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Diagnosis and treatment of transthyretin-related amyloidosis cardiomyopathy.

ABSTRACT: Transthyretin-related amyloidosis (ATTR) is a subgroup of amyloidosis that results from extracellular misassembled and toxic amyloid deposits affecting multiple organ systems, and cardiac tissues in particular. Because ATTR often presents as heart failure with preserved ejection fraction (HFpEF), it has been largely underdiagnosed. Once considered incurable with a grave prognosis, ATTR cardiomyopathy has seen the development of promising alternatives for diagnosis and treatment, with early diagnosis and treatment of ATTR cardiomyopathy highly beneficial due to its high mortality rate. For instance, diagnosing ATTR cardiomyopathy previously required a cardiac biopsy, but new modalities, such as cardiac magnetic resonance imaging and radionuclide bone scans, show promise in accurately diagnosing ATTR cardiomyopathy. Ongoing research and clinical trials have focused on identifying new treatments which primarily target amyloid fiber formation by inhibiting TTR gene expression, stabilizing the TTR tetramer, preventing oligomer aggregation, or affecting degradation of amyloid fibers. In this review, we describe the advances made in the diagnosis and treatment of ATTR in order to increase awareness of the disease and encourage a lower threshold for ATTR workup. Our review also highlights the need for improving the screening, diagnosis, and treatment guidelines for ATTR cardiomyopathy.

SUBMITTER: Teng C

PROVIDER: S-EPMC7661658 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Diagnosis and treatment of transthyretin-related amyloidosis cardiomyopathy.

Teng Catherine C Li Pengyang P Bae Ju Young JY Pan Su S Dixon Richard A F RAF Liu Qi Q

Clinical cardiology 20200729 11

Transthyretin-related amyloidosis (ATTR) is a subgroup of amyloidosis that results from extracellular misassembled and toxic amyloid deposits affecting multiple organ systems, and cardiac tissues in particular. Because ATTR often presents as heart failure with preserved ejection fraction (HFpEF), it has been largely underdiagnosed. Once considered incurable with a grave prognosis, ATTR cardiomyopathy has seen the development of promising alternatives for diagnosis and treatment, with early diagn ...[more]

PMID: 32725834

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Project description:ObjectivesOur primary aim was to evaluate the healthcare resource use associated with the diagnosis of transthyretin amyloidosis cardiomyopathy. Second, we aim to assess the effect of the number of diagnostic tests and clinical contact points on the total time and costs between symptom onset and diagnosis defining a quantitative hypothetical optimized diagnostic pathway.SettingClinical and cost data were collected from patients presenting between 2010 and 2018 in a tertiary referral institution in South London involving two participating hospitals.ParticipantsThirty-eight adult patients with a definite diagnosis of transthyretin amyloidosis cardiomyopathy were included, mostly male (n = 28, 74%) and of African-Caribbean descent (n = 23, 64%). We excluded patients without a confirmed transthyretin amyloidosis cardiomyopathy or those on inotersen, patisiran, or diflunisal at point of referral.Primary and secondary outcome measuresThe average time between first presentation and final diagnosis, and the cost per patient per month. By comparing to a more optimal clinical pathway towards diagnosis, we considered what could be the theoretical gain in terms of time to diagnosis and financial savings.ResultsThe average time between first presentation and final diagnosis was 2.74 years. The average cost per patient per month was higher with progressive heart failure symptoms. A hypothetical optimal pathway reduces time to diagnosis of 1.65 to 1.74 years per patient. The potential financial savings are estimated within the range of £3000 to £4800 per patient.ConclusionsPatients diagnosed with transthyretin amyloidosis cardiomyopathy have substantial healthcare resource utilization and costs starting from symptom onset. Higher costs were observed with progression in symptoms and appear linked to a delayed diagnosis. The number of additional diagnostic tests and clinical contact points may contribute to this and could represent a path to explore further for important health and cost savings, with more efficient pathways for these patients to be managed.

Project description:BackgroundHereditary Transthyretin-Related Amyloidosis, a clinically heterogeneous autosomal dominant disease caused by pathogenic variants in the TTR gene, is characterized by the deposition of insoluble misfolded protein fibrils. The diagnosis, especially in non-endemic areas, is typically delayed by 4-5 years; a misdiagnosis due to clinical heterogeneity is common. The study objective was to define the prevalence of Hereditary Transthyretin-Related Amyloidosis in patients with polyneuropathy and/or cardiomyopathy of no obvious aetiology.MethodA multicenter observational "Epidemiological analysis for the hereditary Transthyretin-Related AMyloidosis"-TRAM study was performed in Germany, Austria, and Switzerland.ResultsA total of 5141 participants were recruited by 50 neurologic and 27 cardiologic specialized centres. Genetic analysis demonstrated a 1.1% Hereditary Transthyretin-Related Amyloidosis positivity rate among patients with polyneuropathy and/or cardiomyopathy of not obvious aetiology. Twenty-one various TTR variants (TTR-positive) were identified. Body Mass Index was lower in the TTR-positive patients as an indicator for the involvement of the autonomic nervous system; the age of onset of clinical manifestations was higher in TTR-positive patients. There were no other genotype-phenotype correlations or the prevalence of specific clinical manifestations in TTR-positive patients.ConclusionsOur data support the fact that Hereditary Transthyretin-Related Amyloidosis is underdiagnosed in polyneuropathy and cardiomyopathy patients. Routine implementation of genetic testing is recommended in patients with unexplained polyneuropathy and/or cardiomyopathy to accelerate the earlier diagnosis and the time-sensitive treatment initiation.KEY MESSAGESMore than 5.000 participants with CM and/or PNP of no obvious aetiology were recruited in the observational "Epidemiological analysis for the hereditary Transthyretin-Related AMyloidosis" TRAM study and screened for pathogenic TTR variants.The study demonstrated >1% of patients with CM and/or PNP of unclear aetiology are positive for a pathogenic TTR variant.Routine genetic testing is recommended in patients with unexplained CM and/or PNP to accelerate the initial diagnosis and timely treatment initiation.

Project description:Transthyretin (TTR)-related amyloidosis (ATTR) is a devastating disease which affects a combination of organs including the heart and the peripheral nerves, and which has a fatal outcome if not treated within a average of 10 years. Tafamidis, or 2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylic acid, selectively binds to TTR with negative cooperativity and kinetically stabilizes wild-type native TTR and mutant TTR; tafamidis therefore has the potential to halt the amyloidogenic cascade initiated by TTR tetramer dissociation, monomer misfolding, and aggregation. The first tafamidis trial, Fx-005, evaluated the effect of 18 months of tafamidis treatment (20 mg once daily) on disease progression, as well as assessing its safety in TTR-FAP Val30Met patients. The secondary objective of this trial was to study the pharmacodynamic stabilization of mutated TTR. Tafamidis proved effective in reducing the progress of neuropathy, and in maintaining the nutritional status and quality of life of stage 1 (able to walk without support) Val3OMet TTR-FAP patients. Furthermore, TTR stabilization was achieved in more than 90% of patients. An extension study, Fx-006, was conducted to determine the long-term safety and tolerability of tafamidis and to assess the efficacy of the drug on slowing disease progression. No significant safety or tolerability issues were noticed. Taken together, the results from both trials indicated that the beneficial effects of tafamidis were sustained over a 30-month period and that starting treatment early is desirable. Results are expected from an extended open-label study but data that have already been presented show that long-term use of tafamidis in Val30Met patients is associated with reduced progression in polyneuropathy. Tafamidis was initially approved for commercial use in Europe in 2011 and has since been approved for use in Japan, Mexico, and Argentina where it is used as a first-line treatment option for patients with early-stage TTR-FAP. Patients should be carefully followed at referral centers to ascertain the individual response to treatment. In cases of discontinuation, liver transplantation and enrollment in clinical trials of novel drugs aimed mostly toward suppression of TTR production are options.

Dataset Information

Diagnosis and treatment of transthyretin-related amyloidosis cardiomyopathy.

Publications

Diagnosis and treatment of transthyretin-related amyloidosis cardiomyopathy.

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