Efficacy of Disease-Modifying Treatments in Transthyretin Amyloid Cardiomyopathy: A Systematic Review and Meta-Analysis of Five Phase III Randomized Controlled Trials
- 1National Taiwan University College of Medicine and Hospital
Abstract
BackgroundSeveral disease-modifying agents for transthyretin amyloid cardiomyopathy (ATTR-CM) have been investigated, but differences in trial design and background stabilizer use complicate interpretation of their efficacy. This meta-analysis assessed their efficacy overall and by background stabilizer use.
MethodsPubMed, Embase, and the Cochrane Library were searched through September 2026 for phase III randomized, placebo-controlled trials of disease-modifying therapy in ATTR-CM. Primary endpoints were all-cause mortality, 6-minute walk distance (6MWD), Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score, and N-terminal pro-B-type natriuretic peptide (NT-proBNP), pooled with a random-effects model. Treatment effects were compared between the monotherapy and baseline stabilizer strata using a mixed-effects model.
ResultsFive trials (ATTR-ACT, APOLLO-B, ATTRibute-CM, HELIOS-B, CARDIO-TTRansform; N=3497) were included. Disease-modifying therapy reduced all-cause mortality (risk ratio, 0.76; 95% confidence interval [CI], 0.66-0.87; I2=0%) and improved 6MWD (pooled standardized mean difference [SMD], 0.43; 95% CI, 0.20-0.67), KCCQ-OS score (SMD, 0.37; 95% CI, 0.19-0.55), and NT-proBNP (SMD, - 0.53; 95% CI, -0.89 to -0.18). The mortality benefit was similar whether therapy was given alone or added to a background stabilizer (pooled risk ratio, 0.77 vs. 0.71; P for interaction = 0.59), but treatment effects on 6MWD (pooled SMD, 0.49 vs. 0.14), KCCQ-OS score (0.44 vs. 0.07), and NT-proBNP (-0.65 vs. -0.13) were smaller among patients receiving a background stabilizer (P for interaction = 0.012, <0.001, and 0.029, respectively).
ConclusionDisease-modifying treatments reduced all-cause mortality and favored functional capacity, health status, and NT-proBNP outcomes in patients with ATTR-CM. Exploratory subgroup analyses showed smaller treatment effects on 6MWD, KCCQ-OS score, and NT-proBNP among patients receiving a background stabilizer, with no statistically significant difference in the mortality effect according to baseline stabilizer use.
What Is New?O_LIThis meta-analysis of all five phase III randomized controlled trials of disease-modifying therapy in transthyretin amyloid cardiomyopathy (3497 analyzed participants) found a lower risk of all-cause mortality (risk ratio, 0.76; 95% CI, 0.66-0.87) and more favorable 6-minute walk distance, Kansas City Cardiomyopathy Questionnaire-Overall Summary score, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). C_LIO_LIIn subgroup analyses, the mortality effect was similar with and without a background transthyretin stabilizer at randomization, whereas effects on functional capacity, health status, and NT-proBNP were smaller among patients receiving a background stabilizer. C_LI
What Are the Clinical Implications?O_LIAmong patients already receiving a transthyretin stabilizer, adding a second agent was associated with a mortality reduction similar to that seen without background therapy but with smaller incremental gains in functional and biomarker outcomes; because these findings rest on aggregate trial data and subgroup comparisons, they should be interpreted cautiously. C_LI
Related
- Cardiac Myosin Inhibitors in Adults with Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy: A Systematic Review and Meta-analysis of Randomized Controlled Trials
- Conservative and Minimally Invasive Treatments for Temporomandibular Disorders Versus Inactive Controls: A Systematic Review and Meta-Analysis of Randomized Trials
- Closing the Diagnostic Gap in Transthyretin Amyloid Cardiomyopathy
- Delays From Clinical Manifestations to Diagnosis of Transthyretin Amyloid Cardiomyopathy: A National Retrospective Cohort Study
- Diagnostic Concordance of Immediate Versus 1-Hour Technetium-99m Hydroxymethylene Diphosphonate Scintigraphy in Suspected Transthyretin Amyloid Cardiomyopathy
BibTeX
@misc{hung2026efficacy,
title = {{Efficacy of Disease-Modifying Treatments in Transthyretin Amyloid Cardiomyopathy: A Systematic Review and Meta-Analysis of Five Phase III Randomized Controlled Trials}},
author = {Y.-H. Hung and C.-H. Tsai and T.-W. Kao and Y.-W. Wu and W.-C. Yu and S. Carigi and B. W. Sperry and S. Perlini and Y.-H. Lin},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.10.26365208},
url = {https://www.medrxiv.org/content/10.64898/2026.10.10.26365208v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Efficacy of Disease-Modifying Treatments in Transthyretin Amyloid Cardiomyopathy: A Systematic Review and Meta-Analysis of Five Phase III Randomized Controlled Trials
AU - Y.-H. Hung
AU - C.-H. Tsai
AU - T.-W. Kao
AU - Y.-W. Wu
AU - W.-C. Yu
AU - S. Carigi
AU - B. W. Sperry
AU - S. Perlini
AU - Y.-H. Lin
PY - 2026
DA - 2026/10/10
PB - medRxiv
DO - 10.64898/2026.10.10.26365208
UR - https://www.medrxiv.org/content/10.64898/2026.10.10.26365208v1
AB - BackgroundSeveral disease-modifying agents for transthyretin amyloid cardiomyopathy (ATTR-CM) have been investigated, but differences in trial design and background stabilizer use complicate interpretation of their efficacy. This meta-analysis assessed their efficacy overall and by background stabilizer use. MethodsPubMed, Embase, and the Cochrane Library were searched through September 2026 for phase III randomized, placebo-controlled trials of disease-modifying therapy in ATTR-CM. Primary endpoints were all-cause mortality, 6-minute walk distance (6MWD), Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score, and N-terminal pro-B-type natriuretic peptide (NT-proBNP), pooled with a random-effects model. Treatment effects were compared between the monotherapy and baseline stabilizer strata using a mixed-effects model. ResultsFive trials (ATTR-ACT, APOLLO-B, ATTRibute-CM, HELIOS-B, CARDIO-TTRansform; N=3497) were included. Disease-modifying therapy reduced all-cause mortality (risk ratio, 0.76; 95% confidence interval [CI], 0.66-0.87; I2=0%) and improved 6MWD (pooled standardized mean difference [SMD], 0.43; 95% CI, 0.20-0.67), KCCQ-OS score (SMD, 0.37; 95% CI, 0.19-0.55), and NT-proBNP (SMD, - 0.53; 95% CI, -0.89 to -0.18). The mortality benefit was similar whether therapy was given alone or added to a background stabilizer (pooled risk ratio, 0.77 vs. 0.71; P for interaction = 0.59), but treatment effects on 6MWD (pooled SMD, 0.49 vs. 0.14), KCCQ-OS score (0.44 vs. 0.07), and NT-proBNP (-0.65 vs. -0.13) were smaller among patients receiving a background stabilizer (P for interaction = 0.012, <0.001, and 0.029, respectively). ConclusionDisease-modifying treatments reduced all-cause mortality and favored functional capacity, health status, and NT-proBNP outcomes in patients with ATTR-CM. Exploratory subgroup analyses showed smaller treatment effects on 6MWD, KCCQ-OS score, and NT-proBNP among patients receiving a background stabilizer, with no statistically significant difference in the mortality effect according to baseline stabilizer use. What Is New?O_LIThis meta-analysis of all five phase III randomized controlled trials of disease-modifying therapy in transthyretin amyloid cardiomyopathy (3497 analyzed participants) found a lower risk of all-cause mortality (risk ratio, 0.76; 95% CI, 0.66-0.87) and more favorable 6-minute walk distance, Kansas City Cardiomyopathy Questionnaire-Overall Summary score, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). C_LIO_LIIn subgroup analyses, the mortality effect was similar with and without a background transthyretin stabilizer at randomization, whereas effects on functional capacity, health status, and NT-proBNP were smaller among patients receiving a background stabilizer. C_LI What Are the Clinical Implications?O_LIAmong patients already receiving a transthyretin stabilizer, adding a second agent was associated with a mortality reduction similar to that seen without background therapy but with smaller incremental gains in functional and biomarker outcomes; because these findings rest on aggregate trial data and subgroup comparisons, they should be interpreted cautiously. C_LI
ER -