Hereditary transthyretin amyloidosis (hATTR), a rare and autosomal disease, can have a severe impact not only on patients’ health but also on their quality of life (QoL).
A study conducted by Yarlas et al found that “generic QOL [of patients with hATTR] was worse than that seen in the general population, with physical functioning worse than that for patients with multiple sclerosis and congestive heart failure.” The same study suggested that neuropathy‐specific QOL for patients with hATTR was similar to that of patients with type 2 diabetes with diabetic neuropathy.
In addition, an observational study conducted by Inês et al reported severe impairment of health status in patients with hATTR polyneuropathy, as well as more anxiety and depression. Half of the patients interviewed in another study were confirmed to have feelings of frustration and disappointment. Most patients also affirmed that the disease had a negative impact on their work.
However, the tools currently available to assess QoL in hATTR are not specific to the disease. Clinical scales are the main tool available to assess disease severity and outcomes. They measure functional parameters over time to determine the degree of functional impairment and limitations caused by the disease. Scales require office visits since they are compiled by clinicians.
On the other hand, patient-reported outcome measures (PROMs) are completed by patients, reflecting their perception of the disease. Despite being more subjective, the performance of PROMs in evaluating QoL and predicting survival is not inferior to that of clinical scales.
Assessing QoL in ATTR Clinical Trials
Both clinical scales and PROMs have been used to assess QoL in clinical trials, though PROMs are becoming the method of choice. They include measures of general health, as well as specific measures originally created for other cardiac or neurologic disorders. However, all present limitations when used to assess the QoL of patients with ATTR, as discussed by Alberto Aimo et al.
Several tools have been used to assess the general health status of patients with ATTR in clinical trials. The most used PROM is the 36-Item Short Form Survey (SF-36). However, the SF-36 does not measure sleep quality, which is considered an important indicator of health in amyloidosis due to the prevalence of sleep-disordered breathing. Moreover, it seems inadequate to stratify patients with low QoL.
The Euro QoL 5-Dimensions 3-Levels (EQ5D-3L) is a PROM that reflects patients’ perspectives on mobility, self-care, usual activities, pain or discomfort, and anxiety or depression. A newer version (EQ5D-5L) was developed to allow for additional answers and thus avoid a ceiling effect. The efficacy of EQ5D-3L in evaluating QoL in patients with heart failure with preserved ejection fraction is questionable, since it has mostly been used in studies that enrolled patients with heart failure with reduced ejection fraction.
The Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI-SH) investigates employment status, hours missed from work due to the disease, hours missed from work for other reasons, hours effectively worked, and degree of health-related impairment on daily activities. Hence, WPAI-SH cannot be used to assess unemployed patients and it is not appropriate to evaluate patients doing jobs that involve moderate to intense physical activity.
The Hospital Anxiety and Depression Scale has been used to assess anxiety and depression. However, many argue that it does not provide a complete picture of a patient’s depression as it focuses on the anhedonic domain of depression.
Tools originally developed for other diseases, such as the Karnofsky Performance Status Scale and the Patient Global Assessment (PtGA), have also been used. The Karnofsky Performance Status Scale was originally proposed to evaluate general well-being and functional impairment of people with cancer, but it lacks strict criteria for patients’ stratification, which results in high variability. The PtGA is a very simple measure originally proposed to evaluate pain in rheumatoid arthritis during follow-up. Therefore, it should be integrated with a broader and more accurate panel of evaluation.
The 10-meter walking test has been used to assess locomotor capacity and autonomy over a short distance. The Zarit Burden Interview is a questionnaire for caregivers to assess psychological suffering, financial difficulties, shame, guilt, and difficulties in social and family relationships related to caregiving.
The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item PROM that evaluates 6 domains (symptoms, symptom stability, physical functioning, social limitation, QoL, and self-efficacy). Several issues about the KCCQ have been raised which might compromise its use in ATTR clinical trials, including potentially misleading and redundant metrics.
The New York Heart Association (NYHA) classification is commonly used in phase 3 trials to classify patients’ heart failure, albeit a change in NYHA class has been rarely used as an endpoint in ATTR clinical trials. On the other hand, changes in the 6-minute walking test (6MWT), which is used to assess cardiorespiratory fitness, may be used as an endpoint in ATTR clinical trials. However, it seems to correlate with peripheral neuropathy instead of the severity of cardiac involvement in patients with hATTR.
The new version of the Rasch-built Overall Disability Scale (R-ODS), the Familial Amyloid Polyneuropathy specific Rasch-built Overall Disability Scale (FAP-RODS), and 2 variants of the Neuropathy Impairment Score (NIS), mNIS+7Alnylam and the mNIS+7Ionis, were specifically developed to assess the impact of ATTR-associated neuropathy on QoL.
FAP-RODS aims to investigate limitations in physical and social activities. However, the FAP-RODS was only tested in Portugal and the source population was limited to subjects with the Val30Met mutation. Thus, its relevance in patients with other mutations is still unclear.
The Norfolk QoL-Diabetic Neuropathy (QoL-DN) Questionnaire has also been recently validated for hATTR patients with the Val30Met mutation. It has been used in many clinical trials to assess physical functioning, daily life activities, symptoms, small-fiber neuropathy, and autonomic neuropathy.
Other tools that have been used include the Polyneuropathy Disability score (PND), the Kumamoto Neurologic Scale, and the COMPosite Autonomic Symptom Scale 31 (COMPASS-31) Questionnaire. The PND has proved to be useful as a first approach to assess ATTR-related neuropathy. However, it is not an accurate measure of a patient’s clinical status and does not reflect deterioration in neurological function. Studies have shown that patients with amyloidosis can spend up to 5 years with the same score.
The Kumamoto Neurologic Scale is sometimes used in combination with the NIS. Its use as standalone measure is uncommon as it lacks any psychometric analysis. The COMPASS-31 is useful to evaluate dysautonomia, but it is not sufficient to estimate the degree of ATTR-associated polyneuropathy per se.
New Measures on the Horizon
Developing new appropriate measures to assess QoL in patients with ATTR is imperative and they should consider the different forms of ATTR as mentioned by Alberto Aimo et al. “Since ATTRwt and ATTRv amyloidosis are highly heterogeneous, different QoL metrics should be available for these 2 conditions and should allow a global evaluation of the burden of cardiac disease, neurologic impairment and other systemic comorbidities,” they said.
The heterogeneous nature of the disease makes it difficult to identify a single measure or a set of measures able to cover all symptoms. Only one clinical trial (NCT04563286) is currently ongoing, with the main goal of developing and validating 2 specific PROMs for hATTR and wild-type ATTR.
Aimo A, Rapezzi C, Perfetto F, et al. Quality of life assessment in amyloid transthyretin (ATTR) amyloidosis. Eur J Clin Invest. 2021;51(11):e13598. doi:10.1111/eci.13598
Inês M, Coelho T, Conceição I, Ferreira L, de Carvalho M, Costa J. Health-related quality of life in hereditary transthyretin amyloidosis polyneuropathy: a prospective, observational study. Orphanet J Rare Dis. 2020;15(1):67. doi:10.1186/s13023-020-1340-x
Yarlas A, Gertz MA, Dasgupta NR, et al. Burden of hereditary transthyretin amyloidosis on quality of life. Muscle Nerve. 2019;60(2):169-175. doi:10.1002/mus.26515