Frailty and associated outcomes in patients with transthyretin cardiac amyloidosis
Authors: Fumagalli C , Ioannou A , Cappelli F , Razvi Y , Porcari A , Rauf M , Martinez-Naharro A , Venneri L , Whelan C , Hawkins P , Marfella R , Ungar A , Marchionni N , Gillmore J , Fontana M 
Published: October 2024

Abstract

Introduction
Despite older age at diagnosis, the prevalence and clinical impact of frailty, an age-related geriatric syndrome, in patients with transthyretin cardiac amyloidosis (ATTR-CA) is poorly described.

Purpose
To determine: (1) the prevalence of frailty in ATTR amyloidosis patients; (2) the clinical frailty phenotype in ATTR amyloidosis (3) the independent and incremental prognostic value of frailty.

Methods
All consecutive patients diagnosed with ATTR-CA who underwent frailty assessment at two high-volume tertiary care centres from September 2019 to April 2023 were included in the study. Functional assessment was performed with the Rockwood Clinical Frailty Scale (CFS), an established frailty screening tool that stratifies patients on a nine-point scale ranging from 1 (very well) to 9 (terminally ill) providing a useful measure of physiological reserve.
Frailty was defined as CFS &gt;4. Functional status was further categorized as follows: 'non-frail' (CFS 1-3), ‘mild’ frailty (CFS 4-5), and 'moderate-to-severe' frailty (CFS 6-9). Logistic regression analysis was used to identify factors associated with CFS 6-9. Cox regression analysis was used to determine the independent and incremental prognostic value of frailty.

Results
The study comprised 880 patients with ATTR-CA (719 [81.7%] with wt-ATTR-CA, 85 [9.7%] with p.(V142I) hATTR-CA and 76 [8.6%] with a non-p.(V142I) hATTR-CA. Overall, 43.0% (N=378) were considered ‘non-frail’ (CFS 1-3). Prevalence of ‘mild’ frailty (CFS 4-5) was 41.4% (N=364), while prevalence of 'moderate-to-severe' frailty (CFS 6-9) was 15.7% (N=138).
Frail patients were older, more symptomatic and with advanced disease stage as assessed with the National Amyloidosis Centre (NAC) staging system. At logistic regression analysis, age, female gender, non-p.(V142I) variants and NAC stage were associated with 'moderate-to-severe' frailty. Over a median 22 months, 16.8% died, with mortality rising with higher CFS levels. At Cox multivariable analysis, CFS was strongly associated with mortality (CFS 4-5 vs 1-3: Hazard Ratio [HR] 2.821, 95% C.I. 1.724-4.613; CFS 6-9 vs 1-3: HR 6.179, 95% C.I. 3.694-10.335, overall p-value&lt;0.001), along with NAC stage and age. The addition of CFS to the NAC staging system significantly improved the goodness-of-fit of the model (X2: 73.26, p&lt;0.00001), and significantly improved the discriminatory ability of the NAC alone (Figure, Harrell’s C statistics: 0.78, 95% C.I. [0.72-0.83] vs 0.69, 95% C.I. [0.64-0.75], p&lt;0.0001).

CONCLUSION
Frailty is highly prevalent in patients with ATTR-CA, with up to 57% of patients living with some degree of frailty. Older age, female gender, non-p.(V142I) hATTR-CA variants and advanced disease stage were independently associated with moderate to severe frailty. Frailty was independently associated with all-cause mortality after adjusting for known predictors and increased the global predictivity of the NAC Score.Survival by Frailty Status and NAC