tafamidis and Cardiomyopathies

This summary presents the results from an ongoing, long-term extension study that followed an earlier study called ATTR-ACT. People who took part in this extension study and ATTR-ACT have a type of heart disease known as transthyretin amyloid cardiomyopathy (ATTR-CM for short), which causes heart failure and death. In ATTR-ACT, people took either a medicine called tafamidis or a placebo (a pill that looks like the study drug but does not contain any active ingredients) for up to 2½ years. So far, in the long-term extension study, people have continued taking tafamidis, or switched from taking a placebo to tafamidis, for another 2½ years. Researchers looked at how many people died in ATTR-ACT and the extension study. The long-term extension study is expected to end in 2027, so these are interim (not final) results.. In the extension study of ATTR-ACT, the risk of dying was lower in people who took tafamidis continuously throughout ATTR-ACT and the extension study than in people who took placebo in ATTR-ACT and switched to tafamidis in the extension study.. Taking tafamidis increases how long people with ATTR-CM live. People with ATTR-CM who take tafamidis early and continuously are more likely to live longer than those who do not. These results highlight the importance of early detection and treatment in people with ATTR-CM.

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Humans; Prealbumin

Tafamidis was associated with a reduction in cardiovascular hospitalizations and all-cause mortality in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) in the ATTR-ACT trial. However, real-world data on the efficacy of tafamidis are limited. We conducted a retrospective, observational cohort study using the TriNetX research network. Patients with wild-type TTR amyloidosis and heart failure (HF) were divided into 2 groups based on treatment with tafamidis. Propensity score matching (PSM) was performed, and rates of heart failure exacerbations (HFE) and all-cause mortality at 12 months were compared. After PSM, 421 patients were in each group (tafamidis vs nontafamidis). During the 12-month follow-up period, patients treated with tafamidis experienced significantly less HFE and all-cause mortality. A higher probability of event-free survival for HFE and all-cause mortality was noted with tafamidis. This real-world analysis supports that tafamidis use is associated with reduced HFE and all-cause mortality in patients with wild-type TTR amyloidosis and HF. Longer-term follow-up is needed to better understand the utility of tafamidis, given the increasing recognition of ATTR-CM and the high cost of tafamidis.

Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Heart Failure; Humans; Observational Studies as Topic; Prealbumin; Retrospective Studies

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed cause of heart failure and arrhythmia. This differential diagnosis should particularly be considered in older patients with left ventricular hypertrophy (LVH) who are also suffering from heart failure with preserved ejection fraction (HFpEF) or aortic valve stenosis. ATTR-CM is caused either by a genetic variation or by aging processes. The extracellular accumulation of amyloid fibrils in the heart causes a restrictive cardiomyopathy, which leads to typical heart failure symptoms as well as cardiac conduction and repolarization disturbances. Extracardiac problems such as a carpal tunnel syndrome can also be indicative for ATTR-CM. The disease can be diagnosed either by a myocardial biopsy or alternatively by a positive bone scintigraphy with the simultaneous exclusion of monoclonal proteins in blood and urine. Besides a symptomatic treatment, the transthyretin (TTR) stabilizer tafamidis is now available, which can significantly delay the disease progress. In the coming years, the approval of further drugs for the treatment of ATTR-CM is to be expected.. Kardiale Transthyretin-Amyloidosen (ATTR-Amyloidosen) sind eine unterdiagnostizierte Ursache von Herzinsuffizienz und Arrhythmien. Insbesondere bei älteren Patienten mit einer linksventrikulären Hypertrophie (LVH), die gleichzeitig an einer Herzinsuffizienz mit erhaltener Ejektionsfraktion (HFpEF) oder Aortenklappenstenose leiden, sollte an diese Differenzialdiagnose gedacht werden. ATTR-Amyloidosen sind entweder genetisch bedingt oder entstehen durch Alterungsprozesse. Durch die extrazelluläre Akkumulation von Amyloidfibrillen im Herzen kommt es zu einer restriktiven Kardiomyopathie, die zu typischen Herzinsuffizienzsymptomen sowie Erregungsleitungs- und Erregungsrückbildungsstörungen führt. Auch extrakardiale Probleme wie ein Karpaltunnelsyndrom können auf eine kardiale ATTR-Amyloidose hindeuten. Die Erkrankung kann durch eine Myokardbiopsie oder alternativ durch eine positive Skelettszintigraphie bei gleichzeitigem Ausschluss monoklonaler Proteine im Blut und Urin diagnostiziert werden. Neben einer symptomatischen Therapie steht mittlerweile mit dem Transthyretin(TTR)-Stabilisator Tafamidis ein Medikament zur Verfügung, das den Krankheitsverlauf signifikant verlangsamen kann. In den nächsten Jahren ist mit der Zulassung weiterer Medikamente zur Behandlung der kardialen ATTR-Amyloidose zu rechnen.

Topics: Aged; Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Prealbumin; Stroke Volume; Tomography, X-Ray Computed

Cardiac amyloidosis is a rare and severe disease with worse prognosis than classic cardiac insufficiency. Transthyretin amyloïdosis is an underdiagnosed cause of amyloidosis. Technetium scintigraphy allows to confirm diagnosis of transthyretin amyloidosis with great specificity. A new hope is brought by tafamidis, a novel therapeutic option for this specific condition. This medication is the first one that proved a risk reduction in mortality among patients with cardiac amyloidosis in class NYHA I and II. In this article, we review across a clinical case the modalities for the diagnosis and treatment of transthyretin amyloidosis.. L’amyloïdose cardiaque est une maladie rare et sévère. En cas d’insuffisance cardiaque, le pronostic est pire que pour les autres étiologies. L’amyloïdose à transthyrétine est une des formes d’amyloïdose dont le diagnostic peut être posé avec une grande spécificité grâce à la scintigraphie au technétium. Une lueur d’espoir est apportée par l’arrivée du tafamidis, une nouvelle classe thérapeutique. Ce médicament est le premier à avoir démontré une réduction de mortalité parmi les patients en classe NYHA I et II. Dans cet article, nous décrivons, à partir d’un cas clinique, les démarches diagnostiques et thérapeutiques nécessaires à la prise en charge d’un patient présentant une insuffisance cardiaque sur amyloïdose à transthyrétine.

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Humans; Therapies, Investigational

Tafamidis is the only therapy shown to improve survival in transthyretin cardiac amyloidosis (ATTR) based on randomized controlled trial data. We sought to evaluate the impact of tafamidis on survival in a real-world community-based cohort. This was a prospective observational cohort study that included consecutive patients with confirmed ATTR based on biopsy or TcPYP imaging. Baseline characteristics were compared between patients taking tafamidis vs not, and Kaplan-Meier survival analysis was performed to compare survival between these groups. We examined the reasons that ATTR patients were not on tafamidis. Of 107 ATTR patients, median age was 83.9 years, 79% were men, and 63 (59%) of them were on tafamidis. Demographics and baseline cardiovascular risk factors did not differ significantly between those on vs off tafamidis, although there was a higher proportion of NYHA Class III or IV heart failure in those off tafamidis (76% vs 57%, P < 0.01). The most common reasons patients were not on tafamidis included delays in obtaining the drug or financial barriers (59%) and NYHA Class IV heart failure (19.5%). Patients taking tafamidis had a significantly higher median survival compared to those not on tafamidis (median survival 6.70 vs 1.43 years, P < 0.0001). Our study demonstrates significantly improved survival in ATTR patients taking tafamidis. Barriers exist to tafamidis initiation including delayed access and affordability, and efforts should be made to improve patient access.

Topics: Aged, 80 and over; Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Female; Heart Failure; Humans; Male; Observational Studies as Topic; Prospective Studies

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, life-threatening disease characterized by the aggregation and deposition of amyloidogenic misfolded transthyretin (TTR) in the myocardium. The gradual accumulation of insoluble TTR amyloid fibrils can result in restrictive cardiomyopathy and heart failure. Tafamidis (Vyndaqel

Topics: Amyloidogenic Proteins; Benzoxazoles; Cardiomyopathies; Double-Blind Method; Hospitalization; Humans; Multicenter Studies as Topic; Prealbumin; Quality of Life; Randomized Controlled Trials as Topic; Walk Test

Transthyretin (ATTR) amyloidosis is a multisystem disease caused by organ deposition of amyloid fibrils derived from the misfolded transthyretin (TTR) protein. The purpose of this article is to provide an overview of current treatment regimens and summarize important considerations for each agent. A literature search was performed with the PubMed database for articles published through October 2020. Search criteria included therapies available on the market and investigational therapies used for ATTR amyloidosis treatment. Both prospective clinical trials and retrospective studies have been included in this review. Available therapies discussed in this review article are tafamidis, diflunisal, patisiran, and inotersen. Tafamidis is FDA approved for treatment of wild-type ATTR (ATTRwt) and hereditary ATTR (ATTRv) cardiomyopathy, and patisiran and inotersen are FDA approved for ATTRv polyneuropathy. Diflunisal does not have an FDA-labeled indication for amyloidosis but has been studied in ATTRv polyneuropathy and ATTRwt cardiomyopathy. Investigational therapies include a TTR stabilizer, AG10; 2 antifibril agents, PRX004 and doxycycline/tauroursodeoxycholic acid; and 2 gene silencers, vutrisiran and AKCEA-TTR-LRx; and clinical trials are ongoing. ATTR amyloidosis treatment selection is based on subtype and presence of cardiac or neurological manifestations. Additional considerations such as side effects, monitoring, and administration are outlined in this review.

Topics: Amyloid Neuropathies, Familial; Animals; Benzoxazoles; Cardiomyopathies; Cardiovascular Agents; Diflunisal; Genetic Predisposition to Disease; Humans; Mutation; Oligonucleotides; Phenotype; Prealbumin; RNA, Small Interfering; Treatment Outcome

Cardiac amyloidosis is an underrecognized cause of heart failure. We review clinical clues to the diagnoses, a rational approach to testing, and current and emerging therapies.. Advances in the diagnosis of amyloid cardiomyopathy include (1) use of

Topics: Amyloid Neuropathies, Familial; Amyloidosis; Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Immunoglobulin Light-chain Amyloidosis

Often considered a rare disease, cardiac amyloidosis is increasingly recognized by practicing clinicians. The increased rate of diagnosis is in part due the aging of the population and increasing incidence and prevalence of cardiac amyloidosis with advancing age, as well as the advent of noninvasive methods using nuclear scintigraphy to diagnose transthyretin cardiac amyloidosis due to either variant or wild type transthyretin without a biopsy. Perhaps the most important driver of the increased awareness is the elucidation of the biologic mechanisms underlying the pathogenesis of cardiac amyloidosis which have led to the development of several effective therapies with differing mechanisms of actions. In this review, the mechanisms underlying the pathogenesis of cardiac amyloidosis due to light chain (AL) or transthyretin (ATTR) amyloidosis are delineated as well as the rapidly evolving therapeutic landscape that has emerged from a better pathophysiologic understanding of disease development.

Topics: Aging; Alkylating Agents; Amyloid; Amyloid Neuropathies, Familial; Amyloidosis; Antibodies, Monoclonal; Benzoates; Benzoxazoles; Bridged Bicyclo Compounds, Heterocyclic; Cardiomyopathies; Catechol O-Methyltransferase Inhibitors; Heart Transplantation; Humans; Immunomodulating Agents; Oligonucleotides; Proteasome Inhibitors; Protein Folding; Pyrazoles; RNA, Small Interfering; Stem Cell Transplantation; Sulfonamides; Tolcapone

Cardiac amyloidosis (CA) is an infiltrative and restrictive cardiomyopathy that leads to heart failure, reduced quality of life, and death. The disease has two main subtypes, transthyretin cardiac amyloidosis (ATTR-CA) and immunoglobulin light chain cardiac amyloidosis (AL-CA), characterized by the nature of the infiltrating protein. ATTR-CA is further subdivided into wild-type (ATTRwt-CA) and variant (ATTRv-CA) based on the presence or absence of a mutation in the transthyretin gene. CA is significantly underdiagnosed and increasingly recognized as a cause of heart failure with preserved ejection fraction. Advances in diagnosis that employ nuclear scintigraphy to diagnose ATTR-CA without a biopsy and the emergence of effective treatments, including transthyretin stabilizers and silencers, have changed the landscape of this field and render early and accurate diagnosis critical. This review summarizes the epidemiology, pathophysiology, diagnosis, prognosis, and management of CA with an emphasis on the significance of recent developments and suggested future directions.

Topics: Amyloid Neuropathies, Familial; Amyloidosis; Arrhythmias, Cardiac; Benzoates; Benzoxazoles; Biopsy; Cardiac Pacing, Artificial; Cardiomyopathies; Diflunisal; Disease Progression; Early Diagnosis; Early Medical Intervention; Echocardiography; Electrocardiography; Heart Failure; Humans; Immunoglobulin Light-chain Amyloidosis; Immunologic Factors; Magnetic Resonance Imaging; Oligonucleotides; Prealbumin; Prognosis; Proteasome Inhibitors; Pyrazoles; Radionuclide Imaging; RNA, Small Interfering

Transthyretin (TTR) cardiac amyloidosis results from the dissociation of the tetrameric, liver-synthetized transport protein, either because of a mutation (hereditary CA), or spontaneously due to ageing (wild type CA). Monomers self-associate into amyloid fibrils within the myocardium, causing heart failure, arrhythmias and conduction defects. This overlooked disease must be recognized in case of unexplained increased thickness of the myocardium, particularly in subjects of African descent, in patients with heart failure and preserved ejection fraction, and in those with aortic stenosis. Some extra-cardiac symptoms must also be considered as red flags: carpal tunnel syndrome, lumbar canal stenosis, recent deafness, peripheral neuropathy, or dysautonomia. Medical assessment includes an electrocardiogram, biological assessment including troponin, natriuretic peptide and monoclonal protein assay, echocardiography with 2-D strain study, MRI and bone scintigraphy. Once the diagnosis established, cardiologic management must avoid beta-blockers and other rate-slowing drugs, which are deleterious in restrictive cardiomyopathy, and restrain the use of renin-angiotensin system inhibitors, of little use and often poorly tolerated. Congestion must be treated with diuretics. Anticoagulants are often necessary due to the risk of arrhythmias and stroke. Pacemaker or defibrillator implantation should be determined in patients with high risk of sudden death. Until now, etiologic treatments were liver and/or heart transplantation in some rare cases. Tafamidis, a TTR stabilizer has recently been approved, and new therapeutic approaches targeting TTR at the transcriptional level are under investigation.

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Echocardiography; Electrocardiography; Humans

Background The emergence of specific therapies for transthyretin cardiac amyloidosis (CA) warrants the need for a systematic review of the literature. Methods and Results A systematic review of the literature was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search was performed on MEDLINE, PubMed, and Embase databases on November 29, 2019. Studies were selected based on the following predefined eligibility criteria: English-language randomized controlled trials (RCTs), non-RCTs, or observational studies, which included adult patients with variant/wild-type transthyretin-CA, assessed specific therapies for transthyretin-CA, and reported cardiovascular outcomes. Relevant data were extracted to a predefined template. Quality assessment was based on National Institute for Health and Care Excellence recommendations (RCTs) or a checklist by Downs and Black (non-RCTs). From 1203 records, 24 publications were selected, describing 4 RCTs (6 publications) and 16 non-RCTs (18 publications). Tafamidis was shown to significantly improve all-cause mortality and cardiovascular hospitalizations and reduce worsening in 6-minute walk test, Kansas City Cardiomyopathy Questionnaire-Overall Summary score, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) in variant/wild-type transthyretin-CA. Patisiran showed promising results in a subgroup analysis of patients with variant transthyretin-CA, which have to be confirmed in RCTs. Inotersen showed conflicting results on cardiac imaging parameters. The one study on AG10 had only a 1-month duration and cardiovascular end points were exploratory and limited to cardiac biomarkers. Limited evidence from noncomparative single-arm small non-RCTs existed for diflunisal, epigallocatechin-3-gallate (green tea extract), and doxycycline+tauroursodeoxycholic acid/ursodeoxycholic acid. Conclusions This systematic review of the literature supports the use of tafamidis in wild-type and variant transthyretin-CA. Novel therapeutic targets including transthyretin gene silencers are currently under investigation.

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Cardiovascular Agents; Genetic Therapy; Humans

Amyloidosis is caused by extracellular deposition of insoluble abnormal fibrils constituted by misfolded proteins, which can modify tissue anatomy and hinder the function of multiple organs including the heart. Amyloidosis that can affect the heart includes mostly systemic amyloidosis (amyloid light chain, AL) and transthyretin amyloidosis (ATTR). The latter can be acquired in elderly patients (ATTRwt), or be inherited in younger individuals (ATTRm). The diagnosis is demanding given the high phenotypic heterogeneity of the disease. Therefore, "red flags," which are suggestive features giving support to diagnostic suspicion, are extremely valuable. However, the lack of broad awareness among clinicians represents a major obstacle for early diagnosis and treatment of ATTR. Furthermore, recent implementation of noninvasive diagnostic techniques has revisited the need for endomyocardial biopsy (EMB). In fact, unlike AL amyloidosis, which requires tissue confirmation and typing for diagnosis, ATTR can now be diagnosed noninvasively with the combination of bone scintigraphy and the absence of a monoclonal protein. Securing the correct diagnosis is pivotal for the newly available therapeutic options targeting both ATTRm and ATTRwt, and are directed to either stabilization of the abnormal protein or the reduction of the production of transthyretin. The purpose of this article is to review the contemporary aspects of diagnosis and management of transthyretin amyloidosis with cardiac involvement, summarizing also the recent therapeutic advances with tafamidis, patisiran, and inotersen.

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Biomarkers; Cardiomyopathies; Diagnosis, Differential; Echocardiography; Electrocardiography; Humans; Magnetic Resonance Imaging; Oligonucleotides; Radionuclide Imaging; RNA, Small Interfering

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-threatening, progressive, infiltrative disease caused by the deposition of transthyretin amyloid fibrils in the heart, and can often be overlooked as a common cause of heart failure. Delayed diagnosis due to lack of disease awareness and misdiagnosis results in a poorer prognosis. Early accurate diagnosis is therefore key to improving patient outcomes, particularly in the context of both the recent approval of tafamidis in some countries (including the United States) for the treatment of ATTR-CM, and of other promising therapies under development. With the availability of scintigraphy as an inexpensive, noninvasive diagnostic tool, the rationale to screen for ATTR-CM in high-risk populations of patients is increasingly warranted. Here the authors propose a framework of clinical scenarios in which screening for ATTR-CM is recommended, as well as diagnostic "red flags" that can assist in its diagnosis among the wider population of patients with heart failure.

Topics: Age Factors; Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Delayed Diagnosis; Diagnostic Errors; Early Diagnosis; Early Medical Intervention; Heart Failure; Humans; Stroke Volume

Transthyretin amyloidosis is a rare, life-threatening disease resulting from aggregation and deposition of transthyretin amyloid fibrils in various tissues. There are 2 predominate phenotypic presentations of the disease: transthyretin familial amyloid polyneuropathy, which primarily affects the peripheral nerves, and transthyretin cardiomyopathy (TTR-CM), which primarily affects the heart. However, there is a wide overlap with symptoms at presentation and disease course being highly variable and influenced by the underlying transthyretin mutation, age of the affected individual, sex, and geographic location. Treatment of transthyretin amyloidosis is typically focused on symptom management. Although tafamidis has been shown to delay neurologic progression of transthyretin familial amyloid polyneuropathy, there are no approved pharmacologic therapies shown to improve survival in TTR-CM. The natural history of TTR-CM is poorly characterized, which presents difficulties for the design of large-scale trials for new treatments. This review provides a brief overview of TTR-CM and the challenges of identifying clinically meaningful end points and study parameters to determine the efficacy of treatments for rare diseases. The design and rationale behind the ongoing phase 3 ATTR-ACT study (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial), an international, multicenter, double-blind, placebo-controlled, randomized clinical trial, is also outlined. The ATTR-ACT study will provide important insight into the efficacy and safety of tafamidis for the treatment of TTR-CM.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01994889.

Topics: Administration, Oral; Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Clinical Trials, Phase III as Topic; Disease Management; Disease Progression; Humans; Randomized Controlled Trials as Topic

Transthyretin-cardiac amyloidoses (ATTR-CA) are an underdiagnosed but increasingly recognized cause of heart failure. Extracellular deposition of fibrillary proteins into tissues due to a variety of inherited transthyretin mutations in ATTRm or due to advanced age in ATTRwt eventually leads to organ failure. In the heart, amyloid deposition causes diastolic dysfunction, restrictive cardiomyopathy with progressive loss of systolic function, arrhythmias, and heart failure. While traditional treatments have consisted of conventional heart failure management and supportive care for systemic symptoms, numerous disease-modifying therapies have emerged over the past decade. From organ transplantation to transthyretin stabilizers (diflunisal, tafamidis, AG-1), TTR silencers (ALN-ATTR02, ISIS-TTR(Rx)), and degraders of amyloid fibrils (doxycycline/TUDCA), the potential for effective transthyretin amyloid therapy is greater now than ever before. In light of these multiple agents under investigation in human clinical trials, clinicians should be familiar with the systemic cardiac amyloidoses, their differing pathophysiology, natural histories, and unique treatment strategies.

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Biomarkers; Cardiomyopathies; Cyclooxygenase Inhibitors; Defibrillators, Implantable; Diflunisal; Doxycycline; Heart Failure; Humans; Oligonucleotides, Antisense; Organ Transplantation; Pacemaker, Artificial; RNA, Small Interfering

Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) experience infiltrative cardiomyopathy and heart failure symptoms requiring costly hospitalizations. The Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT) demonstrated the efficacy of tafamidis on the frequency of cardiovascular (CV)-related hospitalizations in patients with ATTR-CM.. As length of stay can affect the total hospitalization burden, our study aimed to better understand the impact of tafamidis on the number of CV-related hospital days avoided in the management of ATTR-CM patients.. Data from ATTR-ACT were used to calculate the total burden of CV-related hospitalization (days) by treatment arm in this post hoc analysis.. In the total trial population, patients receiving tafamidis had significantly fewer CV-related hospitalizations per year (relative risk reduction [RRR] 0.68; 0.4750 vs. 0.7025, p < 0.0001) and a shorter mean length of stay per CV-related hospitalization event (8.6250 vs. 9.5625 days) than patients receiving placebo. Taken together, tafamidis prevented 2.62 CV-related hospitalization days per patient per year. A subgroup analysis showed that with earlier treatment initiation of tafamidis, the annual number of CV-related hospitalizations was significantly lowered by 52% compared with placebo (RRR 0.48; 0.3378 vs. 0.7091, p < 0.0001). With 1.14 fewer days per hospitalization, tafamidis reduced the annual number of CV-related hospitalization days by 3.96 days per New York Heart Association class I/II patient.. In patients with ATTR-CM, tafamidis was associated with a lower rate of CV-related hospitalizations and shorter length of hospital stay. Timely diagnosis and treatment with tafamidis could further decrease the total number of CV-related hospitalization days per year.. NCT01994889.

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Hospitalization; Humans; Prealbumin

The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) demonstrated the effectiveness of tafamidis for the treatment of patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Tafamidis reduced mortality in all subgroups of patients studied. Tafamidis also reduced observed frequency of cardiovascular (CV)-related hospitalizations in all subgroups except those who were New York Heart Association (NYHA) class III at baseline who, paradoxically, had a higher frequency of CV-related hospitalizations than placebo. Given the greater mortality rate with placebo, this analysis assessed the impact of the confounding effect of death on the frequency of CV-related hospitalization in ATTR-ACT.. In ATTR-ACT, patients with ATTR-CM were randomized to tafamidis (n = 264) or placebo (n = 177) for 30 months. Post hoc analyses first defined and compared the effect of tafamidis treatment in the subset of NYHA class III patients from each treatment arm alive at month 30. The impact of a potential survivor bias was then adjusted for using principal stratification, estimating the frequency of CV-related hospitalization in NYHA class III patients who would have survived regardless of assigned treatment group (defined as the survivor average causal effect [SACE]).. In the subset of NYHA class III patients alive at month 30, tafamidis reduced the relative risk of CV-related hospitalization versus placebo (relative risk: 0.95 [95% CI: 0.55-1.65]). In the principal stratification analyses of those patients who would survive to 30 months regardless of treatment, tafamidis treatment was associated with a 24% lower risk of CV-related hospitalization (relative risk: 0.76 [95% CI: 0.45-1.24]). Similarly, there was a larger reduction in CV-related hospitalization frequency with tafamidis in NYHA class I or II patients in the SACE than was initially observed in ATTR-ACT.. Initial data from ATTR-ACT likely underestimated the effect of tafamidis on CV-related hospitalizations due to the confounding effect of death. When SACE was used to adjust for survivor bias, there was a 24% reduction in the frequency of CV-related hospitalization in NYHA class III patients treated with tafamidis.

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Hospitalization; Humans; Prealbumin

The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) showed that tafamidis reduced all-cause mortality and cardiovascular-related hospitalizations in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). This study aimed to estimate the impact of tafamidis on survival and quality-adjusted life-years (QALYs).. A multi-state, cohort, Markov model was developed to simulate the disease course of ATTR-CM throughout a lifetime. For survival extrapolation, survival curves were fitted by treatment arm and New York Heart Association (NYHA) Class I/II (68% of patients) and NYHA Class III (32% of patients) cohorts using the individual patient-level data from both the ATTR-ACT and the corresponding long-term extension study. Univariate and multivariate sensitivity analyses were conducted. The predicted mean survival for the total population (NYHA Class I/II + III) was 6.73 years for tafamidis and 2.85 years for the standard of care (SoC), resulting in an incremental mean survival of 3.88 years [95% confidence interval (CI) 1.32-5.66]. Of the 6.73 life-years, patients on tafamidis spend, on average, 4.82 years in NYHA Class I/II, while patients on SoC spend an average of 1.60 life-years in these classes. The combination of longer survival in lower NYHA classes produced a QALY gain of 5.39 for tafamidis and 2.11 for SoC, resulting in 3.29 incremental QALYs (95% CI 1.21-4.74) in favour of tafamidis.. Based on the disease simulation model results, tafamidis is expected to more than double the life expectancy and QALYs of ATTR-CM patients compared to SoC. Longer-term follow-up data from the ATTR-ACT extension study will further inform these findings.. NCT01994889 (date of registration: 26 November 2013).

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Humans; Prealbumin

Tafamidis is an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM) in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). While ATTR-ACT was not designed for a dose-specific assessment, further analysis from ATTR-ACT and its long-term extension study (LTE) can guide determination of the optimal dose.. In ATTR-ACT, patients were randomized (2:1:2) to tafamidis 80 mg, 20 mg, or placebo for 30 months. Patients completing ATTR-ACT could enrol in the LTE (with placebo-treated patients randomized to tafamidis 80 or 20 mg; 2:1) and all patients were subsequently switched to high-dose tafamidis. All-cause mortality was assessed in ATTR-ACT combined with the LTE (median follow-up 51 months). In ATTR-ACT, the combination of all-cause mortality and cardiovascular-related hospitalizations over 30 months was significantly reduced with tafamidis 80 mg (P = 0.0030) and 20 mg (P = 0.0048) vs. placebo. All-cause mortality vs. placebo was reduced with tafamidis 80 mg [Cox hazards model (95% confidence interval): 0.690 (0.487-0.979), P = 0.0378] and 20 mg [0.715 (0.450-1.137), P = 0.1564]. The mean (standard error) change in N-terminal pro-B-type natriuretic peptide from baseline to Month 30 was -1170.51 (587.31) (P = 0.0468) with tafamidis 80 vs. 20 mg. In ATTR-ACT combined with the LTE there was a significantly greater survival benefit with tafamidis 80 vs. 20 mg [0.700 (0.501-0.979), P = 0.0374]. Incidence of adverse events in both tafamidis doses were comparable to placebo.. Tafamidis, both 80 and 20 mg, effectively reduced mortality and cardiovascular-related hospitalizations in patients with ATTR-CM. The longer-term survival data and the lack of dose-related safety concerns support tafamidis 80 mg as the optimal dose.. ClinicalTrials.gov NCT01994889; NCT02791230.

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Prealbumin

In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial, tafamidis significantly reduced all-cause mortality and cardiovascular-related hospitalizations in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). ATTR-CM is associated with a significant burden of disease; further analysis of patient-reported quality of life will provide additional data on the efficacy of tafamidis. In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial, 441 adult patients with ATTR-CM were randomized (2:1:2) to tafamidis 80 mg, tafamidis 20 mg, or placebo for 30 months, with pooled tafamidis (80 mg and 20 mg) compared with placebo. Change in Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) domain scores, EQ-5D-3L scores, and patient global assessment, were prespecified exploratory end points. A greater proportion of patients improved KCCQ-OS score at month 30 with tafamidis (41.8%) versus placebo (21.4%). Tafamidis significantly reduced the decline in all 4 KCCQ-OS domains (p <0.0001 for all), and in EQ-5D-3L utility (0.09 [confidence interval 0.05 to 0.12]; p <0.0001) and EQ visual analog scale (9.11 [confidence interval 5.39 to 12.83]; p <0.0001) scores at month 30 versus placebo. A larger proportion of tafamidis-treated patients reported their patient global assessment improved at month 30 (42.3% vs 23.8% with placebo). In conclusion, tafamidis effectively reduced the decline in patient-reported outcomes, providing further insight into its efficacy in health-related quality of life in patients with ATTR-CM.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Cost of Illness; Female; Humans; Male; Patient Reported Outcome Measures; Quality of Life; Self Efficacy; Social Participation

In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), tafamidis significantly reduced mortality and cardiovascular (CV)-related hospitalizations compared with placebo in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). This analysis aimed to assess the causes of CV-related death and hospitalization in ATTR-ACT to provide further insight into the progression of ATTR-CM and efficacy of tafamidis. ATTR-ACT was an international, double-blind, placebo-controlled, and randomized study. Patients with hereditary or wild-type ATTR-CM were randomized to tafamidis (n = 264) or placebo (n = 177) for 30 months. The independent Endpoint Adjudication Committee determined whether certain investigator-reported events met the definition of disease-related efficacy endpoints using predefined criteria. Cause-specific reasons for CV-related deaths (heart failure [HF], arrhythmia, myocardial infarction, sudden death, stroke, and other CV causes) and hospitalizations (HF, arrhythmia, myocardial infarction, transient ischemic attack/stroke, and other CV causes) were assessed. Total CV-related deaths was 53 (20.1%) with tafamidis and 50 (28.2%) with placebo, with HF (15.5% tafamidis, 22.6% placebo), followed by sudden death (2.7% tafamidis, 5.1% placebo), the most common causes. The number of patients with a CV-related hospitalization was 138 (52.3%) with tafamidis and 107 (60.5%) with placebo; with HF the most common cause (43.2% tafamidis, 50.3% placebo). All predefined causes of CV-related death or hospitalization were less frequent with tafamidis than placebo. In conclusion, these data provide further insight into CV disease progression in patients with ATTR-CM, with HF the most common adjudicated cause of CV-related hospitalization or death in ATTR-ACT. Clinical trial registration ClinicalTrials.gov: NCT01994889.

Topics: Aged; Amyloid Neuropathies, Familial; Amyloidosis; Arrhythmias, Cardiac; Benzoxazoles; Cardiomyopathies; Cardiovascular Diseases; Cause of Death; Death, Sudden, Cardiac; Double-Blind Method; Female; Heart Failure; Hospitalization; Humans; Ischemic Attack, Transient; Male; Myocardial Infarction; Prealbumin; Proportional Hazards Models; Stroke

Tafamidis, a non-nonsteroidal anti-inflammatory benzoxazole derivative, acts as a transthyretin (TTR) stabilizer to slow progression of TTR amyloidosis (ATTR). Tafamidis meglumine, available as 20-mg capsules, is approved in more than 40 countries worldwide for the treatment of adults with early-stage symptomatic ATTR polyneuropathy. This agent, administered as an 80-mg, once-daily dose (4 × 20-mg capsules), is approved in the United States, Japan, Canada, and Brazil for the treatment of hereditary and wild-type ATTR cardiomyopathy in adults. An alternative single solid oral dosage formulation (tafamidis 61-mg free acid capsules) was developed and introduced for patient convenience (approved in the United States, United Arab Emirates, and European Union). In this single-center, open-label, randomized, 2-period, 2-sequence, crossover, multiple-dose phase 1 study, the rate and extent of absorption were compared between tafamidis 61-mg free acid capsules (test) and tafamidis meglumine 80-mg (4 × 20-mg) capsules (reference) after 7 days of repeated oral dosing under fasted conditions in 30 healthy volunteers. Ratios of adjusted geometric means (90%CI) for the test/reference formulations were 102.3 (98.0-106.8) for area under the concentration-time profile over the dosing interval and 94.1 (89.1-99.4) for the maximum observed concentration, satisfying prespecified bioequivalence acceptance criteria (90%CI, 80-125). Both tafamidis regimens had an acceptable safety/tolerability profile in this population.

Topics: Administration, Oral; Adult; Amyloid Neuropathies; Amyloid Neuropathies, Familial; Benzoxazoles; Brazil; Canada; Cardiomyopathies; Cross-Over Studies; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Compounding; Fasting; Female; Healthy Volunteers; Humans; Japan; Male; Middle Aged; Prealbumin; Safety; Therapeutic Equivalency; United States

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Case-Control Studies; Echocardiography; Hospitalization; Humans; Mutation; Placebos; Prealbumin; Survival Analysis

Transthyretin amyloid cardiomyopathy is caused by the deposition of transthyretin amyloid fibrils in the myocardium. The deposition occurs when wild-type or variant transthyretin becomes unstable and misfolds. Tafamidis binds to transthyretin, preventing tetramer dissociation and amyloidogenesis.. In a multicenter, international, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 441 patients with transthyretin amyloid cardiomyopathy in a 2:1:2 ratio to receive 80 mg of tafamidis, 20 mg of tafamidis, or placebo for 30 months. In the primary analysis, we hierarchically assessed all-cause mortality, followed by frequency of cardiovascular-related hospitalizations according to the Finkelstein-Schoenfeld method. Key secondary end points were the change from baseline to month 30 for the 6-minute walk test and the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS), in which higher scores indicate better health status.. In the primary analysis, all-cause mortality and rates of cardiovascular-related hospitalizations were lower among the 264 patients who received tafamidis than among the 177 patients who received placebo (P<0.001). Tafamidis was associated with lower all-cause mortality than placebo (78 of 264 [29.5%] vs. 76 of 177 [42.9%]; hazard ratio, 0.70; 95% confidence interval [CI], 0.51 to 0.96) and a lower rate of cardiovascular-related hospitalizations, with a relative risk ratio of 0.68 (0.48 per year vs. 0.70 per year; 95% CI, 0.56 to 0.81). At month 30, tafamidis was also associated with a lower rate of decline in distance for the 6-minute walk test (P<0.001) and a lower rate of decline in KCCQ-OS score (P<0.001). The incidence and types of adverse events were similar in the two groups.. In patients with transthyretin amyloid cardiomyopathy, tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo. (Funded by Pfizer; ATTR-ACT ClinicalTrials.gov number, NCT01994889 .).

Topics: Administration, Oral; Aged; Aged, 80 and over; Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Disease Progression; Double-Blind Method; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Prealbumin; Quality of Life; Survival Analysis; Walk Test

A phase 2, open-label study in 21 patients with non-Val30Met and non-Val122Ile hereditary transthyretin amyloidosis showed that tafamidis (20 mg daily for 12 months) stabilized these transthyretin variants. We assessed cardiac amyloid infiltration and cardiac abnormalities in this same study population. At baseline, median age was 64.3 years, 11 patients were in NYHA class II, 13 had conduction abnormalities, 14 N-terminal pro-hormone brain natriuretic peptide concentrations >300 pg/ml, and 17 interventricular septal thickness >12 mm. Mean (SD) left ventricular ejection fraction was 60.3% (9.96). Patients with normal heart rate variability increased from 4/19 at baseline to 8/19 at month 12 (p < 0.05). Cardiac biomarkers remained stable. Although four patients had increases in interventricular septal thickness ≥ 2 mm, the remainder had stable septal wall thickness. There were no clinically relevant changes in mean echocardiographic/electrocardiographic variables and no safety concerns.

Topics: Adult; Aged; Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Europe; Female; Fibrosis; Genetic Predisposition to Disease; Heart Failure; Humans; Male; Middle Aged; Mutation; Myocardium; Phenotype; Prealbumin; Risk Factors; Time Factors; Treatment Outcome; United States

Transthyretin (TTR) amyloidosis is a progressive systemic disorder caused by misfolded TTR monomers that cumulatively deposit in the heart and systemically as amyloid.. This phase 2 open-label trial evaluated the stabilization of TTR tetramers using 20 mg of tafamidis daily at week 6 (primary end point), month 6, and month 12, as well as safety of tafamidis treatment and efficacy with respect to progression of TTR amyloid cardiomyopathy. Thirty-one wild-type patients (median age, 76.7 years; 93.5% men) with a median disease duration of 55.6 months and mild to moderate heart failure (96.8%; New York Heart Association, classes I-II) were enrolled. Thirty of 31 patients (96.8%) achieved TTR stabilization after 6 weeks and 25 of 28 patients (89.3%) after 12 months. After 12 months of treatment, 3 patients discontinued prematurely, 2 patients died, 7 patients were hospitalized because of cardiovascular events, 20 of 28 patients demonstrated preserved New York Heart Association classification status, but 15 of 31 (48.4%) patients had clinical progression (eg, admission for cardiac failure, atrial fibrillation, and syncope). N-terminal prohormone brain natriuretic peptide levels did not increase significantly over time, troponin I and troponin T increased moderately, and no consistent clinically relevant changes were seen in echocardiographic cardiac assessments. Tafamidis treatment was generally well tolerated although 7 of 31 patients had bouts of diarrhea.. Tafamidis treatment effectively achieved and maintained TTR stabilization and was well tolerated. The absence of significant changes in most biochemical and echocardiographic parameters suggests that further evaluation of tafamidis in TTR amyloid cardiomyopathy is warranted.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00694161.

Topics: Aged; Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Disease Progression; Drug Administration Schedule; Female; Humans; Male; Mutation; Myocardium; Prealbumin; Protein Folding; Protein Multimerization; Protein Stability; Protein Structure, Quaternary; Time Factors; Treatment Outcome; United States

The purpose of this study was to carefully analyse the therapeutic benefit of tafamidis in patients with wild-type transthyretin amyloidosis (ATTRwt) and cardiomyopathy (ATTRwt-CM) after one year of therapy based on serial multi-parametric cardiovascular magnetic resonance (CMR) imaging.. Non-sponsored data based on multi-parametric CMR regarding the effect of tafamidis on the cardiac phenotype of patients with ATTRwt-CM are not available so far.. The present study comprised N = 40 patients with ATTRwt-CM who underwent two serial multi-parametric CMR studies within a follow-up period of 12 ± 3 months. Baseline (BL) clinical parameters, serum biomarkers and CMR findings were compared to follow-up (FU) values in patients treated "with" tafamidis 61 mg daily (n = 20, group A) and those "without" tafamidis therapy (n = 20, group B). CMR studies were performed on a 1.5-T system and comprised cine-imaging, pre- and post-contrast T1-mapping and additional calculation of extracellular volume fraction (ECV) values.. While left ventricular ejection fraction (LV-EF), left ventricular mass index (LVMi), left ventricular wall thickness (LVWT), native T1- and ECV values remained unchanged in the tafamidis group A, a slight reduction in LV-EF (p = 0.003) as well as a subtle increase in LVMi (p = 0.034), in LVWT (p = 0.001), in native T1- (p = 0.038) and ECV-values (p = 0.017) were observed in the untreated group B. Serum NT-proBNP levels showed an overall increase in both groups, however, with the untreated group B showing a relatively higher increase compared to the treated group A. Assessment of NYHA class did not result in significant intra-group differences when BL were compared with FU, but a trend to improvement in the treated group A compared to a worsening trend in the untreated group B (∆p = 0.005).. As expected, tafamidis does not improve cardiac phenotype in patients with ATTRwt-CM after one year of therapy. However, tafamidis seems to slow down cardiac disease progression in patients with ATTRwt-CM compared to those without tafamidis therapy based on multi-parametric CMR data already after one year of therapy.

Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Humans; Magnetic Resonance Imaging; Magnetic Resonance Imaging, Cine; Magnetic Resonance Spectroscopy; Myocardium; Predictive Value of Tests; Stroke Volume; Ventricular Function, Left

The impact of tafamidis on myocardial strain in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) have been barely investigated. We aimed to determine tafamidis-induced changes using serial speckle tracking echocardiography and to identify imaging parameters for specific therapy monitoring.. ATTR-CM patients underwent serial TTE with two-dimensional (2 D) speckle tracking imaging. Patients receiving tafamidis free acid 61 mg (. Treatment with tafamidis free acid 61 mg in ATTR-CM patients delays the deterioration of LA and LV longitudinal function, resulting in significant clinical benefits compared with natural history. Serial TTE with 2 D speckle tracking imaging may be appropriate for disease-specific therapy monitoring.

Topics: Amyloidosis; Cardiomyopathies; Echocardiography; Humans; Myocardium; Prealbumin; Ventricular Function, Left

Topics: Amyloidosis; Cardiomyopathies; Humans; Prealbumin; Radionuclide Imaging; Tomography, X-Ray Computed

Tafamidis inhibits progression of transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) by binding TTR tetramer and inhibiting dissociation to monomers capable of denaturation and deposition in cardiac tissue. While the phase 3 ATTR-ACT trial demonstrated the efficacy of tafamidis, the degree to which the approved dose captures the full potential of the mechanism has yet to be assessed.. We developed a model of dynamic TTR concentrations in plasma to relate TTR occupancy by tafamidis to TTR stabilisation. We then developed population pharmacokinetic-pharmacodynamic models to characterise the relationship between stabilisation and measures of disease progression.. Modelling individual patient data of tafamidis exposure and increased plasma TTR confirmed that single-site binding provides complete tetramer stabilisation. These findings support the value of TTR stabilisation as a clinically beneficial treatment option in ATTR-CM and the ability of tafamidis to realise nearly the full therapeutic benefit of this mechanism.. NCT01994889.

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Disease Progression; Humans; Prealbumin

Topics: Amyloid Neuropathies, Familial; Amyloidosis; Cardiomyopathies; Diphosphates; Heart Failure; Humans; Prealbumin; Radionuclide Imaging; Radiopharmaceuticals; Technetium

A recently published expert consensus document recommended a multiparametric tool to monitor cardiac disease progression in patients with transthyretin cardiac amyloidosis (ATTR-CA). We aimed to evaluate the effect of the transthyretin stabiliser drug, tafamidis, by applying this integrative tool.. We retrospectively applied a multiparametric tool in a group of ATTR-CA patients who were given tafamidis between the years 2019-2021 and were followed in a dedicated clinic. We used three pre-specified follow-up timepoints: at 6, 12 and 18 months.. Based on a multiparametric tool, the use of tafamidis promoted disease stabilisation in the majority of patients at 18-month follow-up. Further study should focus on monitoring disease improvement in patients with ATTR-CA.

Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Consensus; Disease Progression; Humans; Prealbumin; Retrospective Studies

Hereditary transthyretin (TTR) amyloidosis (ATTRv) initially presents as a polyneuropathy and/or a cardiomyopathy. Central nervous system (CNS) pathology in ATTRv amyloidosis, including focal neurological episodes, dementia, cerebrovascular bleeding, and seizures, appears around a decade later. Wild-type (WT) TTR amyloidosis (ATTRwt) causes a cardiomyopathy. CNS pathology risk likely also increases in these patients as cardiomyopathy progresses. Herein, we study tafamidis-mediated TTR kinetic stabilisation in cerebrospinal fluid (CSF).. Varying tafamidis concentrations (50-1000 nM) were added to CSF from healthy donors or ATTRv patients, and TTR stabilisation was measured. Tafamidis meglumine (Vyndaqel) can be dosed at 20 or 80 mg QD. The latter dose is bioequivalent to a 61 mg QD dose of tafamidis free acid (Vyndamax). The tafamidis CSF concentration in ATTRv patients on 20 mg Vyndaqel is ∼125 nM. By linear extrapolation, we expect a CSF concentration of ∼500 nM at the higher dose. When tafamidis is added to healthy donor CSF at 125 or 500 nM, the WT TTR dissociation rate decreases by 42% or 87%, respectively.. Tafamidis stabilises TTR in CSF to what is likely a clinically meaningful extent at CSF concentrations achieved by the normal tafamidis dosing regimen.

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Humans; Prealbumin

Topics: Atrial Fibrillation; Cardiomyopathies; Humans; Incidence; Prealbumin

The efficacy of a therapy for patients with transthyretin amyloid cardiomyopathy (ATTR-CM) has not been proven, but tafamidis has been associated with favorable outcomes. However, echocardiographic details of the association of tafamidis with cardiac morphology remain undetermined. Moreover, whether the efficacy of tafamidis varies with the degree of cardiac involvement remains unknown. Using echocardiography, this study investigated the impact of tafamidis on the cardiac morphology of patients with ATTR-CM.Methods and Results: Of 52 consecutive patients with biopsy-proven ATTR-CM at Kobe University Hospital, we included 41 for whom details of follow-up echocardiographic examinations after the administration of tafamidis were available. All patients underwent standard and speckle-tracking echocardiography before and a mean (±SD) of 16±8 months after the administration of tafamidis. No significant changes were observed in any representative echocardiographic parameters after the administration of tafamidis. Furthermore, there were no significant changes observed in subgroup analyses (e.g., left ventricular [LV] ejection fraction ≥50% vs. <50%; LV mass index <150 vs. ≥150 g/m. Tafamidis may prevent worsening of various representative echocardiographic parameters of patients with ATTR-CM. This effect is also seen in patients with relatively advanced disease and in those who are elderly.

Topics: Aged; Amyloid Neuropathies, Familial; Cardiomyopathies; Echocardiography; Humans; Prealbumin

Topics: Amyloid Neuropathies, Familial; Amyloidosis; Cardiomyopathies; Diphosphates; Humans; Prealbumin; Predictive Value of Tests

Tafamidis treatment positively affects left ventricular (LV) structure and function and improves outcomes in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). We aimed to investigate the relationship between treatment response and cardiac amyloid burden identified by serial quantitative 99mTc-DPD SPECT/CT. We furthermore aimed to identify nuclear imaging biomarkers that could be used to quantify and monitor response to tafamidis therapy.. Forty wild-type ATTR-CM patients who underwent 99mTc-DPD scintigraphy and SPECT/CT imaging at baseline and after treatment with tafamidis 61 mg once daily [median, 9.0 months (interquartile range 7.0-10.0)] were divided into two cohorts based on the median (-32.3%) of the longitudinal percent change in standardized uptake value (SUV) retention index. ATTR-CM patients with a reduction greater than or equal to the median (n = 20) had a significant decrease in SUV retention index (P < 0.001) at follow-up, which translated into significant benefits in serum N-terminal prohormone of brain natriuretic peptide levels (P = 0.006), left atrial volume index (P = 0.038), as well as LV [LV global longitudinal strain: P = 0.028, LV ejection fraction (EF): P = 0.027, LV cardiac index (CI): P = 0.034] and right ventricular (RV) [RVEF: P = 0.025, RVCI: P = 0.048] functions compared with patients with a decrease less than the median (n = 20).. Treatment with tafamidis in ATTR-CM patients results in a significant reduction in SUV retention index, associated with significant benefits for LV and RV function and cardiac biomarkers. Serial quantitative 99mTc-DPD SPECT/CT imaging with SUV may be a valid tool to quantify and monitor response to tafamidis treatment in affected patients.. 99mTc-DPD SPECT/CT imaging with determination of SUV retention index as part of a routine annual examination can provide evidence of treatment response in ATTR-CM patients receiving disease-modifying therapy. Further long-term studies with 99mTc-DPD SPECT/CT imaging may help to evaluate the relationship between tafamidis-induced reduction in SUV retention index and outcome in patients with ATTR-CM and will demonstrate whether highly disease-specific 99mTc-DPD SPECT/CT imaging is more sensitive than routine diagnostic monitoring.

Topics: Amyloid Neuropathies, Familial; Amyloidosis; Cardiomyopathies; Humans; Prealbumin; Single Photon Emission Computed Tomography Computed Tomography

Tafamidis has been used for treatment of transthyretin cardiac amyloidosis (ATTR-CA). However, Tc-99 m pyrophosphate (PYP) cardiac scan for follow-up after tafamidis therapy has not been reported.. From May 2017 to March 2022, five patients with or without tafamidis therapy had received two Tc-99 m PYP cardiac scans. Tc-99 m PYP cardiac scan was performed with planar image and single photon emission computed tomography/computed tomography (SPECT/CT) 3 h after administration of Tc-99 m PYP. Perugini grading system was applied to determine positive or negative result of the scan. Heart to contralateral lung (H/CL) ratio as well as the difference of H/CL ratio between first and second Tc-99 m PYP cardiac scans (ΔH/CL ratio) was calculated.. In the five patients participated in this study, three received tafamidis therapy and H/CL ratio was significantly decreased (p = 0.02) after tafamidis therapy. Besides, the ΔH/CL ratio was larger in patients with tafamidis therapy than that in those without tafamidis therapy, albeit not reaching statistical significance (p = 0.2).. A decrease in H/CL ratio was found after tafamidis therapy in patients with ATTR-CA, albeit the magnitude of changes in the H/CL ratio (ΔH/CL ratio) was not significantly different from that of patients without tafamidis therapy. Future study with larger population might be required to further clarify the effect of tafamidis therapy on myocardial uptake of Tc-99 m PYP.. No clinical trial was conducted in our retrospective study.

Topics: Amyloidosis; Cardiomyopathies; Diphosphates; Follow-Up Studies; Humans; Prealbumin; Retrospective Studies; Technetium Tc 99m Pyrophosphate

Tafamidis improves prognosis in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). However, real-world data on the therapeutic effect of tafamidis are lacking. This study aimed to evaluate the clinical course, outcomes, and effectivity monitoring of the therapeutic effect of tafamidis in patients with ATTR-CM.. This is a single-centre, retrospective observational study. We evaluated the clinical characteristics and outcomes in 125 consecutive patients with wild-type ATTR-CM (ATTRwt-CM) treated with tafamidis (treatment group) and 55 untreated patients (treatment-naïve group). We monitored the therapeutic effect of tafamidis for 12 months by evaluating serial cardiac biomarker and imaging findings. The treatment group had significantly more favourable outcome in all-cause mortality and hospitalization due to heart failure than the treatment-naïve group in both the entire cohort (P < 0.01) and the propensity score-matched cohort (P < 0.05). Kaplan-Meier survival curves showed that tafamidis treatment significantly reduced all-cause mortality (P = 0.03, log-rank test), with the curves diverging after approximately 18 months of treatment in the propensity score-matched cohort. On inverse probability of treatment weighting analysis, tafamidis treatment showed a reduced all-cause mortality [hazard ratio (HR), 0.31; 95% confidence interval (CI), 0.11-0.93; P = 0.04]. High-sensitivity cardiac troponin T (hs-cTnT) > 0.05 ng/mL, B-type natriuretic peptide (BNP) > 250 pg/mL, and estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m. The prognosis of patients with ATTRwt-CM treated with tafamidis was more favourable than that of untreated patients. Patient stratification combined with biomarkers (hs-cTnT, BNP, and eGFR) predicted clinical outcomes. hs-cTnT may be a useful biomarker for evaluating the therapeutic effect of tafamidis.

Topics: Amyloidosis; Biomarkers; Cardiomyopathies; Heart Failure; Humans; Prealbumin

Topics: Amyloidosis; Cardiomyopathies; Humans; Prealbumin; Single Photon Emission Computed Tomography Computed Tomography

Cardiac transthyretin amyloidosis is an infiltrative cardiomyopathy with high mortality. To date, there are no specific biomarkers to directly assess disease activity and response to specific treatments. Our aim was to evaluate scintigraphic changes after treatment with the transthyretin stabilizer tafamidis.

Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Humans; Organotechnetium Compounds; Prealbumin

Transthyretin cardiac cardiomyopathy (ATTR-CM) is a rare but life-threatening disease. Tafamidis is an effective treatment for patients with ATTR-CM, however its long-term effects on cardiac remodeling and cardiac amyloid deposition are unknown. This study aimed to used cardiac magnetic resonance (CMR) to investigate the effects of tafamidis on patients with hereditary A97S ATTR-CM.. We retrospectively analyzed a prospective cohort of ATTR-CM patients, including 14 with hereditary A97S ATTR-CM and 17 healthy controls with baseline CMR data. All ATTR-CM patients received tafamidis treatment and received CMR with extracellular volume (ECV) at baseline and after 1 year of follow-up.. Baseline N-terminal pro-B-type natriuretic peptide, left ventricular (LV) mass, LV ejection fraction, global radial, circumferential and longitudinal strain, T1 mapping and ECV were significantly worse in the patients with ATTR-CM compared with the healthy controls. After 1 year of tafamidis treatment, ECV decreased from 51.5 ± 8.9% to 49.0 ± 9.4% (P = 0.041), however there were no significant changes in LV mass, LV ejection fraction, global radial strain, global circumferential strain, global longitudinal strain and T1 mapping.. After a one-year treatment period, tafamidis exhibited subtle but statistically significant reductions in ECV, potentially indicating a decrease in amyloid deposition among patients diagnosed with hereditary A97S ATTR-CM.

Topics: Amyloidosis; Cardiomyopathies; Follow-Up Studies; Humans; Prealbumin; Prospective Studies; Retrospective Studies

This plain language summary describes the results of a study called ATTR-ACT, which was published in the

Topics: Adult; Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Language; Prealbumin; Quality of Life

Tafamidis improves outcomes in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). However, it is not yet known whether tafamidis affects cardiac amyloid deposition and structural changes in the myocardium. We aimed to determine disease-modifying effects on myocardial amyloid progression and to identify imaging parameters that could be applied for specific therapy monitoring.. ATTR-CM patients underwent serial cardiac magnetic resonance (CMR) imaging using T1 mapping techniques to derive extracellular volume (ECV). Patients receiving tafamidis 61 mg (n = 35) or 20 mg (n = 15) once daily showed stable measurements at follow-up (FU) {61 mg: 9.0 [interquartile range (IQR) 7.0-11.0] months, 20 mg: 11.0 (IQR 8.0-18.0) months} in left ventricular (LV) ejection fraction (LVEF; 61 mg: 47.6% vs. 47.5%, P = 0.935; 20 mg: 52.4% vs. 52.1%, P = 0.930), LV mass index (LVMI; 61 mg: 110.2 vs. 106.2 g/m2, P = 0.304; 20 mg: 114.5 vs. 115.4 g/m2, P = 0.900), and ECV (61 mg: 47.5% vs. 47.7%, P = 0.861; 20 mg: 56.7% vs. 57.5%, P = 0.759), whereas treatment-naïve ATTR-CM patients (n = 19) had clear signs of disease progression at the end of the observation period [12.0 (IQR 10.0-21.0) months; LVEF: 53.3% vs. 45.7%, P = 0.031; LVMI: 98.9 vs. 106.9 g/m2, P = 0.027; ECV: 49.3% vs. 54.6%, P = 0.023]. Between-group comparison at FU revealed positive effects in tafamidis 61 mg-treated compared to treatment-naïve patients (LVEF: P = 0.035, LVMI: P = 0.036, ECV: P = 0.030), while those treated with 20 mg showed no difference in the above LV measurements when compared with treatment-naïve (P = 0.120, P = 0.287, P = 0.158). However, both treatment groups showed clinically beneficial effects compared to the natural course [61 mg, 6-min walk distance (6-MWD): P = 0.005, N-terminal prohormone of brain natriuretic peptide (NT-proBNP): P = 0.002; 20 mg, 6-MWD: P = 0.023, NT-proBNP: P = 0.003].. Tafamidis delays myocardial amyloid progression in ATTR-CM patients, resulting in structural, functional, and clinical benefits compared to the natural course. Serial CMR including measurement of ECV may be appropriate for disease-specific therapy monitoring.

Topics: Amyloidosis; Benzoxazoles; Cardiomyopathies; Heart Ventricles; Humans; Prealbumin; Time-to-Treatment

Tafamidis is approved in many countries for the treatment of transthyretin amyloid cardiomyopathy. This study reports data on the long-term efficacy of tafamidis from an ongoing long-term extension (LTE) to the pivotal ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial).. Patients with transthyretin amyloid cardiomyopathy who completed ATTR-ACT could enroll in an LTE, continuing with the same tafamidis dose or, if previously treated with placebo, randomized (2:1) to tafamidis meglumine 80 or 20 mg. All patients in the LTE transitioned to tafamidis free acid 61 mg (bioequivalent to tafamidis meglumine 80 mg) following a protocol amendment. In this interim analysis, all-cause mortality was assessed in patients treated with tafamidis meglumine 80 mg in ATTR-ACT continuing in the LTE, compared with those receiving placebo in ATTR-ACT transitioning to tafamidis in the LTE.. In the LTE, patients initially treated with tafamidis in ATTR-ACT had substantially better survival than those first treated with placebo, highlighting the importance of early diagnosis and treatment in transthyretin amyloid cardiomyopathy. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01994889 and NCT02791230.

Topics: Aged; Aged, 80 and over; Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Prealbumin; Proportional Hazards Models; Time

Tafamidis has emerged as an effective treatment for patients with wild-type transthyretin cardiac amyloidosis (ATTRwt CA). The early experience of tafamidis treatment for Japanese patients with ATTRwt CA is reported here.Methods and Results: Over the past 2 years, in 82 patients with ATTRwt CA (mean age of 81.7±6.0 years), tafamidis treatment was initiated for 38 patients. The remaining 44 patients were not administered tafamidis. The most frequent reason for non-administration of tafamidis was advanced heart failure and the second most reason was the patient's frailty. In patients who received tafamidis treatment, there was no discontinuation of tafamidis due to adverse events, the rate of cardiovascular-related hospitalizations per year was 0.19, and the 1-year survival rate was 92%. In the patients who continued tafamidis for 12-18 months, there was no significant deterioration from baseline for high-sensitivity cardiac troponin T level, plasma B-type natriuretic peptide level, left ventricular ejection fraction, inter-ventricular septum wall thickness, or value of left ventricular longitudinal strain.. Tafamidis treatment was introduced for approximately half of the study patients with ATTRwt CA in real-world practice. Tafamidis is likely to be safe and may maintain the status of disease severity in the short-term in selected Japanese patients with ATTRwt CA. Further research is needed to determine appropriate patient selection for tafamidis treatment and efficacy of tafamidis in the long term.

Topics: Aged; Aged, 80 and over; Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Humans; Japan; Prealbumin; Stroke Volume; Ventricular Function, Left

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Humans; Prealbumin

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Prealbumin

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Prealbumin

Cardiac amyloidosis usually presents with diastolic dysfunction, but sometimes systolic dysfunction develops, particularly at its advanced stage. However, the therapeutic strategy for patients with cardiac amyloidosis and systolic dysfunction remains unknown. We report a 77-year-old man who was diagnosed with wild-type cardiac amyloidosis and systolic dysfunction with a left ventricular ejection fraction of 27%. Following 6-month medical therapy of tafamidis 80 mg and neurohormonal blockers (carvedilol 5.0 mg, enalapril 2.5 mg, and spironolactone 25 mg), the left ventricular ejection fraction improved to 55%. Tafamidis-incorporated neurohormonal blocker therapy might be a promising strategy to facilitate cardiac reverse remodeling in patients with cardiac amyloidosis and systolic dysfunction.

Topics: Aged; Amyloidosis; Benzoxazoles; Cardiomyopathies; Carvedilol; Humans; Male; Stroke Volume; Ventricular Function, Left

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Prealbumin; Prognosis

Transthyretin cardiomyopathy (ATTR-CM) is an under-recognized cause of heart failure, but it has received increasing attention due to the availability of treatment options. We present a case of hereditary transthyretin cardiomyopathy (A97S, an under-represented variant in current clinical studies) who presented with heart failure. Timely diagnosis and intervention with tafamidis demonstrated reversed cardiac remodelling via multiple imaging techniques (echocardiography, cardiac magnetic resonance imaging and technetium-99m pyrophosphate scintigraphy). The echocardiography and cardiac magnetic resonance imaging demonstrated improved global strain. Cardiac magnetic resonance imaging showed decreased extracellular volume. The technetium-99m pyrophosphate scintigraphy demonstrated decreased heart-to-contralateral ratio. This case highlights the potential reversible effect of tafamidis on A97S amyloidosis cardiomyopathy.

Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Diphosphates; Heart Failure; Humans; Prealbumin; Technetium; Ventricular Remodeling

Transthyretin (TTR) tetramer dissociation is rate limiting for aggregation and subunit exchange. Slowing of TTR tetramer dissociation

Topics: Amyloid; Amyloid Neuropathies, Familial; Benzoates; Benzoxazoles; Cardiomyopathies; Diflunisal; Humans; Kinetics; Prealbumin; Protein Aggregates; Protein Binding; Protein Multimerization; Protein Subunits; Pyrazoles; Tolcapone

Topics: Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Prealbumin

Tafamidis is an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM), this study aimed to determine whether there is a differential effect between variant transthyretin amyloidosis (ATTRv) and wild-type transthyretin (ATTRwt).. ATTR-CM is a progressive, fatal disorder resulting from mutations in the ATTRv or the deposition of denatured ATTRwt.. In pre-specified analyses from ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial), baseline characteristics, all-cause mortality, and change from baseline to month 30 in 6-min walk test distance and Kansas City Cardiomyopathy Questionnaire Overall Summary score were compared in patients with ATTRwt and ATTRv.. There were 335 patients with ATTRwt (201 tafamidis, 134 placebo) and 106 with ATTRv (63 tafamidis, 43 placebo) enrolled in ATTR-ACT. Patients with ATTRwt (vs. ATTRv) had less advanced disease at baseline and a lower rate of disease progression over the study. The reduction in all-cause mortality with tafamidis compared with placebo was not different between ATTRwt (hazard ratio: 0.706 [95% confidence interval (CI): 0.474 to 1.052]; p = 0.0875) and ATTRv (hazard ratio: 0.690 [95% CI: 0.408 to 1.167]; p = 0.1667). Tafamidis was associated with a similar reduction (vs. placebo) in the decline in 6-min walk test distance in ATTRwt (mean ± SE difference from placebo, 77.14 ± 10.78; p < 0.0001) and ATTRv (79.61 ± 29.83 m; p = 0.008); and Kansas City Cardiomyopathy Questionnaire Overall Summary score in ATTRwt (12.72 ± 2.10; p < 0.0001) and ATTRv (18.18 ± 7.75; p = 0.019).. Pre-specified analyses from ATTR-ACT confirm the poor prognosis of untreated ATTRv-related cardiomyopathy compared with ATTRwt, but show the reduction in mortality and functional decline with tafamidis treatment is similar in both disease subtypes. (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy [ATTR-ACT]; NCT01994889).

Topics: Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Prealbumin

Topics: Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Prealbumin

Topics: Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Prealbumin

Topics: Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Prealbumin

ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial) demonstrated the efficacy and safety of tafamidis in transthyretin amyloid cardiomyopathy (ATTR-CM). Model-based analyses from ATTR-ACT can examine predictor effects on dose-response/exposure-response relationships.. Parametric hazard distributions were developed for all-cause mortality and frequency of cardiovascular-related hospitalization. Time-to-event models were fitted to survival data, and repeated time-to-event models were fitted to hospitalization data. Disease-specific characteristics were assessed as baseline predictors of event hazards.. There were 441 patients in this analysis. At month 30, 70.5% (tafamidis) and 57.1% (placebo) of patients were alive, with 154/441 deaths reported; 495 cardiovascular-related hospitalizations occurred. The cumulative risk of death was 42.1% (95% confidence interval [CI] 24.2-58.0) lower with tafamidis than with placebo, regardless of New York Heart Association (NYHA) class; significant predictors of decreased risk were genotype (wild-type), greater 6-Minute Walk Test (6MWT) distance, higher left ventricular ejection fraction (LVEF), and lower blood urea nitrogen (BUN) and N-terminal pro-B-type natriuretic peptide concentrations. The average cumulative risk of cardiovascular-related hospitalization up to 30 months was 40.8% (95% CI 31.0-49.7) lower with tafamidis in NYHA class I/II patients. Significant predictors of reduced risk were greater 6MWT distance, higher LVEF, and lower BUN and troponin I concentrations.. Tafamidis reduced cumulative mortality and hospitalization risk versus placebo in patients with ATTR-CM. Baseline predictors of outcome were consistent with the cardiovascular nature of the disease and suggested that earlier treatment may improve outcomes. CLINICAL TRIALS.. NCT01994889 (date of registration: November 26, 2013).

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Hospitalization; Humans; Models, Statistical; Survival Analysis

Topics: Amyloid; Benzoxazoles; Cardiomyopathies; Drug Compounding; Drug Costs; Humans; Prealbumin; Randomized Controlled Trials as Topic; Treatment Outcome

In patients with transthyretin amyloid cardiomyopathy, tafamidis reduces all-cause mortality and cardiovascular hospitalizations and slows decline in quality of life compared with placebo. In May 2019, tafamidis received expedited approval from the US Food and Drug Administration as a breakthrough drug for a rare disease. However, at $225 000 per year, it is the most expensive cardiovascular drug ever launched in the United States, and its long-term cost-effectiveness and budget impact are uncertain. We therefore aimed to estimate the cost-effectiveness of tafamidis and its potential effect on US health care spending.. We developed a Markov model of patients with wild-type or variant transthyretin amyloid cardiomyopathy and heart failure (mean age, 74.5 years) using inputs from the ATTR-ACT trial (Transthyretin Amyloidosis Cardiomyopathy Clinical Trial), published literature, US Food and Drug Administration review documents, healthcare claims, and national survey data. We compared no disease-specific treatment ("usual care") with tafamidis therapy. The model reproduced 30-month survival, quality of life, and cardiovascular hospitalization rates observed in ATTR-ACT; future projections used a parametric survival model in the control arm, with constant hazards reduction in the tafamidis arm. We discounted future costs and quality-adjusted life-years by 3% annually and examined key parameter uncertainty using deterministic and probabilistic sensitivity analyses. The main outcomes were lifetime incremental cost-effectiveness ratio and annual budget impact, assessed from the US healthcare sector perspective. This study was independent of the ATTR-ACT trial sponsor.. Compared with usual care, tafamidis was projected to add 1.29 (95% uncertainty interval, 0.47-1.75) quality-adjusted life-years at an incremental cost of $1 135 000 (872 000-1 377 000), resulting in an incremental cost-effectiveness ratio of $880 000 (697 000-1 564 000) per quality-adjusted life-year gained. Assuming a threshold of $100 000 per quality-adjusted life-year gained and current drug price, tafamidis was cost-effective in 0% of 10 000 probabilistic simulations. A 92.6% price reduction from $225 000 to $16 563 would be necessary to make tafamidis cost-effective at $100 000/quality-adjusted life-year. Results were sensitive to assumptions related to long-term effectiveness of tafamidis. Treating all eligible patients with transthyretin amyloid cardiomyopathy in the United States with tafamidis (n=120 000) was estimated to increase annual healthcare spending by $32.3 billion.. Treatment with tafamidis is projected to produce substantial clinical benefit but would greatly exceed conventional cost-effectiveness thresholds at the current US list price. On the basis of recent US experience with high-cost cardiovascular medications, access to and uptake of this effective therapy may be limited unless there is a large reduction in drug costs.

Topics: Aged; Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Cost-Benefit Analysis; Female; Humans; Male; Quality of Life

Topics: Benzoxazoles; Cardiomyopathies; Cost-Benefit Analysis; Humans; Prealbumin

Topics: Amyloidosis; Benzoxazoles; Cardiomyopathies; Humans; Japan; Prognosis; Treatment Outcome

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Cost-Benefit Analysis; Humans; Prealbumin

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Cost-Benefit Analysis; Humans; Prealbumin

Transthyretin cardiac amyloidosis is a progressive and life-threating disease that is significantly underdiagnosed, and the actual number of patients with the disease is presently unknown. Accumulation of wild-type transthyretin-derived amyloid in the heart is a common finding in very elderly patients. Recent clinical trials demonstrated that tafamidis reduced all-cause death and the number of cardiovascular hospitalizations when compared with placebo. The Japanese Ministry of Health, Labour and Welfare approved tafamidis (Vyndaqel

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Humans

Plasma protein transthyretin (TTR) can undergo conformational change resulting in the formation of amyloid fibrils that can then cause amyloidosis. This can occur spontaneously in individuals over the age of 70-80 resulting in wild-type transthyretin amyloidosis (ATTR) (with cardiomyopathy). This then progresses to fatal cardiac failure. TTR can also undergo conformational change in individuals who have a genetic abnormality in the structure of TTR resulting in hereditary ATTR amyloidosis. This is usually first manifested as polyneuropathy but can progress to cardiomyopathy with time. Until recently, there has been no specific treatment for these conditions. However, a detailed search for compounds that stabilize TTR resulted in the discovery of tafamidis. This compound stabilizes TTR and has been found to significantly reduce the progression of both wild-type ATTR amyloidosis and hereditary ATTR amyloidosis.

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Humans; Prealbumin

Topics: Aged; Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Heart; Humans; Magnetic Resonance Angiography; Male; Treatment Outcome

Tafamidis meglumine, a transthyretin (TTR) stabilizer, is effective in delaying the progression of neuropathy in TTR amyloidosis with Val30Met mutations. However, its efficacy in TTR amyloid cardiomyopathy is not fully elucidated. Herein, we report a 73-year-old Japanese man with a diagnosis of TTR amyloid cardiomyopathy with Val30Met mutation treated with tafamidis. To evaluate treatment response, cardiac magnetic resonance imaging was performed before and after 12 months of tafamidis treatment. Native T1, extracellular volume, and left ventricular mass showed no obvious worsening, and findings of other diagnostic studies also supported the efficacy of tafamidis to delay the progression of amyloid cardiomyopathy. Our case suggests that serial native T1 and extracellular volume may be novel non-invasive imaging methods to monitor the treatment response to TTR stabilizers in cardiac amyloidosis and also that tafamidis may be effective in suppressing cardiac progression in TTR amyloid cardiomyopathy with Val30Met mutation.

Topics: Aged; Amyloid Neuropathies, Familial; Benzoxazoles; Biopsy; Cardiomyopathies; Electrocardiography; Follow-Up Studies; Humans; Magnetic Resonance Imaging, Cine; Male; Myocardium

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Humans; Prealbumin

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Humans; Prealbumin

Topics: Aged; Aged, 80 and over; Amyloid Neuropathies, Familial; Angiotensin-Converting Enzyme Inhibitors; Benzoxazoles; Cardiomyopathies; Cardiovascular Agents; Clinical Trials as Topic; Diuretics; Female; Humans; Male; Rare Diseases

Transthyretin is a transport protein for thyroxine and retinol-binding protein, which is mainly produced in the liver. Hereditary transthyretin-related amyloidosis (ATTR) is caused by one of more than 120 point mutations in the transthyretin gene and inherited as an autosomal dominant disorder. The mutations cause a reduction in the stability of the tetrameric structure and dissociation into dimers and monomers as the rate-limiting step in amyloid formation is promoted. Clinical symptoms are related to the specific mutation, the age of onset, the ethnic background and environmental factors. The nerves, heart, eyes and intestines are paticularly affected. In general, two different age peaks are observed. An accumulation occurs at the age of 25-35 years with predominantly neurological symptoms. The second peak occurs between the ages of 55 and 65 years and is commonly associated with cardiac involvement with or without polyneuropathy. Characteristic for the nerve involvement are the symmetrical small fiber polyneuropathy and an autonomous polyneuropathy. The typical picture of cardiac involvement is biventricular hypertrophy with diastolic dysfunction finally resulting in restrictive cardiomyopathy. In addition to the symptomatic treatment for the alleviation of individual organ disorders, for many years liver transplantation was the only causal therapy of ATTR amyloidosis. Since 2011 tafamidis, a highly selective transthyretin stabilizer, has been the first drug approved for treatment of ATTR resulting in reduction of the progression of polyneuropathic symptoms. Other therapeutic approaches to reduce amyloid formation (patisiran and inotersen) effectively reduce transthyretin blood levels, leading to a reduction in polyneuropathy and improved quality of life. The approval is expected in 2018.

Topics: Aged; Amyloid; Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Drug Approval; Humans; Middle Aged; Mutation; Polyneuropathies; Prealbumin; Quality of Life

Topics: Amyloidosis; Benzoxazoles; Cardiomyopathies; Humans; Prealbumin

Transthyretin familial amyloid polyneuropathy is an autosomal dominant inherited sensorimotor and autonomic polyneuropathy, which if untreated, leads to death in approximately 10 years. In Brazil, liver transplant and tafamidis are the only disease-modifying treatments available. This review consists of a consensus for the diagnosis, management and treatment for transthyretin familial amyloid polyneuropathy from the Peripheral Neuropathy Scientific Department of the Brazilian Academy of Neurology. The first and last authors produced a draft summarizing the main views on the subject and emailed the text to 10 other specialists. Relevant literature on this subject was reviewed by each participant and used for the individual review of the whole text. Each participant was expected to review the text and send a feedback review by e-mail. Thereafter, the 12 panelists got together at the city of Fortaleza, discussed the controversial points, and reached a consensus for the final text.

Topics: Amyloid Neuropathies, Familial; Animals; Benzoxazoles; Brazil; Cardiomyopathies; Diagnosis, Differential; Humans; Oligonucleotides; Randomized Controlled Trials as Topic; RNA, Small Interfering

Transthyretin amyloidosis is a systemic disorder caused by extracellular deposition of insoluble amyloid fibrils in peripheral and autonomic nerves, heart, kidney, gastrointestinal tract, and other organs. Hereditary transthyretin amyloidosis is an autosomal dominant disease. More than 120 mutations have been reported in the transthyretin gene with considerable phenotypic heterogeneity and geographic diversity. Among them, a sporadic case of hereditary transthyretin amyloidosis with cardiac-predominant phenotype is very rare, progressive, and potentially fatal if left undiagnosed. However, a clinical diagnosis of cardiac amyloidosis still remains challenging due to non-specific symptoms, and less sensitivity and specificity of medical examinations.. A 60-year-old Japanese man with a history of embolic stroke and hypertrophic cardiomyopathy visited our department for heart failure. The present case exhibited only cardiomyopathy without any clinical signs of systemic amyloidosis manifested as carpal tunnel syndrome, polyneuropathy, or autonomic dysfunction. An echocardiogram revealed severe asymmetric left ventricular hypertrophy, biatrial dilatation, pericardial effusion, and preserved left ventricular ejection fraction of 50% with severe diastolic dysfunction. Technetium pyrophosphate scintigraphy indicated marked diffuse myocardial uptake of technetium pyrophosphate, strongly suggesting transthyretin cardiac amyloidosis, which was firmly confirmed by a left ventricular endomyocardial biopsy. Genetic analysis demonstrated a transthyretin C70T (Pro24Ser) heterozygous mutation. Tafamidis, a transthyretin stabilizer, was started. His cardiac symptoms remained unchanged for 12 months.. Here we report the case of a patient with hereditary cardiac amyloidosis associated with a Pro24Ser mutation in transthyretin, which is the first case reported in Japan. Technetium pyrophosphate scintigraphy was extremely useful for definitive diagnosis. Thus, we propose that the nuclear imaging technique should be taken into account even for an exploratory diagnosis of transthyretin cardiac amyloidosis.

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Diuretics; Echocardiography; Genes, Dominant; Humans; Male; Middle Aged; Mutation; Prealbumin; Radionuclide Imaging; Treatment Outcome

Placebo-controlled clinical trials are useful for identifying the dose of a drug candidate that produces a meaningful clinical response in a patient population. Currently, Pfizer, Inc. is enrolling a 400-person clinical trial to test the efficacy of 20 or 80 mg of tafamidis to ameliorate transthyretin (TTR)-associated cardiomyopathy using clinical endpoints. Herein, we provide guidance for how to optimize the dose of tafamidis for each WT TTR cardiomyopathy patient using its mechanism of action as the key readout, i.e. we identify the dose of tafamidis that maximally kinetically stabilizes TTR in the blood. Tetramer dissociation is rate limiting for TTR aggregation, which appears to drive the pathology of the TTR amyloidoses. Hence, we measure the TTR tetramer dissociation rate (kinetic stability) in the patient's plasma as a function of tafamidis dose to optimize the dose employed to maximize kinetic stability. Historical data tell us that a subset of patients exhibiting higher tafamidis plasma concentrations are maximally kinetically stabilized at the 20-mg tafamidis dose, whereas the patient studied herein required a 60 mg once daily dose to achieve maximum kinetic stabilization. We anticipate that establishing the dose of tafamidis that achieves maximal TTR kinetic stabilization will translate into a maximal clinical effect, but that remains to be demonstrated.

Topics: Aged, 80 and over; Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Drug Dosage Calculations; Drug Monitoring; Escherichia coli; Gene Expression; Humans; Kinetics; Male; Neuroprotective Agents; Prealbumin; Precision Medicine; Protein Stability; Recombinant Proteins

The misassembly of soluble proteins into toxic aggregates, including amyloid fibrils, underlies a large number of human degenerative diseases. Cardiac amyloidoses, which are most commonly caused by aggregation of Ig light chains or transthyretin (TTR) in the cardiac interstitium and conducting system, represent an important and often underdiagnosed cause of heart failure. Two types of TTR-associated amyloid cardiomyopathies are clinically important. The Val122Ile (V122I) mutation, which alters the kinetic stability of TTR and affects 3% to 4% of African American subjects, can lead to development of familial amyloid cardiomyopathy. In addition, aggregation of WT TTR in individuals older than age 65 y causes senile systemic amyloidosis. TTR-mediated amyloid cardiomyopathies are chronic and progressive conditions that lead to arrhythmias, biventricular heart failure, and death. As no Food and Drug Administration-approved drugs are currently available for treatment of these diseases, the development of therapeutic agents that prevent TTR-mediated cardiotoxicity is desired. Here, we report the development of AG10, a potent and selective kinetic stabilizer of TTR. AG10 prevents dissociation of V122I-TTR in serum samples obtained from patients with familial amyloid cardiomyopathy. In contrast to other TTR stabilizers currently in clinical trials, AG10 stabilizes V122I- and WT-TTR equally well and also exceeds their efficacy to stabilize WT and mutant TTR in whole serum. Crystallographic studies of AG10 bound to V122I-TTR give valuable insights into how AG10 achieves such effective kinetic stabilization of TTR, which will also aid in designing better TTR stabilizers. The oral bioavailability of AG10, combined with additional desirable drug-like features, makes it a very promising candidate to treat TTR amyloid cardiomyopathy.

Topics: Amyloid; Amyloidosis; Animals; Area Under Curve; Benzoates; Benzoxazoles; Cardiomyopathies; Cell Line; Cell Line, Tumor; Cell Survival; Crystallography, X-Ray; Dose-Response Relationship, Drug; HeLa Cells; Humans; MCF-7 Cells; Mice; Mice, Inbred ICR; Models, Molecular; Molecular Structure; Mutation; Prealbumin; Protein Binding; Protein Stability; Protein Structure, Tertiary; Pyrazoles; Rats; Rats, Wistar