Tafamidis

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Mathew S Maurer - One of the best experts on this subject based on the ideXlab platform.

  • cost effectiveness of Tafamidis therapy for transthyretin amyloid cardiomyopathy
    Circulation, 2020
    Co-Authors: Dhruv S Kazi, Brandon K Bellows, Suzanne J Baron, Changyu Shen, David J Cohen, John A Spertus, Suzanne V Arnold, Brett W Sperry, Mathew S Maurer
    Abstract:

    Background: In patients with transthyretin amyloid cardiomyopathy, Tafamidis reduces all-cause mortality and cardiovascular hospitalizations and slows decline in quality of life compared with place...

  • efficacy and safety of Tafamidis doses in the Tafamidis in transthyretin cardiomyopathy clinical trial attr act
    Journal of Cardiac Failure, 2019
    Co-Authors: Mazen Hanna, Thibaud Damy, Pablo Garciapavia, Daniel P Judge, Giampaolo Merlini, Mathew S Maurer, Balarama Gundapaneni, Terrell A Patterson, Jeffrey H Schwartz, Marla B Sultan
    Abstract:

    Introduction Tafamidis was shown to be an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM) in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). Hypothesis While ATTR-ACT was not designed for a definitive assessment by dose, further analysis may assist determination of the optimal dose. Methods In ATTR-ACT, adult patients with ATTR-CM (variant or wild-type) were randomized (2:1:2) to Tafamidis 80 mg, Tafamidis 20 mg, or placebo for 30 months, with pooled Tafamidis (80mg and 20mg) compared with placebo. In this analysis, Tafamidis 80 mg and 20 mg are presented separately. Efficacy outcomes included the hierarchical combination of all-cause mortality and frequency of cardiovascular-related hospitalisations, all-cause mortality, and change in NT-proBNP. Results The combination of all-cause mortality and cardiovascular-related hospitalizations over 30 months vs placebo was significantly reduced with both Tafamidis 80 mg (P=0.003) and 20 mg (P=0.005). All-cause mortality was significantly reduced with Tafamidis 80 mg (Cox-proportional hazard model [95% CI], 0.690 [0.487, 0.979], P=0.0378), and there was a trend towards reduction with Tafamidis 20 mg (0.715 [0.450-1.137], P=0.1564), compared with placebo. The increase in NT-proBNP was reduced with Tafamidis 80 mg, compared with both 20 mg (P=0.0468) and placebo (P Conclusions Tafamidis 80 mg and Tafamidis 20 mg effectively reduced the combination of mortality and cardiovascular-related hospitalizations. Given the lack of dose-related safety concerns, and the NT-proBNP and survival data, Tafamidis 80 mg is the preferred dose.

  • Tafamidis reduced the decline in health related quality of life in the Tafamidis in transthyretin cardiomyopathy clinical trial attr act
    Journal of Cardiac Failure, 2019
    Co-Authors: Mazen Hanna, Balarama Gundapaneni, Terrell A Patterson, Jeffrey H Schwartz, Michelle Stewart, Marla S Sultan, Mathew S Maurer
    Abstract:

    Introduction In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), Tafamidis reduced all-cause mortality and cardiovascular-related hospitalizations in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). ATTR-CM is associated with a significant burden of disease and Tafamidis reduced the decline in health-related quality of life (as assessed by the Kansas City Cardiomyopathy Questionnaire-Overall Summary [KCCQ-OS] score). Hypothesis Analysis of the changes in KCCQ-OS domains in patients with ATTR-CM over 30 months, together with the impact of Tafamidis on these changes, will provide new data on the progression of disease and the efficacy of Tafamidis. Methods In ATTR-ACT, 441 adult patients with ATTR-CM (variant or wild-type) were randomized (2:1:2) to Tafamidis 80 mg, Tafamidis 20 mg, or placebo for 30 months, with pooled Tafamidis (80mg and 20mg) compared with placebo. Change from baseline in the four KCCQ-OS domain scores were pre-specified exploratory endpoints and analyzed using a mixed model, repeated measures ANCOVA. The KCCQ is a 23-item self-administered questionnaire in which scores range from 0 to 100, with higher scores reflecting better health status. Results Tafamidis significantly reduced the decline in the KCCQ-OS and all four of its domains (P Conclusions Treatment with Tafamidis effectively reduced the decline in all components of the KCCQ-OS, providing further insight into its efficacy in health-related quality of life in patients with ATTR-CM.

  • Tafamidis increases serum ttr prealbumin levels in both attrh and attrwt cardiac amyloidosis
    Journal of Cardiac Failure, 2019
    Co-Authors: Danilo Gamino, Stephen Helmke, Sergio Teruya, Jeffeny De Los Santos, Samantha Guadalupe, Mathew S Maurer
    Abstract:

    Background Transthyretin cardiac amyloidosis (ATTR-CA) is caused by misfolded monomers or oligomers of the normally tetrameric protein transthyretin (TTR or prealbumin) that deposit in the myocardium. Tafamidis, a TTR stabilizer, binds to TTR, preventing dissociation of TTR, the rate-limiting step in amyloidgenesis and reduces morbidity and mortality in subjects with ATTR-CA. We evaluated whether administration of Tafamidis was associated with increases in TTR levels. Methods 31 patients with ATTR-CA 78±7.4 years (mean±SD), 81% males including 7 with ATTRh (6 with Val122Ile and 1 with Thr60Ala) and 25 with ATTRwt had serum TTR measures performed clinically before and after administration of Tafamidis for at least 1.7 months (52 days). Serum TTR (prealbumin) levels were measured by immunoturbidimetric assay. Results Serum TTR levels pre-stabilize administration were 20.6±5.6 mg/dL (mean±SD) and did differ between ATTRwt and ATTRh patients. TTR levels increased in from 18.5±7.2 to 28±7.4 mg/dl in ATTRh subjects (a median increase of 37%. p=0.046) and from 21.3±4.8 to 29.9±6.0 in ATTRwt subjects (a median increase of 40%. p Conclusion Tafamidis administration results in significant increases in TTR concentrations suggesting target engagement. Whether such increases are associated with clinical outcomes requires further study.

  • efficacy of Tafamidis in patients with hereditary or wild type transthyretin amyloid cardiomyopathy further results from the attr act trial
    Journal of Heart and Lung Transplantation, 2019
    Co-Authors: Martha Grogan, Balarama Gundapaneni, Terrell A Patterson, Jeffrey H Schwartz, Marla B Sultan, Ronald M Witteles, Sanijv J Shah, Mathew S Maurer
    Abstract:

    Purpose Transthyretin amyloid cardiomyopathy (ATTR-CM), an underdiagnosed, fatal disease caused by the deposition of transthyretin amyloid fibrils in the heart leading to heart failure, can be hereditary, due to mutations in the transthyretin gene, or wild-type. Tafamidis, a selective transthyretin stabilizer which prevents tetramer dissociation and amyloidogenesis, was recently shown to be an effective treatment for ATTR-CM patients in the international, multicenter, double-blind, placebo-controlled, randomized, Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). Methods Pre-specified and post-hoc analyses of data from ATTR-ACT compared all-cause mortality, and the key secondary outcomes of change from baseline to Month 30 in six-minute walk test (6MWT) distance and Kansas City Cardiomyopathy Questionnaire overall score (KCCQ-OS), with Tafamidis meglumine (80 mg or 20 mg) and placebo across hereditary and wild-type ATTR-CM patients. Results 106 hereditary (63 Tafamidis, 43 placebo) and 335 wild-type patients (201 Tafamidis, 134 placebo) were enrolled. The reduction in all-cause mortality with Tafamidis compared with placebo was similar in hereditary (31.0%) and wild-type (29.4%) patients. This reduction was more pronounced in NYHA Class I and II patients (41.6% hereditary; 43.4% wild-type) than in NYHA Class III patients (20.5% hereditary; 11.6% wild-type). There was a significant and similar reduction in the decline in 6MWT distance in hereditary (mean [SE] difference from placebo, 79.61 [29.83] m; P=0.008) and wild-type (77.14 [10.78] m; P Conclusion ATTR-ACT, the largest randomized controlled trial in ATTR-CM, demonstrated that Tafamidis significantly and clinically meaningfully improved survival, function and quality of life in patients with ATTR-CM. These analyses further support the efficacy of Tafamidis in both wild-type and hereditary patients, and highlight the importance of early diagnosis and treatment. Together, these results provide strong evidence that Tafamidis is an effective therapy for all patients with ATTR-CM.

Jeffrey H Schwartz - One of the best experts on this subject based on the ideXlab platform.

  • 1169Interim analysis of data from a long-term, extension trial of Tafamidis meglumine in patients with transthyretin amyloid cardiomyopathy
    European Heart Journal, 2019
    Co-Authors: Perry M Elliott, Balarama Gundapaneni, Jeffrey H Schwartz, Ben Ebede, Brian M Drachman, Stephen S Gottlieb, James E Hoffman, Scott L Hummel, Daniel J. Lenihan, Marla B Sultan
    Abstract:

    Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM), is an underdiagnosed, fatal disease caused by the deposition of transthyretin amyloid fibrils in the heart leading to heart failure. The Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), an international, multi-center, double-blind, placebo-controlled, randomized study, demonstrated the efficacy and safety of Tafamidis treatment for patients with ATTR-CM due to variant (ATTRm) or wild-type (ATTRwt) TTR. Purpose This is a pooled analysis of data from ATTR-ACT and interim data from the ongoing, long-term, extension study to evaluate longer term data on the efficacy of Tafamidis in patients with ATTR-CM. Methods Patients who completed ATTR-ACT (which had a duration of 30 months) were eligible to be enrolled in a long-term, extension study in which patients either continued to receive Tafamidis meglumine at the same dose (the Tafamidis/Tafamidis [T/T] group) or, for patients previously treated with placebo, were randomised (in a 1:2 ratio) to Tafamidis meglumine 20 mg or 80 mg (the placebo/Tafamidis [P/T] group) for up to 60 months. The primary efficacy outcome was all-cause mortality. This analysis combined data from the completed ATTR-ACT with interim data from the extension study (cut-off date: 15 Feb, 2018), and included patients treated with Tafamidis meglumine across the two studies with a median follow up of 36 months. Results All-cause mortality was significantly lower in the T/T group (n=264; 88 events, 33.3%) compared with the P/T group (n=177; 88 events, 50.3%); hazard ratio (95% CI), 0.64 (0.47, 0.85); P=0.001. In the subgroup of ATTRwt patients, all-cause mortality was significantly reduced in the T/T group (55/201; 27.4%) compared with the P/T group (60/134; 44.8%); 0.64 (0.44, 0.92); P=0.002. In the 106 (24.0%) ATTRm patients, there was a trend towards a reduction in all-cause mortality in the T/T group (33/63; 52.4%) compared with the P/T group (29/43; 67.4%); 0.66 (0.39, 1.09); P=0.17. In patients who were NYHA Class I or II at baseline, all-cause mortality was significantly reduced in the T/T group (38/186; 20.4%) compared with the P/T group (45/114; 39.5%); 0.49 (0.32, 0.75); P=0.001. In those patients with more severe symptoms at baseline (NYHA Class III), there were fewer deaths in the T/T group (50/78; 64.1%) compared with the P/T group (44/63; 69.8%); 0.80 (0.53, 1.21), but this difference was not statistically significant (P=0.50). Conclusions In ATTR-ACT, Tafamidis was shown to significantly improve survival, functional capacity, and quality of life in patients with ATTR-CM. This pooled analysis with data from the ongoing extension study further supports the efficacy of Tafamidis in patients over a longer period of time and the importance of early diagnosis and treatment. Acknowledgement/Funding This study was sponsored by Pfizer.

  • efficacy and safety of Tafamidis doses in the Tafamidis in transthyretin cardiomyopathy clinical trial attr act
    Journal of Cardiac Failure, 2019
    Co-Authors: Mazen Hanna, Thibaud Damy, Pablo Garciapavia, Daniel P Judge, Giampaolo Merlini, Mathew S Maurer, Balarama Gundapaneni, Terrell A Patterson, Jeffrey H Schwartz, Marla B Sultan
    Abstract:

    Introduction Tafamidis was shown to be an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM) in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). Hypothesis While ATTR-ACT was not designed for a definitive assessment by dose, further analysis may assist determination of the optimal dose. Methods In ATTR-ACT, adult patients with ATTR-CM (variant or wild-type) were randomized (2:1:2) to Tafamidis 80 mg, Tafamidis 20 mg, or placebo for 30 months, with pooled Tafamidis (80mg and 20mg) compared with placebo. In this analysis, Tafamidis 80 mg and 20 mg are presented separately. Efficacy outcomes included the hierarchical combination of all-cause mortality and frequency of cardiovascular-related hospitalisations, all-cause mortality, and change in NT-proBNP. Results The combination of all-cause mortality and cardiovascular-related hospitalizations over 30 months vs placebo was significantly reduced with both Tafamidis 80 mg (P=0.003) and 20 mg (P=0.005). All-cause mortality was significantly reduced with Tafamidis 80 mg (Cox-proportional hazard model [95% CI], 0.690 [0.487, 0.979], P=0.0378), and there was a trend towards reduction with Tafamidis 20 mg (0.715 [0.450-1.137], P=0.1564), compared with placebo. The increase in NT-proBNP was reduced with Tafamidis 80 mg, compared with both 20 mg (P=0.0468) and placebo (P Conclusions Tafamidis 80 mg and Tafamidis 20 mg effectively reduced the combination of mortality and cardiovascular-related hospitalizations. Given the lack of dose-related safety concerns, and the NT-proBNP and survival data, Tafamidis 80 mg is the preferred dose.

  • Tafamidis reduced the decline in health related quality of life in the Tafamidis in transthyretin cardiomyopathy clinical trial attr act
    Journal of Cardiac Failure, 2019
    Co-Authors: Mazen Hanna, Balarama Gundapaneni, Terrell A Patterson, Jeffrey H Schwartz, Michelle Stewart, Marla S Sultan, Mathew S Maurer
    Abstract:

    Introduction In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), Tafamidis reduced all-cause mortality and cardiovascular-related hospitalizations in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). ATTR-CM is associated with a significant burden of disease and Tafamidis reduced the decline in health-related quality of life (as assessed by the Kansas City Cardiomyopathy Questionnaire-Overall Summary [KCCQ-OS] score). Hypothesis Analysis of the changes in KCCQ-OS domains in patients with ATTR-CM over 30 months, together with the impact of Tafamidis on these changes, will provide new data on the progression of disease and the efficacy of Tafamidis. Methods In ATTR-ACT, 441 adult patients with ATTR-CM (variant or wild-type) were randomized (2:1:2) to Tafamidis 80 mg, Tafamidis 20 mg, or placebo for 30 months, with pooled Tafamidis (80mg and 20mg) compared with placebo. Change from baseline in the four KCCQ-OS domain scores were pre-specified exploratory endpoints and analyzed using a mixed model, repeated measures ANCOVA. The KCCQ is a 23-item self-administered questionnaire in which scores range from 0 to 100, with higher scores reflecting better health status. Results Tafamidis significantly reduced the decline in the KCCQ-OS and all four of its domains (P Conclusions Treatment with Tafamidis effectively reduced the decline in all components of the KCCQ-OS, providing further insight into its efficacy in health-related quality of life in patients with ATTR-CM.

  • a comprehensive safety profile of Tafamidis in patients with transthyretin amyloid polyneuropathy
    Amyloid, 2019
    Co-Authors: Peter Huber, Balarama Gundapaneni, Marla B Sultan, Ben Ebede, Huihua Li, Denise Rill, Alison Flynn, Jeffrey H Schwartz
    Abstract:

    Background: Tafamidis is approved in over 40 countries to delay neurologic progression in patients with transthyretin amyloid polyneuropathy (ATTR-PN). A comprehensive, integrated analysis of safet...

  • efficacy of Tafamidis in patients with hereditary or wild type transthyretin amyloid cardiomyopathy further results from the attr act trial
    Journal of Heart and Lung Transplantation, 2019
    Co-Authors: Martha Grogan, Balarama Gundapaneni, Terrell A Patterson, Jeffrey H Schwartz, Marla B Sultan, Ronald M Witteles, Sanijv J Shah, Mathew S Maurer
    Abstract:

    Purpose Transthyretin amyloid cardiomyopathy (ATTR-CM), an underdiagnosed, fatal disease caused by the deposition of transthyretin amyloid fibrils in the heart leading to heart failure, can be hereditary, due to mutations in the transthyretin gene, or wild-type. Tafamidis, a selective transthyretin stabilizer which prevents tetramer dissociation and amyloidogenesis, was recently shown to be an effective treatment for ATTR-CM patients in the international, multicenter, double-blind, placebo-controlled, randomized, Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). Methods Pre-specified and post-hoc analyses of data from ATTR-ACT compared all-cause mortality, and the key secondary outcomes of change from baseline to Month 30 in six-minute walk test (6MWT) distance and Kansas City Cardiomyopathy Questionnaire overall score (KCCQ-OS), with Tafamidis meglumine (80 mg or 20 mg) and placebo across hereditary and wild-type ATTR-CM patients. Results 106 hereditary (63 Tafamidis, 43 placebo) and 335 wild-type patients (201 Tafamidis, 134 placebo) were enrolled. The reduction in all-cause mortality with Tafamidis compared with placebo was similar in hereditary (31.0%) and wild-type (29.4%) patients. This reduction was more pronounced in NYHA Class I and II patients (41.6% hereditary; 43.4% wild-type) than in NYHA Class III patients (20.5% hereditary; 11.6% wild-type). There was a significant and similar reduction in the decline in 6MWT distance in hereditary (mean [SE] difference from placebo, 79.61 [29.83] m; P=0.008) and wild-type (77.14 [10.78] m; P Conclusion ATTR-ACT, the largest randomized controlled trial in ATTR-CM, demonstrated that Tafamidis significantly and clinically meaningfully improved survival, function and quality of life in patients with ATTR-CM. These analyses further support the efficacy of Tafamidis in both wild-type and hereditary patients, and highlight the importance of early diagnosis and treatment. Together, these results provide strong evidence that Tafamidis is an effective therapy for all patients with ATTR-CM.

Balarama Gundapaneni - One of the best experts on this subject based on the ideXlab platform.

  • causes of cardiovascular hospitalization and death in the Tafamidis in transthyretin cardiomyopathy clinical trial attr act
    Journal of the American College of Cardiology, 2020
    Co-Authors: Alan B Miller, Balarama Gundapaneni, Terrell A Patterson, Marla B Sultan, James Januzzi, Blair J Oneill, Jose Lopezsendon
    Abstract:

    In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), Tafamidis significantly reduced mortality and cardiovascular (CV)-related hospitalizations compared with placebo in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). This analysis assessed the causes of CV-

  • efficacy of Tafamidis in transthyretin amyloid cardiomyopathy in the attr act trial
    Heart & Lung, 2020
    Co-Authors: John L Berk, Mazen Hanna, Thibaud Damy, Balarama Gundapaneni, Brian M Drachman, Perry M Elliott, Stephen S Gottlieb, Martha Grogan, James E Hoffman, Scott L Hummel
    Abstract:

    Background Transthyretin cardiomyopathy (ATTR-CM) is an underdiagnosed, fatal disease caused by the deposition of transthyretin amyloid fibrils in the heart leading to heart failure (HF). It can be hereditary due to mutations in the TTR gene (ATTRm) or acquired (wild-type [ATTRwt]). Tafamidis is a selective transthyretin stabilizer which prevents tetramer dissociation and amyloidogenesis. The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) was an international, multicenter, double-blind, placebo-controlled, randomized trial of Tafamidis in patients with ATTR-CM. Objectives Given the limited number of patients with ATTR-CM, a novel study design was utilized to enable rigorous testing of the efficacy of Tafamidis on hard cardiovascular (CV) endpoints in a study of relatively modest size compared with traditional CV trials. The primary results of this trial were further supported through the application of pre-specified sensitivity analyses. Methods Patients with ATTR-CM were randomized (2:1:2) to Tafamidis (80 mg or 20 mg of Tafamidis meglumine), or placebo (orally, once daily), for 30 months. Enrollment was stratified by NYHA class and genotype. The primary efficacy analysis was a hierarchical combination of all-cause mortality and frequency of CV-related hospitalizations comparing the pooled Tafamidis groups (20 mg and 80 mg) vs. the placebo group using the Finkelstein-Schoenfeld (F-S) method. The primary efficacy analysis result was examined using a series of sensitivity analyses. Key secondary endpoints were change from baseline to Month 30 in the six-minute walk test distance and the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall score. Safety assessments included adverse events, vital signs, and clinical laboratory tests. Results A total of 441 patients were randomized (Tafamidis=264, placebo=177). Tafamidis was associated with a significant reduction in the hierarchical combination of all-cause mortality and CVrelated hospitalizations (P Conclusions ATTR-ACT, the largest randomized controlled trial in ATTR-CM, showed that Tafamidis is the first treatment to improve survival and quality of life in ATTR-CM. Significant and clinically meaningful improvements were observed in functional capacity as measured by the six-minute walk distance and quality of life by KCCQ overall score. Sensitivity analyses confirmed the robustness of these results. Tafamidis was safe and well tolerated. The primary trial results, along with the sensitivity analyses described here, provide strong rationale for the use of Tafamidis as first-line therapy in ATTR-CM.

  • 1169Interim analysis of data from a long-term, extension trial of Tafamidis meglumine in patients with transthyretin amyloid cardiomyopathy
    European Heart Journal, 2019
    Co-Authors: Perry M Elliott, Balarama Gundapaneni, Jeffrey H Schwartz, Ben Ebede, Brian M Drachman, Stephen S Gottlieb, James E Hoffman, Scott L Hummel, Daniel J. Lenihan, Marla B Sultan
    Abstract:

    Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM), is an underdiagnosed, fatal disease caused by the deposition of transthyretin amyloid fibrils in the heart leading to heart failure. The Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), an international, multi-center, double-blind, placebo-controlled, randomized study, demonstrated the efficacy and safety of Tafamidis treatment for patients with ATTR-CM due to variant (ATTRm) or wild-type (ATTRwt) TTR. Purpose This is a pooled analysis of data from ATTR-ACT and interim data from the ongoing, long-term, extension study to evaluate longer term data on the efficacy of Tafamidis in patients with ATTR-CM. Methods Patients who completed ATTR-ACT (which had a duration of 30 months) were eligible to be enrolled in a long-term, extension study in which patients either continued to receive Tafamidis meglumine at the same dose (the Tafamidis/Tafamidis [T/T] group) or, for patients previously treated with placebo, were randomised (in a 1:2 ratio) to Tafamidis meglumine 20 mg or 80 mg (the placebo/Tafamidis [P/T] group) for up to 60 months. The primary efficacy outcome was all-cause mortality. This analysis combined data from the completed ATTR-ACT with interim data from the extension study (cut-off date: 15 Feb, 2018), and included patients treated with Tafamidis meglumine across the two studies with a median follow up of 36 months. Results All-cause mortality was significantly lower in the T/T group (n=264; 88 events, 33.3%) compared with the P/T group (n=177; 88 events, 50.3%); hazard ratio (95% CI), 0.64 (0.47, 0.85); P=0.001. In the subgroup of ATTRwt patients, all-cause mortality was significantly reduced in the T/T group (55/201; 27.4%) compared with the P/T group (60/134; 44.8%); 0.64 (0.44, 0.92); P=0.002. In the 106 (24.0%) ATTRm patients, there was a trend towards a reduction in all-cause mortality in the T/T group (33/63; 52.4%) compared with the P/T group (29/43; 67.4%); 0.66 (0.39, 1.09); P=0.17. In patients who were NYHA Class I or II at baseline, all-cause mortality was significantly reduced in the T/T group (38/186; 20.4%) compared with the P/T group (45/114; 39.5%); 0.49 (0.32, 0.75); P=0.001. In those patients with more severe symptoms at baseline (NYHA Class III), there were fewer deaths in the T/T group (50/78; 64.1%) compared with the P/T group (44/63; 69.8%); 0.80 (0.53, 1.21), but this difference was not statistically significant (P=0.50). Conclusions In ATTR-ACT, Tafamidis was shown to significantly improve survival, functional capacity, and quality of life in patients with ATTR-CM. This pooled analysis with data from the ongoing extension study further supports the efficacy of Tafamidis in patients over a longer period of time and the importance of early diagnosis and treatment. Acknowledgement/Funding This study was sponsored by Pfizer.

  • efficacy and safety of Tafamidis doses in the Tafamidis in transthyretin cardiomyopathy clinical trial attr act
    Journal of Cardiac Failure, 2019
    Co-Authors: Mazen Hanna, Thibaud Damy, Pablo Garciapavia, Daniel P Judge, Giampaolo Merlini, Mathew S Maurer, Balarama Gundapaneni, Terrell A Patterson, Jeffrey H Schwartz, Marla B Sultan
    Abstract:

    Introduction Tafamidis was shown to be an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM) in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). Hypothesis While ATTR-ACT was not designed for a definitive assessment by dose, further analysis may assist determination of the optimal dose. Methods In ATTR-ACT, adult patients with ATTR-CM (variant or wild-type) were randomized (2:1:2) to Tafamidis 80 mg, Tafamidis 20 mg, or placebo for 30 months, with pooled Tafamidis (80mg and 20mg) compared with placebo. In this analysis, Tafamidis 80 mg and 20 mg are presented separately. Efficacy outcomes included the hierarchical combination of all-cause mortality and frequency of cardiovascular-related hospitalisations, all-cause mortality, and change in NT-proBNP. Results The combination of all-cause mortality and cardiovascular-related hospitalizations over 30 months vs placebo was significantly reduced with both Tafamidis 80 mg (P=0.003) and 20 mg (P=0.005). All-cause mortality was significantly reduced with Tafamidis 80 mg (Cox-proportional hazard model [95% CI], 0.690 [0.487, 0.979], P=0.0378), and there was a trend towards reduction with Tafamidis 20 mg (0.715 [0.450-1.137], P=0.1564), compared with placebo. The increase in NT-proBNP was reduced with Tafamidis 80 mg, compared with both 20 mg (P=0.0468) and placebo (P Conclusions Tafamidis 80 mg and Tafamidis 20 mg effectively reduced the combination of mortality and cardiovascular-related hospitalizations. Given the lack of dose-related safety concerns, and the NT-proBNP and survival data, Tafamidis 80 mg is the preferred dose.

  • Tafamidis reduced the decline in health related quality of life in the Tafamidis in transthyretin cardiomyopathy clinical trial attr act
    Journal of Cardiac Failure, 2019
    Co-Authors: Mazen Hanna, Balarama Gundapaneni, Terrell A Patterson, Jeffrey H Schwartz, Michelle Stewart, Marla S Sultan, Mathew S Maurer
    Abstract:

    Introduction In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), Tafamidis reduced all-cause mortality and cardiovascular-related hospitalizations in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). ATTR-CM is associated with a significant burden of disease and Tafamidis reduced the decline in health-related quality of life (as assessed by the Kansas City Cardiomyopathy Questionnaire-Overall Summary [KCCQ-OS] score). Hypothesis Analysis of the changes in KCCQ-OS domains in patients with ATTR-CM over 30 months, together with the impact of Tafamidis on these changes, will provide new data on the progression of disease and the efficacy of Tafamidis. Methods In ATTR-ACT, 441 adult patients with ATTR-CM (variant or wild-type) were randomized (2:1:2) to Tafamidis 80 mg, Tafamidis 20 mg, or placebo for 30 months, with pooled Tafamidis (80mg and 20mg) compared with placebo. Change from baseline in the four KCCQ-OS domain scores were pre-specified exploratory endpoints and analyzed using a mixed model, repeated measures ANCOVA. The KCCQ is a 23-item self-administered questionnaire in which scores range from 0 to 100, with higher scores reflecting better health status. Results Tafamidis significantly reduced the decline in the KCCQ-OS and all four of its domains (P Conclusions Treatment with Tafamidis effectively reduced the decline in all components of the KCCQ-OS, providing further insight into its efficacy in health-related quality of life in patients with ATTR-CM.

Marla B Sultan - One of the best experts on this subject based on the ideXlab platform.

  • causes of cardiovascular hospitalization and death in the Tafamidis in transthyretin cardiomyopathy clinical trial attr act
    Journal of the American College of Cardiology, 2020
    Co-Authors: Alan B Miller, Balarama Gundapaneni, Terrell A Patterson, Marla B Sultan, James Januzzi, Blair J Oneill, Jose Lopezsendon
    Abstract:

    In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), Tafamidis significantly reduced mortality and cardiovascular (CV)-related hospitalizations compared with placebo in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). This analysis assessed the causes of CV-

  • the bioequivalence of Tafamidis 61 mg free acid capsules and Tafamidis meglumine 4 20 mg capsules in healthy volunteers
    Clinical pharmacology in drug development, 2020
    Co-Authors: Peter Lockwood, Terrell A Patterson, Marla B Sultan, Vu Le, Melissa Ogorman, Ekaterina Tankisheva, Qiang Wang, Steve Riley
    Abstract:

    : Tafamidis, a non-nonsteroidal anti-inflammatory benzoxazole derivative, acts as a transthyretin (TTR) stabilizer to slow progression of TTR amyloidosis (ATTR). Tafamidis meglumine, available as 20-mg capsules, is approved in more than 40 countries worldwide for the treatment of adults with early-stage symptomatic ATTR polyneuropathy. This agent, administered as an 80-mg, once-daily dose (4 × 20-mg capsules), is approved in the United States, Japan, Canada, and Brazil for the treatment of hereditary and wild-type ATTR cardiomyopathy in adults. An alternative single solid oral dosage formulation (Tafamidis 61-mg free acid capsules) was developed and introduced for patient convenience (approved in the United States, United Arab Emirates, and European Union). In this single-center, open-label, randomized, 2-period, 2-sequence, crossover, multiple-dose phase 1 study, the rate and extent of absorption were compared between Tafamidis 61-mg free acid capsules (test) and Tafamidis meglumine 80-mg (4 × 20-mg) capsules (reference) after 7 days of repeated oral dosing under fasted conditions in 30 healthy volunteers. Ratios of adjusted geometric means (90%CI) for the test/reference formulations were 102.3 (98.0-106.8) for area under the concentration-time profile over the dosing interval and 94.1 (89.1-99.4) for the maximum observed concentration, satisfying prespecified bioequivalence acceptance criteria (90%CI, 80-125). Both Tafamidis regimens had an acceptable safety/tolerability profile in this population.

  • The Bioequivalence of Tafamidis 61-mg Free Acid Capsules and Tafamidis Meglumine 4 × 20-mg Capsules in Healthy Volunteers.
    Clinical pharmacology in drug development, 2020
    Co-Authors: Peter Lockwood, Terrell A Patterson, Marla B Sultan, Vu Le, Ekaterina Tankisheva, Qiang Wang, Melissa O'gorman, Steve Riley
    Abstract:

    : Tafamidis, a non-nonsteroidal anti-inflammatory benzoxazole derivative, acts as a transthyretin (TTR) stabilizer to slow progression of TTR amyloidosis (ATTR). Tafamidis meglumine, available as 20-mg capsules, is approved in more than 40 countries worldwide for the treatment of adults with early-stage symptomatic ATTR polyneuropathy. This agent, administered as an 80-mg, once-daily dose (4 × 20-mg capsules), is approved in the United States, Japan, Canada, and Brazil for the treatment of hereditary and wild-type ATTR cardiomyopathy in adults. An alternative single solid oral dosage formulation (Tafamidis 61-mg free acid capsules) was developed and introduced for patient convenience (approved in the United States, United Arab Emirates, and European Union). In this single-center, open-label, randomized, 2-period, 2-sequence, crossover, multiple-dose phase 1 study, the rate and extent of absorption were compared between Tafamidis 61-mg free acid capsules (test) and Tafamidis meglumine 80-mg (4 × 20-mg) capsules (reference) after 7 days of repeated oral dosing under fasted conditions in 30 healthy volunteers. Ratios of adjusted geometric means (90%CI) for the test/reference formulations were 102.3 (98.0-106.8) for area under the concentration-time profile over the dosing interval and 94.1 (89.1-99.4) for the maximum observed concentration, satisfying prespecified bioequivalence acceptance criteria (90%CI, 80-125). Both Tafamidis regimens had an acceptable safety/tolerability profile in this population.

  • 1169Interim analysis of data from a long-term, extension trial of Tafamidis meglumine in patients with transthyretin amyloid cardiomyopathy
    European Heart Journal, 2019
    Co-Authors: Perry M Elliott, Balarama Gundapaneni, Jeffrey H Schwartz, Ben Ebede, Brian M Drachman, Stephen S Gottlieb, James E Hoffman, Scott L Hummel, Daniel J. Lenihan, Marla B Sultan
    Abstract:

    Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM), is an underdiagnosed, fatal disease caused by the deposition of transthyretin amyloid fibrils in the heart leading to heart failure. The Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), an international, multi-center, double-blind, placebo-controlled, randomized study, demonstrated the efficacy and safety of Tafamidis treatment for patients with ATTR-CM due to variant (ATTRm) or wild-type (ATTRwt) TTR. Purpose This is a pooled analysis of data from ATTR-ACT and interim data from the ongoing, long-term, extension study to evaluate longer term data on the efficacy of Tafamidis in patients with ATTR-CM. Methods Patients who completed ATTR-ACT (which had a duration of 30 months) were eligible to be enrolled in a long-term, extension study in which patients either continued to receive Tafamidis meglumine at the same dose (the Tafamidis/Tafamidis [T/T] group) or, for patients previously treated with placebo, were randomised (in a 1:2 ratio) to Tafamidis meglumine 20 mg or 80 mg (the placebo/Tafamidis [P/T] group) for up to 60 months. The primary efficacy outcome was all-cause mortality. This analysis combined data from the completed ATTR-ACT with interim data from the extension study (cut-off date: 15 Feb, 2018), and included patients treated with Tafamidis meglumine across the two studies with a median follow up of 36 months. Results All-cause mortality was significantly lower in the T/T group (n=264; 88 events, 33.3%) compared with the P/T group (n=177; 88 events, 50.3%); hazard ratio (95% CI), 0.64 (0.47, 0.85); P=0.001. In the subgroup of ATTRwt patients, all-cause mortality was significantly reduced in the T/T group (55/201; 27.4%) compared with the P/T group (60/134; 44.8%); 0.64 (0.44, 0.92); P=0.002. In the 106 (24.0%) ATTRm patients, there was a trend towards a reduction in all-cause mortality in the T/T group (33/63; 52.4%) compared with the P/T group (29/43; 67.4%); 0.66 (0.39, 1.09); P=0.17. In patients who were NYHA Class I or II at baseline, all-cause mortality was significantly reduced in the T/T group (38/186; 20.4%) compared with the P/T group (45/114; 39.5%); 0.49 (0.32, 0.75); P=0.001. In those patients with more severe symptoms at baseline (NYHA Class III), there were fewer deaths in the T/T group (50/78; 64.1%) compared with the P/T group (44/63; 69.8%); 0.80 (0.53, 1.21), but this difference was not statistically significant (P=0.50). Conclusions In ATTR-ACT, Tafamidis was shown to significantly improve survival, functional capacity, and quality of life in patients with ATTR-CM. This pooled analysis with data from the ongoing extension study further supports the efficacy of Tafamidis in patients over a longer period of time and the importance of early diagnosis and treatment. Acknowledgement/Funding This study was sponsored by Pfizer.

  • efficacy and safety of Tafamidis doses in the Tafamidis in transthyretin cardiomyopathy clinical trial attr act
    Journal of Cardiac Failure, 2019
    Co-Authors: Mazen Hanna, Thibaud Damy, Pablo Garciapavia, Daniel P Judge, Giampaolo Merlini, Mathew S Maurer, Balarama Gundapaneni, Terrell A Patterson, Jeffrey H Schwartz, Marla B Sultan
    Abstract:

    Introduction Tafamidis was shown to be an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM) in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). Hypothesis While ATTR-ACT was not designed for a definitive assessment by dose, further analysis may assist determination of the optimal dose. Methods In ATTR-ACT, adult patients with ATTR-CM (variant or wild-type) were randomized (2:1:2) to Tafamidis 80 mg, Tafamidis 20 mg, or placebo for 30 months, with pooled Tafamidis (80mg and 20mg) compared with placebo. In this analysis, Tafamidis 80 mg and 20 mg are presented separately. Efficacy outcomes included the hierarchical combination of all-cause mortality and frequency of cardiovascular-related hospitalisations, all-cause mortality, and change in NT-proBNP. Results The combination of all-cause mortality and cardiovascular-related hospitalizations over 30 months vs placebo was significantly reduced with both Tafamidis 80 mg (P=0.003) and 20 mg (P=0.005). All-cause mortality was significantly reduced with Tafamidis 80 mg (Cox-proportional hazard model [95% CI], 0.690 [0.487, 0.979], P=0.0378), and there was a trend towards reduction with Tafamidis 20 mg (0.715 [0.450-1.137], P=0.1564), compared with placebo. The increase in NT-proBNP was reduced with Tafamidis 80 mg, compared with both 20 mg (P=0.0468) and placebo (P Conclusions Tafamidis 80 mg and Tafamidis 20 mg effectively reduced the combination of mortality and cardiovascular-related hospitalizations. Given the lack of dose-related safety concerns, and the NT-proBNP and survival data, Tafamidis 80 mg is the preferred dose.

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  • P0052EMERGING CONCEPTS IN KIDNEY ATTR AMYLOIDOSIS: CHRONIC ADMINISTRATION OF Tafamidis
    Nephrology Dialysis Transplantation, 2020
    Co-Authors: Joana Tavares, Marcio Cardoso, Isabel Fonseca, Andreia Campos, Ana Rocha, Idalina Beirão, Ana M. G. Silva, Cristina Alves, Ana E. Sousa, Teresa Coelho
    Abstract:

    Abstract Background and Aims Transthyretin (TTR) amyloidosis is a disease characterized by destabilization of the native TTR tetramer. It can be caused by aging or due to pathogenic mutations, and its diagnosis is often missed. Hereditary transthyretin amyloidosis (ATTRv), due to Val50Met mutation, is frequently linked with polyneuropathy but it can cause nephropathy too, causing wide range levels of albuminuria and renal dysfunction. Tafamidis, a TTR tetramer stabilizer, has been associated with significant decrease of albuminuria in ATTRv. However, TTR nephropathy is not an approved indication for its use. Plus, the renal effects of chronic oral administration of this TTR stabilizer are yet to be understood. This study evaluated longitudinal changes of eGFR-EPI within 72 months of therapy with Tafamidis and identified factors associated with these changes. Method A retrospective cohort, single centre study was conducted. We have followed consecutive ATTRv Val50Met patients on Tafamidis therapy from July 2012 to March 2019. Men and women aged 18-85 years were eligible if they had neuropathy stage I, were anti-amyloid treatment-naïve patients that accomplished at least 60 months of Tafamidis therapy and had eGFR over 45 ml/min/1.73m2 with any grade of albuminuria. Exclusion criteria were: pregnancy, malignancies, diabetes and concurrent etiologies for nephropathy. Statistical analyses included Mann-Whitney test and linear mixed models to analyze the longitudinal changes in eGFR of the two groups of patients (albumunuric/ non-albuminuric at baseline), by controlling for variables that could be associated with eGFR EPI Cystatin C course. Results From 366 patients, biopsy-proven ATTR amyloidosis, treated with Tafamidis, 122 patients met our criteria (56 males, 66 females) and had a median age of 36 (IQR: 32-46) years old. Twenty-eight had pathological urinary albumin-to-creatinine ratio (ACR), defined by ACR >30 mg/dL, and ACR >300 mg/dL was only found in females. In univariate analysis no significant differences were found between median eGFR decline in albuminuric versus non-albuminuric patients (p=0.330). At all time points, mean eGFR levels were significantly lower in baseline albuminuric patients. According to our estimation, eGFR at baseline was 11.2 mL/min/1.73 m2 lower in baseline albuminuric patients, adjusted for age at the disease onset and time between symptom onset and Tafamidis initiation. Baseline albuminuria status (p=0,005), age at the disease onset (p<0,001) and time between initiation of symptoms and initiation of Tafamidis (p=0,016) were the only independent factors associated with longitudinal changes of eGFR (higher age at the disease onset and higher time between symptom onset and Tafamidis initiation were associated with lower levels of eGFR). Figure 1 shows the predicted eGFR EPI trajectories over time for baseline albuminuric/ non-albuminuric subjects. Conclusion This study represents a real-life experience of oral chronic administration of Tafamidis and its effects on ATTR nephropathy, concerning albuminuria reduction and renal function decline. Our analysis had shown similar decline rates in eGFR, irrespectively the degree of albuminuria at baseline, differently from what would be expected, since higher grades of albuminuria are related with more rapidly kidney function deterioration. Besides its capacity of stabilizing TTR tetramers, Tafamidis could have an enhancing role in the podocyte regeneration process through potential cofactors for amyloid fibrils toxic effect, that could be present in the glomerular basement membrane and mesangium. This nephroprotector effect should be considered when a switch of therapy is demanded by the neuropathy status and a second line treatment is considered. Presence of renal disease may be an indication for Tafamidis maintenance and combined therapy.

  • Evaluation of Mortality During Long-Term Treatment with Tafamidis for Transthyretin Amyloidosis with Polyneuropathy: Clinical Trial Results up to 8.5 Years
    Neurology and Therapy, 2020
    Co-Authors: Giampaolo Merlini, Teresa Coelho, Michelle Stewart, Huihua Li, Márcia Waddington Cruz, Ben Ebede
    Abstract:

    Introduction The effects of Tafamidis on mortality in Val30Met and non-Val30Met patients with transthyretin amyloidosis with polyneuropathy (ATTR-PN) were evaluated. Methods The analyses were based on cumulative data from the Val30Met patients in the 18-month double-blind registration study and its 12-month open-label extension study, the non-Val30Met patients of the 12-month open-label study, and both patient groups in the ongoing 10-year extension study. Kaplan–Meier analyses of time to death from first treatment dose were performed. For the Val30Met group, two treatment groups were analyzed: those who received Tafamidis in both the parent and extension studies (T–T) and those who received placebo in the parent study and switched to Tafamidis in the extension studies (P–T). Results Kaplan–Meier estimates (95% confidence interval [CI]) were available up to 9 years for the Val30Met group, at which time 85.9% (53.1–96.4) and 91.1% (77.9–96.6) of the patients in the T–T and P–T groups, respectively, were alive. For the non-Val30Met group, estimates were available up to 8 years from the first dose, and the percentage of patients alive was 75.9% (47.7–90.2). Conclusion Long-term Tafamidis treatment may confer survival benefit in patients with ATTR-PN. Trial registration ClinicalTrials.gov identifier: NCT00409175, NCT00791492, NCT00630864, and NCT00925002.

  • predictive model of response to Tafamidis in hereditary attr polyneuropathy
    JCI insight, 2019
    Co-Authors: Cecília Monteiro, Carla Rodrigues, Evan T Powers, Marta Novais, Jaleh S Mesgazardeh, Joao Anselmo, Joana Fernandes, Gabriel J Brighty, David L Powers, Teresa Coelho
    Abstract:

    BACKGROUNDThe hereditary transthyretin (TTR) amyloidoses are a group of diseases for which several disease-modifying treatments are now available. Long-term effectiveness of these therapies is not yet fully known. Moreover, the existence of alternative therapies has resulted in an urgent need to identify patient characteristics that predict response to each therapy.METHODSWe carried out a retrospective cohort study of 210 patients with hereditary TTR amyloidosis treated with the kinetic stabilizer Tafamidis (20 mg qd). These patients were followed for a period of 18-66 months, after which they were classified by an expert as responders, partial responders, or nonresponders. Correlations between baseline demographic and clinical characteristics, as well as plasma biomarkers and response to therapy, were investigated.RESULTS34% of patients exhibited an almost complete arrest of disease progression (classified by an expert as responders); 36% had a partial to complete arrest in progression of some but not all disease components (partial responders); whereas the remaining 30% continued progressing despite therapy (nonresponders). We determined that disease severity, sex, and native TTR concentration at the outset of treatment were the most relevant predictors of response to Tafamidis. Plasma Tafamidis concentration after 12 months of therapy was also a predictor of response for male patients. Using these variables, we built a model to predict responsiveness to Tafamidis.CONCLUSIONOur study indicates long-term effectiveness for Tafamidis, a kinetic stabilizer approved for the treatment of hereditary TTR amyloidosis. Moreover, we created a predictive model that can be potentially used in the clinical setting to inform patients and clinicians in their therapeutic decisions.

  • natural history and survival in stage 1 val30met transthyretin familial amyloid polyneuropathy
    Neurology, 2018
    Co-Authors: Teresa Coelho, Isabel Conceicao, Monica Ines, Marta Soares, Mamede De Carvalho, Joao Costa
    Abstract:

    Objective To assess the natural history and treatment effect on survival among patients with transthyretin-associated familial amyloid polyneuropathy (TTR-FAP) stage 1 Val30Met. Methods Multi-institutional, hospital-based study of patients with TTR-FAP Val30Met prospectively followed up until December 2016, grouped into untreated (n = 1,771), liver transplant (LTx)-treated (n = 957), or Tafamidis-treated (n = 432) cohorts. Standardized mortality ratios, Kaplan-Meier, and Cox methods were used to estimate excess mortality, survival, and adjusted hazard ratios (HRs) for all-cause mortality. Results Disease-modifying treatments decreased TTR-FAP excess mortality from 10 to 4 (standardized mortality ratio 3.92, 95% confidence interval [CI] 2.64–5.59). Median overall survival of untreated and LTx-treated cohorts was 11.61 (95% CI 11.14–11.87) and 24.73 years (95% CI 22.90–27.09), respectively, and was not reached in the Tafamidis-treated cohort (maximum follow-up, 10 years). Both disease-modifying treatments improved survival. Among early-onset patients (younger than 50 years of age), Tafamidis reduced the mortality risk compared with untreated patients by 91% (HR 0.09, 95% CI 0.03–0.25, p p = 0.050). Previous Tafamidis treatment did not affect mortality risk after LTx (HR 0.83, 95% CI 0.25–2.78, p = 0.763). Among late-onset patients (50 years and older), Tafamidis reduced mortality risk by 82% compared with untreated patients (HR 0.18, 95% CI 0.06–0.49, p = 0.001). Conclusion LTx and Tafamidis convey substantial survival benefits, but TTR-FAP mortality remains higher than in the general population. These results strongly reinforce the importance of timely diagnosis and earlier treatment, boosting the pursuit for an increased life expectancy. Classification of evidence This study provides Class III evidence that for patients with stage 1 Val30Met TTR-FAP, LTx and Tafamidis increase survival.

  • Natural history and survival in stage 1 Val30Met transthyretin familial amyloid polyneuropathy
    Neurology, 2018
    Co-Authors: Teresa Coelho, Isabel Conceicao, Monica Ines, Marta Soares, Mamede De Carvalho, Joao Costa
    Abstract:

    OBJECTIVE: To assess the natural history and treatment effect on survival among patients with transthyretin-associated familial amyloid polyneuropathy (TTR-FAP) stage 1 Val30Met. METHODS: Multi-institutional, hospital-based study of patients with TTR-FAP Val30Met prospectively followed up until December 2016, grouped into untreated (n = 1,771), liver transplant (LTx)-treated (n = 957), or Tafamidis-treated (n = 432) cohorts. Standardized mortality ratios, Kaplan-Meier, and Cox methods were used to estimate excess mortality, survival, and adjusted hazard ratios (HRs) for all-cause mortality. RESULTS: Disease-modifying treatments decreased TTR-FAP excess mortality from 10 to 4 (standardized mortality ratio 3.92, 95% confidence interval [CI] 2.64-5.59). Median overall survival of untreated and LTx-treated cohorts was 11.61 (95% CI 11.14-11.87) and 24.73 years (95% CI 22.90-27.09), respectively, and was not reached in the Tafamidis-treated cohort (maximum follow-up, 10 years). Both disease-modifying treatments improved survival. Among early-onset patients (younger than 50 years of age), Tafamidis reduced the mortality risk compared with untreated patients by 91% (HR 0.09, 95% CI 0.03-0.25, p < 0.001) and with LTx-treated patients by 63% (HR 0.37, 95% CI 0.14-1.00, p = 0.050). Previous Tafamidis treatment did not affect mortality risk after LTx (HR 0.83, 95% CI 0.25-2.78, p = 0.763). Among late-onset patients (50 years and older), Tafamidis reduced mortality risk by 82% compared with untreated patients (HR 0.18, 95% CI 0.06-0.49, p = 0.001). CONCLUSION: LTx and Tafamidis convey substantial survival benefits, but TTR-FAP mortality remains higher than in the general population. These results strongly reinforce the importance of timely diagnosis and earlier treatment, boosting the pursuit for an increased life expectancy. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with stage 1 Val30Met TTR-FAP, LTx and Tafamidis increase survival.

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