Age- and Sex-Related Differences in Patients With Wild-Type Transthyretin Amyloidosis: Insights From THAOS.

Background: Wild-type transthyretin amyloidosis (ATTRwt amyloidosis) is primarily diagnosed in elderly men but diagnoses in younger patients and women have recently increased. Objectives: The purpose of this study was to examine age- and sex-related differences in patients with ATTRwt amyloidosis enrolled in the THAOS (Transthyretin Amyloidosis Outcomes Survey). Methods: THAOS was a global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both hereditary and wild-type disease, and asymptomatic carriers of pathogenic transthyretin gene variants. Patient characteristics at enrollment were analyzed by age at enrollment and sex (data cutoff date: August 1, 2022). Results: Of 1,251 patients with ATTRwt amyloidosis, 13.7%, 49.1%, 34.5%, and 2.8% were aged <70 years, 70 to 79 years, 80 to 89 years, and ≥90 years, respectively. The proportion of women increased with age, from 4.1% in patients aged <70 years to 14.3% in patients aged ≥90 years. In the respective age groups, median time from symptom onset to diagnosis overall (male, female) was 1.7 (1.3, 5.2), 2.0 (2.0, 2.2), 1.8 (1.9, 0.8), and 0.7 (0.6, 2.5) years. A Karnofsky Performance Status score ≤70 was observed in 17.1%, 30.1%, 46.1%, and 44.4% of patients aged <70 years, 70 to 79 years, 80 to 89 years, and ≥90 years, respectively. Conclusions: In this THAOS analysis of patients with ATTRwt amyloidosis, patients were diagnosed an average of 2 years after symptom onset, with the greatest diagnostic delay in women aged <70 years at 5 years. Patients were predominantly men, but the proportion of women increased with age. A substantial proportion of patients had significant functional impairment regardless of age. (Transthyretin Amyloidosis Outcome Survey [THAOS]; NCT00628745).

Long-term tafamidis efficacy in patients with transthyretin amyloid cardiomyopathy by baseline left ventricular ejection fraction.

AIMS: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) present with diverse left ventricular ejection fraction (LVEF). This study assessed tafamidis efficacy by baseline LVEF in the phase 3 Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and its long-term extension (LTE) study. METHODS AND RESULTS: Patients were randomized to 30 months of tafamidis or placebo treatment in ATTR-ACT. On completion, patients could join an LTE study to receive tafamidis. All-cause mortality (death, heart transplant, or cardiac mechanical assist device implantation) from baseline to the end of follow-up was assessed in patients continuously treated with tafamidis (80 mg meglumine or 61 mg free acid) or delayed tafamidis treatment (placebo in ATTR-ACT; tafamidis in the LTE study) according to baseline LVEF (<50% or ≥50%). Supportive outcomes were evaluated over a shorter follow-up. Patients with baseline LVEF <50% (n = 177: 88 tafamidis- and 89 placebo-treated) had signs of more severe heart failure, a higher proportion were Black, and had variant ATTR-CM than those with LVEF ≥50% (n = 171: 85 tafamidis- and 86 placebo-treated). At the end of follow-up (median 60-64 months), all-cause mortality was numerically higher in patients with baseline LVEF <50%; however, consistent with supportive findings, continuous tafamidis treatment was associated with a 47% reduction in mortality risk compared with delayed tafamidis treatment in patients with LVEF <50% and ≥50% (hazard ratio 0.53 [95% confidence interval 0.367-0.758]; p < 0.001, and 0.53 [0.344-0.818]; p < 0.01, respectively). CONCLUSIONS: Early initiation of tafamidis is associated with reduced mortality in patients with ATTR-CM, irrespective of initial LVEF value. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01994889, NCT02791230.

Survival in a Real-World Cohort of Patients With Transthyretin Amyloid Cardiomyopathy Treated With Tafamidis: An Analysis From the Transthyretin Amyloidosis Outcomes Survey (THAOS).

BACKGROUND: In the pivotal Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), tafamidis significantly reduced mortality rates, leading to its approval in many countries for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM). Real-world evidence on survival in patients with ATTR-CM following tafamidis treatment has not been extensively reported. METHODS AND RESULTS: The Transthyretin Amyloidosis Outcomes Survey (THAOS) was a longitudinal, observational, phase 4 study of patients with transthyretin amyloidosis and asymptomatic participants carrying pathogenic transthyretin variants. Patients from THAOS with a predominantly cardiac phenotype at enrollment were included, and survival was analyzed according to tafamidis treatment status (treated or untreated). Results are based on the completed THAOS dataset. In tafamidis-treated (n = 587) and tafamidis-untreated (n = 854) patients, respectively, median age at enrollment was 77.7 and 76.4 years, 91.8% and 90.0% were male, and 91.8% and 83.8% had wild-type disease. Survival rates (95% CI) at 30 and 42 months, respectively, were 84.4% (80.5-87.7) and 76.8% (70.9-81.7) in tafamidis-treated patients, and 70.0% (66.4-73.2) and 59.3% (55.2-63.0) in tafamidis-untreated patients. Survival rates in genotype subgroups (wild-type and variant) were similar to those of the overall cohort. Survival rates were better in a contemporary cohort, as reflected by a sensitivity analysis performed in patients enrolled after vs before 2019. No new safety signals were identified. CONCLUSIONS: In this real-world cohort of patients with ATTR-CM, survival rates were higher than in ATTR-ACT and consistent with more recent reports, suggesting early diagnosis and treatment with tafamidis has improved life expectancy in ATTR-CM. These results provide further evidence supporting tafamidis' safety and effectiveness. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00628745.

Treatment characteristics of patients with hereditary transthyretin amyloidosis: a cohort study.

BACKGROUND: There are novel medications approved for the treatment of hereditary transthyretin amyloidosis (ATTRv), classified as transthyretin (TTR) stabilizers or gene silencers. While many patients may be on both classes of medications, there is no data available on the safety and efficacy of combination therapy. OBJECTIVES: To describe ATTRv patient and TTR-targeted therapy characteristics in a US cohort, and compare outcomes with combination therapy versus monotherapy. METHODS: We performed a retrospective cohort study with electronic health record data of patients with ATTRv seen at a single institution between January 2018 and December 2022. We collected data on symptomatology, gene mutation, disease severity, ATTRv treatment, hospitalizations, and mortality. RESULTS: One hundred sixty-two patients with ATTRv were identified. The average age at diagnosis was 65 years. 86 patients (53%) had the V122I variant. 119 patients were symptomatic, of whom 103 were started on ATTRv-specific treatment. 41 patients (40%) had cardiomyopathy only, and 53 (51%) had a mixed phenotype of cardiomyopathy and neuropathy. 38 patients (37%) received therapy with both a gene silencer and protein stabilizer. 9 patients (15%) in the monotherapy group had two or more cardiac hospitalizations after starting treatment, compared to 3 patients (9%) on combination therapy (p=0.26). The adjusted hazard ratio of all-cause mortality for the patients on combination therapy compared to monotherapy was 0.37 (0.08-1.8, p=0.21). CONCLUSIONS: While the efficacy is unproven, over one-third of patients with ATTRv are on both a stabilizer and a silencer. There were no safety issues for combination therapy. There was a trend towards improved hospitalizations and survival in patients in the combination group but this was not statistically significant. Larger studies with longer follow-up are necessary to determine benefit of combination therapy.

Deep learning approach for automated segmentation of myocardium using bone scintigraphy single-photon emission computed tomography/computed tomography in patients with suspected cardiac amyloidosis.

BACKGROUND: We employed deep learning to automatically detect myocardial bone-seeking uptake as a marker of transthyretin cardiac amyloid cardiomyopathy (ATTR-CM) in patients undergoing 99mTc-pyrophosphate (PYP) or hydroxydiphosphonate (HDP) single-photon emission computed tomography (SPECT)/computed tomography (CT). METHODS: We identified a primary cohort of 77 subjects at Brigham and Women's Hospital and a validation cohort of 93 consecutive patients imaged at the University of Pennsylvania who underwent SPECT/CT with PYP and HDP, respectively, for evaluation of ATTR-CM. Global heart regions of interest (ROIs) were traced on CT axial slices from the apex of the ventricle to the carina. Myocardial images were visually scored as grade 0 (no uptake), 1 (uptakeribs). A 2D U-net architecture was used to develop whole-heart segmentations for CT scans. Uptake was determined by calculating a heart-to-blood pool (HBP) ratio between the maximal counts value of the total heart region and the maximal counts value of the most superior ROI. RESULTS: Deep learning and ground truth segmentations were comparable (p=0.63). A total of 42 (55%) patients had abnormal myocardial uptake on visual assessment. Automated quantification of the mean HBP ratio in the primary cohort was 3.1±1.4 versus 1.4±0.2 (p<0.01) for patients with positive and negative cardiac uptake, respectively. The model had 100% accuracy in the primary cohort and 98% in the validation cohort. CONCLUSION: We have developed a highly accurate diagnostic tool for automatically segmenting and identifying myocardial uptake suggestive of ATTR-CM.

APOLLO-B, a study of patisiran in patients with transthyretin cardiac amyloidosis: primary long-term results from the open-label extension period

INTRODUCTION: The Phase 3 APOLLO-B study evaluates patisiran in patients (pts) with transthyretin (ATTR) cardiac amyloidosis over a 12-month (M) double-blind (DB) period, followed by an open-label extension (OLE) period when all pts receive patisiran (NCT03997383). Hypothesis: Patisiran provides long-term benefit in pts with ATTR cardiac amyloidosis. Aims: Describe safety and efficacy of patisiran during the APOLLO-B OLE (18M+). METHODS: Pts (18-85 yrs) with ATTR cardiac amyloidosis and heart failure history were randomized 1:1 to patisiran or placebo (pbo). Pts completing DB period were eligible to receive patisiran in the OLE for ≤36M. Results summarized based on DB treatment arm. Exploratory assessments include change from study baseline (CFB) in 6-minute walk test (6MWT), KCCQ-OS, NT-proBNP, and troponin I. RESULTS: In the DB period, 359 pts (pbo n=178; patisiran n=181) received study drug (median [range] age, 76.0 [41, 85] yrs; male, 89%; wtATTR, 80%; tafamidis at baseline, 25%); 334 (93%) entered the OLE. In patisiran arm, M12 and M18 results, respectively, were similar for each endpoint: 6MWT and KCCQ-OS (mean [SEM] CFB) −8.09 [5.73] vs −9.21 [6.04] meters (m) and 0.60 [1.36] vs 0.22 [1.48]; NT-proBNP and troponin I (geometric mean fold-CFB [95%CI]) 1.10 [1.03, 1.17] vs 1.17 [1.07, 1.27] and 1.11 [1.05, 1.18] vs 1.09 [1.01, 1.17]). In pbo arm, patisiran initiation in OLE was associated with a slower rate of worsening or relative stability across endpoints; CFB at M12 vs M18, respectively: 6MWT, −25.43 [5.61] vs −31.08 [5.45] m; KCCQ-OS, −3.41 [1.33] vs −4.02 [1.49]; NT-proBNP, 1.39 [1.28, 1.51] vs 1.53 [1.38, 1.71]; and troponin I, 1.29 [1.21, 1.38] vs 1.21 [1.13, 1.30]. Patisiran had an acceptable safety profile; no new concerns. OLE analyses are ongoing; updated data to be presented. CONCLUSIONS: The M18 results provide evidence that beneficial effects observed in DB period on functional capacity, health status, and quality of life were maintained by continued treatment with patisiran during the OLE. Pbo-treated pts initiating patisiran at M12 showed slowed worsening or stabilization in most endpoints at M18. Early treatment initiation is important: pbo-treated pts did not recover functional capacity or health lost prior to initiating OLE patisiran.