Background <p>Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive cause of heart failure in an elderly and multimorbid population. Although tafamidis improves clinical outcomes, its real-world effectiveness relies on long-term treatment persistence, which may be compromised by therapeutic complexity and drug-related issues. Evidence on integrated care models addressing these challenges in routine cardiology practice remains limited.</p> Aims <p>Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) treated with tafamidis are typically elderly, multimorbid, and exposed to high pharmacological complexity, which may compromise long-term treatment persistence and safety. We aimed to characterize the therapeutic complexity and pharmacological profile of a real-world ATTR-CM population and to evaluate the association between a structured telepharmacy-supported multidisciplinary management model and medication adherence, treatment persistence, and clinical outcomes.</p> Methods and results <p>We conducted a retrospective observational study including 125 patients with ATTR-CM treated with tafamidis between December 2021 and December 2024. Ninety-seven patients received at least one structured telepharmacy consultation, while 28 patients received standard cardiology care alone. Baseline disease severity was assessed using New York Heart Association (NYHA) class and National Amyloidosis Centre (NAC) staging. The study population is limited to patients in NYHA class I–II, as per Italian reimbursement criteria which require treatment discontinuation upon progression to NYHA class III–IV.&#xa0;Adherence and the composite outcome were assessed for all patients, while therapeutic complexity and drug-drug interactions were systematically evaluated only in the telepharmacy group, as these assessments were part of the intervention and not available for controls from the Italian Medicines Agency (AIFA) registry.&#xa0;Patients in the telepharmacy group exhibited high therapeutic complexity, with a median Medication Regimen Complexity Index (MRCI) of 15 (interquartile range [IQR] 12–19), and frequent clinically relevant drug-drug interactions. Despite a significantly longer observation period, adherence remained excellent in telepharmacy-managed patients (median proportion of days covered 95.2%, IQR 92.7–97.5). Over follow-up, telepharmacy support was associated with a lower incidence of the composite endpoint of treatment discontinuation for clinical decision or all-cause death. Kaplan–Meier analysis showed early and sustained separation of event-free probability curves, and Cox regression adjusted for age and NAC stage confirmed an independent association between telepharmacy management and reduced risk of the composite endpoint.</p> Conclusions <p>In this real-world cohort of patients with early-stage ATTR-CM (NYHA class I-II), a multidisciplinary care model including telepharmacy was associated with more favorable tafamidis persistence and clinical outcomes compared to standard care in exploratory analyses. These findings suggest that integrating structured pharmacological surveillance into cardiology pathways may support long-term disease-modifying therapy management. Given the observational, non-randomized design, the small control group, and the incomplete data for controls, these results are preliminary and hypothesis-generating; they require confirmation in larger, prospective studies with balanced comparator groups.</p> Graphical Abstract <p></p>