Key Data

Decline in Quality of Life

Both ATTRv-CM and ATTRwt-CM are associated with markedly poor QOL at the time of diagnosis, and the direction of change of QOL scores was overwhelmingly negative in all cohorts and for all domains with the fastest decline in ATTRv patients [2]

Study of ATTR-CM patients at the UK NAC between 2000 and 2017

(n = 711 patients with ATTRwt-CM, 205 with V122I-ATTRv-CM, and 118 with) non-V122I-ATTRv-CM

Patients with V122I-ATTRv-CM were more impaired functionally (and had worse measures of cardiac disease at the time of diagnosis, a greater decline in QOL, and poorer survival (P<0.001) in comparison with the other subgroups
Overall KCCQ domain scores within the first 12 months of diagnosis, obtained from 158 patients, showed poor HRQOL across all 3 genotypic subgroups of ATTR-CM
- The lowest scoring domains were physical limitation, social limitation, and symptom stability in all 3 cohorts
The magnitude and direction of change of QOL scores in each domain were measured in each cohort between 12 and 36 months. The direction of change of QOL scores was overwhelmingly negative in all cohorts and for all domains.

Notably, overall QOL scores appeared to worsen more rapidly in ATTRv-CM than ATTRwt-CM, likely due to the impact of neuropathy present in 96% of non–V122I-ATTRv-CM study patients, on physical performance and QoL, coupled with the generally poorer outcomes in V122I-ATTRv-CM than in ATTRwt-CM

KCCQ QOL Scores 12-36 Mos. Following Dx (n=158)

Overall summary score = clinical summary score + QOL score + social limitation score; a median difference of 5 points on the overall summary score is considered a clinically significant change

HRQOL as measured by the KCCQ in 158 patients within the first 12 months of diagnosis stratified by genotype

(A score of 100 indicates perfect health)

Notes: IQR = interquartile range; KCCQ = Kansas City Cardiomyopathy Questionnaire; NAC = National Amyloidosis Center; HRQOL = health related quality of life

Notes: Study of 711 patients with wild-type ATTR-CM, 205 with V122I-ATTRv-CM at the UK National Amyloidosis Center between 2000 and 2017.

Lane, T, et al. May 21, 2019. Natural History, Quality of Life, and Outcome in Cardiac Transthyretin Amyloidosis. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.038169.
ALXN: ATTR Amyloidosis: Epidemiology Dossier. Elissa Wilker & Shona Fang. September 2021. 18_ATTR Amyloidosis Epi Dossier.

Quality of Life: 6MWT & Health Service Usage

The UK NAC study also reported a decline in 6MWT over 36 months, and significant health service usage both pre- and post-diagnosis

Study of ATTR-CM patients at the UK NAC between 2000 and 2017

(n = 711 patients with ATTRwt-CM, 205 with V122I-ATTRv-CM, and 118 with non-V122I-ATTRv-CM)

6MWT change over time among ATTRwt patients

Mean range in decline in 6MWT over 2 years was approximately 100m (80-111) across all genotypic subgroups assessed

The mean (range) rates of decline in eGFR and decline in 6MWT distance from baseline over the course of 2 years were remarkably consistent between genotypic subgroups

Hospital service usage following diagnosis for all ATTR-CM subtypes

Median No. of hospital inpatient episodes (admissions) per patient was 2, with 30% of patients admitted as inpatients to hospital at least 3 times during the period
Median No. of outpatient visits = 8
Median No. of ER visits = 1

Hospital service usage pre- and post-diagnosis*

Median No. of hospital inpatient admissions per surviving patient was 2 in the 2nd year after Dx and 3 in the 3rd year after Dx with no difference between genotypic subgroups [1,2]

Notes: 6MWT = 6-minute walk test; eGFR = estimated glomerular filtration rate; NAC = National Amyloidosis Center; QoL = quality of life

Notes: Study of 711 patients with wild-type ATTR-CM, 205 with V122I-ATTRv-CM, and 118 with non-V122I-ATTRv-CM at the UK National Amyloidosis Center between 2000 and 2017.

Notes: * Data demonstrate huge delays in establishing the diagnosis of ATTR-CM following presentation with cardiac symptoms, this taking >4 years in >40% patients with ATTRwt-CM on a background of a median 17 hospital attendances during the 3 years before diagnosis. This long delay in the face of a progressive disease is likely to have contributed to the identified poor QoL by the time diagnosis was finally established.

Lane, T, et al. May 21, 2019. Natural History, Quality of Life, and Outcome in Cardiac Transthyretin Amyloidosis. Circulation 2019;140:16–26. DOI: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.038169.

Characterizing the High Disease Burden

Investigations into the QOL of people living with ATTR typically employ approaches utilizing validated quantitative instruments (e.g., the KCCQ), and have reported a lower QOL vs. the general population and to people living with other long-term, chronic diseases [1,2]

Indeed, ATTR has a severe impact on QOL as confirmed by many observational studies, e.g.:

ATTR-CM only (hereditary & wild-type)*

In a small US study, patients with ATTR-CM alone (n = 6) or both ATTR-CM and ATTR-PN (n = 11) completed the KCCQ [a]
The overall mean score was 43.2 ± 20.0, which roughly aligns with the NYHA class IV criteria of “severe limitations; experiences symptoms even while at rest; mostly bedbound patients”
Overall scores were lower (worse) for patients with ATTR-CM alone than for those with both types of ATTR amyloidosis (CM & PN) [3]

In the same study, all ATTR** patients who completed the SF-36 also reported scores up to 2 standard deviations below those seen in the general population for physical health, QoL, and work productivity [3]

ATTR Caregivers

Caregivers (n=32) who completed the ZBI [b] questionnaire also reported poor mental health, poor work productivity, and a considerable amount of time required to provide care (mean, 45.9 hours/week) [3]

Compare ATTRv only (CM &/or PN)

In a separate report on ATTRv (n=172), generic QoL, as measured with the SF-36, was also worse than that seen in the general population, and physical functioning was worse than that for patients with multiple sclerosis and congestive HF [4]
The neuropathy-specific QoL for patients with ATTRv was nearly equivalent to that of patients with type 2 diabetes with diabetic neuropathy accompanied by a history of ulceration, gangrene, or amputation [4]

. . . however, limited attention has been paid to QoL so far,
and no specific tools for QoL assessment in ATTR amyloidosis currently exist

Notes: CM = cardiomyopathy; KCCQ = Kansas City Cardiomyopathy Questionnaire; NYHA = New York Heart Association; PN = polyneuropathy; QOL = quality of life; SF-36 = 36-Item Short Form Health Survey; ZBI = Zarit Burden Interview

Notes: * Patients and caregivers in the USA and Spain were recruited through patient advocacy groups to complete a cross-sectional survey. Assessments included the 12-Item Short Form Health Survey, the Work Productivity and Activity Impairment Questionnaire, the Zarit Burden Interview, pain and symptom measures, health care resource use measures, and caregiving burden measures. Respondents included 60 ATTR amyloidosis patients and 32 caregivers. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item patient-completed questionnaire that assesses health status and health-related QOL in patients with HF was given to ATTR-CM patients only.

Notes: ** Includes all patients, ATTRwt, and ATTRv CM and/or PN.3

Notes: *** As measured with the Norfolk QOL-Diabetic Neuropathy questionnaire.4

Rintell, D., Heath, D., Braga Mendendez, F. et al. Patient and family experience with transthyretin amyloid cardiomyopathy (ATTR-CM) and polyneuropathy (ATTR-PN) amyloidosis: results of two focus groups. Orphanet J Rare Dis 16, 70 (2021). https://doi.org/10.1186/s13023-021-01706-7.
Gertz, M., Adams, D., Ando, Y. et al. Avoiding misdiagnosis: expert consensus recommendations for the suspicion and diagnosis of transthyretin amyloidosis for the general practitioner. BMC Fam Pract 21, 198 (2020). https://doi.org/10.1186/s12875-020-01252-4
Stewart M, et al. Characterizing the High Disease Burden of Transthyretin Amyloidosis for Patients and Caregivers. Neurol Ther. 2018 Dec; 7(2):349-364. Patients and caregivers in the USA and Spain were recruited through patient advocacy groups to complete a cross-sectional survey. Assessments included the 12-Item Short Form Health Survey, the Work Productivity and Activity Impairment Questionnaire, the Zarit Burden Interview, pain and symptom measures, health care resource use measures, and caregiving burden measures. Respondents included 60 ATTR amyloidosis patients and 32 caregivers.
Yarlas A, et al. Burden of hereditary transthyretin amyloidosis on quality of life. Muscle Nerve. 2019 Aug; 60(2):169-175.
Aimo A, et al. Quality of life assessment in amyloid transthyretin (ATTR) amyloidosis. Eur J Clin Invest. 2021;51:e13598. DOI: https://doi.org/10.1111/eci.13598.

Limitations on Existing QOL Assessment Tools

Clinical trials on ATTR amyloidosis have used measures of general health status (e.g., SF-36), tools developed in other disease settings (e.g., KCCQ), or adaptations of other scales; however, limitations exist

Notes: CHF = chronic heart failure; COMPASS-31 = COMPosite Autonomic Symptom Scale 31 Questionnaire; EQ5D-3L = Euro QoL 5-Dimensions 3-Levels Questionnaire; HADS = Hospital Anxiety and Depression Scale; Karnofsky = Karnofsky Performance Scale; KCCQ = Kansas City Cardiomyopathy Questionnaire; NIS = Neuropathy Impairment Score; PGA = Patient General Assessment; PN = peripheral neuropathies; PND = PolyNeuropathy Disability score; PROMs = patient-related outcome measures; QoL-DN = Norfolk QoL-Diabetic Neuropathy Questionnaire; R-ODS = Rasch-built Overall Disability Scale; SF-36 = 36-Item Short Form Survey; WPAI-SH = Work Productivity and Activity Impairment Questionnaire: Specific Health Problem

Aimo A, et al. Quality of life assessment in amyloid transthyretin (ATTR) amyloidosis. Eur J Clin Invest. 2021;51:e13598. DOI: https://doi.org/10.1111/eci.13598.

No ATTR-Specific QOL Assessment Tools

Scales or PROMs for ATTR would be useful to better characterize newly diagnosed patients, and assess disease progression and Tx response, as no specific tools for QOL assessment in ATTR currently exist; the ongoing ITALY study aims to develop such PROMs

The ongoing ITALY (Impact of Transthyretin Amyloidosis on Life qualitY) study aims to develop and validate 2 PROMs** encompassing the whole phenotypic spectrum of ATTRwt and ATTRv for patient management and possible surrogate endpoints for clinical trials:

At study entry, patients are asked to fill the new PROM, the SF-36, and the KCCQ; NYHA, 6MWT distance, NT-proBNP, and high-sensitivity troponin are also determined, and patients undergo a transthoracic echocardiogram
Patients are then classified according to the occurrence of HF hospitalization over 6 months
- Patients who are hospitalized for HF enter the responsiveness cohort and repeat the baseline examinations at the time of hospitalization
- Conversely, patients who are not hospitalized for 6 months after enrolment are re-evaluated at 6 months and enter the reliability cohort

Scales and PROMs are reported in italic and in bold, respectively

The goal is to assess whether score values change during an HF hospitalization or display limited variations when patients remain clinically stable—the same design was used to develop the KCCQ

Notes: 6MWT = 6-minute walking distance; HF = heart failure; KCCQ = Kansas City Cardiomyopathy Questionnaire; NT-proBNP = N-terminal pro-B-type natriuretic peptide; NYHA = New York Heart Association; PROMs = patient-related outcome measures; SF-36 = 36-Item Short Form Survey

Notes: ATTR clinical trials have used measures of general health status (e.g., SF-36), tools developed in other disease settings (e.g., KCCQ), or adaptations of other scales

Notes: ** A panel of cardiologists, internal medicine specialists, neurologists, rare disease specialists, geriatricians and health management specialists selected the most clinically relevant domains for patients with ATTRwt or ATTRv amyloidosis independently. They then chose 10 items for each domain. Afterwards, 2 groups of 25 patients with ATTRwt or ATTRv amyloidosis were selected trying to recapitulate the full spectrum of these conditions, including the cardiac, neurologic and mixed phenotypes of ATTRv amyloidosis. Patients were asked to grade the relevance of each item from 1 to 10. In this way, the 30 most relevant items for ATTRwt or ATTRv amyloidosis were identified. A question was created for each item, resulting in 2 sets of 30 questions with 5 possible answers.

Aimo A, et al. Quality of life assessment in amyloid transthyretin (ATTR) amyloidosis. Eur J Clin Invest. 2021;51:e13598. DOI: https://doi.org/10.1111/eci.13598.

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