Transthyretin amyloid cardiomyopathy (ATTR-CM) is an under-recognized cause of heart failure, and is associated with poor prognosis. Although tafamidis stabilizes transthyretin and improves survival, the role of adjunctive heart failure therapies in this population remains uncertain.

To evaluate the association between contemporary pharmacotherapies, including sodium-glucose cotransporter 2 (SGLT2) inhibitors, mineralocorticoid receptor antagonists (MRAs), sacubitril/valsartan, glucagon-like peptide-1 (GLP-1) receptor agonists and beta-blockers, and clinical outcomes among tafamidis-treated patients with ATTR-CM.

We conducted a multicentre retrospective cohort study using the TriNetX Research Network. Adult patients with ATTR-CM who were prescribed tafamidis between 2019 and 2025 were included. Medication exposure was defined within 90 days of tafamidis initiation. Propensity score matching was applied for each drug class comparison. Outcomes included all-cause mortality, cardiovascular events, hospitalizations, emergency department visits and renal complications assessed at 1 and 5 years.

Among 5683 patients with tafamidis-treated ATTR-CM, the mean age was 78.1 years, and 81% were male. SGLT2 inhibitor use was associated with lower all-cause mortality at 1 and 5 years, with hazard ratios of 0.56 and 0.62, respectively, as well as lower rates of heart failure hospitalization and major adverse cardiovascular events at 5 years. MRAs were not associated with a mortality benefit, but were associated with higher risks of atrial fibrillation, acute kidney injury and emergency department visits. Sacubitril/valsartan was associated with lower rates of major adverse cardiovascular events and hospitalization at 5 years. GLP-1 receptor agonist use showed favourable trends in hospitalization-related outcomes, but the analysis was limited by the small sample size, and should be considered exploratory. Beta-blockers were associated with higher rates of adverse cardiovascular events and emergency department visits, without evidence of survival benefit. These adverse signals should be interpreted as hypothesis generating.

In tafamidis-treated patients with ATTR-CM, SGLT2 inhibitor use was associated with lower mortality and improved cardiovascular outcomes. In contrast, MRAs and beta-blockers were not associated with survival benefit, and showed unfavourable associations with morbidity and healthcare utilization. Sacubitril/valsartan and GLP-1 receptor agonists appeared safe, and showed favourable trends in selected outcomes. These findings require prospective confirmation before influencing clinical practice.