RNA-targeting therapies for amyloid transthyretin cardiomyopathy: A systematic review and meta-analysis

Abstract

Introduction: Amyloid transthyretin (TTR) cardiomyopathy is a progressive disease caused by TTR amyloid deposition, leading to heart failure and mortality. RNA interference (RNAi) therapies reduce amyloid formation by silencing hepatic TTR mRNA. This meta-analysis evaluates their efficacy and safety.

Methods: A systematic search conducted in February 2025 in Cochrane Central, PubMed, and Embase identified RCTs comparing RNAi therapies with placebo. Primary outcomes were all-cause mortality and cardiac adverse events. Safety outcomes included any adverse events and serious cardiac adverse events. A leave-one-out sensitivity analysis assessed robustness. Statistical analyses used inverse-variance common-effects and DerSimonian-Laird random-effects models. Heterogeneity was evaluated using REML and I² statistics, with 95 % confidence intervals (CI).

Results: Three RCTs (1,199 patients) met inclusion criteria. RNAi therapy did not significantly reduce all-cause mortality (OR 0.97; 95 % CI 0.26-3.62; I² 72.4 %). However, excluding the ENDEAVOR trial, mortality reduction was significant (OR 0.65; 95 % CI 0.45-0.95; I² 0 %). RNAi therapy reduced cardiac adverse events in pooled (OR 0.72; 95 % CI 0.57-0.90; I² 38 %) and subgroup analyses (OR 0.66; 95 % CI 0.51-0.84; I² 0 %). No significant differences were found in serious cardiac adverse events (OR 0.98; 95 % CI 0.77-1.27; I² 0 %). Safety analyses showed no increase in overall adverse events (OR 0.78; 95 % CI 0.42-1.44; I² 49.8 %).

Conclusion: RNAi therapies reduce cardiac adverse events and may improve survival in selected patients. Further studies should refine patient selection and assess long-term outcomes.

Keywords: Amyloid Transthyretin Cardiomyopathy; Cardiomyopathies; Meta-Analysis; RNA Interference Therapy; Systematic Review; Transthyretin Amyloidosis.