Transthyretin Amyloidosis Outcomes Survey Research Articles

Clinical and Genotype Characteristics and Symptom Migration in Patients With Mixed Phenotype Transthyretin Amyloidosis from the Transthyretin Amyloidosis Outcomes Survey.

Transthyretin amyloidosis (ATTR amyloidosis) is primarily associated with a cardiac or neurologic phenotype, but a mixed phenotype is increasingly described. This study describes the mixed phenotype cohort in the Transthyretin Amyloidosis Outcomes Survey (THAOS). THAOS is an ongoing, longitudinal, observational survey of patients with ATTR amyloidosis, including both hereditary (ATTRv) and wild-type disease, and asymptomatic carriers of pathogenic transthyretin variants. Baseline characteristics of patients with a mixed phenotype (at enrollment or reclassified during follow-up) are described (data cutoff: January 4, 2022). Approximately one-third of symptomatic patients (n = 1185/3542; 33.5%) were classified at enrollment or follow-up as mixed phenotype (median age, 66.5years). Of those, 344 (29.0%) were reclassified to mixed phenotype within a median 1-2years of follow-up. Most patients with mixed phenotype had ATTRv amyloidosis (75.7%). The most frequent genotypes were V30M (38.9%) and wild type (24.3%). These THAOS data represent the largest analysis of a real-world mixed phenotype ATTR amyloidosis population to date and suggest that a mixed phenotype may be more prevalent than previously thought. Patients may also migrate from a primarily neurologic or cardiologic presentation to a mixed phenotype over time. These data reinforce the need for multidisciplinary evaluation at initial assessment and follow-up of all patients with ATTR amyloidosis. ClinicalTrials.gov: NCT00628745.

A 15-year consolidated overview of data in over 6000 patients from the Transthyretin Amyloidosis Outcomes Survey (THAOS)

BackgroundTransthyretin amyloidosis (ATTR amyloidosis) is a progressive, multisystemic, life-threatening disease resulting from the deposition of variant or wild-type (ATTRwt amyloidosis) transthyretin amyloid fibrils in various tissues and organs.MethodsEstablished in 2007, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is the largest ongoing, global, longitudinal, observational study of patients with ATTR amyloidosis, including both hereditary and wild-type disease, and asymptomatic carriers of pathogenic TTR mutations. This analysis describes the baseline characteristics of symptomatic patients and asymptomatic gene carriers enrolled in THAOS since its inception in 2007 (data cutoff: August 1, 2022), providing a consolidated overview of 15-year data from the THAOS registry.ResultsThis analysis included 4428 symptomatic patients and 1707 asymptomatic gene carriers. The majority of symptomatic patients were male (70.8%) with a mean (standard deviation [SD]) age at symptom onset of 56.6 (17.9) years. Compared with the 14-year analysis, V30M remained the most prevalent genotype in Europe (62.2%), South America (78.6%), and Japan (74.2%) and ATTRwt remained most common in North America (56.2%). Relative to the 14-year analysis, there was an increase of mixed phenotype (from 16.6 to 24.5%) and a reduction of predominantly cardiac phenotype (from 40.7 to 31.9%). The proportion of patients with predominantly neurologic phenotype remained stable (from 40.1 to 38.7%). Asymptomatic gene carriers were 58.5% female with a mean age at enrollment of 41.9 years (SD 15.5).ConclusionsThis overview of > 6000 patients enrolled over 15 years in THAOS represents the largest registry analysis of ATTR amyloidosis to date and continues to emphasize the genotypic and phenotypic heterogeneity of the disease. Nearly a quarter of the symptomatic population within THAOS was mixed phenotype, underscoring the need for multidisciplinary management of ATTR amyloidosis.Trial registrationClinicalTrials.gov Identifier: NCT00628745.

Genetic and clinical characteristics of transthyretin cardiac amyloidosis in Koreans

Abstract Background/Introduction Transthyretin amyloidosis with mutations (aTTRv amyloidosis) have over 100 recognized pathogenic mutations of the TTR gene and its clinical manifestations are very heterogenous. Through the global THAOS (Transthyretin Amyloidosis Outcomes Survey) patient registry, different and several types of mutants and clinical differences have been identified. Awareness of aTTRv amyloidosis is now becoming somewhat significant amongst physicians all over the world. This is a detailed look at such efforts in Korea. Purpose We aimed to seek the geologic significance of aTTRv amyloidosis in South Korea. Methods This was an analysis of 638 Korean amyloidosis patients in a single center over a period of 16 years from 1995 to October 2021. 95 individuals were found with aTTR mutations. Results aTTRv amyloidosis constituted 14.8% (n=95) of amyloidosis patients, and the most commonly involved organ being the heart (61.7%, n=58). Unlike the rest of the world, the mixed phenotype was most common (51.0%, n=48) in Korea and the most universal mutation in Koreans were Asp38Ala, which only constitutes about 1.0% in the THAOS registry. Val30Met mutation, which comprises 76% of the mutation in the THAOS registry, was mostly associated the neurologic phenotypes. However, the same mutations in Korea mixed phenotypes with cardiac (38.4%) and neurologic (37%) symptoms. Conclusion aTTRv amyloidosis in Korea is different from other patients worldwide. The mixed phenotype was most common, emphasizing the need for heart failure management in the Korean population. Genotype wise, Koreans held a less common mutation of Asp38Ala. The most common mutation of Val30Met was more likely to be associated cardiac symptoms, which concurs with other studies that suggesting that geological features are more important than mutations itself. Funding Acknowledgement Type of funding sources: None.

A natural history analysis of asymptomatic TTR gene carriers as they develop symptomatic transthyretin amyloidosis in the Transthyretin Amyloidosis Outcomes Survey (THAOS)

Background Hereditary transthyretin amyloidosis (ATTRv amyloidosis) results from pathogenic mutations in the transthyretin (TTR) gene. This analysis aimed to better understand ATTRv amyloidosis development in asymptomatic TTR gene carriers. Methods The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both inherited and wild-type disease, and asymptomatic TTR gene carriers. Asymptomatic TTR gene carriers were assessed longitudinally to identify those who developed ATTRv amyloidosis after enrolment in THAOS (data cut-off: 1 August 2021). Results Of 740 asymptomatic TTR gene carriers, 268 (36.2%) (Val30Met, 212/613 [34.6%]; non-Val30Met, 48/111 [43.2%]) developed ATTRv amyloidosis within a median 2.2 years after enrolment. The most common first symptoms were sensory (49.5%) and autonomic (37.3%) neuropathy in Val30Met patients, and sensory neuropathy (45.8%) and cardiac disorder (22.9%) in non-Val30Met patients. Most patients first presented with a predominantly neurologic phenotype (Val30Met, 77.8%; non-Val30Met, 70.8%). Conclusions More than one-third of asymptomatic TTR gene carriers in THAOS developed ATTRv amyloidosis within a median 2 years of enrolment. Val30Met versus non-Val30Met patients had a lower transition rate. Given the importance of early treatment, these findings underscore the need for identification and careful monitoring of at-risk TTR gene carriers to enable prompt treatment. Trial registration ClinicalTrials.gov: NCT00628745.

Clinical and genetic profile of patients enrolled in the Transthyretin Amyloidosis Outcomes Survey (THAOS): 14-year update

BackgroundTransthyretin amyloidosis (ATTR amyloidosis) is a rare, life-threatening disease caused by the accumulation of variant or wild-type (ATTRwt amyloidosis) transthyretin amyloid fibrils in the heart, peripheral nerves, and other tissues and organs.MethodsEstablished in 2007, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is the largest ongoing, global, longitudinal observational study of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic carriers of pathogenic TTR mutations. This descriptive analysis examines baseline characteristics of symptomatic patients and asymptomatic gene carriers enrolled in THAOS since its inception in 2007 (data cutoff: August 1, 2021).ResultsThis analysis included 3779 symptomatic patients and 1830 asymptomatic gene carriers. Symptomatic patients were predominantly male (71.4%) and had a mean (standard deviation [SD]) age of symptom onset of 56.3 (17.8) years. Val30Met was the most common genotype in symptomatic patients in South America (80.9%), Europe (55.4%), and Asia (50.5%), and more patients had early- versus late-onset disease in these regions. The majority of symptomatic patients in North America (58.8%) had ATTRwt amyloidosis. The overall distribution of phenotypes in symptomatic patients was predominantly cardiac (40.7%), predominantly neurologic (40.1%), mixed (16.6%), and no phenotype (2.5%). In asymptomatic gene carriers, mean (SD) age at enrollment was 42.4 (15.7) years, 42.4% were male, and 73.2% carried the Val30Met mutation.ConclusionsThis 14-year global overview of THAOS in over 5000 patients represents the largest analysis of ATTR amyloidosis to date and highlights the genotypic and phenotypic heterogeneity of the disease.ClinicalTrials.gov Identifier: NCT00628745.

Sex Differences in Wild-Type Transthyretin Amyloidosis: An Analysis from the Transthyretin Amyloidosis Outcomes Survey (THAOS).

IntroductionWild-type transthyretin amyloidosis (ATTRwt amyloidosis) is a progressive disease resulting from the accumulation of wild-type transthyretin (TTR) amyloid fibrils, and is diagnosed primarily in males. This analysis examined sex differences in patients with ATTRwt amyloidosis from the Transthyretin Amyloidosis Outcomes Survey (THAOS).MethodsTHAOS is an ongoing, global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both inherited and wild-type disease, and asymptomatic carriers of TTR mutations. THAOS data were analyzed to identify potential differences in demographic and clinical characteristics between males and females with ATTRwt amyloidosis (data cutoff: August 1, 2021).ResultsOf 1386 patients with ATTRwt amyloidosis, 84 (6%) were female and 1302 (94%) were male. Females had a higher median age at enrollment (80 vs. 78 years; p = 0.002) and symptom onset (75 vs. 73 years; p = 0.045) than males. Mean left ventricular (LV) ejection fraction was higher (53% vs. 48%; p = 0.001) and mean LV diastolic diameter lower (42 vs. 46 mm; p < 0.001) in females versus males, but sex was not identified as a predictor of LV mean wall thickness adjusted for height (beta coefficient − 0.22; p = 0.460) or a predominantly cardiac phenotype (odds ratio 1.60; p = 0.191). Modified polyneuropathy disability scores differed between groups (p < 0.001), with a larger proportion of scores ≥ IIIa among females (23% vs. 7%).ConclusionsFemales with ATTRwt amyloidosis in THAOS tended to present at a later age and showed signs of less severe cardiac impairment and more severe walking impairment.Trial RegistrationClinicalTrials.gov: NCT00628745.

Characteristics of patients with autonomic dysfunction in the Transthyretin Amyloidosis Outcomes Survey (THAOS)

Background Autonomic dysfunction is common in transthyretin amyloidosis (ATTR amyloidosis), but its frequency, characteristics, and quality-of-life (QoL) impact are not well understood. Methods The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal survey of patients with ATTR amyloidosis, including patients with inherited (ATTRv) and wild-type (ATTRwt) disease and asymptomatic patients with TTR mutations (ClinicalTrials.gov: NCT00628745). In a descriptive analysis, characteristics and Norfolk QoL-DN total (TQoL) scores at enrolment were compared in patients with vs without autonomic dysfunction (analysis cut-off: 1 August 2020). Results Autonomic dysfunction occurred in 1181/2922 (40.4%) symptomatic patients, and more commonly in ATTRv (1107/1181 [93.7%]) than ATTRwt (74/1181 [6.3%]) amyloidosis. Time (mean [SD]) from ATTR amyloidosis symptom onset to first autonomic dysfunction symptom was shorter in ATTRv (3.4 [5.7] years) than ATTRwt disease (9.7 [10.4]). In ATTRv disease, patients with vs without autonomic dysfunction had worse QoL (TQoL, 47.3 [33.2] vs 16.1 [18.1]); in ATTRwt disease, those with vs without autonomic dysfunction had similar QoL (23.0 [18.2] vs 19.9 [20.5]). Conclusions Autonomic dysfunction was more common and presented earlier in symptomatic ATTRv than ATTRwt amyloidosis and adversely affected QoL in ATTRv disease. These THAOS findings may aid clinicians in diagnosing and treating patients with ATTR amyloidosis. Trial registration: ClinicalTrials.gov: NCT00628745

A Consolidated Overview Of 14 Years Of Global Data From The Transthyretin Amyloidosis Outcomes Survey

Introduction The Transthyretin Amyloidosis Outcomes Survey (THAOS) is a global, longitudinal, observational study of patients with transthyretin amyloidosis (ATTR amyloidosis), including both inherited (ATTRv amyloidosis) and wild-type (ATTRwt amyloidosis) disease, and asymptomatic patients with transthyretin (TTR) mutations (NCT00628745). Methods This descriptive analysis provides a consolidated overview of 14 years of global demographics and clinical characteristics of patients with ATTR amyloidosis enrolled in THAOS as of January 4, 2021. The data period spans 2007 to 2021. Results There were 3604 symptomatic patients and 1772 asymptomatic carriers enrolled in THAOS. Of the symptomatic patients, 1055 had ATTRwt amyloidosis (93.8% male) and 2549 had ATTRv amyloidosis (61.6% male); the most prevalent TTR mutation was Val30Met (1493/2549; 58.6%). Median age at symptom onset was higher in patients with ATTRwt amyloidosis (73.0 years) vs patients with Val30Met (40.0 years), non-Val30Met (excluding cardiac; 51.5 years), and cardiac (64.5 years) mutations. In North America, the majority of patients had ATTRwt amyloidosis (58.8%), whereas in Europe, South America, and Japan ATTRv amyloidosis was more common. The most common phenotype was cardiac in North America (73.1%) and neurologic in South America (66.1%), Europe (52.1%), and Japan (56.9%). Of the asymptomatic carriers, 41.9% were male and median age at enrollment was 39.8 years. The most prevalent mutation was Val30Met (70.9%), followed by non-Val30Met (excluding cardiac; 18.3%), and cardiac (10.8%) mutations. Conclusions These results revealed regional differences in relative rates of ascertainment of ATTRwt vs ATTRv amyloidosis and predominant phenotypes. However, this registry analysis may be limited by under-ascertainment and underreporting. The Transthyretin Amyloidosis Outcomes Survey (THAOS) is a global, longitudinal, observational study of patients with transthyretin amyloidosis (ATTR amyloidosis), including both inherited (ATTRv amyloidosis) and wild-type (ATTRwt amyloidosis) disease, and asymptomatic patients with transthyretin (TTR) mutations (NCT00628745). This descriptive analysis provides a consolidated overview of 14 years of global demographics and clinical characteristics of patients with ATTR amyloidosis enrolled in THAOS as of January 4, 2021. The data period spans 2007 to 2021. There were 3604 symptomatic patients and 1772 asymptomatic carriers enrolled in THAOS. Of the symptomatic patients, 1055 had ATTRwt amyloidosis (93.8% male) and 2549 had ATTRv amyloidosis (61.6% male); the most prevalent TTR mutation was Val30Met (1493/2549; 58.6%). Median age at symptom onset was higher in patients with ATTRwt amyloidosis (73.0 years) vs patients with Val30Met (40.0 years), non-Val30Met (excluding cardiac; 51.5 years), and cardiac (64.5 years) mutations. In North America, the majority of patients had ATTRwt amyloidosis (58.8%), whereas in Europe, South America, and Japan ATTRv amyloidosis was more common. The most common phenotype was cardiac in North America (73.1%) and neurologic in South America (66.1%), Europe (52.1%), and Japan (56.9%). Of the asymptomatic carriers, 41.9% were male and median age at enrollment was 39.8 years. The most prevalent mutation was Val30Met (70.9%), followed by non-Val30Met (excluding cardiac; 18.3%), and cardiac (10.8%) mutations. These results revealed regional differences in relative rates of ascertainment of ATTRwt vs ATTRv amyloidosis and predominant phenotypes. However, this registry analysis may be limited by under-ascertainment and underreporting.

Sex-related Differences In Cardiac Involvement In Wild-type Transthyretin Amyloidosis

<h3>Introduction</h3> Transthyretin amyloidosis (ATTR amyloidosis) is a rare but life-threatening disease that may arise from mutations in the transthyretin (<i>TTR</i>) gene (ATTRv amyloidosis) or from nonmutated, wild-type TTR (ATTRwt amyloidosis). Evidence suggests that female sex may be protective against cardiac involvement in ATTRv amyloidosis, but sex differences in cardiac involvement in ATTRwt amyloidosis have not been assessed. <h3>Hypothesis</h3> Cardiac involvement in patients with ATTRwt amyloidosis differs by sex. <h3>Methods</h3> The Transthyretin Amyloidosis Outcomes Survey (THAOS) is a global, longitudinal, observational survey of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic patients with <i>TTR</i> mutations (NCT00628745). Data from THAOS (data cutoff: January 4, 2021) were analyzed to evaluate sex-based differences in cardiac symptoms in patients with ATTRwt amyloidosis. <h3>Results</h3> There were 1272 patients (females, n=76; males, n=1196) with ATTRwt amyloidosis enrolled in THAOS. Median age at enrollment (80.7 vs 77.6 years; <i>P</i><0.05) and symptom onset (75.5 vs 73.0 years; <i>P</i><0.05) were higher in females vs males, whereas median time from symptom onset to diagnosis was similar between the groups (1.09 vs 1.55 years). Females had a significantly higher mean left ventricular (LV) ejection fraction (53% vs 48%; <i>P</i><0.05). The lower mean LV wall thickness (16 vs 17 mm) and mean LV mass index (161 vs 189 g/m²) observed in females vs males were not statistically significant. LV wall thickness (mm) divided by height (m) was similar in females vs males (9.8 vs 9.6). Sex was not found to be a predictor of mean LV wall thickness divided by height in a linear regression analysis. <h3>Conclusions</h3> Females with ATTRwt amyloidosis were older and had a higher mean LV ejection fraction compared with males. Although there were signs of sex-related differences in cardiac involvement, the relatively low number of females in this analysis may have limited the ability to draw firmer conclusions.

Temporal Trends of Wild-Type Transthyretin Amyloid Cardiomyopathy in the Transthyretin Amyloidosis Outcomes Survey

BackgroundTransthyretin amyloid cardiomyopathy results from the accumulation of wild-type (ATTRwt) or variant (ATTRv) transthyretin amyloid fibrils in the myocardium. THAOS (Transthyretin Amyloidosis Outcomes Survey) is a global, longitudinal, observational survey of patients with ATTRv and ATTRwt amyloidosis and asymptomatic patients with transthyretin mutations. ObjectivesThis study explored temporal trends in ATTRwt amyloidosis diagnoses using data from THAOS. MethodsUsing THAOS data from December 2007 to January 2020, the following comparisons were made according to year: ATTRwt amyloidosis diagnoses in the United States versus rest of the world, ATTRwt versus ATTRv amyloidosis with cardiac-associated mutations diagnoses, and ATTRwt amyloidosis diagnoses by tissue biopsy versus bone scintigraphy. ResultsThere were 1,069 patients with ATTRwt amyloidosis and 525 with ATTRv amyloidosis with cardiac mutations enrolled in THAOS. The median time from symptom onset to ATTRwt amyloidosis diagnosis did not change over the past 5 years (>60 months from 2015–2019). ATTRwt amyloidosis diagnoses increased from 2 in 2005 to >100 per year from 2016, with a more pronounced increase in the United States compared with the rest of the world. Diagnoses of ATTRwt amyloidosis by tissue biopsy increased yearly and peaked in 2014 before declining, whereas diagnoses by bone scintigraphy increased markedly since 2011. ATTRv amyloidosis with cardiac mutation diagnoses increased from 3 in 2005 to 37 in 2011, then plateaued. The proportion of patients with ATTRwt amyloidosis diagnosed with New York Heart Association functional class III/IV heart failure decreased from 2012 (46.4%) to 2019 (16.0%). ConclusionsIn the past decade, ATTRwt amyloidosis diagnoses increased worldwide. Despite the growing utilization of bone scintigraphy, patients are diagnosed several years after symptom onset. (Transthyretin Amyloidosis Outcomes Survey [THAOS]; NCT00628745)

Sex-Related Risk of Cardiac Involvement in Hereditary Transthyretin Amyloidosis: Insights From THAOS

ObjectivesBecause patients with ATTRv cardiomyopathy are more likely to be male, this analysis aimed to increase information on associations between sex and genotype, phenotype, and degree of myocardial involvement in ATTRv amyloidosis. BackgroundTransthyretin amyloid cardiomyopathy is a progressive, fatal disease that occurs due to accumulation of wild-type or variant (ATTRv) transthyretin amyloid fibrils in the myocardium. MethodsThe Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing global longitudinal observational survey of patients with ATTR amyloidosis and asymptomatic carriers with TTR mutations. Data from THAOS (data cutoff: January 6, 2020) were analyzed to determine any sex-based differences in genotype, phenotype, and presence of cardiac and neurological symptoms in patients with ATTRv amyloidosis and in patients with ATTRv amyloidosis and cardiomyopathy. ResultsThere were 2,790 patients with ATTRv amyloidosis enrolled in THAOS, with male patients more likely to have symptoms of cardiac involvement and a cardiac phenotype. Male prevalence was greater in patients with more severe cardiac manifestations of disease, as assessed with N-terminal pro–B-type natriuretic peptide, left-ventricular (LV) ejection fraction, mean LV wall thickness divided by height, and LV mass index divided by height. Sex, age at disease onset, and genotype category were identified by multivariate analyses as risk factors for the development of cardiomyopathy (defined as increased LV septum thickness divided by height). ConclusionsIn this analysis, myocardial involvement was more frequent and pronounced in male patients with ATTRv amyloidosis, suggesting that there may be biological characteristics that inhibit myocardial amyloid infiltration in females or facilitate it in males.

A Descriptive Analysis of ATTR Amyloidosis in Spain from the Transthyretin Amyloidosis Outcomes Survey.

IntroductionTransthyretin amyloidosis (ATTR amyloidosis) is a clinically heterogeneous disease caused by mutations in the transthyretin (TTR) gene or aggregation of wild-type transthyretin (ATTRwt). In Spain, there are two large endemic foci of ATTR amyloidosis caused by the Val30Met variant, with additional cases across the country; however, these data may be incomplete, as there is no centralized patient registry. The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal, observational survey of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic patients with TTR mutations. This analysis aimed to gain a deeper understanding of the clinical profile of patients with ATTR amyloidosis in Spain.MethodsThis was a descriptive analysis of the demographic and clinical characteristics of symptomatic patients enrolled at six sites geographically dispersed throughout Spain (data cutoff: January 6, 2020). Patient data at enrollment, including genotype, demographics, and clinical presentation for symptomatic patients, were recorded. Patients were grouped by predominant phenotype based on clinical measures at enrollment: predominantly cardiac, predominantly neurologic, or mixed (cardiac and neurologic).ResultsThere were 379 patients (58.0% male; 63.3% symptomatic) enrolled in the six THAOS sites in Spain. Predominant genotypes were the Val30Met mutation (69.1%) or ATTRwt (15.6%). Predominant phenotype distribution was neurologic (50.4%), mixed (35.8%), and cardiac (13.8%) for all symptomatic patients (n = 240); neurologic (67.8%), mixed (21.2%), and cardiac (11.0%) for symptomatic Val30Met (n = 146); and mixed (64.9%), cardiac (22.8%), and neurologic (12.3%) for symptomatic ATTRwt (n = 57). Symptomatic patients reported a range of ATTR amyloidosis signs and symptoms at enrollment, with autonomic neuropathy and sensory neuropathy common in all phenotypes.ConclusionsThese results from THAOS highlight the phenotypic heterogeneity associated with ATTR amyloidosis in Spain and the importance of comprehensive neurologic and cardiac evaluations in all patients with ATTR amyloidosis.Trial registration ClinicalTrials.gov: NCT00628745.

Phenotypic Differences of Glu89Gln Genotype in ATTR Amyloidosis From Endemic Loci: Update From THAOS.

IntroductionTransthyretin amyloidosis (ATTR amyloidosis) is a progressive, clinically heterogeneous disease with spontaneous (wild-type) and hereditary (ATTRv) forms. The Glu89Gln variant is primarily associated with cardiomyopathy and prevalent in Italy and Bulgaria. The objective of this analysis was to better understand the profile of patients with ATTRv Glu89Gln amyloidosis in the Transthyretin Amyloidosis Outcomes Survey (THAOS).MethodsTHAOS is an ongoing, global, longitudinal, observational survey of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic carriers with mutations in the transthyretin gene. Demographic and clinical characteristics of all symptomatic patients with the ATTRv Glu89Gln variant enrolled in THAOS are described (data cutoff, January 6, 2020).ResultsThere were 91 patients with ATTRv Glu89Gln amyloidosis with the majority from Bulgaria (n = 53) or Italy (n = 29). All patients were Caucasian and 50.5% were male. Patients from Bulgaria had a mean (standard deviation) age at enrollment of 57.1 (8.2) years, and duration of symptoms of 8.6 (9.6) years, compared with 54.8 (8.6) and 5.0 (4.1) years in Italy. In Bulgaria, 39.6% of patients were of a predominantly cardiac phenotype, 18.9% predominantly neurologic, and 41.5% mixed. In Italy, 3.4% of patients were predominantly cardiac, 62.1% predominantly neurologic, and 34.5% mixed.ConclusionsThe majority of patients with ATTRv Glu89Gln amyloidosis in THAOS are from Bulgaria or Italy. There were notable phenotypic differences, with the cardiac phenotype more common in Bulgaria and the neurologic phenotype more common in Italy. Over one-third of patients had a mixed phenotype, suggesting a potential role of multiple genetic and/or environmental factors and the need for comprehensive assessment of all patients.Trial RegistrationClinicalTrials.gov: NCT00628745.

Characteristics of Patients with Late- vs. Early-Onset Val30Met Transthyretin Amyloidosis from the Transthyretin Amyloidosis Outcomes Survey (THAOS).

IntroductionHereditary transthyretin amyloidosis (ATTRv amyloidosis) is a clinically heterogeneous disease caused by mutations in the transthyretin (TTR) gene. The most common mutation, Val30Met, can manifest as an early- or late-onset disease.MethodsThe Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both inherited and wild-type disease and asymptomatic patients with TTR mutations. This is a descriptive analysis of symptomatic patients with ATTRv Val30Met amyloidosis with late- (age at least 50 years) vs. early-onset (age less than 50 years) disease in THAOS (data cutoff August 1, 2019).ResultsOf 1389 patients with ATTRv Val30Met amyloidosis, 491 (35.3%) had late-onset disease. Compared with early-onset, patients with late-onset were more likely to be male (66.2% vs. 53.6%) and have a longer mean (standard deviation [SD]) time from onset to diagnosis (3.8 [3.4] vs. 2.7 [4.1] years). Late-onset disease was associated with more severe neurological impairment at enrollment (median [10th, 90th percentile] derived Neuropathy Impairment Score in the Lower Limbs, 25.0 [4.0, 69.3] vs. 8.0 [0, 54.8]; Neurologic Composite Score, 42.0 [2.0, 155.0] vs. 21.0 [0, 102.0]). Cardiac findings were more prominent in late-onset disease. An overall interpretation of electrocardiogram as abnormal was reported in 72.1% of late-onset patients (vs. 44.3% early-onset). A left-ventricular septal thickness of at least 12 mm was reported in 69.7% of late-onset patients (vs. 14.6% early-onset). All differences were statistically significant (p < 0.001).ConclusionIn THAOS, late-onset ATTRv Val30Met amyloidosis is common, presenting with more severe neurologic and cardiac findings at enrollment. Heterogeneity of disease may make it more difficult to diagnose. Increased recognition of late-onset ATTRv Val30Met amyloidosis could lead to more timely diagnosis and improve patient outcomes.Trial RegistrationClinicalTrials.gov NCT00628745.

Feasibility of assessing progression of transthyretin amyloid polyneuropathy using nerve conduction studies: Findings from the Transthyretin Amyloidosis Outcomes Survey (THAOS).

Patients with transthyretin amyloid polyneuropathy (ATTR‐PN) show decreased motor and sensory nerve amplitudes and conduction. Electrophysiological changes over time may be sensitive indicators of progression. This analysis from the Transthyretin Amyloidosis Outcomes Survey (THAOS) assessed longitudinal changes in nerve conduction as signals of neurologic disease progression in patients with hereditary ATTR (ATTRv) amyloidosis. Patients with ATTRv in THAOS with recorded nerve conduction values were included (data cut‐off: January 6, 2020); changes in nerve amplitude and velocity over time were assessed. Patients (n = 1389) were 45.0% male; 80.4% were the Val30Met (p.Val50Met) genotype. Mean (SD) age at enrollment was 43.6 (14.5) years; duration of symptoms was 9.3 (6.4) years. Median (10th, 90th percentile) sural nerve amplitude and velocity was 18.0 (4.9, 35.0) μV and 50.7 (41.0, 57.9) m/s; peroneal conduction was 13.0 (4.4, 27.0) μV and 51.0 (41.7, 59.7) m/s, respectively. Median (10th, 90th percentile) percentage change from baseline in sural nerve amplitude was variable, but generally decreased over time from −7.4 (−43.2, 52.4) at year 1 to −14.4 (−76.9, 46.7) at year 8. Percent change from baseline in sural nerve velocity declined similarly: −0.1 (−14.5, 15.3) at year 1 and − 6.4 (−21.3, 10.5) at year 8. The decline was more pronounced in patients with greater disability at baseline. Similar patterns were observed for the peroneal nerve. These data show an association between nerve amplitudes and velocities and disease severity, suggesting progressive deterioration in nerve conduction may be an indicator of ATTRv amyloidosis disease progression.

Temporal Trends of Wild-type Attr Amyloidosis in the Transthyretin Amyloidosis Outcomes Survey

Introduction Wild-type transthyretin amyloidosis (ATTRwt) is an infiltrative cardiomyopathy (CM) underdiagnosed in older adults. The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, observational survey of patients with inherited (ATTRv) and ATTRwt amyloidosis, and asymptomatic gene carriers. Temporal trends in ATTRwt diagnosis were explored in this analysis. Hypothesis ATTRwt CM diagnosis has trended up since introducing scintigraphy. Methods Demographic and diagnostic data of CM patients enrolled in THAOS up to the 06January2020 data cut-off were analyzed. Diagnosis frequency between ATTRwt and ATTRv with cardiac phenotype (p.Val142Ile, p.Leu131Met, p.Thr60Ala, p.Ile88Leu), and ATTRwt diagnostic modality, were compared by year. Results A total of 1,069 ATTRwt patients (94.6% male) from 15 countries were identified. Symptoms were reported at a mean (SD) age of 68.8 (11.1) years and diagnosis made at 76.1 (7.1) years. Median (Q1, Q3) time to diagnosis from symptom onset was 4.7 (1.0, 10.9) years. ATTRwt diagnoses increased from single digits to >100 per year, whereas ATTRv with cardiac phenotype increased after 2007 then plateaued after 2011 (Panel A). ATTRwt diagnosis with biopsies increased and peaked in 2014 with a subsequent decline, compared to an increase in diagnosis with scintigraphy since 2012 (Panel B). Conclusions In the last decade, ATTRwt CM amyloidosis diagnoses increased with a concomitant shift from using biopsy to scintigraphy. Despite rising use of scintigraphy, half of the patients experienced diagnosis delays of >4.7 years.

Health-related quality of life in hereditary transthyretin amyloidosis polyneuropathy: a prospective, observational study

BackgroundHereditary Transthyretin Amyloidosis Polyneuropathy is a rare life-threatening neurologic disease that imposes considerable mortality and it is associated with progressive related disabilities. In this study, we aimed to assess the effect of the disease across health-related quality of life dimensions, in both carriers of the mutation and patients, to compare health-related quality of life with general population, as well as to explore health-related quality of life prognostic factors among patients, including disease progression and treatment.MethodsThis study was a multi-institutional, longitudinal, prospective, observational study of hereditary Transthyretin Amyloidosis Polyneuropathy Portuguese adult subjects (621 asymptomatic carriers and 733 symptomatic patients) enrolled in the Transthyretin Amyloidosis Outcomes Survey. Health-related quality of life was captured with the preference-based instrument EQ-5D-3 L. For general population the dataset included all subjects enrolled in a representative national study (n = 1500). Different econometric models were specified; multivariate probit, generalized linear model and generalized estimating equations model; including demographic and clinical covariates.ResultsHereditary Transthyretin Amyloidosis Polyneuropathy patients have their health status severely impaired in all quality of life dimensions and more anxiety/depression problems were found among asymptomatic carriers. No differences on utility were found between carriers and general population (p = 0.209). Among patients, the utility value is estimated to be 0.51 (0.021), a decrement of 0.27 as compared with general population utility. Higher disease duration, advanced disease stage and not receiving treatment are associated with impaired health-related quality of life. No differences were found between genders (p = 0.910) or between late (≥50 years) and early-onset patients (p = 0.254). The utility estimate ranged from 0.63 (0.009) in stage I to 0.01 (0.005) in stage IV.ConclusionsHereditary Transthyretin Amyloidosis Polyneuropathy symptoms and progressive associated disabilities substantially decrease patient’s health-related quality of life. Clinical strategies focused on health-related quality of life preservation such as close follow-up of asymptomatic carriers, prompt diagnosis and adequate, early treatment would benefit patient’s long-term outcomes, slowing the progressive decline in health-related quality of life.

Blood pressure and orthostatic hypotension as measures of autonomic dysfunction in patients from the transthyretin amyloidosis outcomes survey (THAOS).

Autonomic dysfunction, an early symptom of transthyretin amyloidosis (ATTR amyloidosis), requires investigations not readily available in many clinics. Although monitoring of orthostatic hypotension (OH) will not be a substitute for more specialized tests, it can add important information about initiation of dysautonomia. The aim of this study was to investigate whether simple blood pressure (BP) monitoring may be a useful tool for evaluation of disease progression and an early sign of autonomic dysfunction. BP and OH data were from subjects enrolled in the Transthyretin Amyloidosis Outcomes Survey (THAOS). Characteristics associated with changes in BP and orthostatic difference were identified by regression analyses. OH tended to be present relatively early in the course of disease and was more common at enrollment (11.7%) than either diarrhea (2.4%) or unintentional weight loss (3.1%). In subjects with OH at enrollment, progressive increase in systolic and diastolic orthostatic difference was observed. OH was also associated with significantly worse quality of life. BP variability is a useful tool for assessing disease onset and severity in ATTR amyloidosis, particularly in patients with OH. Trial registration ClinicalTrials.gov: NCT00628745.

P336A descriptive analysis of patients with wild-type ATTR cardiomyopathy from the transthyretin amyloidosis outcomes survey

Abstract Introduction Transthyretin amyloidosis (ATTR amyloidosis) is a rare, life-threatening disorder caused by the deposition of amyloid fibrils composed of misfolded transthyretin (TTR). ATTR amyloidosis may arise from mutations in TTR or from aggregation of wild-type TTR (ATTRwt). ATTR amyloidosis with predominantly symptoms of cardiomyopathy (ATTR-CM) includes both hereditary and wild-type forms of the disease. Purpose To describe clinical history and disease presentation in a large population of patients with wild-type ATTR-CM from the Transthyretin Amyloidosis Outcomes Survey (THAOS). THAOS is an ongoing, global, longitudinal, observational survey of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic patients with TTR mutations. Methods Data from ATTRwt patients were extracted from THAOS (cut-off date: January 16, 2019) and demographic and clinical characteristics reported using descriptive statistics. Results There were 758 ATTRwt patients in THAOS (95% male). The majority of patients (69.3%) were in the United States, with the remainder in Italy (11.1%), Germany (7.3%), Spain (5.3%), and other countries (7.1%). Most patients (86.3%) were Caucasian, with 3.3% being of African Descent and 3.1% being of other races/ethnicities (7.4% missing data). The median (10–90th percentile) age at symptom onset was 69.7 (54.0–81.3) years and the median (10–90th percentile) time from symptom onset to diagnosis was 3.9 (0.1–17.8) years. Median (10–90th percentile) age at enrollment in THAOS was 76.4 (67.2–85.2) years. Nearly all subjects had either a cardiac (59.6%) or mixed cardiac and neurologic (36.5%) phenotype. At enrollment, 97.1% (577 of 594 patients assessed) had an abnormal ECG, with the prevalence of low voltage being 20.8% (115 of 552) and prevalence of left-ventricular hypertrophy being 2.1% (16 of 758). Atrial fibrillation was documented in 55% of patients (208 of 378). The mean (standard deviation [SD]) left-ventricular septum thickness was 17.5 (3.5) mm (n=505; 94.9% with thickness &gt;12 mm) and mean (SD) left-ventricular ejection fraction (LVEF) was 48.3% (13.2) (n=511; 48.0% with LVEF &lt;50.0%). Other signs and symptoms at enrollment were compatible with a sensory neuropathy in 54.2% of patients, autonomic neuropathy in 33.5% of patients, and motor neuropathy in 29.1% of patients. Gastrointestinal symptoms related to ATTR amyloidosis were present in 10.4% of patients. Conclusions Although patients with wild-type ATTR-CM tend to be older Caucasian men with a mostly cardiac disease phenotype, the clinical spectrum of ATTRwt is heterogeneous and differs from the classic phenotype. Our findings show that ATTRwt should not be considered an exclusively cardiac disease and there is a need for both cardiologic and neurologic assessment of these patients. Further study is needed to determine if the non-cardiac manifestations are due to amyloidosis or more common causes in this older population. Acknowledgement/Funding This study was sponsored by Pfizer.

A comprehensive safety profile of tafamidis in patients with transthyretin amyloid polyneuropathy

Background: Tafamidis is approved in over 40 countries to delay neurologic progression in patients with transthyretin amyloid polyneuropathy (ATTR-PN). A comprehensive, integrated analysis of safety data from interventional, observational and surveillance studies of tafamidis in ATTR-PN patients was conducted.Methods: Safety data from all sponsored, completed, or ongoing, Phase 2/3 studies of tafamidis in ATTR-PN patients as of 3 January 2017 were pooled. Also assessed were safety data from the ongoing Transthyretin Amyloidosis Outcomes Survey (THAOS) as of 3 January 2017 and post-marketing surveillance reports as of 31 March 2017.Results: There were 137 patients in Phase 2/3 studies (mean duration of tafamidis exposure, 44.2 months), with 134 (97.8%) experiencing ≥1 treatment-emergent adverse event (TEAE) and 46 (33.6%) ≥1 treatment-emergent serious adverse event (TESAE). The most common TEAEs were diarrhoea (26.3%), urinary tract infection (UTI; 25.5%) and influenza (21.2%). In THAOS, 661 subjects had tafamidis exposure (mean duration, 27.6 months), with 250 (37.8%) experiencing ≥1 TEAE and 96 (14.5%) ≥1 TESAE. The most common TEAE was UTI (6.1%). Post-marketing surveillance reports generally reflected the known safety profile of tafamidis.Conclusions: This analysis did not reveal any significant new safety findings; tafamidis was generally safe and well tolerated in ATTR-PN patients. Trial registration: ClinicalTrials.gov identifier: NCT00409175.Trial registration: ClinicalTrials.gov identifier: NCT00791492.Trial registration: ClinicalTrials.gov identifier: NCT00630864.Trial registration: ClinicalTrials.gov identifier: NCT01435655.Trial registration: ClinicalTrials.gov identifier: NCT00925002.Trial registration: ClinicalTrials.gov identifier: NCT00628745.