The efficacy and safety of specific therapies for cardiac Transthyretin-mediated amyloidosis: a systematic review and meta-analysis of randomized trials

Abstract

Background: Transthyretin (TTR) Cardiomyopathy (ATTR-CM) is characterized by the deposition of misfolded TTR monomers in the heart, leading to progressive heart failure. TTR-specific therapies offer a pharmacological approach to slow disease progression. However, there remains limited data on the efficacy, comparative effectiveness, and safety of these therapies. Therefore, we aim to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing TTR-specific therapies with placebo in patients with ATTR-CM.

Methods: We searched through Pubmed, Cochrane, and Embase databases. Our primary outcome was: (1) All Cause Mortality. We also performed a subgroup analysis comparing TTR stabilizers versus TTR knock-down therapies (RNA inhibitors and antisense oligonucleotides).

Results: Nine RCTs were included, involving 2,713 patients, of whom 1,160 (59.34%) were assigned to the TTR-specific therapies group. In the pooled analysis, TTR-specific therapies were associated with a significant reduction in all-cause mortality (RR 0.70; 95% CI 0.60, 0.83; p < 0.01; I² = 0%), with both TTR stabilizers and knock-down therapies showing equally effective reductions (p = 0.97). Additionally, TTR-specific therapies improved LV longitudinal strain (SMD - 0.22; 95% CI -0.34, -0.10; p < 0.01; I² = 17%) and reduced LV mass (SMD - 9.11 g; 95% CI -16.4 g, -1.82 g; p = 0.01; I² = 0%).

Conclusion: This meta-analysis highlights the potential of TTR-targeting therapies as an effective option for managing ATTR-CM, with significant improvements in survival. No efficacy differences were found between TTR stabilizers and knock-down therapies.

Keywords: Transthyretin cardiac amyloidosis; Transthyretin gene RNA inhibitors; Transthyretin gene antisense oligonucleotides; Transthyretin stabilizers.

Fig. 1

PRISMA Flow Diagram. PRISMA flow diagram of study screening and selection

Fig. 2

Forest Plot for All Cause Mortality. TTR-specific therapies showed a significant reduction in all-cause mortality compared to placebo. Abbreviations: CI: Confidence Interval; RR: Risk Ratio; TTR: Transthyretin

Fig. 3

A. Forest Plot for LV Longitudinal Strain. TTR-specific therapies significantly reduced LV longitudinal strain compared to placebo. Abbreviations: CI: Confidence Interval; SMD: Standardized Mean Difference; LV: Left Ventricle; TTR: Transthyretin. B. Forest Plots for LV Mass. TTR-specific therapies led to a consistent reduction in LV mass compared to placebo Abbreviations: CI: Confidence Interval; SMD: Standardized Mean Difference; LV: Left Ventricle; TTR: Transthyretin

Fig. 4

A. Forest Plot for CV Mortality. TTR-specific therapies did not show a statistically significant reduction in CV mortality compared to placebo. Abbreviations: CI: Confidence Interval; RR: Risk Ratio; CV: Cardiovascular; TTR: Transthyretin. B. Forest Plot for All Cause Hospitalization. There was no statistically significant difference in all-cause hospitalization between patients receiving TTR-specific therapies and placebo. Abbreviations: CI: Confidence Interval; RR: Risk Ratio; TTR: Transthyretin. C. Forest Plot for HF Hospitalization. TTR-specific therapies did not lead to a statistically significant difference in HF hospitalization compared to placebo. Abbreviations: CI: Confidence Interval; RR: Risk Ratio; HF: Heart Failure; TTR: Transthyretin

Fig. 5

Forest Plot for Subgroup analysis of All Cause Mortality. TTR knock-down therapies and TTR stabilizers showed an equally effective reduction in all-cause mortality compared to placebo. Abbreviations: CI: Confidence Interval; RR: Risk Ratio; TTR: Transthyretin