Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and challenging disease characterized by deposition of misfolded transthyretin (TTR) protein in the myocardial interstitium. Until recently, treatment options for ATTR-CM were limited, with tafamidis emerging as the primary therapeutic agent targeting the stabilization of TTR tetramers to prevent amyloid fibril formation. However, advancements in understanding the underlying mechanisms of ATTR-CM have led to developing novel therapeutic strategies to address various aspects of the disease process. This review explores current therapeutic options for treating ATTR-CM. It encompasses strategies ranging from inhibiting TTR synthesis using RNA silencing methods, such as small interfering RNA (siRNA
e.g., the HELIOS-B trial with vutrisiran), antisense oligonucleotides (ASO
e.g., the CARDIO-TTRansform trial with eplontersen), and gene-editing technologies such as CRISPR/Cas9 (e.g., the MAGNITUDE trial with NTLA-2001). Additionally, it explores TTR stabilization approaches beyond tafamidis, such as next-generation acoramidis, which showed success in the ATTRibute-CM trial. It also examines therapies promoting TTR degradation and removal, which includes the use of monoclonal antibodies (e.g., DepleTTR-CM with ALXN2220) and other compounds, such as doxycycline or epigallocatechin-3-gallate (a green tea component), which, despite long-standing recognition, remain underexplored. Novel approaches, such as seeding inhibitors and molecular tweezers, which aim to inhibit TTR fibril formation, are also discussed as potential future management strategies. The review further highlights the role of ongoing clinical trials in evaluating the efficacy and safety of these innovative therapies, emphasizing their potential to expand treatment options and improve outcomes for patients with ATTR-CM. Advancements in supportive therapies are also discussed to offer a comprehensive overview of the evolving therapeutic landscape.