Aortic Stenosis and Cardiac Amyloidosis

Aortic Stenosis and Cardiac Amyloidosis: A Pragmatic, Streamlined International

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

1. thorough characterization of this condition
2. assessment of log-term clinical outcomes of AS-CA
3. assessment of effectiveness of amyloid-specific treatment on top of valve replacement

Study Overview

• Status: Recruiting
• Conditions: Aortic Stenosis; Cardiac Amyloidosis
• Intervention / Treatment: Other: No amyloid-specific treatment; Drug: Amyloid-specific treatment

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 300

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Recruiting
    • Medical University of Vienna
    • Contact: Christian Nitsche, MD, PhD; Phone Number: 01 40400 46142; Email: christian.nitsche@meduniwien.ac.at
• United Kingdom
  • London, United Kingdom
    • Recruiting
    • University College London
    • Contact: Thomas Treibel, MD, PhD; Phone Number: 020 3386 9000; Email: thomas.treibel.12@ucl.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with a dual pathology of significant aortic stenosis and concomitant cardiac amyloidosis

Description

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)

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
AS-CA without amyloid-specific treatment; Patients with no amyloid-specific treatment	Other: No amyloid-specific treatment; No amyloid-specific treatment
AS-CA with amyloid-specific treatment; Patients receiving newly available amyloid-specific drugs	Drug: Amyloid-specific treatment; Amyloid-specific treatment

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Collaborators: Medical University of South Carolina; IRCCS Azienda Ospedaliero-Universitaria di Bologna; Columbia University; University of Trieste; Royal Free Hospital NHS Foundation Trust; Wolfson Medical Center; Université Catholique de Louvain; Laval University; Allina Health System; Vilnius University Hospital Santaros Klinikos

Publications and helpful links

General Publications

• Nitsche C, Scully PR, Patel KP, Kammerlander AA, Koschutnik M, Dona C, Wollenweber T, Ahmed N, Thornton GD, Kelion AD, Sabharwal N, Newton JD, Ozkor M, Kennon S, Mullen M, Lloyd G, Fontana M, Hawkins PN, Pugliese F, Menezes LJ, Moon JC, Mascherbauer J, Treibel TA. Prevalence and Outcomes of Concomitant Aortic Stenosis and Cardiac Amyloidosis. J Am Coll Cardiol. 2021 Jan 19;77(2):128-139. doi: 10.1016/j.jacc.2020.11.006. Epub 2020 Nov 9.
• Nitsche C, Aschauer S, Kammerlander AA, Schneider M, Poschner T, Duca F, Binder C, Koschutnik M, Stiftinger J, Goliasch G, Siller-Matula J, Winter MP, Anvari-Pirsch A, Andreas M, Geppert A, Beitzke D, Loewe C, Hacker M, Agis H, Kain R, Lang I, Bonderman D, Hengstenberg C, Mascherbauer J. Light-chain and transthyretin cardiac amyloidosis in severe aortic stenosis: prevalence, screening possibilities, and outcome. Eur J Heart Fail. 2020 Oct;22(10):1852-1862. doi: 10.1002/ejhf.1756. Epub 2020 Feb 20.
• Nitsche C, Koschutnik M, Dona C, Radun R, Mascherbauer K, Kammerlander A, Heitzinger G, Dannenberg V, Spinka G, Halavina K, Winter MP, Calabretta R, Hacker M, Agis H, Rosenhek R, Bartko P, Hengstenberg C, Treibel T, Mascherbauer J, Goliasch G. Reverse Remodeling Following Valve Replacement in Coexisting Aortic Stenosis and Transthyretin Cardiac Amyloidosis. Circ Cardiovasc Imaging. 2022 Jul;15(7):e014115. doi: 10.1161/CIRCIMAGING.122.014115. Epub 2022 Jul 8.
• Patel KP, Scully PR, Nitsche C, Kammerlander AA, Joy G, Thornton G, Hughes R, Williams S, Tillin T, Captur G, Chacko L, Kelion A, Sabharwal N, Newton JD, Kennon S, Ozkor M, Mullen M, Hawkins PN, Gillmore JD, Menezes L, Pugliese F, Hughes AD, Fontana M, Lloyd G, Treibel TA, Mascherbauer J, Moon JC. Impact of afterload and infiltration on coexisting aortic stenosis and transthyretin amyloidosis. Heart. 2022 Jan;108(1):67-72. doi: 10.1136/heartjnl-2021-319922. Epub 2021 Sep 8.
• Scully PR, Patel KP, Saberwal B, Klotz E, Augusto JB, Thornton GD, Hughes RK, Manisty C, Lloyd G, Newton JD, Sabharwal N, Kelion A, Kennon S, Ozkor M, Mullen M, Hartman N, Cavalcante JL, Menezes LJ, Hawkins PN, Treibel TA, Moon JC, Pugliese F. Identifying Cardiac Amyloid in Aortic Stenosis: ECV Quantification by CT in TAVR Patients. JACC Cardiovasc Imaging. 2020 Oct;13(10):2177-2189. doi: 10.1016/j.jcmg.2020.05.029. Epub 2020 Aug 5.
• Scully PR, Patel KP, Treibel TA, Thornton GD, Hughes RK, Chadalavada S, Katsoulis M, Hartman N, Fontana M, Pugliese F, Sabharwal N, Newton JD, Kelion A, Ozkor M, Kennon S, Mullen M, Lloyd G, Menezes LJ, Hawkins PN, Moon JC. Prevalence and outcome of dual aortic stenosis and cardiac amyloid pathology in patients referred for transcatheter aortic valve implantation. Eur Heart J. 2020 Aug 1;41(29):2759-2767. doi: 10.1093/eurheartj/ehaa170.
• Treibel TA, Fontana M, Gilbertson JA, Castelletti S, White SK, Scully PR, Roberts N, Hutt DF, Rowczenio DM, Whelan CJ, Ashworth MA, Gillmore JD, Hawkins PN, Moon JC. Occult Transthyretin Cardiac Amyloid in Severe Calcific Aortic Stenosis: Prevalence and Prognosis in Patients Undergoing Surgical Aortic Valve Replacement. Circ Cardiovasc Imaging. 2016 Aug;9(8):e005066. doi: 10.1161/CIRCIMAGING.116.005066.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2023
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: November 2, 2023
• First Submitted That Met QC Criteria: November 8, 2023
• First Posted (Estimated): November 13, 2023

Study Record Updates

• Last Update Posted (Estimated): November 13, 2023
• Last Update Submitted That Met QC Criteria: November 8, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Metabolic Diseases; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Ventricular Outflow Obstruction; Proteostasis Deficiencies; Aortic Valve Stenosis; Amyloidosis; Constriction, Pathologic
• Other Study ID Numbers: 2218_2016

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No