View details for DOI 10.1016/j.jchf.2025.102887

View details for PubMedID 41511427

Abstract

Timely diagnosis and treatment are critical to reduce morbidity and mortality for patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM). Limited existing data suggest underdiagnosis of ATTR-CM and inequity in predictors of diagnosis patterns.This study sought to describe the time from heart failure (HF) diagnosis to ATTR-CM diagnosis and identify predictors for delayed diagnosis of ATTR-CM.This retrospective cohort study used Veterans Health Administration (VHA) data. We identified patients with HF and ATTR-CM diagnosed between 2016 and 2022 using an algorithm based on diagnoses and medications. The primary outcome was the time to diagnosis of ATTR-CM and was defined as the number of days between each patient's first HF diagnosis and their first ATTR-CM diagnosis. We also evaluated the number of days between first HF hospitalization or first loop diuretic prescription and ATTR-CM diagnosis. We used multivariable logistic regression to assess demographic, clinical, and socioeconomic predictors of time to ATTR-CM diagnosis using >6 months as a meaningful delay.A total of 2,557 patients with HF and ATTR-CM were identified. The mean age at the time of ATTR-CM diagnosis was 81 years. Most veterans were male (2,544; 99.5%) and White (1,440; 56%). The median time to diagnosis to ATTR-CM was 490 days. For the 1,882 veterans with a loop diuretic prescription before ATTR-CM diagnosis, the median time between initial loop prescription and ATTR-CM diagnosis was 835 days (Q1-Q3: 250-1850). Across Department of Veterans Affairs sites, the median number of days to diagnosis ranged from 169 to 1,070 days. After adjustment, Black race (OR: 0.71; 95% CI: 0.57-0.88) and older age (OR: 0.66; 95% CI: 0.59-0.73) were associated with a shorter time to diagnosis, whereas a history of atrial fibrillation (OR: 1.21; 95% CI: 1.00-1.45), coronary artery disease (OR: 1.38; 95% CI: 1.15-1.64), or chronic kidney disease (OR: 1.79; 95% CI: 1.50-2.15) was associated with longer time to diagnosis.There are clinically important delays between incident HF and diagnosis of ATTR-CM. Carrying a diagnosis of atrial fibrillation, coronary artery disease, or chronic kidney disease was associated with a longer delay to diagnosis. These findings uncover an opportunity for clinicians to consider concomitant ATTR-CM in patients with alternate etiologies for their cardiomyopathy, as expediting evaluation for ATTR-CM following HF diagnosis is critical to reduce the morbidity of this progressive condition.

View details for DOI 10.1016/j.jacc.2025.10.021

View details for PubMedID 41405528

Abstract

Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive disease caused by the deposition of transthyretin as amyloid in the myocardium. Current therapies may slow disease progression but do not clear existing deposits. Coramitug is a humanized monoclonal antibody that targets misfolded transthyretin, designed to promote clearance of transthyretin amyloid through antibody-mediated phagocytosis.This phase 2, double-blind, placebo-controlled trial randomized participants with ATTR-CM to receive infusions every 4 weeks of either coramitug at two dosages (10 mg/kg or 60 mg/kg) or placebo in a 1:1:1 ratio for 52 weeks. The primary endpoints were the change from baseline to week 52 in the six-minute walk test (6MWT) and N-terminal pro-brain type natriuretic peptide (NT-proBNP) levels. Safety was assessed for up to 64 weeks by assessing treatment-emergent adverse events, all-cause mortality, and number of cardiovascular (CV) events comprising hospitalization due to CV events or urgent heart failure visits.In total, 104 participants (median age 77 years; 93% men; 84% New York Heart Association class II; 13% with variant ATTR-CM) were randomized and dosed: 34 to coramitug 10 mg/kg, 35 to coramitug 60 mg/kg, 35 to placebo. Median NT-proBNP was 1985 pg/mL (interquartile range: 1224, 3406 pg/mL). In total, 90% of participants were on disease-modifying therapy; 84% were treated with tafamidis and 7 (6.7%) with TTR silencers (patisiran, n=4; vutrisiran, n=3). From baseline to week 52, coramitug 60 mg/kg significantly reduced NT-proBNP levels compared with placebo (-48%; 95% CI: -65%, -22%; P=0.0017). The change in 6MWT from baseline to week 52 was not statistically different from placebo with either dose. Coramitug 60 mg/kg was associated with improved functional echocardiographic parameters and was well tolerated.This phase 2 trial showed that coramitug, an antibody targeting misfolded transthyretin in ATTR-CM, was well tolerated and at a dose of 60 mg/kg resulted in a statistically significant reduction in NT-proBNP, a validated marker of disease progression, with no statistically significant effect on 6MWT within 52 weeks.

View details for DOI 10.1161/CIRCULATIONAHA.125.077304

View details for PubMedID 41212997

Abstract

Amyloidosis represents a heterogeneous group of disorders characterized by extracellular deposition of misfolded protein fibrils, leading to progressive organ dysfunction and death. Despite its clinical significance, there is a paucity of large-scale epidemiologic data characterizing mortality trends associated with amyloidosis in the United States.To evaluate temporal trends and demographic patterns in amyloidosis-related mortality across the US population from 1999 to 2023.This population-based, retrospective cohort study utilized publicly available mortality data from the Centers for Disease Control and Prevention (CDC) Wide-ranging Online Data for Epidemiologic Research (WONDER) database spanning from 1999 to 2023. The study included individuals of all ages in whom amyloidosis was listed as either an underlying or contributing cause of death-on-death certificates. The primary outcome was the age-adjusted mortality rate for amyloidosis-related deaths per 100,000 population. Age-adjusted mortality rates (AAMRs) were stratified by sex, race and ethnicity, US census region, state, place of death, and age group. Annual percentage changes (APCs) and 95% confidence intervals (CIs) were calculated to assess temporal trends.From 1999 to 2023, a total of 52,659 amyloidosis-related deaths were recorded in the US. Most deaths occurred in medical facilities and homes. The overall AAMR nearly doubled from 4.95 (95% CI: 4.68 to 5.21) in 1999 to 10.30 (95% CI: 9.99 to 10.60) in 2022. After an initial period of relative stability from 1999-2012, AAMRs significantly increased from 2012-2018 [APC: 5.24; 95% CI: 3.87 to 10.36] and again from 2018-2023 [APC: 11.13; 95% CI: -48.67 to 17.07]. Males consistently exhibited higher mortality rates than females (8.24 vs. 4.20), and among racial/ethnic groups, Non-Hispanic (NH) Black individuals had the highest AAMR (11.26), while NH Asians had the lowest (3.46). Since 2014, all U.S. census regions have shown a significant rise in amyloidosis-related AAMRs, following earlier periods of stability or modest increases. States such as Massachusetts, Vermont, Minnesota, and the District of Columbia exhibited the highest mortality burdens, whereas states like Louisiana, Arkansas, and Mississippi had the lowest. Mortality rates increased with advancing age, with individuals aged ≥85 years exhibiting the highest crude mortality rate (CMR: 64.29).Amyloidosis-related mortality has markedly increased over the past two decades in the United States, with significant disparities across sex, age, racial/ethnic, and geographic groups. These rising mortality rates likely reflect heightened diagnostic recognition rather than therapeutic failure, underscoring the need for earlier diagnosis, equitable access to care, and targeted screening of high-risk populations.

View details for DOI 10.1016/j.cardfail.2025.10.006

View details for PubMedID 41213321

Abstract

Transthyretin amyloid cardiomyopathy (ATTR-CM), a progressive disease caused by misfolded transthyretin (TTR), occurs as wild-type (ATTRwt-CM) or variant (ATTRv-CM) forms. p.Val142Ile is the most common variant in the US, linked to rapid progression and increased mortality. Acoramidis achieves near-complete (≥90%) TTR stabilization and showed clinical benefit in the 30-month ATTRibute-CM trial and through month 42 in the ongoing open-label extension (OLE).To evaluate the efficacy of acoramidis in ATTRwt-CM, ATTRv-CM, and variant subgroups (p.Val142Ile and non-p.Val142Ile).This international, multicenter, phase 3, randomized placebo-controlled study took place from April 2019 to May 2023 with ongoing OLE (month 42). ATTRibute-CM enrolled 632 participants with ATTR-CM; 611 of 632 were included in the modified intention-to-treat (mITT) population. There were 380 participants who continued into the OLE. These data were analyzed from January 2025 to July 2025.Oral acoramidis, 712 mg, or placebo twice daily for 30 months, followed by 12 months of open-label treatment.All-cause mortality (ACM), cardiovascular-related hospitalizations (CVH), serum TTR, 6-minute walk distance, Kansas City Cardiomyopathy Questionnaire Overall Summary score, and N-terminal pro B-type natriuretic peptide in participants with ATTRwt-CM and ATTRv-CM. Post-hoc analyses were conducted in variant subgroups, including p.Val142Ile.Overall, 552 participants with wild-type ATTR-CM (mean [SD] age, 78 [6.3] years; 92.0% male and 8.0% female) and 59 participants with variant ATTR-CM (mean [SD] age, 73 [7.7] years; 77.3% male and 22.7% female) were randomized (mITT population), including 35 with p.Val142Ile. Consistent efficacy was observed in wild-type and variant subgroups for ACM/CVH through month 30 and ACM through month 42. At month 30, acoramidis reduced the risk of ACM/first CVH vs placebo by 31% in ATTRwt-CM (hazard ratio [HR], 0.69; 95% CI, 0.52-0.90; P = .007) and by 59% in ATTRv-CM (HR, 0.41; 95% CI, 0.21-0.81; P = .01). ACM was reduced through month 42 with HRs of 0.70 (95% CI, 0.50-0.98; P = .04) and 0.41 (95% CI, 0.19-0.93; P = .03) in the ATTRwt-CM and ATTRv-CM groups, respectively. Consistent treatment benefit was observed in participants with ATTRwt-CM and ATTRv-CM for secondary end points. Within variant subgroups (p.Val142Ile vs non-p.Val142Ile), consistent treatment benefits were observed for ACM/CVH through month 30 and ACM through month 42.The beneficial effect of acoramidis was observed consistently in ATTRwt-CM and ATTRv-CM groups. These hypothesis-generating results indicate that further studies are warranted to better characterize the therapeutic benefit of acoramidis in variant subgroups.ClinicalTrials.gov Identifiers: NCT03860935; NCT04988386.

View details for DOI 10.1001/jamacardio.2025.4477

View details for PubMedID 41205147