# Impact of Tafamidis on survival in elderly patients: Insights from the Healthcare European Amyloidosis Registry

Antoine Jobbé-Duval, Mounira Kharoubi, Erwan Donal, Fabrice Bauer, Amaury Broussier, Arnaud Bisson, Océane Bouchot, Phillipe Charron, Jérôme Costa, Pierre-Yves Courand, et al.

► To cite this version:

Antoine Jobbé-Duval, Mounira Kharoubi, Erwan Donal, Fabrice Bauer, Amaury Broussier, et al. Impact of Tafamidis on survival in elderly patients: Insights from the Healthcare European Amyloidosis Registry. International Journal of Cardiology, 2025, 437, pp.133522. 10.1016/j.ijcard.2025.133522. hal-05134670

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# Impact of Tafamidis on survival in elderly patients: Insights from the Healthcare European Amyloidosis Registry

Antoine Jobbé-Duval<sup>a,b,1,*</sup>, Mounira Kharoubi<sup>c,d,e,1</sup>, Erwan Donal<sup>f,1</sup>, Fabrice Bauer<sup>g,1</sup>, Amaury Broussier<sup>h,i,1</sup>, Arnaud Bisson<sup>j,1</sup>, Océane Bouchot<sup>k,1</sup>, Phillipe Charron<sup>l,ai,aj,1</sup>, Jérôme Costa<sup>m,1</sup>, Pierre-Yves Courand<sup>n,ak,1</sup>, Charlotte Dagrenat<sup>o,1</sup>, François Delelis<sup>p,1</sup>, Jean-Christophe Eicher<sup>q,1</sup>, Antoine Fraix<sup>r,1</sup>, Barnabas Gellen<sup>s,1</sup>, Jean-Pierre Gueffet<sup>t,1</sup>, Gilbert Habib<sup>u,1</sup>, Jocelyn Inamo<sup>v,1</sup>, Julien Jeanneteau<sup>w,1</sup>, Damien Galallois<sup>x,1</sup>, Léa Margerit<sup>y,1</sup>, Basile Mouhat<sup>z,1</sup>, Nicolas Piriou<sup>aa,1</sup>, Tania Puscas<sup>ab,1</sup>, Patricia Réant<sup>ac,1</sup>, François Roubille<sup>ad,1</sup>, Romain Trésorier<sup>ae,1</sup>, Jean-Jacques Von Hunolestein<sup>af,1</sup>, Charles Taieb<sup>ag,1</sup>, Amira Zaroui<sup>c,d,e,1</sup>, Olivier Lairez<sup>ah,1</sup>, Thibaud Damy<sup>c,d,e,1</sup>

<footnote><sup>a</sup> Department of Cardiology, Médipôle Hôpital Mutualiste, 69100 Villeurbanne, France</footnote>

<footnote><sup>b</sup> Department of Cardiology, Hôpital Louis Pradel, Hospices Civil de Lyon, 69500 Bron, France</footnote>

<footnote><sup>c</sup> Department of Cardiology, Referral Center for Cardiac Amyloidosis, Filière Cardiogen, GRC Amyloid Research Institute all at APHP CHU Henri Mondor, 94010 Créteil, France</footnote>

<footnote><sup>d</sup> HEART'S Foundation, 94300 Vincennes, France</footnote>

<footnote><sup>e</sup> Clinical Epidemiology and Ageing (CEpiA) at Henri Mondor University Hospital and Institut National de la Santé et de la Recherche Médicale (INSERM) U955, Institut Henri Mondor University Hospital, F-94010 Créteil, France</footnote>

<footnote><sup>f</sup> University of Rennes, CHU Rennes, Inserm, LTSI - UMR 1099, F-35000 Rennes, France</footnote>

<footnote><sup>g</sup> Department of Cardiology, Hôpital Bicêtre AP-HP, 94270 Le Kremlin-Bicêtre, France</footnote>

<footnote><sup>h</sup> Department of Geriatrics, APHP, Henri Mondor/Emile Roux Hospitals, Limeil-Brevannes, France</footnote>

<footnote><sup>i</sup> University Paris Est Creteil, INSERM, IMRB, F-94010 Creteil, France</footnote>

<footnote><sup>j</sup> Department of Cardiology, CHRU de Tours, 37000 Tours, France</footnote>

<footnote><sup>k</sup> Department of Cardiology, Centre Hospitalier Annecy Genevois, 74370 Epagny Metz-Tessy, France</footnote>

<footnote><sup>l</sup> Department of Cardiology, APHP CHU Pitié-Salpétrière, 75013 Paris, France</footnote>

<footnote><sup>m</sup> Department of Cardiology, CHU de Reims, 51100 Reims, France</footnote>

<footnote><sup>n</sup> Fédération de cardiologie, Hôpital de la Croix-Rousse et Hôpital Lyon Sud, Hospices Civils de Lyon, Lyon, France</footnote>

<footnote><sup>o</sup> Department of Cardiology, Centre Hospitalier Haguenau, 67500 Hagueneau, France</footnote>

<footnote><sup>p</sup> Department of Cardiology, GHICL Hôpital St Vincent et St Philibert, 59160 Lille, France</footnote>

<footnote><sup>q</sup> Department of Cardiology, CHRU de Dijon Bourgogne, 21000 Dijon, France</footnote>

<footnote><sup>r</sup> Department of Cardiology, CHRU de Nancy - Hopitaux Brabois, 54500 Vandoeuvre-lès Nancy, France</footnote>

<footnote><sup>s</sup> ELSAN, Polyclinique de Poitiers, 86000 Poitiers, France</footnote>

<footnote><sup>t</sup> Department of Cardiology, Hôpital Privé Confluent, 44000 Nantes, France</footnote>

<footnote><sup>u</sup> Department of Cardiology, Assistance Publique Hopitaux de Marseille, CHU de La Timone, 13385 Marseille Cedex 5, France</footnote>

<footnote><sup>v</sup> Department of Cardiology, CHU de Martinique, 97261 Fort de France, France</footnote>

<footnote><sup>w</sup> Department of Cardiology, Clinique Saint Joseph, 49800 Trelaze, France</footnote>

<footnote><sup>x</sup> Department of Cardiology, CHU de Caen, 1400 Caen, France</footnote>

<footnote><sup>y</sup> Department of Cardiology, Groupe Hospitalier Mutualiste, 38000 Grenoble, France</footnote>

<footnote><sup>z</sup> Department of Cardiology, CHU de Besançon, 25030 Besançon Cedex, France</footnote>

<footnote><sup>aa</sup> Nantes University, CHU Nantes, INSERM, Cardiology Department, CIC 1413, l'institut du thorax, F-44000 Nantes, France</footnote>

<footnote><sup>ab</sup> Department of Cardiology, APHP Centre Hospitalier Georges Pompidou, 75015 Paris, France</footnote>

<footnote><sup>ac</sup> University and University hospital center of Bordeaux, 33000 Bordeaux, France</footnote>

<footnote><sup>ad</sup> PhyMedExp, Cardiology Department, Université de Montpellier, INSERM, CNRS, INI-CRT, CHU de Montpellier, France</footnote>

<footnote><sup>ae</sup> Department of Cardiology, CHU de Clermont Ferrand, 63000 Clermont Ferrand, France</footnote>

<footnote><sup>af</sup> Department of Cardiology, Cardiology Department, Hôpitaux Universitaires Strasbourg, Strasbourg, France</footnote>

<footnote><sup>ag</sup> Emma Clinic, 94120 Fontenay sous Bois, France</footnote>

<footnote><sup>ah</sup> Department of Cardiology, CHU de Toulouse, 31400 Toulouse, France</footnote>

<footnote><sup>ai</sup> Paris Descartes University, Sorbonne Paris Cité, Faculty of Medicine, 75006 Paris, France</footnote>

<footnote><sup>aj</sup> INSERM, UMR-970, Paris Cardiovascular Research Center, 75015 Paris, France</footnote>

<footnote>* Corresponding author at: Department of Cardiology, Médipôle Hôpital Mutualiste, 158 rue Léon Blum, 69100 Villeurbanne, France.
E-mail address: a.jobbeduval@resamut.fr (A. Jobbé-Duval).</footnote>
ARTICLE INFO

Keywords:

ATTR-CM

Cardiac transthyretin amyloidosis

Elderly

Survival

Tafamidis

ABSTRACT

**Background:** Cardiac transthyretin amyloidosis (ATTR-CM) is a life-threatening cardiomyopathy. Tafamidis has been demonstrated to be an effective treatment. Our aim was to analyze clinical characteristics and survival of patients with ATTR-CM aged ≥80 years diagnosed after November 2018, treated with tafamidis 80/61 mg, and compare them with a non-treated group diagnosed before that date.

**Methods:** Data from the two groups were extracted from the Healthcare European Amyloidosis Registry (HEAR). Propensity score matching was used to adjust for baseline differences between the groups. Kaplan-Meier survival curves and Cox regression analyses were applied to assess survival outcomes.

**Results:** Out of 1380 patients, 1194 were treated with tafamidis 80/61 mg. Treated patients were significantly less severe at baseline, with a lower occurrence of NYHA class III-IV compared to the untreated group (24 vs. 46%, p < 0.001). The median NT-proBNP at baseline was lower in the treated group (2330 vs. 4854 pg/ml, p < 0.001), as was the average level of high-sensitivity troponin T (55 vs. 74 ng/ml, p < 0.001), and the interventricular septal thickness (16 vs. 18 mm, p < 0.001). The 3-year survival rate for treated patients was 57%, and 40% for untreated patients. In the treated group, the 3-year survival rate was 68% for patients aged 80–85 years and 58% for those over 85 years. Survival rates were confirmed after propensity score analyses.

**Conclusions:** This study demonstrates that tafamidis provides significant survival benefits for elderly patients with ATTR-CM, even in those over 85 years old. The findings emphasize the importance of early diagnosis and treatment.

1. Introduction

Amyloid Cardiomyopathy (CM) is a condition characterized by the extracellular and intracellular deposition of amyloid fibrils at the cardiac level [1]. These amyloid proteins disrupt the normal function of the heart, and may lead to severe cardiac insufficiency [2]. Transthyretin (ATTR) is one of the nine amyloidogenic proteins that may accumulate in the myocardium and cause significant cardiac disease [3]. ATTR cardiomyopathy (ATTR-CM) may be hereditary (ATTRv), caused by pathogenic variants in the transthyretin gene, or it may occur as a wild-type form (ATTRwt), which is not associated with genetic mutations and typically affects elderly individuals. [4]

In France, the incidence of ATTR-CM is estimated at 3.6 cases per 100,000 inhabitants per year, with a male-to-female sex ratio of 2.23. The median age at diagnosis is 84 years [5], and the mortality rate is estimated at 35% at 2 years [6]. Risk stratification is possible based on the NT-proBNP level and creatinine clearance. [7–9]

The treatment of ATTR-CM includes managing complications and employing disease-modifying therapies aimed at delaying amyloid deposition. Tafamidis is currently the only approved disease-modifying treatment for ATTR-CM in France. [10] Tafamidis is a TTR stabilizer [11] that binds to the thyroxin-binding sites of TTR tetramers, [12] thereby preventing TTR from misfolding and forming amyloid fibrils. [13] The ATTR-ACT clinical trial, [14] conducted on 441 patients with ATTR-CM demonstrated that tafamidis was superior to placebo in reducing the combination of all-cause mortality and cardiovascular-related hospitalizations. Further analyses on the efficacy of different doses [15] identified tafamidis 80 mg (bioequivalent to tafamidis free acid 61 mg) as the optimal dose in patients with ATTR-CM. Tafamidis was also shown to slow the increase in biomarkers, including N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (cTnT-HS), which are associated with disease progression in ATTR-CM patients. [16] Moreover, it was demonstrated to be effective in improving health-related quality of life in patients with ATTR-CM. [17] Tafamidis demonstrated its effectiveness also in other studies, [18] showing a significant reduction in morbidity and mortality among treated patients, regardless of genetic status, [19] disease severity, [20] or ejection fraction. [21] Since the 2021 ESC recommendations, [22]

tafamidis is indicated for treating all patients with ATTR-CM, including those who are asymptomatic. The introduction of tafamidis, along with increasing awareness of ATTR-CM among healthcare providers, has deeply transformed the landscape of ATTR-CM management. [23]

Patients with ATTR-CM are often very old, and thus, given the substantial cost of tafamidis, it is reasonable for the cardiology community to critically assess its benefits in the elderly population. Some studies, such as that by Sarkar, [24] have demonstrated no significant difference in mortality between patients over 80 and those under 80. Furthermore, a post-hoc analysis of the ATTR-ACT study focusing on patients over 80 years of age [25] reported improvements in quality of life but failed to show a mortality benefit, likely due to limited statistical power as only 88 patients over the age of 80 were included in the analysis.

To better understand the effects of tafamidis in this older demographic, we conducted a comparison of two cohorts of patients aged over 80 years —one treated with tafamidis and the other serving as a control.

2. Methods

The data of this study are part of the Healthcare European Amyloidosis Registry (HEAR), a French, multicentre registry of patients with suspected or confirmed ATTR-CM. Data collection is still ongoing. The diagnostic criteria for ATTR-CM follow those outlined in the European Society of Cardiology's 2021 expert consensus. [22] Inclusion criteria are: age 18 or over, referral for suspected ATTR-CM or a confirmed diagnosis of ATTR-CM, and coverage by the French social security system. The primary exclusion criterion is refusal to be included in the registry. The registry includes three cohorts: the HEAR RETROSPECTIVE cohort, which includes deceased patients with confirmed diagnosis of ATTR-CM, who have been treated at various centres after 2009; the HEAR RETROPROSPECTIVE cohort, which includes patients with a confirmed diagnosis of ATTR-CM and real-life follow-up from the date of inclusion of patients, who have been treated after 2009 and are still being monitored; and the HEAR PROSPECTIVE cohort, which includes patients referred to the participating centres for suspected ATTR-CM. Demographic, clinical, laboratory, imaging, and quality of life data are collected using a structured e-CRF. In addition, treatment details are recorded. Each year, outcomes are registered (i.e., deaths, cause of death, hospital readmissions, lost at follow-up). Patients are classified according to the New York Heart Association (NYHA) Classification for Heart Failure.

<footnote n="1">¹ These authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.</footnote>
In the present study, patients aged ≥80 years with a diagnosis of ATTR-CM have been included. Two cohorts were compared: 1) a historical cohort of patients with ATTR-CM who were not treated with tafamidis, and 2) a prospective cohort of patients with ATTR-CM treated with tafamidis 61 mg/80 mg. The study design is depicted in Fig. S1. Patients were included in the historical cohort if they had been diagnosed before November 2018, when Tafamidis was not available in France. Those patients were either deceased before November 2018 or considered censored on that date. Patients diagnosed after November 2018 were treated with tafamidis 61 mg/80 mg and were followed for 5 years.

The study was conducted and reported in accordance with the principles of the Declaration of Helsinki. The HEAR is registered with the French National Agency for the Safety of Medicines and Health (Agence nationale de sécurité du médicament et des produits de santé (Paris, France); identifier: IDRCB 2019-A02010-57) and [ClinicalTrials.gov](http://ClinicalTrials.gov) (identifier: NCT05101304). The HEAR protocol is strictly observational. It does not modify the patient's usual care and does not require any additional consultations or examinations.

### 3. Statistical analysis

Categorical data were described as counts and percentages, while continuous variables were presented as medians and interquartile range. Categorical variables were compared using the chi-square test, and

continuous variables were compared using Mann-Whitney test. Kaplan-Meier survival curves were used to compare survival between the two cohorts, providing a visual representation of survival probabilities over time. Survival probabilities were compared in subgroups of patients based on age categories (80-85 years vs >85 years), and to NYHA classification (I-II vs III-IV) (Log-rank test). A multivariate Cox regression analysis with backward selection was performed to understand the relationship between various factors and patient survival. Variables included in the analysis were: treatment with tafamidis 80/61 mg vs no tafamidis, NYHA class I-II vs III-IV, age (continuous variable), creatinin (continuous), NT-proBNP (continuous), and Left Ventricular Ejection Fraction, LVEF (continuous).

To balance the two groups, in the absence of randomization, a propensity score, i.e., the probability that a participant received the treatment, given their baseline characteristics, was calculated on our complete cohort. The propensity score was estimated based on the following parameters: age, NYHA, systolic blood pressure, troponin T HS, NT-proBNP, Interventricular Septal Thickness (IVST), LVEF, E/e'ratio, Aspartate Aminotransferase (ASAT), and Alkaline Phosphatase (ALP). Individuals in the treated group were matched with individuals in the untreated group based on similar propensity scores, and survival rates as well as hazard ratios were calculated to compare the outcomes between the two groups.

<table><caption>**Table 1**
Baseline characteristics of the study population according to treatment status.</caption><thead><tr><th>Variables</th><th>Missing</th><th>Overall</th><th>No Tafamidis</th><th>Tafamidis 80/61 mg</th><th>P value<sup>*</sup></th></tr></thead><tbody><tr><td>N (%)</td><td>Data</td><td>1380</td><td>186 (13)</td><td>1194 (87)</td><td></td></tr><tr><td>Demographic data</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Age, years, median [IR]</td><td>0</td><td>85 [83-88]</td><td>83 [82-85]</td><td>86 [84-88]</td><td>&lt;0.001</td></tr><tr><td>Time to diagnosis from 1st CV symptom, months, median [IR]</td><td>118</td><td>13.0 [3.0-64.0]</td><td>14.5 [4.0-65.0]</td><td>13.0 [3.0-52.0]</td><td>0.362</td></tr><tr><td>Men, n(%)</td><td>0</td><td>1075 (77.9)</td><td>140 (75.2)</td><td>934 (78.2)</td><td>0.384</td></tr><tr><td>BMI, kg/m2, median [IR]</td><td>407</td><td>24.8 [22.8-27.1]</td><td>24.6 [23.1-27.1]</td><td>24.8 [22.8-27.1]</td><td>0.611</td></tr><tr><td>Diagnosis</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>ATTRWt, n(%)</td><td>0</td><td>957 (69.4)</td><td>114 (61.1)</td><td>841 (70.4)</td><td>0.017</td></tr><tr><td>ATTRv, n(%)</td><td>0</td><td>75 (5.5)</td><td>32 (17.2)</td><td>47 (3.9)</td><td>&lt;0.001</td></tr><tr><td>ATTR not genotyped, n(%)</td><td>0</td><td>180 (13.0)</td><td>39(21.0)</td><td>143 (12.0)</td><td>0.001</td></tr><tr><td>ATTR undergoing genetic testing, n(%)</td><td>0</td><td>166 (12.1)</td><td>1 (0.7)</td><td>163 (13.7)</td><td>&lt;0.001</td></tr><tr><td>Clinical data</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Diabetes, n(%)</td><td>278</td><td>199 (18.1)</td><td>23 (12.1)</td><td>176 (14.7)</td><td>0.036</td></tr><tr><td>Dyslipidemia, n(%)</td><td>278</td><td>382 (34.6)</td><td>48 (26.5)</td><td>334 (35.7)</td><td>0.017</td></tr><tr><td>Hypertension, n(%)</td><td>278</td><td>688 (62.5)</td><td>103 (55.4)</td><td>58 (63.5)</td><td>0.049</td></tr><tr><td>Carpal tunnel syndrome, n(%)</td><td>190</td><td>510 (42.6)</td><td>55 (29.3)</td><td>455(44.4)</td><td>&lt;0.001</td></tr><tr><td>Lumbar canal stenosis, n(%)</td><td>232</td><td>110 (9.6)</td><td>15 (8.3)</td><td>95 (9.8)</td><td>0.544</td></tr><tr><td>Peripheral neuropathy, n(%)</td><td>215</td><td>157(13.2)</td><td>70(18.5)</td><td>87 (12.6)</td><td>0.041</td></tr><tr><td>NYHA class III-IV, n(%)</td><td>232</td><td>308 (25.1)</td><td>83 (45.5)</td><td>225 (23.5)</td><td>&lt;0.001</td></tr><tr><td>Sinus rhythm, n(%)</td><td>449</td><td>297 (32.2)</td><td>33 (17.8)</td><td>264 (34.1)</td><td>&lt;0.001</td></tr><tr><td>HR, bpm, median [IR]</td><td>420</td><td>75.0 [66.0-86.0]</td><td>75.0 [65.5-87.0]</td><td>77.0 [69.0-85.0]</td><td>0.200</td></tr><tr><td>SBP, mmHg, median [IR]</td><td>413</td><td>134.0 [121.0-146.0]</td><td>128.0 [117.0-143.0]</td><td>134.0 [121.5-146.0]</td><td>&lt;0.001</td></tr><tr><td>DBP, mmHg, median [IR]</td><td>414</td><td>73.0 [66.0-81.0]</td><td>74.0 [66.5-80.5]</td><td>73.0 [66.0-81.0]</td><td>0.008</td></tr><tr><td>Biomarkers</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>NT-proBNP, ng/L, median [IR]</td><td>420</td><td>2492.5 [1264.0-4741.5]</td><td>4854.0 [2049.5-8903.0]</td><td>2330.0 [1202.5-4483.0]</td><td>&lt;0.001</td></tr><tr><td>hs-TnT, ng/L, median [IR]</td><td>711</td><td>56.0 [41.8-80.0]</td><td>74.0 [55.0-108.0]</td><td>55.0 [40.5-77.0]</td><td>&lt;0.001</td></tr><tr><td>Creatinin, mol/L, median [IR]</td><td>292</td><td>106.0 [87.8-131.3]</td><td>117.0 [89.0-140.0]</td><td>106.0 [86.5-130.0]</td><td>0.130</td></tr><tr><td>eGFR, ml/min/1,73 m2, median [IR]</td><td>512</td><td>44.2 [34.2-54.2]</td><td>41.7 [35.85-49.2]</td><td>45.1 [34.1-54.5]</td><td>0.042</td></tr><tr><td>PAL, UI/L, median [IR]</td><td>720</td><td>91.0 [69.0-115.0]</td><td>107.0 [80.5-133.5]</td><td>88.0 [68.5-114.0]</td><td>&lt;0.001</td></tr><tr><td>Hemoglobin, g/dl, median [IR]</td><td>406</td><td>13.1 [12.2-14.2]</td><td>13.0 [11.8-14.0]</td><td>13.2 [12.0-14.2]</td><td>0.049</td></tr><tr><td>Echocardiographic features</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>IVS, mm, median [IR]</td><td>360</td><td>16.2 [14.3-18.7]</td><td>18.0 [15.0-20.0]</td><td>16.0 [14.1-18.0]</td><td>&lt;0.001</td></tr><tr><td>LVEDD, mm, median [IR]</td><td>413</td><td>43.5 [39.0-48.0]</td><td>44.0 [40.0-49.0]</td><td>43.0 [39.0-48.0]</td><td>0.469</td></tr><tr><td>LVEF, %, median [IR]</td><td>358</td><td>54.4 [46.4-61.0]</td><td>48.0 [39.0-56.0]</td><td>55.0 [48.0-62.0]</td><td>&lt;0.001</td></tr><tr><td>GLS, %, median [IR]</td><td>560</td><td>11.7 [9.0-14.0]</td><td>9.7 [7.6-11.7]</td><td>12.0 [9.4-14.4]</td><td>&lt;0.001</td></tr><tr><td>PAPs, mmHg, median [IR]</td><td>838</td><td>29.7 [21.2-36.0]</td><td>32.1 [27.0-37.9]</td><td>29.2 [21.2-36.0]</td><td>0.047</td></tr></tbody></table>

ATTRv: Variant transthyretin amyloidosis; ATTRWt: Wild-type transthyretin amyloidosis; BMI: Body Mass Index; DBP: Diastolic Blood Pressure; eGFR: Estimated Glomerular Filtration Rate; GLS: Global Longitudinal Strain; HR: Heart Rate; hs-TnT: High-sensitivity Troponin T; IR: Interquartile Range; IVS: Interventricular Septum thickness; LVEDD: Left Ventricular End-Diastolic Diameter; LVEF: Left Ventricular Ejection Fraction; NT-proBNP: N-terminal pro-B-type natriuretic peptide; NYHA: New York Heart Association classification; PAL: Alkaline Phosphatase; PAPs: Pulmonary Artery Systolic Pressure; SBP: Systolic Blood Pressure.

<footnote>* From Mann Whitney's test.</footnote>
# 4. Results

## 4.1. Overall results

Between June 2021 and June 2024, the HEAR cohort included 6051 patients with amyloidosis, of whom 4310 were diagnosed with ATTR-CM. Among these, 1380 patients were over 80 years old. Fig. S2 illustrates the flow chart of the participants. Of the patients over 80 years old, 1194 were diagnosed after November 2018 and treated with tafamidis 80/61 mg, while 186 patients were diagnosed before November 2018 and were not treated.

Baseline demographic, clinical, biological, and cardiac imaging characteristics of treated and untreated groups are reported in Table 1. Treated patients were older (86 vs. 83 years, *p* < 0.001) and significantly less severe at baseline, with a significantly lower occurrence of NYHA class III-IV compared to the untreated group (23.5 % vs. 45.5 %, *p* < 0.001). The median NT-proBNP at baseline was significantly lower in the treated group (2330 vs. 4854 pg/ml, *p* < 0.001), as was the average level of high-sensitivity troponin T HS (55 vs. 74 ng/ml, *p* < 0.001). Treated patients also had a lower interventricular septal thickness (16 vs. 18 mm, *p* < 0.001), higher left ventricular ejection fraction (LVEF) (55 vs. 48 %, *p* < 0.001), and better global longitudinal strain (−12 vs. −9.7 %, *p* < 0.001).

Fig. 1 shows the survival curves for the treated and the untreated cohorts. The 3-year survival rate for patients treated with tafamidis was 57 %, while it was 40 % in untreated patients (*p* < 0.001). A survival probability of 50 % was reached at 29 months in the untreated group, while it was not reached in the treated group. Lack of tafamidis treatment significantly increased patient's mortality compared to tafamidis treatment: HR = 2.3 (1.85–2.86), *p* < 0.001 (Fig. S3).

## 4.2. Survival comparison between NYHA class I-II and class III-IV subgroups, with and without tafamidis

The treated and untreated groups were compared based on NYHA functional classes (I-II vs. III-IV) (Table S1). Among patients with less severe symptoms (NYHA I-II), those receiving treatment were significantly older than their untreated counterparts (85 vs. 82 years, *p* <

0.001). Cardiac biomarkers were notably lower in the treated group (NT-proBNP: 2022 vs. 4059 ng/L, *p* = 0.004; hs-Troponin T: 52 vs. 73 ng/L, *p* < 0.001). Echocardiographic parameters indicated better cardiac function in the treated group, with significantly higher values for interventricular septal thickness (IVS: 16 vs. 19 mm, *p* < 0.001), left ventricular ejection fraction (LVEF: 56 vs. 51 %, *p* = 0.030), and global longitudinal strain (GLS: −12.5 vs. −9.9 %, *p* < 0.001).

For patients with more severe symptoms (NYHA III-IV), the results were less clear. Treated patients were again significantly older (86 vs. 83 years, *p* < 0.001), but cardiac biomarker levels did not differ significantly between groups. While LVEF remained significantly higher in the treated group (50 vs. 47 %, *p* = 0.010), GLS values were similar (−9.9 vs. −8.65 %, *p* = 0.626).

Survival analyses revealed that treated patients with NYHA I-II symptoms had a 3-year survival rate of around 60 % (Fig. S4), with median survival not yet reached. Similarly, treated patients with NYHA III-IV symptoms also demonstrated a 3-year survival rate of 61 %, with median survival not reached. In the untreated group, the 3-year survival rate was 57 % for NYHA I-II patients (median survival not reached) but dropped to 35 % for NYHA III-IV patients, with a mean survival of 30 months.

## 4.3. Survival comparison between age class (80–85 or > 85 years old) subgroups in patients treated or not with Tafamidis 80/61 mg

Similar results were observed when comparing treated and untreated patients by age groups (80–85 years and > 85 years, Table 2), with treated patients being less severe in both classes. Biomarkers and echocardiographic parameters were significantly more favorable in the treated group.

In the treated group, the 3-year survival rate was 68 % for patients aged 80–85 years and 58 % for those over 85 years, with median survival not yet reached in either group (Fig. 2). Among untreated patients aged 80–85 years, the 3-year survival rate was 47 %, with a mean survival of 31 months. For untreated patients over 85 years, the 3-year survival rate was 38 %, with a mean survival of 24 months.

<figure><img src="image_4.png" /><figcaption>Fig. 1. Survival in patients over 80 years old treated with tafamidis 80/61mg versus no treatment: Kaplan-Meier curve.</figcaption></figure>
<caption>**Table 2**</caption>

Baseline characteristics of the study population according to age and treatment status.

<table><thead><tr><th rowspan="2">Variable</th><th colspan="2">Age 80-85 years</th><th rowspan="2">P value<sup>*</sup></th><th colspan="2">Age &gt; 85 years</th><th rowspan="2">P value<sup>*</sup></th></tr><tr><th>No Tafamidis</th><th>Tafamidis 80/61 mg</th><th>No Tafamidis</th><th>Tafamidis 80/61 mg</th></tr></thead><tbody><tr><td>N</td><td>119</td><td>612</td><td></td><td>67</td><td>582</td><td></td></tr><tr><td>Demographic data</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Age, years, median [IR]</td><td>83 [82-84]</td><td>83 [82-84]</td><td>0.120</td><td>86[86-89]</td><td>88 [87-90]</td><td>0.003</td></tr><tr><td>Time to diagnosis from 1st CV symptom, months, median [IR]</td><td>26.0 [9.0-64.5]</td><td>10.0 [2.0-64.0]</td><td>0.068</td><td>12.0 [3.0-30.0]</td><td>15.0 [3.0-72.0]</td><td>0.402</td></tr><tr><td>Men n(%)</td><td>94 (79.0)</td><td>505 (82.5)</td><td>0.360</td><td>42 (63.2)</td><td>429 (73.7)</td><td>0.155</td></tr><tr><td>BMI, kg/m2, median [IR]</td><td>25.2 [23.2-27.5]</td><td>25.5 [23.4-27.7]</td><td>0.540</td><td>23.1 [22.0-24.6]</td><td>24.6 [22.5-27.3]</td><td>0.164</td></tr><tr><td>Diagnosis</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>ATTRWt</td><td>73 (61.3)</td><td>424 (69.3)</td><td>0.089</td><td>40 (60.5)</td><td>417 (71.6)</td><td>0.143</td></tr><tr><td>ATTRV</td><td>23 (19.3)</td><td>24 (3.9)</td><td>&lt;0.001</td><td>7 (10.5)</td><td>23 (4.0)</td><td>0.059</td></tr><tr><td>ATTR non-genotyped</td><td>22 (18.5)</td><td>75 (12.3)</td><td>0.067</td><td>19 (28.9)</td><td>68 (11.7)</td><td>0.001</td></tr><tr><td>ATTR undergoing genetic testing</td><td>1 (0.8)</td><td>89 (14.5)</td><td>&lt;0.001</td><td>0 (0)</td><td>74 (12.7)</td><td></td></tr><tr><td>Clinical data</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Diabetes</td><td>15 (12.6)</td><td>118 (19.3)</td><td>0.091</td><td>71 (10.5)</td><td>108 (18.6)</td><td>0.379</td></tr><tr><td>Dyslipidemia</td><td>34 (28.6)</td><td>231 (37.7)</td><td>0.056</td><td>12.3 (18.4)</td><td>195 (33.5)</td><td>0.020</td></tr><tr><td>Hypertension</td><td>66 (55.5)</td><td>378 (61.8)</td><td>0.197</td><td>37 (55.3)</td><td>380 (65.3)</td><td>0.028</td></tr><tr><td>Carpal tunnel syndrome</td><td>35 (29.4)</td><td>309 (50.5)</td><td>&lt;0.001</td><td>18 (28.9)</td><td>221 (38.0)</td><td>0.210</td></tr><tr><td>Lumbar canal stenosis</td><td>10 (8.4)</td><td>74 (12.1)</td><td>0.248</td><td>5 (7.9)</td><td>43 (7.4)</td><td>0.908</td></tr><tr><td>Peripheral neuropathy</td><td>22 (18.5)</td><td>76 (12.4)</td><td>0.075</td><td>12 (18.4)</td><td>74 (12.7)</td><td>0.311</td></tr><tr><td>NYHA class III-IV</td><td>52/117 (45.0)</td><td>101/486 (20.6)</td><td>&lt;0.001</td><td>28/60 (47.1)</td><td>124/469 (26.4)</td><td>0.060</td></tr><tr><td>Sinus rhythm, n(%)</td><td>24 (20.2)</td><td>224 (36.6)</td><td>&lt;0.001</td><td>4 (10.5)</td><td>183 (31.4)</td><td>0.006</td></tr><tr><td>HR, bpm, median [IR]</td><td>75.0 [66.5-85.0]</td><td>74.0 [64.0-85.0]</td><td>0.924</td><td>86.0 [72.0-102.0]</td><td>72.0 [64.0-82.2]</td><td>0.004</td></tr><tr><td>SBP, mmHg, median [IR]</td><td>129 [112-142]</td><td>134.[122-146]</td><td>0.013</td><td>127.[104.- 130]</td><td>137 [121-149]</td><td>0.012</td></tr><tr><td>DBP, mmHg, median [IR]</td><td>73 [66-82]</td><td>75 [68-83]</td><td>0.011</td><td>64.0 [56-79]</td><td>66 [74-83]</td><td>0.110</td></tr><tr><td>Biomarkers</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>NT-proBNP, ng/L, median [IR]</td><td>4059 [1679-10,253]</td><td>2159 [1170.- 4097]</td><td>&lt;0.001</td><td>6552 [4912-9140]</td><td>2707 [1369-5592]</td><td>0.004</td></tr><tr><td>hs-TnT, ng/L, median [IR]</td><td>74.0 [55.0-110.0]</td><td>51.0 [36.0-71.0]</td><td>&lt;0.001</td><td>80.0 [50.2-109.0]</td><td>59.0 [3.0-83.0]</td><td>0.027</td></tr><tr><td>Creatinin, umol/L, median [IR]</td><td>128.0 [92.0-149.0]</td><td>103.0 [86.0-121.0]</td><td>0.001</td><td>84.5 [72.0-84.2]</td><td>109.0 [88.0-136.0]</td><td>0.063</td></tr><tr><td>eGFR, ml/min/1,73 m2, median [IR]</td><td>39.2 [33.3-47.4]</td><td>48.3 [36.4-58.9]</td><td>0.004</td><td>42.4 [30.2-58.3]</td><td>37.6 [26.7-48.2]</td><td>0.110</td></tr><tr><td>PAL, UI/L, median [IR]</td><td>99.0 [79.0-130.0]</td><td>91.0 [71.0-114.0]</td><td>0.005</td><td>113.5 [95.0-137.5]</td><td>87.0 [67.0-112.0]</td><td>0.014</td></tr><tr><td>Hemoglobin, g/dl, median [IR]</td><td>13.10 [12.2-14.3]</td><td>13.3 [12.2-14.4]</td><td>0.038</td><td>11.7 [10.6-12.8]</td><td>13.2 [12.2-14.0]</td><td>0.102</td></tr><tr><td>Echocardiographic features</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>IVS, mm, median [IR]</td><td>18.0 [15.2-21.0]</td><td>16.3 [14.0-18.0]</td><td>&lt;0.001</td><td>18.0 [13. - 19.0]</td><td>16.0 [4.3-18.3]</td><td>0.083</td></tr><tr><td>LVEDD, mm, median [IR]</td><td>45.0 [39.2-48.7]</td><td>44.0 [40.0-49.0]</td><td>0.697</td><td>42.0 [0.0-51.0]</td><td>42.0 [38.0-47.0]</td><td>0.681</td></tr><tr><td>LVEF, %, median [IR]</td><td>50.5 [39.5-55.7]</td><td>56.0 [48.0-62.0]</td><td>&lt;0.001</td><td>46.0 [38.0-60.0]</td><td>54.2 [47.0-61.8]</td><td>0.023</td></tr><tr><td>GLS, %, median [IR]</td><td>8.8 [6.4-10.8]</td><td>12.1 [9.5-14.3]</td><td>&lt;0.001</td><td>9.8 [7.6-13.7]</td><td>12.0 [9.2-14.3]</td><td>0.088</td></tr><tr><td>PAPs, mmHg, median [IR]</td><td>30.1 [25.1-36.5]</td><td>28.1 [20.2-36.0]</td><td>0.053</td><td>38.9 [29.6-46.2]</td><td>30.4 [21.8-36.0]</td><td>0.228</td></tr></tbody></table>

ATTRW: Variant transthyretin amyloidosis; ATTRWt: Wild-type transthyretin amyloidosis; BMI: Body Mass Index; DBP: Diastolic Blood Pressure; eGFR: Estimated Glomerular Filtration Rate; GLS: Global Longitudinal Strain; HR: Heart Rate; hs-TnT: High-sensitivity Troponin T; IR: Interquartile Range; IVS: Interventricular Septum thickness; LVEDD: Left Ventricular End-Diastolic Diameter; LVEF: Left Ventricular Ejection Fraction; NT-proBNP: N-terminal pro-B-type natriuretic peptide; NYHA: New York Heart Association classification; PAL: Alkaline Phosphatase; PAPs: Pulmonary Artery Systolic Pressure; SBP: Systolic Blood Pressure.

## 4.4. Variables independently associated with survival

The results of the multivariate Cox analysis at 36 months adjusted by tafamidis treatment 80/61 mg are presented in Table S2. The group without tafamidis treatment showed a significant increase in risk (HR: 1.544, 95 % CI: [1.112-3.455], *p* = 0.002), and patients with severe symptoms (NYHA III-IV) had a 1.673 times higher risk of death (95 % CI: [1.012-6.455], *p* = 0.001) compared to those with milder symptoms (NYHA I-II). Higher plasma creatinine levels (HR: 1.050, 95 % CI: [1.002-1.055], *p* = 0.002) and NT-proBNP (HR: 1.023, 95 % CI: [1.022-1.045], *p* = 0.021) significantly increased the risk, whereas lower LVEF appeared protective (HR: 0.789, 95 % CI: [0.567-0.765], *p* = 0.005).

## 4.5. Propensity score

The boxplots of the overall distribution of propensity scores for the treated and untreated groups are shown in Fig. S5A. Fig. S5B presents the boxplots of propensity score distributions across quantile-based groups for treated and untreated individuals. The overlap of scores

within each quantile indicates the comparability of treated and untreated groups after stratification. Higher separation observed in the upper quantiles suggests successful matching of propensity scores between treated and untreated patients. We found a significant excess mortality in the untreated group with a Hazard ratio of 2.2 (1.75, 2.77), *p* < 0.001 (Fig. S5C). The 3-year survival rate in the treated group was 60 %, and median survival was not reached. The 3-year survival rate in the untreated group was 40 %, with a mean survival of 33 months. (*p* < 0.001, Fig. S5D).

## 5. Discussion

In this multicenter, retrospective, observational study of patients with ATTR-CM aged over 80 years, we observed significant differences in disease characteristics and management between untreated patients enrolled before November 2018 and those treated with tafamidis after November 2018. This difference was observed even among the oldest patients. Patients enrolled after 2018 benefited from earlier diagnoses at less advanced stages, characterized by less cardiac infiltration and milder heart failure symptoms. These patients presented with less severe

<footnote>* From Mann Whitney's test.</footnote>
<figure><img src="image_5.png" /><figcaption>Fig. 2. Survival in patients over 80 years old treated with tafamidis 80/61 mg versus no treatment based on age class (80–85 vs >85 years): Kaplan-Meier curve.</figcaption></figure>

disease, higher ejection fractions, lower cardiac stress markers, and fewer symptoms compared to those managed before 2018, with access to specific treatment. Awareness of the disease by clinicians has improved, probably due to the creation of networks, such as the Amylose Network in France, with a consequent easier dissemination of information. Moreover, advancements in cardiac imaging, and disease-specific laboratory tests (monoclonal gammopathy tests and genetic screening) have made diagnosing CM significantly easier [26] even in older patients in France. A study conducted at a French Cardiac Amyloidosis Referral Centre (CARC) from 2010 to 2021 [23] reported an increase in patients diagnosed at earlier stages (NAC Stage 1) and a decline in Stage III presentations over time. Early diagnosis alone, even without tafamidis treatment, significantly reduces mortality, as demonstrated in Ioannou's study. [27] These findings are consistent with the recently published worldwide THAOS registry, which suggests that earlier diagnosis has contributed to improved life expectancy in patients with ATTR-CM, [18] despite less severe presentations. The average age at screening has increased over time, indicating an effort to include more older patients in the process.

We observed a significant difference in mortality between treated and untreated groups, with a 3-year survival rate of 57 % in tafamidis-treated patients versus 40 % in untreated ones. Age, plasma creatinine levels, NT-proBNP levels, and LVEF were all significant predictors of survival. In particular, higher age, creatinine, and NT-proBNP levels increased the risk, while higher LVEF (better heart function) decreased the risk. Similar to our study, a recent study [28] involving 253 octogenarians treated with tafamidis vs. untreated octogenarians showed improved unadjusted survival (P < 0.001), with 5 % 1-year and 24 % 3-year mortality. In propensity score-matched cohort 1-year and 3-year mortality rate were 15 % and 46 %, respectively. As reported in our study, they identified substantial changes over the past 2 decades in the clinical phenotype of patients with ATTR-CM, with patients recently being diagnosed earlier in the disease process, and surviving for longer after diagnosis.

Our cohort represents the largest known group of octogenarian patients treated with tafamidis. This provides critical insights into a population underrepresented in prior studies; for instance, the ATTR-ACT study [25] included only 88 patients over 80, 51 treated with tafamidis

and 37 with placebo. In that study, octogenarians who received tafamidis experienced a less pronounced decline in both quality of life and functional capacity, as well as a smaller alteration in a heart function biomarker over 30 months, compared to those given a placebo. However, patients treated with tafamidis showed a non-significant trend towards a longer survival compared to placed, probably due to the small sample size. The large size of our cohort allowed us to extend the analyses to even older patients, over 85 years old. In this group, the 3-year survival rate was 60 % in treated patients, demonstrating the efficacy of tafamidis even at a very old age. Recent findings by Sarkar et al. [24] align with ours, showing no significant difference in 30-month mortality reduction between patients over and under 80 years treated with tafamidis. We chose to classify our patients according to the New York Heart Association (NYHA) Classification for Heart Failure, since emerging prognostic tools have revealed that the NAC classification is inadequate for patients over 75 years old, [29] underscoring the need to refine severity criteria for elderly patients and tailor treatments accordingly.

The key strength of our study lies in comparing treated and untreated patients aged over 80 years using propensity score matching, which reduces confounding biases. We demonstrated a specific survival benefit of tafamidis in our population, with a hazard ratio of 2.2 indicating lower mortality in treated patients. The only randomized study on octogenarian patients -a sub-study of ATTR-ACT- reported a smaller decline in quality of life in patients treated with tafamidis versus placebo, but no significant survival difference, likely due to insufficient power. [25] Although propensity scoring is imperfect, our analysis strongly supports the survival benefit of tafamidis for patients over 80. These findings should prompt reconsideration of treatment criteria for older cardiac amyloidosis patients, as chronological age alone should not be a barrier to tafamidis use.

Beyond age, assessing geriatric frailty is critical. Geriatric frailty increases mortality risk by 1.5 to 2 times in heart failure, [30] and ATTRwt-CM has been linked to a distinct frailty phenotype associated with heart failure. [31] Evaluating geriatric frailty—regardless of age—can enhance our understanding of patient symptoms, improve prognostic assessments, and guide optimal treatment decisions.
## 6. Study limitations

A limitation of this study is the lack of randomization, which resulted in different baseline characteristics between treated and untreated patients. However, by using propensity score matching to adjust for these differences, our findings on the benefit of tafamidis treatment remained significant. Nevertheless, we cannot exclude the possibility of other unmeasured confounders, as propensity score matching may not fully account for all potential biases. The findings from the present study should be confirmed with prospective randomized trials that include only elderly patients. Therefore, placebo-controlled clinical trials of tafamidis would not be ethical and would not align with ESC guidelines.

## 7. Conclusions

This study highlights that tafamidis provides meaningful clinical benefits for elderly patients with ATTR-CM, supporting improved outcomes and a survival advantage even in this advanced age group. Furthermore, it underscores the progress made in recent years regarding the timely diagnosis of ATTR-CM, facilitated by increased awareness and advancements in diagnostic tools. Earlier recognition of the disease has enabled interventions at less advanced stages, resulting in better management of cardiac symptoms and overall disease burden. The data provided on the evolution of the population's characteristics and survival should aid in designing future trials on ATTR-CM, with tafamidis as the standard of care. These findings should encourage clinicians to treat patients with cardiac amyloidosis based on their geriatric frailty rather than their chronological age. Close collaboration with geriatricians is essential to ensure the best therapy is offered to the right patient.

Supplementary data to this article can be found online at https://doi.org/10.1016/j.ijcard.2025.133522.

### CRediT authorship contribution statement

**Antoine Jobbé-Duval:** Writing – original draft, Supervision, Methodology, Investigation, Data curation, Conceptualization.
**Mounira Kharoubi:** Writing – review & editing, Supervision, Methodology, Investigation, Data curation, Conceptualization.
**Erwan Donal:** Writing – review & editing, Supervision, Investigation, Data curation.
**Fabrice Bauer:** Writing – review & editing, Investigation, Data curation.
**Amaury Broussier:** Writing – review & editing, Investigation, Data curation.
**Arnaud Bisson:** Writing – review & editing, Investigation, Data curation.
**Océane Bouchot:** Writing – review & editing, Investigation, Data curation.
**Phillipe Charron:** Writing – review & editing, Investigation, Data curation.
**Jérôme Costa:** Writing – review & editing, Investigation, Data curation.
**Pierre-Yves Courand:** Writing – review & editing, Investigation, Data curation.
**Charlotte Dagrenat:** Writing – review & editing, Investigation, Data curation.
**François Delelis:** Writing – review & editing, Investigation, Data curation.
**Jean-Christophe Eicher:** Writing – review & editing, Investigation, Data curation.
**Antoine Fraix:** Writing – review & editing, Investigation, Data curation.
**Barnabas Gellen:** Writing – review & editing, Investigation, Data curation.
**Jean-Pierre Gueffet:** Writing – review & editing, Investigation, Data curation.
**Gilbert Habib:** Writing – review & editing, Investigation, Data curation.
**Jocelyn Inamo:** Writing – review & editing, Investigation, Data curation.
**Julien Jeanneteau:** Writing – review & editing, Investigation, Data curation.
**Damien Legallois:** Writing – review & editing, Investigation, Data curation.
**Léa Margerit:** Writing – review & editing, Investigation, Data curation.
**Basile Mouhat:** Writing – review & editing, Investigation, Data curation.
**Nicolas Piriou:** Writing – review & editing, Investigation, Data curation.
**Tania Puscas:** Writing – review & editing, Investigation, Data curation.
**Patricia Réant:** Writing – review & editing, Investigation, Data curation.
**François Roubille:** Writing – review & editing, Investigation, Data curation.
**Romain Trésorier:** Writing – review & editing, Investigation, Data curation.
**Jean-Jacques Von Hunolestein:** Writing – review & editing,

**Investigation, Data curation.** **Charles Taieb:** Writing – review & editing, Investigation, Data curation.
**Amira Zaroui:** Writing – review & editing, Investigation, Formal analysis, Data curation.
**Olivier Lairez:** Writing – review & editing, Investigation, Data curation, Conceptualization.
**Thibaud Damy:** Writing – original draft, Supervision, Investigation, Funding acquisition, Data curation, Conceptualization.

### Grant support

This work was supported by Alexion, Alnylam, Bayer, and Pfizer. Philippe Charron had support from the Pathfinder Cardiogenomics program of the European Innovation Council of the European Union (DCM-NEXT project). The funding institutions had no influence whatsoever on the study design or its results.

### Declaration of competing interest

Antoine Jobbé-Duval reports speaking/consulting fees from Alnylam Pharmaceuticals, Amicus Therapeutics, AstraZeneca, BMS, Pfizer, Bayer, and Sanofi-Genzyme. Arnaud Bisson received consultancy fees from BMS and Pfizer. Océane Bouchot reports honoraria from Biotronik.

Amaury Broussier has received consultancy fees from Pfizer, Novartis, Vifor Pharma, Boehringer, and Astra Zeneca. Philippe Charron has received personal consultancy fees, outside the present work, for Amicus, Bristol Myers Squibb, Owkins, Pfizer, Sanofi and Servier. Jérôme Costa has received speaker fees from Edimark, Pfizer, Boehringer, Novartis, Servier, Amgen, BMS, Viatris, Alnylam, funding from Pfizer, and was part of an advisory board for Alnylam, Pfizer, Novartis Grand Est, Novonordisk, and Sanofi Genzyme. Pierre-Yves Courand reports honoraria/consulting fees from Abbvie, Amgen, Astellas, AstraZeneca, Boehringer Ingelheim/Lilly, Bristol Myers Squibb, Medtronic, Organon, and Pfizer. Charlotte Dagrenat received consultancy fees from Pfizer and Alnylam. Antoine Fraix reports honoraria/consulting fees from Pfizer and Amgen. Julien Jeanneteau received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from BMS, AstraZeneca, Pfizer, and Novo Nordisk, and support for attending meetings and/or travel from Novartis, Medtronic, Boston, Abbott, and Biotronik. Olivier Lairez reports speaking/consulting fees from Alnylam Pharmaceuticals, Amicus Therapeutics, AstraZeneca, BMS, Bridgebio, Cytokinetics, Pfizer, Sanofi-Genzyme, and Siemens Healthiners.

Damien Legallois reports honoraria/consulting fees from Astra Zeneca, Boehringer Ingelheim, Lilly, Pfizer and Takeda. Nicolas Piriou received consultancy fees from Pfizer, Alnylam, and Bayer. Patricia Réant received consultancy fees from Pfizer and Alnylam. François Roubille reports honoraria/fees from Astra Zeneca, Servier, Boehringer, Astra Zeneca, Vifor, Bayer, Pfizer, Novartis, Servier, Novonordisk, Air liquid, Abbott, QuidelOrtho, Newcard, MSD, BMS, Sanofi, Alnylam, Zoll, Implicity, GSK, and BMS. The remaining authors have nothing to disclose.

### Acknowledgements

Dr. Charron and Legrand thank Miassa Slimani (CRA) for collecting data at Pitié-Salpêtrière hospital.

### References

[1] M. Bézard, A. Zaroui, M. Kharoubi, et al., Internalisation of immunoglobulin light chains by cardiomyocytes in AL amyloidosis: what can biopsies tell us? Amyloid 31 (2024) 209–219, https://doi.org/10.1080/13506129.2024.2373748.

[2] J.M. Griffin, H. Rosenblum, M.S. Maurer, Pathophysiology and therapeutic approaches to cardiac amyloidosis, Circ. Res. 128 (2021) 1554–1575, https://doi.org/10.1161/CIRCRESAHA.121.31817.

[3] M.D. Benson, J.N. Buxbaum, D.S. Eisenberg, et al., Amyloid nomenclature 2018: recommendations by the International Society of Amyloidosis (ISA) nomenclature committee, Amyloid 25 (2018) 215–219, https://doi.org/10.1080/13506129.2018.1549825.
[4] C. Rapezzi, G. Merlini, C.C. Quarta, et al., Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types, Circulation 120 (2009) 1203-1212, https://doi.org/10.1161/CIRCULATIONAHA.108.843334.

[5] T. Damy, G. Bourel, M. Slama, et al., Incidence and survival of transthyretil amyloid cardiomyopathy from a French nationwide study of in- and out-patient databases, Orphanet J. Rare Dis. 18 (1) (2023 Nov 6) 345, https://doi.org/10.1186/S13023-023-02933-W.

[6] T. Damy, A. Jaccard, A. Guellich, et al., Identification of prognostic markers in transthyretil and AL cardiac amyloidosis, Amyloid 23 (2016) 194-202, https://doi.org/10.1080/13506129.2016.1221815.

[7] J.D. Gillmore, T. Damy, M. Fontana, et al., A new staging system for cardiac transthyretil amyloidosis, Eur. Heart J. 39 (2018) 2799-2806, https://doi.org/10.1093/EURHEARTJ/EHX589.

[8] S. Law, A. Petrie, L. Chacko, et al., Disease progression in cardiac transthyretil amyloidosis is indicated by serial calculation of National Amyloidosis Centre transthyretil amyloidosis stage, ESC Heart Fail. 7 (2020) 3942-3949, https://doi.org/10.1002/EHF2.12989.

[9] S. Law, A. Petrie, L. Chacko, et al., Change in N-terminal pro-B-type natriuretic peptide at 1 year predicts mortality in wild-type transthyretil amyloid cardiomyopathy, Heart 108 (2022) 474-478, https://doi.org/10.1136/HEARTJNL-2021-319063.

[10] D. Bampatsias, A. Wardhere, M.S. Maurer, Treatment of transthyretil cardiac amyloidosis, Curr. Opin. Cardiol. 39 (5) (2024 Sep 1) 407-416, https://doi.org/10.1097/HCO.0000000000001156.

[11] D. Kim, J. Choi, E. Jeon, Tafamidis for cardiac transthyretil amyloidosis, Cardiovasc. Prev. Pharmacother. 3 (2021) 1-9.

[12] T. Coelho, G. Merlini, C.E. Bulawa, et al., Mechanism of action and clinical application of tafamidis in hereditary transthyretil amyloidosis, Neurol. Ther. 5 (1) (2016 Jun) 1-25, https://doi.org/10.1007/S40120-016-0040-X.

[13] C.E. Bulawa, S. Connelly, M. DeVit, et al., Tafamidis, a potent and selective transthyretil kinetic stabilizer that inhibits the amyloid cascade, Proc. Natl. Acad. Sci. U. S. A. 109 (2012) 9629-9634, https://doi.org/10.1073/PNAS.1121005109.

[14] M.S. Maurer, J.H. Schwartz, B. Gundapaneni, et al., Tafamidis treatment for patients with transthyretil amyloid cardiomyopathy, N. Engl. J. Med. 379 (2018) 1007-1016, https://doi.org/10.1056/NEJMOA1805689.

[15] T. Damy, P. Garcia-Pavia, M. Hanna, et al., Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretil Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension study, Eur. J. Heart Fail. 23 (2021) 277-285, https://doi.org/10.1002/EHFJ.2027.

[16] S. Oghina, C. Josse, M. Bézard, et al., Prognostic value of N-terminal pro-brain natriuretic peptide and high-sensitivity troponin T levels in the natural history of transthyretil amyloid cardiomyopathy and their evolution after tafamidis treatment, J. Clin. Med. 10 (21) (2021 Oct 22) 4868, https://doi.org/10.3390/jcm10214868.

[17] M. Hanna, T. Damy, M. Grogan, et al., Impact of Tafamidis on health-related quality of life in patients with transthyretil amyloid cardiomyopathy (from the Tafamidis in transthyretil cardiomyopathy clinical trial), Am. J. Cardiol. 141 (2021) 98-105, https://doi.org/10.1016/J.AMJCARD.2020.10.066.

[18] P. Garcia-Pavia, A.V. Kristen, B. Drachman, et al., Survival in a real-world cohort of patients with transthyretil amyloid cardiomyopathy treated with Tafamidis: an

analysis from the transthyretil amyloidosis outcomes survey (THAOS), J. Card. Fail. S1071-9164 (24) (2024 Jun 21) 00222-00227, https://doi.org/10.1016/J.CARDFAIL.2024.06.003.

[19] C. Rapezzi, P. Elliott, T. Damy, et al., Efficacy of Tafamidis in patients with hereditary and wild-type transthyretil amyloid cardiomyopathy: further analyses from ATTR-ACT, JACC Heart Fail. 9 (2021) 115-123, https://doi.org/10.1016/J.JCHF.2020.09.011.

[20] P. Elliott, B. Gundapaneni, M.B. Sultan, M. Ines, P. Garcia-Pavia, Improved long-term survival with tafamidis treatment in patients with transthyretil amyloid cardiomyopathy and severe heart failure symptoms, Eur. J. Heart Fail. 25 (2023) 2060-2064, https://doi.org/10.1002/EJHF.2974.

[21] B. Drachman, T. Damy, M. Hanna, R. Wang, F.S. Angeli, P. Garcia-Pavia, Long-term tafamidis efficacy in patients with transthyretil amyloid cardiomyopathy by baseline left ventricular ejection fraction, Eur. J. Heart Fail. 26 (9) (2024 Sep) 2038-2046, https://doi.org/10.1002/EJHF.3330.

[22] T.A. McDonagh, M. Metra, M. Adamo, et al., 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure, Eur. Heart J. 42 (2021) 3599-3726, https://doi.org/10.1093/EURHEARTJ/EHAB368.

[23] T. Damy, A. Zaroui, M. de Tournemire, et al., Changes in amyloidosis phenotype over 11 years in a cardiac amyloidosis referral centre cohort in France, Arch. Cardiovasc. Dis. 116 (2023) 433-446, https://doi.org/10.1016/J.ACVD.2023.07.003.

[24] A. Sarkar, A. Sanchez-Nadales, S.K. Kunutsor, M.A. Hanna, C.R. Asher, D. G. Wolinsky, Outcomes of octogenarian patients treated with Tafamidis for transthyretil amyloid cardiomyopathy, Am. J. Cardiol. 214 (2024) 144-148, https://doi.org/10.1016/J.AMJCARD.2023.08.036.

[25] P. Garcia-Pavia, M.B. Sultan, B. Gundapaneni, et al., Tafamidis efficacy among octogenarian patients in the phase 3 ATTR-ACT and ongoing long-term extension study, JACC Heart Fail. 12 (2024) 150-160, https://doi.org/10.1016/J.JCHF.2023.08.032.

[26] P. Garcia-Pavia, C. Rapezzi, Y. Adler, et al., Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC working group on myocardial and pericardial diseases, Eur. Heart J. 42 (2021) 1554-1568, https://doi.org/10.1093/EURHEARTJ/EHAB072.

[27] A. Ioannou, R.K. Patel, Y. Razvi, et al., Impact of earlier diagnosis in cardiac ATTR amyloidosis over the course of 20 years, Circulation 146 (2022) 1657-1670, https://doi.org/10.1161/CIRCULATIONAHA.122.060852.

[28] P. Debonnaire, K. Dujardin, N. Verheyen, et al., Tafamidis in octogenarians with wild-type transthyretil cardiac amyloidosis: an international cohort study, Eur. Heart J. 46 (11) (2025 Mar 13) 1057-1070, https://doi.org/10.1093/eurheartj/ehae923.

[29] E. Volpentesta, M. Kharoubi, C. Donadio, et al., Phenotype and prognostic factors in geriatric and non-geriatric patients with transthyretil cardiomyopathy, ESC Heart Fail. 11 (6) (2024 Dec) 3814-3832, https://doi.org/10.1002/EHF2.14793.

[30] K.M. Talha, A. Pandey, M. Fudim, J. Butler, S.D. Anker, M.S. Khan, Frailty and heart failure: state-of-the-art review, J. Cachexia. Sarcopenia Muscle 14 (2023) 1959-1972, https://doi.org/10.1002/JCSM.13306.

[31] A. Broussier, M. Paugam, N. Liu, et al., Frailty in heart failure according to the presence or absence of wild-type transthyretil cardiac amyloidosis, ESC Heart Fail. 12 (1) (2025 Feb) 281-289, https://doi.org/10.1002/EHF2.15026.