Study design and patient population
The study design and eligibility criteria of THAOS have been described . All study sites received ethical or institutional review board approval prior to patient enrollment, and each patient provided written informed consent. The study followed the Good Pharmacoepidemiology Practice guidelines and the principles of the Declaration of Helsinki.
The analysis population consisted of all patients enrolled in THAOS (data cutoff date: August 1, 2021). Symptomatic patients were those with at least one symptom reported as definitely related to ATTR amyloidosis at enrollment. Asymptomatic gene carriers were those with a pathogenic disease-causing TTR genetic variant and no definitely ATTR amyloidosis–related symptom at enrollment, with the requirement that all symptoms be assessed at enrollment. Patients with no definitely ATTR amyloidosis–related symptoms at enrollment who were not assessed for all symptoms were considered to have a missing symptomatic status.
Demographics, clinical characteristics, and patient-reported outcomes collected at enrollment were analyzed in the overall cohort of symptomatic patients and by the following genotype subgroups: ATTRwt amyloidosis; Val30Met with early-onset disease (age ≤ 50 years, based on age at diagnosis); Val30Met with late-onset disease (age > 50 years); ‘cardiac mutations’ (Val122Ile [p.Val142Ile] , Leu111Met [p.Leu131Met] , Thr60Ala [p.Thr80Ala] , and Ile68Leu [p.Ile88Leu] ); and non-Val30Met excluding cardiac mutations.
Phenotype at enrollment was further analyzed in symptomatic patients by region (North America, South America, Europe, and Asia). Phenotype categories were defined as follows: Predominantly cardiac included patients with at least one of the following symptoms: heart failure, dyspnea, or abnormal electrocardiogram due to rhythm disturbance, and no more than mild neurologic or gastrointestinal (GI) symptoms (excluding erectile dysfunction, constipation, and carpal tunnel syndrome); cardiac symptoms did not need to be ongoing at a given visit. Predominantly neurologic included patients with neurologic or GI symptoms of any severity without heart failure, dyspnea, or abnormal electrocardiogram due to rhythm disturbance; neurologic and GI symptoms had to be ongoing. Mixed included patients with heart failure, dyspnea, or abnormal electrocardiogram due to rhythm disturbance and neurologic or GI symptoms of any severity but did not satisfy the criteria for predominantly cardiac or predominantly neurologic. No phenotype included all other symptomatic patients who did not meet criteria for any of these phenotypes. All patients with ATTRwt amyloidosis were classified as predominantly cardiac unless they had any neurologic symptoms definitely related to ATTR amyloidosis, in which case they were classified as mixed phenotype.
Symptoms at baseline were categorized as autonomic neuropathy, cardiac disorder, gastrointestinal manifestations, motor neuropathy, sensory neuropathy, and other. Autonomic neuropathy included dizziness, palpitations, dry eye, constipation, diarrhea, diarrhea/constipation, early satiety, fecal incontinence, nausea, vomiting, recurrent urinary tract infections, urinary incontinence, urinary retention, dyshidrosis, and erectile dysfunction; cardiac disorder included coronary artery disease, dyspnea, heart failure, myocardial infarction, rhythm disturbance, syncope, arterial hypertension, cardiomyopathy, and other cardiovascular disease. Gastrointestinal manifestations included constipation, diarrhea, diarrhea/constipation, early satiety, fecal incontinence, nausea, unintentional weight loss, and vomiting. Motor neuropathy included muscle weakness and walking disability. Sensory neuropathy included balance abnormality, neuropathic arthropathy, neuropathic pain/paresthesia, numbness, temperature or pain insensitivity, and tingling. Symptom categories were not mutually exclusive.
Demographics collected at enrollment were also analyzed in the overall cohort of asymptomatic gene carriers and by genotype category (Val30Met, cardiac mutations, and non-Val30Met excluding cardiac).
Patients’ ability to perform normal daily life activities and their need for assistance was assessed in symptomatic patients using the Karnofsky Performance Status Scale score, ranging from 10 (moribund; fatal processes progressing rapidly) to 100 (normal; no complaints). Neurologic impairment was measured in symptomatic patients using the derived Neuropathy Impairment Score in the Lower Limbs (NIS-LL; ranges from 0 to 88) . Higher scores indicate greater impairment, and the NIS-LL scale includes reflex, motor, and sensory subscales. Modified Polyneuropathy Disability (mPND) scores were analyzed in symptomatic patients with a predominantly neurologic or mixed phenotype. The mPND score is a measure of walking disability and ranges from 0 to IV, where 0 indicates no sensory disturbances in the feet and able to walk without difficulty; I indicates sensory disturbance in the feet but preserved walking capacity; II indicates some difficulties walking, but can walk without aid; IIIa indicates 1 stick or crutch required for walking; IIIb indicates 2 sticks or crutches required for walking; and IV indicates patients confined to a wheelchair or bed.
Measures of cardiac disease in symptomatic patients were left ventricular (LV) septal thickness and LV ejection fraction. Additional cardiac findings, including troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and New York Heart Association (NYHA) functional class, were analyzed in symptomatic patients with a predominantly cardiac or mixed phenotype.
Quality of life (QoL) was assessed in symptomatic patients using the EQ-5D-3L and the Norfolk Quality of Life – Diabetic Neuropathy questionnaire. The EQ-5D-3L is a measure of self-reported health status. The first part assesses health on five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each with three levels: no problems, some problems, extreme problems/unable to. Health state profiles are assigned a summary index score ranging from 0 (death) to 1 (perfect health). The second part is a visual analog scale on which participants rate perceived health from 0 (worst) to 100 (best). The 35-item Norfolk Quality of Life – Diabetic Neuropathy questionnaire assesses diabetic neuropathy across five domains: physical functioning/large fiber neuropathy, activities of daily living, symptoms, small-fiber neuropathy, and autonomic neuropathy. Scores range from − 4 to 136, with higher scores indicating worse QoL.
This was a descriptive analysis. Continuous data are presented as mean (standard deviation [SD]) or median (10th, 90th percentile), and categorical data are presented as count (percentage).