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The New England Journal of Medicine Jan 2024Transthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded monomeric transthyretin (TTR) in the heart. Acoramidis is a high-affinity TTR... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Transthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded monomeric transthyretin (TTR) in the heart. Acoramidis is a high-affinity TTR stabilizer that acts to inhibit dissociation of tetrameric TTR and leads to more than 90% stabilization across the dosing interval as measured ex vivo.
METHODS
In this phase 3, double-blind trial, we randomly assigned patients with transthyretin amyloid cardiomyopathy in a 2:1 ratio to receive acoramidis hydrochloride at a dose of 800 mg twice daily or matching placebo for 30 months. Efficacy was assessed in the patients who had an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m of body-surface area. The four-step primary hierarchical analysis included death from any cause, cardiovascular-related hospitalization, the change from baseline in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and the change from baseline in the 6-minute walk distance. We used the Finkelstein-Schoenfeld method to compare all potential pairs of patients within strata to generate a P value. Key secondary outcomes were death from any cause, the 6-minute walk distance, the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary, and the serum TTR level.
RESULTS
A total of 632 patients underwent randomization. The primary analysis favored acoramidis over placebo (P<0.001); the corresponding win ratio was 1.8 (95% confidence interval [CI], 1.4 to 2.2), with 63.7% of pairwise comparisons favoring acoramidis and 35.9% favoring placebo. Together, death from any cause and cardiovascular-related hospitalization contributed more than half the wins and losses to the win ratio (58% of all pairwise comparisons); NT-proBNP pairwise comparisons yielded the highest ratio of wins to losses (23.3% vs. 7.0%). The overall incidence of adverse events was similar in the acoramidis group and the placebo group (98.1% and 97.6%, respectively); serious adverse events were reported in 54.6% and 64.9% of the patients.
CONCLUSIONS
In patients with transthyretin amyloid cardiomyopathy, the receipt of acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo. Adverse events were similar in the two groups. (Funded by BridgeBio Pharma; ATTRibute-CM ClinicalTrials.gov number, NCT03860935.).
Topics: Humans; Amyloidosis; Cardiomyopathies; Heart; Hospitalization; Prealbumin; Treatment Outcome; Double-Blind Method; Cardiovascular Agents; Natriuretic Peptide, Brain; Functional Status
PubMed: 38197816
DOI: 10.1056/NEJMoa2305434 -
Advances in Clinical and Experimental... Oct 2022Heart failure with preserved ejection fraction (HFpEF) is an increasingly widespread medical condition, with excessive morbidity and mortality. Recently, for the first... (Review)
Review
Heart failure with preserved ejection fraction (HFpEF) is an increasingly widespread medical condition, with excessive morbidity and mortality. Recently, for the first time in HFpEF, a reduction in the primary composite outcome of cardiovascular death or HF hospitalization was shown with empagliflozin. The failure of previous clinical trials in HFpEF might have resulted from suboptimal patient selection and inclusion of patients without "true" or clinically significant HFpEF. Another important factor might be the heterogeneity of HFpEF, and thus there is a growing interest in HFpEF phenotyping. This phenotyping can be based on clinical presentation (e.g., subtypes with predominant atrial fibrillation, obesity, pulmonary hypertension and right ventricular failure, coronary artery disease (CAD), or noncardiac comorbidities), but also on HFpEF etiology. Specific therapies, such as tafamidis in transthyretin-related amyloidosis (ATTR) or mavacamten in hypertrophic cardiomyopathy, have demonstrated their efficacy. However, pathomechanisms leading to the development of different phenotypes of HFpEF seem more complex and subtle. Machine learning and neural network models might help identify specific subgroups within the HFpEF population that either cluster patients with similar genetic, biochemical, echocardiographic or clinical characteristics, or respond similarly to a given treatment. Herein, we review different approaches to HFpEF phenotyping and present some distinct HFpEF subtypes.
Topics: Humans; Heart Failure; Stroke Volume; Prealbumin; Prognosis; Echocardiography; Ventricular Function, Left
PubMed: 35581935
DOI: 10.17219/acem/149728 -
The New England Journal of Medicine Oct 2023Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin.
METHODS
In this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months.
RESULTS
A total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges-Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P = 0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group.
CONCLUSIONS
In this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.).
Topics: Humans; Cardiomyopathies; Prealbumin; RNA, Small Interfering; Amyloidosis, Familial; Liver; Double-Blind Method; Amyloidosis
PubMed: 37888916
DOI: 10.1056/NEJMoa2300757 -
JACC. Heart Failure Feb 2021Tafamidis is an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM), this study aimed to determine whether there is a differential effect between...
OBJECTIVES
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).
BACKGROUND
ATTR-CM is a progressive, fatal disorder resulting from mutations in the ATTRv or the deposition of denatured ATTRwt.
METHODS
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.
RESULTS
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).
CONCLUSIONS
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
PubMed: 33309574
DOI: 10.1016/j.jchf.2020.09.011 -
Journal of the Peripheral Nervous... Dec 2022Transthyretin-mediated amyloidosis (ATTR) is a rare, under-recognized, progressively debilitating, fatal disease caused by the aggregation and extracellular deposition... (Review)
Review
Transthyretin-mediated amyloidosis (ATTR) is a rare, under-recognized, progressively debilitating, fatal disease caused by the aggregation and extracellular deposition of amyloid transthyretin (TTR) fibrils in multiple organs and tissues throughout the body. TTR is predominantly synthesized by the liver and normally circulates as a homotetramer, while misfolded monomers aggregate to form amyloid fibrils. One strategy to treat ATTR amyloidosis is to reduce the amount of TTR produced by the liver using drugs that directly target the TTR mRNA or gene. This narrative review focuses on how TTR gene silencing tools act to reduce TTR production, describing strategies for improved targeted delivery of these agents to hepatocytes where TTR is preferentially expressed. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), termed RNA silencers, cause selective degradation of TTR mRNA, while a TTR gene editing tool reduces TTR expression by introducing nonsense mutations into the TTR gene. Two strategies to facilitate tissue-specific delivery of these nucleic acid-based drugs employ endogenous receptors expressed by hepatocytes. Lipid nanoparticles (LNPs) that recruit apolipoprotein E support low-density lipoprotein receptor-mediated uptake of unconjugated siRNA and are now used for CRISPR gene editing tools. Additionally, conjugating N-acetylgalactosamine (GalNAc) moieties to ASOs or siRNAs facilitates receptor-mediated uptake by the asialoglycoprotein receptor. In summary, ATTR is a progressive disease with various clinical manifestations due to TTR aggregation, deposition, and amyloid formation. Receptor-targeted ligands (eg, GalNAc) and nanoparticle encapsulation (eg, LNPs) are technologies to deliver ASOs, siRNAs, and gene editing tools to hepatocytes, the primary location of TTR synthesis.
Topics: Humans; Amyloid Neuropathies, Familial; Liposomes; Liver; Prealbumin; RNA, Messenger; RNA, Small Interfering
PubMed: 36345805
DOI: 10.1111/jns.12519 -
Geriatrie Et Psychologie... Mar 2022Résumé L'amylose cardiaque dite sénile, également dénommée « sauvage », était considérée comme une maladie rare. Actuellement, grâce à des moyens...
Résumé L'amylose cardiaque dite sénile, également dénommée « sauvage », était considérée comme une maladie rare. Actuellement, grâce à des moyens diagnostiques non invasifs et à partir d'études autopsiques, nous estimons la prévalence à environ 10 à 20 % des sujets de plus de 80 ans. De même, l'amylose était un diagnostic sans conséquence thérapeutique, mis à part le traitement de l'insuffisance cardiaque et des troubles de conduction. De nouveaux traitements permettent de stabiliser le tétramère de transthyrétine et de diminuer la production d'oligomères, sources des dépôts d'amylose, en cas de formes héréditaires et sauvage d'amylose à transthyrétine. Deux médicaments bloquant la production de transthyrétine (anti-sens et oligonucléotides) sont également en phase d'essais cliniques dans les amyloses cardiaques. Ainsi, le diagnostic et la prise en charge de l'amylose cardiaque deviennent des démarches diagnostiques de pratique clinique et doivent être connus des cardiologues, mais également des gériatres qui permettront une prise en charge précoce et donc plus efficace. Abstract So-called senile cardiac amyloidosis was considered rare. Nowadays, thanks to non-invasive diagnostic means and autopsy studies, we estimate the prevalence to be about 20% of subjects over 75 years of age. Similarly, amyloidosis was a diagnosis with no therapeutic consequences, apart from the treatment of heart failure and conduction disorders. New treatments make it possible to stabilise the transthyretin tetramer and to reduce the production of oligomers that are the source of amyloid deposits, by acting in a non-genetic way and therefore adapted to the "wild" transthyretin forms of so-called senile cardiac amyloidosis. Thus, the diagnosis and management of cardiac amyloidosis are becoming diagnostic procedures in clinical practice and must be known by cardiologists, but also by geriatricians, who will allow early and therefore more effective management.
Topics: Amyloidosis; Amylose; Humans; Prealbumin
PubMed: 35652845
DOI: 10.1684/pnv.2022.1026 -
Annals of Clinical Biochemistry Jan 2022Prealbumin is a small protein which has been widely evaluated as a nutritional and a prognostic marker. The small size and concentration of prealbumin in blood proposes... (Review)
Review
Prealbumin is a small protein which has been widely evaluated as a nutritional and a prognostic marker. The small size and concentration of prealbumin in blood proposes challenges on measuring it with high sensitivity and specificity. Over the years, a number of analytical methodologies have been developed, which may help establish prealbumin as a useful biomarker in routine clinical practice. The aim of the short review was to explore the current literature on the clinical utility of prealbumin and the advances made in the analytical methodologies of prealbumin. We searched MEDLINE, EMBASE and the Cochrane Library for articles published between January 1980 and July 2019, with the general search terms of 'prealbumin', 'prognostic marker', 'nutritional marker', 'analytical methodologies' and 'malnutrition'. Additionally, we selected relevant articles and comprehensive overviews from reference lists of identified studies. The routine use of prealbumin in clinical practice remains debatable; however; it can complement clinical history, anthropometric assessment and physical examination to assess malnutrition with more certainty. Consensus on the clinical applications of prealbumin in the management of malnutrition is warranted.
Topics: Anthropometry; Biomarkers; Humans; Malnutrition; Nutritional Status; Prealbumin
PubMed: 32429677
DOI: 10.1177/0004563220931885 -
Orphanet Journal of Rare Diseases Nov 2023Transthyretin amyloidosis (ATTR amyloidosis) is a progressive, multisystemic, life-threatening disease resulting from the deposition of variant or wild-type (ATTRwt... (Observational Study)
Observational Study
BACKGROUND
Transthyretin amyloidosis (ATTR amyloidosis) is a progressive, multisystemic, life-threatening disease resulting from the deposition of variant or wild-type (ATTRwt amyloidosis) transthyretin amyloid fibrils in various tissues and organs.
METHODS
Established in 2007, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is the largest ongoing, global, longitudinal, observational study of patients with ATTR amyloidosis, including both hereditary and wild-type disease, and asymptomatic carriers of pathogenic TTR mutations. This analysis describes the baseline characteristics of symptomatic patients and asymptomatic gene carriers enrolled in THAOS since its inception in 2007 (data cutoff: August 1, 2022), providing a consolidated overview of 15-year data from the THAOS registry.
RESULTS
This analysis included 4428 symptomatic patients and 1707 asymptomatic gene carriers. The majority of symptomatic patients were male (70.8%) with a mean (standard deviation [SD]) age at symptom onset of 56.6 (17.9) years. Compared with the 14-year analysis, V30M remained the most prevalent genotype in Europe (62.2%), South America (78.6%), and Japan (74.2%) and ATTRwt remained most common in North America (56.2%). Relative to the 14-year analysis, there was an increase of mixed phenotype (from 16.6 to 24.5%) and a reduction of predominantly cardiac phenotype (from 40.7 to 31.9%). The proportion of patients with predominantly neurologic phenotype remained stable (from 40.1 to 38.7%). Asymptomatic gene carriers were 58.5% female with a mean age at enrollment of 41.9 years (SD 15.5).
CONCLUSIONS
This overview of > 6000 patients enrolled over 15 years in THAOS represents the largest registry analysis of ATTR amyloidosis to date and continues to emphasize the genotypic and phenotypic heterogeneity of the disease. Nearly a quarter of the symptomatic population within THAOS was mixed phenotype, underscoring the need for multidisciplinary management of ATTR amyloidosis.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT00628745.
Topics: Adult; Female; Humans; Male; Middle Aged; Amyloid Neuropathies, Familial; Longitudinal Studies; Prealbumin; Registries; Surveys and Questionnaires
PubMed: 37946256
DOI: 10.1186/s13023-023-02962-5 -
International Journal of Molecular... Dec 2022Amyloidoses are a group of diseases associated with deposits of amyloid fibrils in different tissues. So far, 36 different types of amyloidosis are known, each due to... (Review)
Review
Amyloidoses are a group of diseases associated with deposits of amyloid fibrils in different tissues. So far, 36 different types of amyloidosis are known, each due to the misfolding and accumulation of a specific protein. Amyloid deposits can be found in several organs, including the heart, brain, kidneys, and spleen, and can affect single or multiple organs. Generally, amyloid-forming proteins become prone to aggregate due to genetic mutations, acquired environmental factors, excessive concentration, or post-translational modifications. Interestingly, amyloid aggregates are often composed of proteolytic fragments, derived from the degradation of precursor proteins by yet unidentified proteases, which display higher amyloidogenic tendency compared to precursor proteins, thus representing an important mechanism in the onset of amyloid-based diseases. In the present review, we summarize the current knowledge on the proteolytic susceptibility of three of the main human amyloidogenic proteins, i.e., transthyretin, β-amyloid precursor protein, and α-synuclein, in the onset of amyloidosis. We also highlight the role that proteolytic enzymes can play in the crosstalk between intestinal inflammation and amyloid-based diseases.
Topics: Humans; Proteolysis; Amyloidosis; Amyloid; Amyloid beta-Protein Precursor; Protein Precursors; Prealbumin; Peptide Hydrolases
PubMed: 36614141
DOI: 10.3390/ijms24010699 -
Innere Medizin (Heidelberg, Germany) Sep 2023Transthyretin amyloidosis (ATTR) is a rare disease in which the protein transthyretin (TTR) is deposited in the form of amyloid fibrils in various tissues and organs... (Review)
Review
Transthyretin amyloidosis (ATTR) is a rare disease in which the protein transthyretin (TTR) is deposited in the form of amyloid fibrils in various tissues and organs and secondarily leads to functional impairment, especially in peripheral nerves and the heart. A differentiation is made between hereditary and sporadic forms. The hereditary variant is inherited in an autosomal dominant manner and usually occurs in the younger to middle-aged, while the sporadic form occurs in older age and has no known genetic cause. Typical signs of hereditary ATTR amyloidosis (ATTRv, v for variant) include a rapidly progressing sensorimotor and autonomic polyneuropathy (PNP), cardiac dysfunction as well as ocular and gastrointestinal symptoms. A carpal tunnel syndrome often precedes the manifestation. Various options (tafamidis, patisiran, inotersen or vutrisiran) are available for the treatment of patients with ATTRv with PNP in Germany, depending on the severity. In the sporadic variant of wild-type ATTR amyloidosis (ATTRwt), symptoms of progressive cardiomyopathy are usually prominent; however, neurological assessment of these patients often also reveals a concomitant sensory ataxic PNP. The tetramer stabilizer tafamidis can be used for treatment. Because of this complex presentation, the management of patients with ATTR amyloidosis should be performed in interdisciplinary centers specialized in amyloidosis.
Topics: Middle Aged; Humans; Prealbumin; Amyloid Neuropathies, Familial; Polyneuropathies; Cardiomyopathies; Germany
PubMed: 37555967
DOI: 10.1007/s00108-023-01570-6