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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. 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. 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. 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.).

In a randomized trial of bortezomib, cyclophosphamide, and dexamethasone as compared with the same therapy plus daratumumab, patients with light-chain amyloidosis who received daratumumab had a higher frequency of hematologic complete response than those who did not (53.3% vs. 18.1%). Deaths were most commonly due to cardiac failure.

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. 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. 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. 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.).

Background Characteristics of AL amyloidosis across Asia are not well-described in the literature. Thus, we overviewed the incidence and disease characteristics of AL amyloidosis in Korea. Methods We collected medical records of 302 AL amyloidosis patients and compared survival outcomes by predominant treatment strategy and at four time points: 1995–2003, 2004–2008, 2009–2013, and 2014–2018. Results The median age was 62 years (36–83). One hundred forty-one patients were classified as stage III (26.3%) or IV (47.9%). The patients diagnosed between 2014 and 2018 survived longer than those diagnosed at other time points due to the introduction of bortezomib ( p  < 0.01). In addition, patients who received upfront ASCT survived longer than those who received salvage ASCT or chemotherapy alone ( p  < 0.01). However, most of the 85 patients who experienced early death within 6 months were older than 75 years, had BMI less than 20, and had a high disease burden. Conclusions The incidence of AL amyloid has increased and survival outcomes have improved gradually, most likely due to introduction of novel agents and upfront ASCT. However, not all patients are suitable for these potent treatment modalities, and avoiding early death within 6 months remains a challenge.

The perspective on cardiac amyloidosis has deeply changed over the last 10 years following major advances in diagnosis and treatment options. This heterogeneous disease requires the interaction among experts of different specialties and subspecialties. Suspicion of disease, timely recognition and confirmation of final diagnosis, prognostic stratification, overall management and therapeutic strategies represent ongoing challenges in the clinical setting. Missing or delayed diagnosis may have significant impact on patient outcome, especially in light-chain amyloidosis. The present inter-society consensus document aims to provide a standardized approach to the diagnosis of cardiac amyloidosis in Italy, and to discuss the challenging clinical scenarios encountered in routine activity for cardiologists and physicians of different specialties dealing with patients with suspected or established cardiac amyloidosis. This document may be adapted to the setting of each specific region.

Diagnosis of hereditary transthyretin-related amyloidosis (ATTR) is challenging owing to its extremely heterogeneous phenotype. The existence of predominantly cardiac presentations should prompt cardiologists to consider ATTR in patients with otherwise unexplained left ventricular wall thickening. Orthotopic liver transplantation (or combined heart–liver transplantation) can potentially provide surgical 'gene therapy' in patients with ATTR, provided that diagnosis is timely. A nonhereditary form of systemic amyloidosis associated with wild-type transthyretin causes heart involvement predominantly in elderly men (systemic senile amyloidosis, or SSA). However, hereditary transthyretin-related amyloidosis (ATTR) is the most frequent form of familial systemic amyloidosis, a group of severe diseases with variable neurological and organ involvement. ATTR remains a challenging and widely underdiagnosed condition, owing to its extreme phenotypic variability: the clinical spectrum of the disease ranges from an almost exclusive neurologic involvement to a strictly cardiac presentation. Such heterogeneity principally results from differential effects of the various reported transthyretin mutations, the geographic region the patient is from and, in the case of the most common mutation, Val30Met, whether or not large foci of cases occur (endemic versus nonendemic aggregation). Genetic or environmental factors (such as age, sex, and amyloid fibril composition) also contribute to the heterogeneity of ATTR, albeit to a lesser extent. The existence of exclusively or predominantly cardiac phenotypes should lead clinicians to consider the possibility of ATTR in all patients who present with an unexplained increase in left ventricular wall thickness at echocardiography. Assessment of such patients should include an active search for possible red flags that can point to the correct final diagnosis. Key Points Amyloidotic cardiomyopathy is a challenging condition that can mimic many other diseases, such as hypertrophic cardiomyopathy or coronary artery disease Hereditary transthyretin-related amyloidosis (ATTR) is the most frequent form of familial systemic amyloidosis The clinical spectrum of ATTR ranges from almost exclusive neurologic involvement within a clearly familial context, to apparently sporadic cases with a strictly cardiac presentation Phenotypic heterogeneity is linked to at least three different factors: the type of transthyretin mutation, geographic region, and the type of Val30Met aggregation (endemic or nonendemic) Diagnosis of ATTR-related amyloidotic cardiomyopathy generally involves electrocardiography and echocardiography; the specific clinical signs can be very mild and may be missed by the patient Orthotopic liver transplantation or combined heart–liver transplantation can provide surgical 'gene therapy' for amyloidotic cardiomyopathy; the combined procedure can be offered to patients with severe heart failure

Malnutrition is associated with mortality and impaired quality of life (QoL) in systemic immunoglobulin light-chain (AL) amyloidosis. The aim of this study was to determine whether nutritional counseling is beneficial to patients with AL. In this intervention study (ClinicalTrials.gov Identifier: NCT02055534), 144 treatment-naïve outpatients with AL were randomized to usual care (UC; n = 72) and nutritional counseling (NC; n = 72). In the randomized population, although patients in the NC group maintained a stable body weight (weight loss [WL] = 0.6 kg; 95% confidence interval [CI], −1.0 to 2.1; P = 0.214), those in the UC group demonstrated a significant decrease (WL = 2.1 kg; 95% CI, 0.2–4.1; P = 0.003). However, the difference in weight between groups was not significant (mean WL difference = 1.6 kg; 95% CI, −0.7 to 3.9; P = 0.179). Patients in the NC group demonstrated more satisfactory energy intake (≥75% of estimated requirements, odds ratio, 2.18; 95% CI, 1.04–4.57; P = 0.048) and a significant increase in the mental component summary of QoL (Short form-36) at 12 mo (mean difference, 8.1; 95% CI, 2.3–13.9; P = 0.007), which was restored to a mean score of 53 (95% CI, 50–53), over the healthy population norms. NC was also associated with better survival (crude hazard ratio, 0.57; 95% CI, 0.35–0.94; P = 0.028). In outpatients with AL, NC was helpful in preserving body weight, effective in improving mental QoL, and associated with better survival. •We investigated whether nutritional counseling is beneficial to patients with systemic immunoglobulin light-chain amyloidosis.•Nutritional counseling was helpful in preserving body weight in these patients.•Nutritional counseling was effective in improving the mental quality of life of these patients.•Nutritional counseling was associated with better survival in patients with systemic immunoglobulin light-chain amyloidosis.

Background Although the use of bortezomib alone and in combination with steroids has shown efficacy in AL amyloidosis, its role in combination with high-dose melphalan and autologous stem cell transplantation (HDM/SCT) is unknown. In this study, we evaluated bortezomib in combination with dexamethasone (BD) for induction chemotherapy prior to HDM/SCT. Methods This was a single-center, prospective, randomized controlled trial comparing induction therapy consisting of two BD cycles followed by HDM/SCT (BD + HDM/SCT) with HDM/SCT alone in the treatment of patients with newly diagnosed AL amyloidosis. The hematological and organ responses of the patients were assessed every three months post HDM/SCT. Results Fifty-six patients newly diagnosed with renal (100%), cardiac (57.1%), liver (7.1%), or nervous system (8.9%) AL amyloidosis were enrolled in this study; 28 patients were assigned to each arm. Two patients died within 100 days of HDM/SCT (3.6% treatment-related mortality). The overall hematologic response rates in the BD + HDM/SCT arm and HDM/SCT arm at three, six and twelve months were 78.5% versus 50%, 82.1% versus 53.5% and 85.7% versus 53.5%, respectively. In the BD + HDM/SCT arm, 15 (53.5%) patients achieved a hematologic response after BD and before HDM/SCT. An intention-to-treat analysis revealed a higher rate of complete remission in the BD + HDM/SCT arm at both 12 and 24 months (67.9% and 70%, respectively) than with the HDM/SCT-only therapy (35.7% and 35%, respectively, P  = 0.03). After a median follow-up of 28 months, the survival rates at 24 months post-treatment start were 95.0% in the BD + HDM/SCT group and 69.4% in the HDM/SCT alone group ( P  = 0.03). Conclusions Our preliminary data suggest that the outcome of treating AL amyloidosis with BD induction and HDM/SCT was superior to the outcome of the HDM/SCT treatment alone. Trial registration This trial has been registered at clinicaltrials.gov with the number NCT01998503 .

Myeloablative doses of melphalan with rescue by autologous hematopoietic stem cells are currently used in the treatment of immunoglobulin-light-chain (AL) amyloidosis, but the efficacy of the therapy is unproven. This randomized trial compared a regimen of high-dose melphalan with standard doses of melphalan plus high doses of dexamethasone. The aggressive treatment had no survival advantage as compared with conventional treatment with standard-dose melphalan. This trial compared a regimen of high-dose melphalan with standard doses of melphalan plus high doses of dexamethasone. The aggressive treatment had no survival advantage as compared with conventional treatment. The origin of amyloid in systemic immunoglobulin-light-chain (AL) amyloidosis is a clone of plasma cells in the bone marrow that synthesizes monoclonal immunoglobulin light chains. In tissues, these light chains aggregate into amyloid fibrils. The accumulation of amyloid deposits in vital organs leads to progressive disability and death. Life expectancy depends on the degree of organ involvement and ranges from a few years to less than 6 months for patients with severe cardiomyopathy. 1 In the mid-1990s, two randomized trials showed that standard-dose chemotherapy with melphalan and prednisone could prolong survival in patients with AL amyloidosis, 1 , 2 but clinical responses were . . .