
arm group label: Those patients for TAVR
arm group label: Those patients for medical management
arm group label: Those patients for sAVR
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).
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 75 Years
maximum age: N/A
healthy volunteers: No
last name: Paul R Scully, MBBS MRes
phone: 020 3465 6115
email: paul.scully@bartshealth.nhs.uk
last name: James C Moon, MD
phone: 020 3465 6115
email: james.moon@bartshealth.nhs.uk
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
investigator: 
country: United Kingdom
citation: Lindroos M, Kupari M, Heikkila J, Tilvis R. Prevalence of aortic valve abnormalities in the elderly: an echocardiographic study of a random population sample. J Am Coll Cardiol. 1993 Apr;21(5):1220-5. doi: 10.1016/0735-1097(93)90249-z.
PMID: 8459080
citation: Kvidal P, Bergstrom R, Horte LG, Stahle E. Observed and relative survival after aortic valve replacement. J Am Coll Cardiol. 2000 Mar 1;35(3):747-56. doi: 10.1016/s0735-1097(99)00584-7.
PMID: 10716479
citation: Banypersad SM, Moon JC, Whelan C, Hawkins PN, Wechalekar AD. Updates in cardiac amyloidosis: a review. J Am Heart Assoc. 2012 Apr;1(2):e000364. doi: 10.1161/JAHA.111.000364. Epub 2012 Apr 24. No abstract available.
PMID: 23130126
citation: Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation. 2005 Sep 27;112(13):2047-60. doi: 10.1161/CIRCULATIONAHA.104.489187. No abstract available.
PMID: 16186440
citation: Tanskanen M, Peuralinna T, Polvikoski T, Notkola IL, Sulkava R, Hardy J, Singleton A, Kiuru-Enari S, Paetau A, Tienari PJ, Myllykangas L. Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study. Ann Med. 2008;40(3):232-9. doi: 10.1080/07853890701842988.
PMID: 18382889
citation: Coelho T, Adams D, Silva A, Lozeron P, Hawkins PN, Mant T, Perez J, Chiesa J, Warrington S, Tranter E, Munisamy M, Falzone R, Harrop J, Cehelsky J, Bettencourt BR, Geissler M, Butler JS, Sehgal A, Meyers RE, Chen Q, Borland T, Hutabarat RM, Clausen VA, Alvarez R, Fitzgerald K, Gamba-Vitalo C, Nochur SV, Vaishnaw AK, Sah DW, Gollob JA, Suhr OB. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013 Aug 29;369(9):819-29. doi: 10.1056/NEJMoa1208760.
PMID: 23984729
citation: Ackermann EJ, Guo S, Booten S, Alvarado L, Benson M, Hughes S, Monia BP. Clinical development of an antisense therapy for the treatment of transthyretin-associated polyneuropathy. Amyloid. 2012 Jun;19 Suppl 1:43-4. doi: 10.3109/13506129.2012.673140. Epub 2012 Apr 12.
PMID: 22494066
citation: Richards DB, Cookson LM, Berges AC, Barton SV, Lane T, Ritter JM, Fontana M, Moon JC, Pinzani M, Gillmore JD, Hawkins PN, Pepys MB. Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component. N Engl J Med. 2015 Sep 17;373(12):1106-14. doi: 10.1056/NEJMoa1504942. Epub 2015 Jul 15.
PMID: 26176329
citation: Nietlispach F, Webb JG, Ye J, Cheung A, Lichtenstein SV, Carere RG, Gurvitch R, Thompson CR, Ostry AJ, Matzke L, Allard MF. Pathology of transcatheter valve therapy. JACC Cardiovasc Interv. 2012 May;5(5):582-590. doi: 10.1016/j.jcin.2012.03.012.
PMID: 22625199
citation: Kim WK, Rolf A, Liebetrau C, Van Linden A, Blumenstein J, Kempfert J, Bachmann G, Nef H, Hamm C, Walther T, Mollmann H. Detection of myocardial injury by CMR after transcatheter aortic valve replacement. J Am Coll Cardiol. 2014 Jul 29;64(4):349-57. doi: 10.1016/j.jacc.2014.03.052.
PMID: 25060368
citation: Castano A, Bokhari S, Maurer MS. Could late enhancement and need for permanent pacemaker implantation in patients undergoing TAVR be explained by undiagnosed transthyretin cardiac amyloidosis? J Am Coll Cardiol. 2015 Jan 27;65(3):311-2. doi: 10.1016/j.jacc.2014.09.084. No abstract available.
PMID: 25614433
citation: Gonzalez-Lopez E, Gallego-Delgado M, Guzzo-Merello G, de Haro-Del Moral FJ, Cobo-Marcos M, Robles C, Bornstein B, Salas C, Lara-Pezzi E, Alonso-Pulpon L, Garcia-Pavia P. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J. 2015 Oct 7;36(38):2585-94. doi: 10.1093/eurheartj/ehv338. Epub 2015 Jul 28.
PMID: 26224076
citation: Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, Wechalekar AD, Berk JL, Quarta CC, Grogan M, Lachmann HJ, Bokhari S, Castano A, Dorbala S, Johnson GB, Glaudemans AW, Rezk T, Fontana M, Palladini G, Milani P, Guidalotti PL, Flatman K, Lane T, Vonberg FW, Whelan CJ, Moon JC, Ruberg FL, Miller EJ, Hutt DF, Hazenberg BP, Rapezzi C, Hawkins PN. Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. Circulation. 2016 Jun 14;133(24):2404-12. doi: 10.1161/CIRCULATIONAHA.116.021612. Epub 2016 Apr 22.
PMID: 27143678
citation: Treibel TA, Bandula S, Fontana M, White SK, Gilbertson JA, Herrey AS, Gillmore JD, Punwani S, Hawkins PN, Taylor SA, Moon JC. Extracellular volume quantification by dynamic equilibrium cardiac computed tomography in cardiac amyloidosis. J Cardiovasc Comput Tomogr. 2015 Nov-Dec;9(6):585-92. doi: 10.1016/j.jcct.2015.07.001. Epub 2015 Jul 10.
PMID: 26209459
citation: Perugini E, Guidalotti PL, Salvi F, Cooke RM, Pettinato C, Riva L, Leone O, Farsad M, Ciliberti P, Bacchi-Reggiani L, Fallani F, Branzi A, Rapezzi C. Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. J Am Coll Cardiol. 2005 Sep 20;46(6):1076-84. doi: 10.1016/j.jacc.2005.05.073.
PMID: 16168294
responsible party type: Sponsor
mesh term: Aortic Valve Stenosis
mesh term: Amyloidosis
mesh term: Constriction, Pathologic