Aortic Stenosis and Cardiac Amyloidosis

Study Overview
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Brief Summary
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The dual pathology of aortic stenosis (AS) and cardiac amyloidosis (CA) is increasingly recognized. Even tough efforts have been undertaken to bring cohorts together, the largest cohort of AS-ATTR to date is <50 patients. It is the aim of the present international, multi-center registry to collect  300 patients with AS-CA creating a big enough cohort to allow thorough characterization of this condition assessment of log-term clinical outcomes of AS-CA assessment of effectiveness of amyloid-specific treatment on top of valve replacement

Detailed Description
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Calcific aortic stenosis (AS) and transthyretin (ATTR) cardiac amyloidosis are both conditions commonly affecting the elderly. Bone scintigraphy using amyloid-avid tracers (99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid, DPD; 99mTc-pyrophosphate; or 99mTc-hydroxymethylene diphosphonate) represents the key imaging modality for non-invasive ATTR diagnosis. Recent studies have used this technology to screen AS patients and demonstrated that AS and ATTR may coexist in 8 to 16%. This is substantially higher than in non-cardiac referrals for bone scintigraphy (range 1-3% in individuals >80 years), which is considered the most accurate approach to estimate the ATTR prevalence in the general population. While the dual burden of AS and ATTR might suggest adverse prognostic implications, it has been shown that AS-ATTR and lone AS patients benefit equally from transcatheter aortic valve replacement (TAVR) with comparable 1- and 2-year survival rates. Yet, data on long-term outcomes are still missing. With increased recognition and valvular treatment of AS-ATTR, the disease course after TAVR becomes a key issue. Our data suggest significantly different remodeling between lone AS and AS-ATTR, with the latter being transformed into a lone-ATTR cardiomyopathy phenotype at one-year post-TAVR. Novel ATTR-specific treatments are now available, with the potential to further improve prognosis in AS-ATTR on top of valvular replacement. However, patients with significant AS were not included in the ATTR-ACT trial, and treatment effectiveness in this patient population therefore remains unclear. Also, despite increased ATTR screening globally, the case numbers for dual AS-ATTR of individual centers are still low. The present international multi-center study is therefore designed to provide detailed characterization of dual AS-ATTR, inform about long-term clinical outcomes and assess the effect of ATTR specific treatment.

Official Title
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Aortic Stenosis and Cardiac Amyloidosis: A Pragmatic, Streamlined International

Conditions
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Cardiac Amyloidosis, Aortic Stenosis

Intervention / Treatment
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* Drug: Amyloid-specific treatment
* Other: No amyloid-specific treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with significant AS and a concomitant diagnosis of cardiac amyloidosis who are eligible for inclusion as per local permissions Exclusion Criteria: Patients without significant AS (less than moderate AS) Patients with other subtypes of cardiac amyloidosis (e.g., light chain)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| AS-CA without amyloid-specific treatment<br>Patients with no amyloid-specific treatment | Other: No amyloid-specific treatment<br>* No amyloid-specific treatment<br>|
| AS-CA with amyloid-specific treatment<br>Patients receiving newly available amyloid-specific drugs | Drug: Amyloid-specific treatment<br>* Amyloid-specific treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phenotyping of AS with early ATTR infiltration (DPD grade 1) versus advanced ATTR cardiomyopathy (DPD grade 2/3) | Dual pathology patients with DPD grade 1 will be compared to those with DPD grade 2/3 with regards to symptoms (New York Heart Association functional class), functional capacity (6-Minute walk distance), biomarkers (NT-proBNP and high-sensitive Troponin), and imaging markers on transthoracic echocardiography (e.g., left ventricular ejection fraction, global longitudinal strain, stroke volume index, left ventricular mass). Differences between groups for all of these variables will be analyzed with the Wilcoxon rank sum test. | 0 months | 
| All cause mortality in AS-CA with versus without CA-specific treatment | All-cause mortality analyzed by Cox regression analysis and Kaplan Meier estimates in AS-CA with versus without CA-specific treatment | 60 months | 
| Hospitalization for heart failure in AS-CA with versus without CA-specific treatment | Hospitalization for heart failure analyzed by Cox regression analysis and Kaplan Meier estimates in AS-CA with versus without CA-specific treatment | 60 months | 
| Cardiovascular mortality in AS-CA with versus without CA-specific treatment | Cardiovascular mortality analyzed by Cox regression analysis and Kaplan Meier estimates in AS-CA with versus without CA-specific treatment | 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Natural history of AS-ATTR after valve replacement | Trajectory of morphological (left ventricular mass), functional (ejection fraction, global longitudinal strain, New York Heart Association class) and biomarker (NT-proBNP, high-sensitive Troponin) profiles. Longitudinal changes between visits will be compared using the Wilcoxon signed-rank test, McNemar's test, and the Stuart Maxwell test where appropriate. | 60 months | 
| Composite of hospitalization for heart failure and/or death in AS-CA with versus without CA-specific treatment | Composite of hospitalization for heart failure and/or death analyzed by Cox regression analysis and Kaplan Meier estimates in AS-CA with versus without CA-specific treatment | 60 months | 
| Heart failure hospitalzation rate in AS-CA with versus without CA-specific treatment | Differences in heart failure hospitalization rate, calculated as the number of heart failure hospitalizations per total person-years in AS-CA with versus without CA-specific treatment at 1 and 3 years, analyzed by the poisson model. | 36 months |