Efficacy of Disease-Modifying Treatments in Transthyretin Amyloid Cardiomyopathy: A Systematic Review and Meta-Analysis of Five Phase III Randomized Controlled Trials
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Background
Several 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.
Methods
PubMed, 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.
Results
Five 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; I 2 =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).
Conclusion
Disease-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?
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This 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).
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In 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.
What Are the Clinical Implications?
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Among 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.
