Amyloid transthyretin cardiomyopathy (ATTR-CM) is a progressive and life-threatening disorder caused by the misfolding and deposition of transthyretin (TTR) amyloid fibrils in the myocardium, leading to restrictive cardiomyopathy, heart failure, and increased mortality.1,2 The clinical burden of ATTR-CM has become increasingly recognized due to advancements in diagnostic imaging and the availability of targeted therapies.3,4 Patients with ATTR-CM experience progressively debilitating symptoms, leading to significant morbidity and a median survival of 2 to 6 years after diagnosis.5

The pathophysiology of ATTR-CM is driven by the misfolding of TTR proteins, leading to amyloid fibril deposition within the myocardium. This process results in increased myocardial stiffness, impaired diastolic function, and eventual restrictive cardiomyopathy.1,6 By silencing hepatic TTR mRNA, RNAi therapies effectively reduce circulating TTR levels, thereby decreasing the substrate available for amyloid formation7 This mechanism of action provides a strong theoretical basis for the observed reduction in cardiac adverse events, and may be related to improved myocardial compliance, reduced amyloid infiltration, and preserved ventricular function.8, 9, 10 Additionally, emerging preclinical data suggest that lowering TTR levels may facilitate the clearance of existing amyloid deposits by endogenous mechanisms, such as macrophage-mediated phagocytosis.11, 12, 13, 14, 15

If confirmed in long-term studies, this could represent a crucial advantage of RNAi therapy, potentially leading to disease regression rather than merely stabilization. While previous studies have demonstrated that RNAi therapies lower serum TTR levels and may offer cardioprotective benefits, the overall efficacy and efficiency of these treatments require further investigation.16,7,17

This systematic review and meta-analysis represent the first comprehensive synthesis of evidence on RNA-targeting therapies for ATTR-CM. By pooling data from randomized controlled trials, we assess the efficacy and efficiency of these treatments in reducing mortality and adverse cardiac outcomes. Our findings provide a foundation for clinical decision-making and contribute to the understanding of RNAi therapies as a therapeutic strategy for ATTR-CM.