Nativi-Nicolau, José

AbstractBackgroundThe prognosis in patients with advanced cardiac amyloidosis (CA) remains poor.ObjectivesWe sought to describe survival post heart transplantation (HT) in amyloid compared with non‐amyloid recipients, highlight waitlist times within the new allocation system across three Organ Procurement and Transplantation Network (OPTN) regions, and describe multiorgan transplantation (MOT) in hereditary amyloidosis.MethodsThis is a retrospective review of end‐stage CA patients who underwent HT at Mayo Clinic from January 2007 to December 2020. Wait time was compared in the new versus old OPTN allocation era starting December 18, 2018 by Wilcoxon rank sum test. All‐cause mortality for those with and without CA was compared using Kaplan–Meier estimates with log rank analysis, censoring December 16, 2022.ResultsFifty‐five patients with CA underwent HT between 2007 and 2020, 8 light chain amyloidosis (AL) (14.5%), 28 hereditary transthyretin (ATTRv) (50.9%), 17 wildtype transthyretin (ATTRwt) (30.9%), and 2 hereditary apolipoprotein A1 (AApoA1) amyloidosis patients (3.6%). No significant difference in overall survival post‐transplant was seen in amyloid compared with non‐amyloid (p = 0.816). Median time to HT was shorter in the new system, 45 days (IQR 24, 78) versus 174 days (IQR 76.5, 483.5), p = 0.006. There was a decline in MOT in hereditary amyloidosis over time with the concomitant rise in disease‐targeted therapies.ConclusionsHT survival in CA patients was similar to non‐amyloid patients. The new allocation system benefits this cohort with shorter wait times. There is less MOT in hereditary amyloidosis with increased utilization of disease‐targeted therapy.

BACKGROUND: In the phase 3 randomized controlled study ATTRibute-CM (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy), acoramidis, a transthyretin stabilizer, demonstrated significant efficacy on the primary end point. Participants with transthyretin amyloid cardiomyopathy who completed ATTRibute-CM were invited to enroll in an open-label extension study (OLE). We report the efficacy and safety data of acoramidis in participants who completed ATTRibute-CM and enrolled in the ongoing OLE. METHODS: Participants who previously received acoramidis through month 30 in ATTRibute-CM continued to receive it (continuous acoramidis), and those who received placebo through month 30 were switched to acoramidis (placebo to acoramidis). Participants who received concomitant tafamidis in ATTRibute-CM were required to discontinue it to be eligible to enroll in the OLE. Clinical efficacy outcomes analyzed through month 42 included time to event for all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH), ACM alone, first CVH alone, ACM or recurrent CVH, change from baseline in NT-proBNP (N-terminal pro-B-type natriuretic peptide), 6-minute walk distance, serum transthyretin, and Kansas City Cardiomyopathy Questionnaire Overall Summary score. Safety outcomes were analyzed through month 42. RESULTS: Overall, 438 of 632 participants in ATTRibute-CM completed treatment, and 389 enrolled in the ongoing OLE (263 continuous acoramidis and 126 placebo to acoramidis). The hazard ratio for ACM or first CVH was 0.57 (95% CI, 0.46–0.72) at month 42 based on a stratified Cox proportional hazards model ( P <0.0001) favoring continuous acoramidis. Similar analyses were performed on ACM alone and first CVH alone, with hazard ratios of 0.64 (95% CI, 0.47–0.88) and 0.53 (95% CI, 0.41–0.69), respectively, at month 42. Treatment effects for NT-proBNP and 6-minute walk distance also favored continuous acoramidis. On initiation of open-label acoramidis in the placebo-to-acoramidis arm, there was a prompt increase in serum transthyretin. Quality of life assessed by Kansas City Cardiomyopathy Questionnaire Overall Summary score was well preserved in continuous-acoramidis participants compared with the placebo-to-acoramidis participants. No new clinically important safety issues were identified in this long-term evaluation. CONCLUSIONS: Early initiation and continuous use of acoramidis in the ATTRibute-CM study through month 42 of the ongoing OLE study were associated with sustained clinical benefits in a contemporary transthyretin amyloid cardiomyopathy cohort, with no clinically important safety issues newly identified. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04988386.

Background: Acoramidis is a novel, potent, investigational, transthyretin (TTR) stabilizer under development for the treatment of TTR amyloidosis that results in near-complete (≥90%) TTR stabilization. In a phase 3 study, ATTRibute-CM, acoramidis demonstrated improved clinical outcomes in participants with transthyretin amyloid cardiomyopathy (ATTR-CM), including a 50% reduction in the risk of CVH compared to placebo over 30 months. The study also demonstrated that cardiovascular hospitalization (CVH) during the study predicted a higher subsequent mortality in participants with ATTR-CM. Hypothesis: CVH portends a higher risk of mortality in participants with ATTR-CM. Since acoramidis reduces CVH, it can improve the prognosis of participants with ATTR-CM. Aim: To evaluate the relationship between CVH and survival in the acoramidis group within ATTRibute-CM. Methods: In this post-hoc analysis, the relationship between those with or without CVH and survival was analyzed within the acoramidis treatment group using the Kaplan-Meier (KM) estimator method. Results: Demographics and baseline disease characteristics were mostly comparable between acoramidis-treated participants with and without CVH, although participants with CVH had a higher baseline NT-proBNP and lower eGFR. At Month 30, in acoramidis-treated participants, those without any CVH (n=300) had a higher survival [86.8% (95% CI = 82.2, 90.3)] versus 62.4% (95% CI = 52.6, 70.7) in those who had any CVH (n=109); p<0.0001 from log-rank test (Figure). Conclusion: In the ATTRibute-CM study, pts without any CVH receiving acoramidis have a higher survival rate. CVHs remain a powerful predictor of mortality. This reinforces the importance of an effective therapy that reduces CVH and in turn may improve survival in patients with ATTR-CM.

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, fatal condition characterized by worsening heart failure (HF), exercise intolerance, cardiac arrhythmias, aortic stenosis, and orthopedic manifestations. Recent analyses have shown ATTR-CM presents a significant burden to the healthcare system, but data on healthcare resource utilization (HCRU) comparing ATTR-CM to non-ATTR HF in the US are lacking. Aim: To compare HCRU and costs in patients (pts) with ATTR-CM to that of pts with non-ATTR HF using medical and pharmacy claims. Methods: Using the Optum Clinformatics Data Mart (Jan 2016-Sep 2023), pts with ATTR-CM were identified based on presence of HF and/or cardiomyopathy (CM) occurring within 2 years of first amyloidosis diagnosis (excluding light-chain amyloidosis) and followed for at least 12 months after first HF/CM diagnosis. ATTR-CM pts were matched 1:1 to non-ATTR HF pts using propensity score matching. After index diagnosis, both groups were assessed for HCRU, including inpatient acute cardiovascular (CV) hospitalizations (CVH), length of stay, and cost. Hospitalizations were considered CV if a pt received a CV diagnosis during the hospitalization period. Results: There were 4581 pts with ATTR-CM (mean [±SD] age: 76 [9.13] years; 56.2% male) who met inclusion criteria and were matched to 4581 non-ATTR HF pts (mean [±SD] age: 76 [8.86] years; 56.0% male) for comparison (Table). ATTR-CM pts had a higher trend of CVH and a higher number of total CVHs and mean hospitalizations per pt compared to non-ATTR HF pts (p<0.001). The mean cost per hospitalization (p=0.00463) and mean cost per annual hospitalizations per pt (p<0.001) were higher for ATTR-CM compared to non-ATTR HF. ATTR-CM pts were also hospitalized for more mean days annually for CV-related reasons compared to non-ATTR HF pts (p<0.001). On average, pts with ATTR-CM spent 2.3 days more than matched non-ATTR HF pts in the hospital each year. Conclusion: Compared to non-ATTR HF, ATTR-CM is associated with a greater burden on the healthcare system as evaluated by hospitalization rate, costs per hospitalization, annual hospitalization costs, and days hospitalized annually.

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is estimated to occur in 120,000 US adults and remains underdiagnosed. However, awareness of ATTR-CM has improved following the introduction of new diagnostic tools and disease-modifying treatments. Hence, patients (pts) enrolled in contemporary clinical trials could be at an earlier stage of the disease than pts in past clinical studies. Aim: To assess temporal trends in the baseline risk of pts with ATTR-CM enrolled in clinical trials. Methods: Embase, MEDLINE, CENTRAL, and conference websites were searched on November 23, 2023, for peer-reviewed articles and abstracts. Randomized and single-arm clinical trials examining treatments for ATTR-CM were included, and baseline characteristics and outcomes in pts treated with placebo (PBO) were compared across studies. Results: We reviewed 39 publications derived from 4 randomized and 4 single-arm trials. Studies enrolled pts between 2008 and 2021, although 1 study (INOCARD, 2022) did not report years of enrollment. Several baseline characteristics were comparable across studies, including sex, age, race/ethnicity, genotype, and troponin I level. NYHA class at baseline varied with year of enrollment, with fewer NYHA class III pts in recent trials (Figure). Recent trials also showed a trend toward lower NT-proBNP levels (medians ranging from 1911-3178 pg/mL) and higher eGFR levels (means ranging from 54.7-69.0 mL/min/1.73 m 2 ). In PBO groups, all-cause mortality (ACM) rates at 12 months dropped from 9% in ATTR-ACT (enrolled 2013-2015) to 6.9% in ATTRibute-CM (enrolled 2019-2020) and 5.6% in APOLLO-B (enrolled 2019-2021); ACM rates at 30 months dropped from 42.9% in ATTR-ACT to 25.7% in ATTRibute-CM. Conclusions: This systematic review found that disease-modifying treatments and diagnostic advances have led to earlier diagnosis of pts with ATTR-CM. Recent clinical trials appear to have enrolled pts with a better prognosis. Comparisons of results across these trials are limited and should acknowledge the potential impact of variability in baseline risks among trial populations.

Aim: The six-minute walk test (6MWT) is a common measure of functional capacity in patients with heart failure (HF). Primary clinical study end points in cardiomyopathy (CM) trials, including transthyretin-mediated amyloidosis with CM (ATTR-CM), are often limited to hospitalization and mortality. Objective: To investigate the relationship between the 6MWT and hospitalization or mortality in CM, including ATTR-CM. Method: A PRISMA-guided systematic literature review was conducted using search terms for CM, 6MWT, hospitalization and mortality. Results: Forty-one studies were identified that reported 6MWT data and hospitalization or mortality data for patients with CM. The data suggest that a greater 6MWT distance is associated with a reduced risk of hospitalization or mortality in CM. Conclusion: The 6MWT is an accepted alternative end point in CM trials, including ATTR-CM.

ImportanceTafamidis reduced all-cause mortality and cardiovascular-related hospitalizations and minimized patient-reported health status deterioration at 30 months in patients with transthyretin (ATTR) amyloidosis. However, the clinical significance of health status changes remains unclear, particularly in patients with New York Heart Association (NYHA) class III symptoms who experienced more cardiovascular-related hospitalizations than those with NYHA class I-II symptoms.ObjectiveTo evaluate the health status of patients taking tafamidis with baseline NYHA class III symptoms.Design, Setting, and ParticipantsThis randomized clinical trial post hoc analysis evaluated data for patients with transthyretin (ATTR) cardiac amyloidosis and NYHA class I-III symptoms at baseline who were enrolled in ATTR-ACT, a placebo-controlled study of tafamidis held at 48 sites in 13 countries.InterventionsTafamidis meglumine, 80 mg or 20 mg (pooled cohort), vs placebo.Main Outcomes and MeasuresEstablished thresholds for clinical benefit on the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) were used to define response groups (very large decline to very large improvement); the proportion of patients in each group was calculated within each baseline NYHA class.ResultsAmong 441 patients (264 tafamidis, 177 placebo), the mean (SD) age was 74.3 (7.0) years; 398 (90%) were male and 43 (10%) were female. Mean (SD) baseline KCCQ-OS scores were 67.3 (21.4) in the tafamidis group and 65.9 (21.7) in the placebo group (range: 0-100, with 100 indicating the best health). There was a significant shift toward better KCCQ-OS scores in patients receiving tafamidis (odds ratio for 10-point improvement 2.4; 95% CI, 1.6-3.4; P &amp;lt; .001). More patients taking tafamidis were alive and not worse at all time points (37% vs 15% at month 30). These findings were similar in patients with NYHA class III symptoms. In patients with NYHA class III symptoms alive at 30 months, improvements in health status were more common (35% vs 10%) and declines were less common (38% vs 57%) with tafamidis vs placebo.Conclusions and RelevanceIn ATTR-ACT, although patients with baseline NYHA class III symptoms had worse overall outcomes, treatment with tafamidis yielded better health status compared with placebo.Trial RegistrationClinicalTrials.gov Identifier: NCT01994889

AbstractTransthyretin‐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.