RESUMO
AIM: Myocardial uptake on bone scintigraphy has become useful for the detection of transthyretin cardiac amyloidosis (ATTR-CA). This study aimed to assess the prevalence of myocardial uptake in patients over 18 years of age with no clinical suspicion of cardiac amyloidosis (CA) who had undergone bone scintigraphy. METHODS AND RESULTS: This was an observational, retrospective, multicenter study across 21 Spanish hospitals (September-November 2019). Of the 9864 scans analyzed (locally and centrally), incidental cardiac uptake was observed in 71 patients (0.72%), a prevalence that increased with age. A previous diagnosis of heart failure was found in 16.9% of patients with positive uptake, with >50% in NYHA II. ATTR-CA was diagnosed in 10 patients, with a mean delay of 10.4 months (95% CI: 5.1-15.7). All were >70 years old, primarily male, and had greater left ventricular hypertrophy than patients without a confirmed diagnosis (p<0.0001). ATTR-CA patients had higher rates of orthostatic hypotension (30.0% vs. 3.8% in non-ATTR-CA; p=0.025). CONCLUSIONS: This is the first retrospective, national, multicenter study evaluating the prevalence of incidental cardiac uptake in bone scintigraphy performed for non-cardiac reasons, showing a prevalence of 0.72% in this population. Referral of these patients may facilitate early diagnosis of CA with a resulting benefit for patients.
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Neuropatias Amiloides Familiares , Achados Incidentais , Cintilografia , Humanos , Masculino , Feminino , Espanha/epidemiologia , Idoso , Estudos Retrospectivos , Neuropatias Amiloides Familiares/diagnóstico por imagem , Idoso de 80 Anos ou mais , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/metabolismo , Cardiomiopatias/diagnóstico por imagem , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos/farmacocinética , Insuficiência Cardíaca/diagnóstico por imagem , Prevalência , Miocárdio/metabolismoAssuntos
Neuropatias Amiloides Familiares , Disparidades nos Níveis de Saúde , Pré-Albumina , Humanos , Neuropatias Amiloides Familiares/genética , Cardiomiopatias , Disparidades em Assistência à Saúde , Pré-Albumina/genética , Pré-Albumina/metabolismo , Estados Unidos , Pessoa de Meia-Idade , Lactente , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Idoso , Idoso de 80 Anos ou maisRESUMO
OBJECTIVES: To identify and describe the profile of potential transthyretin cardiac amyloidosis (ATTR-CM) cases in the Brazilian public health system (SUS), using a predictive machine learning (ML) model. METHODS: This was a retrospective descriptive database study that aimed to estimate the frequency of potential ATTR-CM cases in the Brazilian public health system using a supervised ML model, from January 2015 to December 2021. To build the model, a list of ICD-10 codes and procedures potentially related with ATTR-CM was created based on literature review and validated by experts. RESULTS: From 2015 to 2021, the ML model classified 262 hereditary ATTR-CM (hATTR-CM) and 1,581 wild-type ATTR-CM (wtATTR-CM) potential cases. Overall, the median age of hATTR-CM and wtATTR-CM patients was 66.8 and 59.9 years, respectively. The ICD-10 codes most presented as hATTR-CM and wtATTR-CM were related to heart failure and arrythmias. Regarding the therapeutic itinerary, 13% and 5% of hATTR-CM and wtATTR-CM received treatment with tafamidis meglumine, respectively, while 0% and 29% of hATTR-CM and wtATTR-CM were referred to heart transplant. CONCLUSION: Our findings may be useful to support the development of health guidelines and policies to improve diagnosis, treatment, and to cover unmet medical needs of patients with ATTR-CM in Brazil.
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Neuropatias Amiloides Familiares , Amiloidose , Cardiomiopatias , Humanos , Brasil/epidemiologia , Pré-Albumina , Saúde Pública , Estudos Retrospectivos , Aprendizado de Máquina , Cardiomiopatias/diagnóstico , Cardiomiopatias/epidemiologia , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/epidemiologiaRESUMO
The aim is to evaluate the diagnostic yield of echocardiography and [99mTc]Tc-DPD scintigraphy in the detection of amyloid cardiomyopathy (CM) and define potential prognostic echocardiographic parameters. 133 patients were retrospectively studied, from 2016 to 2021, with a mean age of 80.2 ± 7.5 years. The final diagnosis was established according to international consensus. Patients had a transthoracic echocardiogram (TTE) and [99mTc]Tc-DPD scintigraphy; RWT, E/e, LS, TAPSE, SAB, and IWT scores were calculated. All patients with ATTR-CM were classified into 3 prognostic stages and were compared with Perugini grades and echocardiographic parameters. CM was confirmed in 85 cases (63.9%), 76 (57.1%) ATTR-CM, and 9 (6.8%) AL-CM. The diagnostic yield of [99mTc]Tc-DPD scintigraphy and echocardiography were calculated, with a sensitivity of 90.7%, specificity of 100%, PPV of 100%, and NPV of 87.2% in myocardial scintigraphy, versus 74.6%, 62.5%, 75.6%, 61.2% in the echocardiogram. According to the IWT score, most patients were classified in the intermediate group; 33 presented with grade 2-3 uptakes. Significant results were obtained when comparing Perugini score with IWT (p: 0.02) and SAB (p: 0.03); and between biomarkers stages and LVEF (p: 0.028), E/e´ (p: 0.001), and GLS% (p: 0.022). [99mTc]Tc-DPD scintigraphy is superior in diagnosing CA. SAB could be the most reliable parameter in an early diagnostic phase, showing a strong correlation with Perugini grades 2 and 3.
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Neuropatias Amiloides Familiares , Cardiomiopatias , Humanos , Idoso , Idoso de 80 Anos ou mais , Pré-Albumina , Neuropatias Amiloides Familiares/diagnóstico por imagem , Estudos Retrospectivos , Valor Preditivo dos Testes , Ecocardiografia , Cintilografia , Cardiomiopatias/diagnóstico por imagemRESUMO
BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed cause of heart failure in clinical practice. 99mTc-pyrophosphate scintigraphy (PYP-scan) improves the accuracy of ATTR-CM detection, enabling timely initiation of tafamidis, a drug that slows the progression of ATTR-CM and lowers the risk of adverse cardiac events. PYP-scans, serum free light-chain (FLC) test and immunofixation electrophoresis (IFE) are critical components of a systematic screening. We assessed the cost-effectiveness of universal systematic screening (USS) compared to standard-of-care (SoC) selected clinical referrals for the systematic screening in patients aged 60 years or older with heart failure with preserved ejection fraction (HFpEF) and ventricular wall thickness of at least 12 mm. METHODS: Two screening strategies, USS versus SoC screening for ATTR-CM were compared in a model-based assessment. Treatment decisions were based upon the accuracy of each screening strategy, which was followed by Markov state transitions across New York Heart Association (NYHA) functional classes and death. Model inputs were identified from a literature review. We calculated lifetime cost in 2022 US dollars and quality adjusted life-years (QALYs) of each strategy. The primary outcome was the incremental cost-effectiveness ratio (ICER). RESULTS: The USS was associated with a significant increase in lifetime costs ($124,380 vs. $70,412) and modest improvement in QALYs (4.42 QALYs vs 4.36 QALYs). The ICER for the USS was $919,509 per QALY gained. ICER was sensitive to the age at the time of ATTR-CM diagnosis, true prevalence rate of ATTR-CM, and daily cost of tafamidis. CONCLUSIONS: Owing to the high cost of treatment with tafamidis, USS along with PYP scan for ATTR-CM in older HFpEF patients with ventricular wall thickening is unlikely to become a cost-effective strategy at a liberal WTP threshold.
Assuntos
Neuropatias Amiloides Familiares , Amiloidose , Cardiomiopatias , Insuficiência Cardíaca , Humanos , Estados Unidos/epidemiologia , Idoso , Análise Custo-Benefício , Pré-Albumina , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/tratamento farmacológico , Volume Sistólico , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/tratamento farmacológico , Neuropatias Amiloides Familiares/diagnóstico por imagem , Neuropatias Amiloides Familiares/tratamento farmacológicoRESUMO
AIMS: To estimate healthcare resource use and direct healthcare costs of Transthyretin Amyloid Cardiomyopathy (ATTR-CM) in Sweden over 12 months across severity stages as defined by the New York Heart Association (NYHA). Secondary to investigate the current diagnostic trajectory for patients with ATTR-CM in Sweden. METHODS: A stratified inclusion of patients with a confirmed diagnosis of ATTR-CM in different NYHA classes. Data was extracted from medical records in two cardiology clinics in Sweden. Healthcare resource use data were retrospectively collected for 12 months. RESULTS: 38 patients were included, of whom 7 were in NYHA class II, 20 in class III and 4 in class IV. The total cost of health care per patient increased from SEK 69,000 (6800) in NYHA stage II, SEK 219,000 (21,500) in NYHA stage III, to SEK 638,000 (62,900) in stage IV, mainly due to an increase in inpatient stays. Mean time (standard deviation, SD) from any cardiac related diagnosis prior to ATTR-CM diagnosis was 3.5 (3.1) years. CONCLUSIONS: Advanced ATTR-CM stages are associated with significant healthcare costs, as patients more often require resource-intensive inpatient care. The current diagnostic trajectory of ATTR-CM in this study was characterized by a diagnostic delay of several years.
This study shows that both healthcare resource use and healthcare costs increased considerably with a higher degree of ATTR-CM severity.The diagnostic trajectory of ATTR-CM in this study was characterized by a diagnostic delay of several years.Greater disease awareness and a lower threshold for screening risk groups for TTR-amyloidosis is prompted to establish an earlier diagnosis.
Assuntos
Neuropatias Amiloides Familiares , Cardiomiopatias , Humanos , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/terapia , Neuropatias Amiloides Familiares/complicações , Pré-Albumina , Diagnóstico Tardio , Estudos Retrospectivos , Suécia/epidemiologia , Efeitos Psicossociais da Doença , Cardiomiopatias/diagnóstico , Cardiomiopatias/terapia , Atenção à SaúdeRESUMO
INTRODUÇÃo: Amiloidose hereditária relacionada a transtirretina é uma doença genética rara autossômica dominante, multissistêmica, progressiva e potencialmente fatal. Após o diagnóstico deve ser determinado o estágio da doença de acordo com a gravidade dos sintomas (Estágio 0 a III), sendo o estágio III o de maior gravidade. Estima-se que a ATTRh afete cerca de 50 mil pessoas no mundo todo. No Brasil, não há dados epidemiológicos publicados sobre sua prevalência. Porém, observou-se um aumento no número de casos de ATTRh registrados no país. Atualmente, o único medicamento disponibilizado pelo SUS para tratar ATTRh é o tafamidis meglumina, indicado para pacientes adultos sintomáticos em estágio inicial (estágio I) e não submetidos a transplante hepático por ATTRh. O transplante hepático deve ser realizado apenas no estágio I da doença, em razão de não ser uma medida terapêutica curativa das lesões, que surgem nos estágios mais avançados da ATTRh. PERGUNTA: O tratamento com patisirana é eficaz, efetivo e seguro para pacientes diagnosticados com amiloidose ATTRh com polineuropatia em estágio 2 ou que apresentam resposta inadequada ao tafamidis? EVIDÊNCIAS CLÍNICAS: Os estudos selecionados demonstram a eficácia do patisirana na redução da progressão neuropática da doença, evidenciada pela diminuição da pontuação na escala mNIS+7 após uso
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Humanos , Polineuropatias/fisiopatologia , Pré-Albumina/efeitos dos fármacos , RNA/uso terapêutico , Neuropatias Amiloides Familiares/tratamento farmacológico , Sistema Único de Saúde , Brasil , Análise Custo-Benefício/economiaRESUMO
BACKGROUND: High out-of-pocket costs can impede access to guideline-directed cardiovascular drugs. The 2022 Inflation Reduction Act (IRA) will eliminate catastrophic coinsurance and cap annual out-of-pocket costs for Medicare Part D patients by 2025. OBJECTIVES: This study sought to estimate the IRA's impact on out-of-pocket costs for Part D beneficiaries with cardiovascular disease. METHODS: The investigators chose 4 cardiovascular conditions that frequently require high-cost guideline-recommended drugs: severe hypercholesterolemia; heart failure with reduced ejection fraction (HFrEF); HFrEF with atrial fibrillation (AF); and cardiac transthyretin amyloidosis. This study included 4,137 Part D plans nationwide and compared projected annual out-of-pocket drug costs for each condition in 2022 (baseline), 2023 (rollout), 2024 (5% catastrophic coinsurance eliminated), and 2025 ($2,000 cap on out-of-pocket costs). RESULTS: In 2022, mean projected annual out-of-pocket costs were $1,629 for severe hypercholesterolemia, $2,758 for HFrEF, $3,259 for HFrEF with AF, and $14,978 for amyloidosis. In 2023, the initial IRA rollout will not significantly change out-of-pocket costs for the 4 conditions. In 2024, elimination of 5% catastrophic coinsurance will lower out-of-pocket costs for the 2 costliest conditions: HFrEF with AF ($2,855, 12% reduction) and amyloidosis ($3,468, 77% reduction). By 2025, the $2,000 cap will lower out-of-pocket costs for all 4 conditions to $1,491 for hypercholesterolemia (8% reduction), $1,954 for HFrEF (29% reduction), $2,000 for HFrEF with AF (39% reduction), and $2,000 for cardiac transthyretin amyloidosis (87% reduction). CONCLUSIONS: The IRA will reduce Medicare beneficiaries' out-of-pocket drug costs for the selected cardiovascular conditions by 8% to 87%. Future studies should assess the IRA's impact on adherence to guideline-directed cardiovascular therapies and health outcomes.
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Neuropatias Amiloides Familiares , Fibrilação Atrial , Doenças Cardiovasculares , Insuficiência Cardíaca , Hipercolesterolemia , Estados Unidos/epidemiologia , Humanos , Idoso , Doenças Cardiovasculares/tratamento farmacológico , Gastos em Saúde , Insuficiência Cardíaca/tratamento farmacológico , Custos de Medicamentos , Medicare , Volume SistólicoRESUMO
INTRODUÇÃO: A amiloidose por transtirretina (TTR) é um distúrbio sistêmico caracterizado pela deposição extracelular de fibrilas amiloides e compostas por TTR, que é uma proteína de transporte plasmático de tiroxina e vitamina A produzida predominantemente pelo fígado. A polineuropatia amiloidótica familiar relacionada à transtirretina (PAF-TTR) é uma doença multissistêmica rara, progressiva, hereditária e altamente incapacitante. É um distúrbio autossômico dominante e até o momento mais de 100 mutações de TTR diferentes foram identificadas em todo o mundo, essas mutações desestabilizam a proteína TRR. PAF-TTR é uma doença multissintomática que pode apresentar neuropatia periférica (sensorial e motora), neuropatia autonômica, comprometimento gastrointestinal, cardiomiopatia, nefropatia ou deposição ocular. As manifestações clínicas da amiloidose sistêmica são determinadas principalmente pela proteína precursora e pelos órgãos envolvidos. No entanto, há considerável sobreposição clínica entre todos os tipos de amiloidose. Estimativas de preva
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Humanos , Pré-Albumina/efeitos dos fármacos , Oligonucleotídeos Antissenso/uso terapêutico , Neuropatias Amiloides Familiares/tratamento farmacológico , Meglumina/antagonistas & inibidores , Sistema Único de Saúde , Brasil , Análise Custo-Benefício/economiaRESUMO
INTRODUCTION: We aimed at investigating whether functional and morphometric tests assessing small-fibre damage, ie quantitative sensory testing, Sudoscan and skin biopsy, reliably reflect neuropathic pain and autonomic symptoms in patients with late-onset hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN). METHODS: In 30 patients with late-onset ATTRv-PN, we collected quantitative sensory testing, Sudoscan and skin biopsy with assessment of intraepidermal, piloerector muscle and sweat gland nerve fibre density. We then correlated these functional and morphometric parameters with neuropathic pain and autonomic symptoms as assessed with the Neuropathic Pain Symptom Inventory (NPSI) and Composite Autonomic Symptom Score-31 (COMPASS-31). RESULTS: 50% of patients showed small-fibre damage in the form of a pure small-fibre neuropathy, 47% in the context of a mixed fibre neuropathy with small and large fibre involvement. All patients complained of at least one autonomic symptom and 60% had neuropathic pain. Whereas quantitative sensory testing and Sudoscan parameters correlated with neuropathic pain and autonomic symptoms as assessed by NPSI and COMPASS-31, intraepidermal, piloerector muscle and sweat gland nerve fibre density quantification did not. CONCLUSIONS: Our findings indicate that functional test parameters reliably reflect neuropathic pain and autonomic symptoms related to small-fibre damage. These findings might help to identify clinically useful biomarkers to assess patient follow-up.
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Neuropatias Amiloides Familiares , Neuralgia , Polineuropatias , Humanos , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/genética , Polineuropatias/diagnóstico , Testes Diagnósticos de RotinaRESUMO
Introduction: Initial clinical manifestations of transthyretin amyloidosis (ATTR) are not well understood, making timely diagnosis challenging. Methods: Patients aged ≥68 years newly diagnosed with ATTR were identified using Medicare Research Identifiable Files. Symptom manifestation and healthcare utilization were measured during 3 years pre-diagnosis; demographics and comorbidity index during 1-year pre-diagnosis. Controls (ATTR-free) were matched 1:1 to patients with ATTR based on age, sex and region; same index date and enrollment as match. Results: We identified 552 matched ATTR-control pairs: mean age 78.3 (standard deviation 6.3) and 64.5% male. Among patients with ATTR (vs controls), cardiovascular conditions (92.9 vs 75.9%) and hospitalization (54.0 vs 35.5%) were frequent during 3 years pre-diagnosis. Conclusion: Patients with ATTR have multiple symptoms and hospitalizations pre-diagnosis, recognition of which may facilitate earlier diagnosis and treatment.
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Neuropatias Amiloides Familiares , Cardiomiopatias , Idoso , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/terapia , Cardiomiopatias/diagnóstico , Feminino , Humanos , Masculino , Medicare , Aceitação pelo Paciente de Cuidados de Saúde , Estados UnidosRESUMO
BACKGROUND: Transthyretin cardiac amyloidosis, also known as transthyretin cardiomyopathy (ATTR-CM) is a poorly-recognized disease with delayed diagnosis and poor prognosis. This nationwide population-based study aimed to identify disease manifestations, economic burden, and mortality of patients with ATTR-CM. METHODS: Data of newly diagnosed patients with ATTR-CM between 2013 and 2018 from the Korean National Health Insurance Service were used, covering the entire population. Patient characteristics included comorbidities, medical procedures, and medication. Healthcare resource utilization and medical costs were observed as measures of the economic burden. The Kaplan-Meier survival curve and years of potential life lost (YPLL) from the general population were estimated for disease burden with ATTR CM. RESULTS: A total of 175 newly diagnosed patients with ATTR-CM were identified. The most common cardiac manifestation was hypertension (51.3%), while the most common non-cardiac manifestation was musculoskeletal disease (68.0%). Mean medical costs at the post-cohort entry date were significantly higher than those at the pre-cohort entry date ($1,864 vs. $400 per patient per month (PPPM), p < 0.001). Of the total medical costs during the study period, the proportion of inpatients cost was 12.9 times higher than the outpatients cost ($1,730 and $134 PPPM, respectively). The median survival time was 3.53 years from the first diagnosis of ATTR-CM, and the mean (SD) YPLL was 13.0 (7.7). CONCLUSIONS: Patients with ATTR-CM had short survival and high medical costs. To reduce the clinical and economic burdens, carefully examining manifestations of disease in patients can help with early diagnosis and treatment.
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Neuropatias Amiloides Familiares , Cardiomiopatias , Neuropatias Amiloides Familiares/diagnóstico , Cardiomiopatias/diagnóstico , Estresse Financeiro , Coração , Humanos , Pré-AlbuminaRESUMO
OBJECTIVE: Hereditary transthyretin-mediated amyloidosis is a treatable condition caused by amyloidogenic variants in the transthyretin-gene resulting in severe peripheral neuropathy or cardiomyopathy. Only about a third of over 130 known variants are clearly pathogenic, most are classified as variants of uncertain significance. A clear delineation of these into pathogenic or non-pathogenic is highly desirable but hampered by low frequency and penetrance. We thus sought to characterize their amylogenic potential by an unbiased in vitro approach. METHODS: Thioflavin T and turbidity assays were used to compare the potential of mammalian cell expressed wt-transthyretin and 12 variant proteins (either variants of uncertain significance, benign, pathogenic) to aggregate and produce amyloid fibrils in vitro. As proof of principle, the assays were applied to transthyretin-Ala65Val, a variant that was newly detected in a family with peripheral neuropathy and amyloid deposits in biopsies. In silico analysis was performed to compare the position of the benign and pathogenic variants. RESULTS: Transthyretin-Ala65Val showed a significantly higher amyloidogenic potential than wt-transthyretin, in both turbidity- and Thioflavin T-assays, comparable to known pathogenic variants. The other eight tested variants did not show an increased amyloidogenic potential. In silico structural analysis further confirmed differences between pathogenic and benign variants in position and interactions. INTERPRETATION: We propose a biochemical approach to assess amyloidogenic potential of transthyretin variants. As exemplified by transthyretin-Ala65Val, data of three assays together with histopathology clearly demonstrates its amyloidogenicity.
Assuntos
Neuropatias Amiloides Familiares , Pré-Albumina , Amiloide/genética , Amiloide/metabolismo , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/metabolismo , Humanos , Pré-Albumina/genéticaRESUMO
Advancement in the diagnosis and treatment of transthyretin amyloid cardiomyopathy has made great strides in recent years. Novel therapeutics for transthyretin amyloidosis such as tafamidis, patisiran, and inotersen have shown significant benefits in a not-so-rare disease but come with high listing price tags ranging from a quarter to more than a half million dollars per year. These costs create significant financial barriers for the majority of patients, especially those with existing Medicare insurance plans. Of 72 patients reviewed, 67% were Medicare beneficiaries. Financial assistance was explored for the majority, and 37 (51%) patients with Medicare Part D received financial assistance that reduced their copayments to $0. Only one-third of our patients were able to afford these medications without any forms of financial assistance. Of these patients, 4 (6%) had the highest copayments ranging from $13 000 to $15 000 per year. To navigate the complexities of prescribing and affordability in amyloidosis, a multidisciplinary team including a dedicated clinical pharmacist is crucial in guaranteeing patients' success to secure these novel therapeutics. In this article, we discuss our experiences with prescribing, acquiring insurance authorizations, and financing these life-saving medications based on patient-specific insurance plans and socioeconomic status.
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Neuropatias Amiloides Familiares , Medicare , Idoso , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/tratamento farmacológico , Humanos , Pré-Albumina/uso terapêutico , Estados UnidosRESUMO
OBJECTIVE: Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a rare disease characterized by rapid neuropathic progression. In pivotal studies of gene-silencing treatments, the modified Neuropathy Impairment Score + 7 tests (mNIS + 7) and Norfolk-Quality of Life (QOL)-Diabetic Neuropathy (DN) questionnaire assessed treatment impact on neuropathic progression. Establishing responder definition (RD) thresholds for these measures would enable evaluation of clinically meaningful treatment benefit. METHODS: mNIS + 7 and Norfolk-QOL-DN were administered at baseline and week 65 to 165 adults with ATTRv-PN receiving inotersen (n = 106) or placebo (n = 59) in the NEURO-TTR study. Anchor-based approaches for estimating RD thresholds were used for Norfolk QOL-DN, while distribution-based approaches were used for both measures. Responders were patients with a score change < RD, indicating improvement or stabilization (i.e., no clinically meaningful progression). Odds ratios (ORs) and Fisher's exact tests compared proportions of responders by treatment. RESULTS: The mean RD estimates were 12.2 points and 8.8 points for mNIS + 7 and Norfolk QOL-DN, respectively. The proportions of patients whose change in score indicated improvement or stabilization were statistically significantly larger for inotersen than placebo for all estimated RD thresholds for mNIS + 7 (64-86% responders for inotersen vs. 27-46% for placebo, ORs = 3.8-7.2, ps < 0.001) and Norfolk QOL-DN (66-81% vs. 35-56%, ORs = 2.4-3.6, ps < 0.05). DISCUSSION: Establishing RD thresholds for these instruments enables evaluation of clinically relevant and individual-level treatment benefit on neuropathic progression. Across RDs estimated using multiple methods, a higher proportion of patients receiving inotersen than placebo showed improved or stabilized neuropathic progression at week 65. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01737398; Date of registration: November 29, 2012.