Tafamidis non-responders in cardiac amyloidosis: clinical characterization of a real-world cohort
I Cruz, R B Ventura, M J Primo, D Martinez, V Lopes, J Rosa, L Leite, M J Ferreira, L GoncalvesAbstract
Background
Tafamidis is the standard disease-modifying therapy for transthyretin cardiac amyloidosis, yet real-world cohorts show substantial heterogeneous treatment response. Characterizing non-responders may improve risk stratification, follow-up planning and therapeutic decision-making.
Objective
To characterize Tafamidis non-responders at 12 months according to a composite definition integrating NYHA class, NT-proBNP, and echocardiographic parameters.
Methods
We conducted a single-centre observational study including 49 consecutive patients who initiated Tafamidis between February 2022 and June 2025. Non-response at 12 months was defined by the presence of ≥1 of the following criteria: worsening NYHA class, NT-proBNP increase ≥15%, or structural echocardiographic deterioration (left ventricular ejection fraction decrease ≥5%, ventricular wall thickness increase ≥1 mm, global longitudinal strain worsening ≥2 points, or left atrial (LA) volume index increase ≥10 mL/m²). Tafamidis discontinuation, heart failure (HF) hospitalization and all-cause mortality were also assessed.
Results
Twenty-four patients (49%) were classified as non-responders (mean age 78.3±10.3 years, 75% male). Cardiovascular risk factors were highly prevalent: hypertension (83%), dyslipidaemia (58%), and atrial fibrillation (67%). Structural heart disease, predominantly moderate-to-severe aortic stenosis, was present in 13%. Baseline NYHA class was mainly II (62.5%), with median NT-proBNP of 2608.5 pg/mL (IQR 1600.5–4426.3). Baseline echocardiography demonstrated mean LVEF was 47.2% ± 12.1%, interventricular septal thickness 18.3 ± 3.0 mm, posterior wall 14.2 ± 2.3 mm, LA volume index 49.4 ± 12.5 mL/m² and E/e′ 16.0 ± 5.9. Median time from diagnosis to Tafamidis initiation was 94.5 days (IQR 39.5–259.8). After 12 months of treatment, one-third of patients demonstrated NYHA class deterioration, while NT-proBNP increased in 50%, with a median rise of 12.9% (IQR 10.2–29.4%). Echocardiographic progression occurred in 29% of reassessed patients, mainly due to LA enlargement. Overall, 8.3% discontinued Tafamidis owing to deterioration in functional or general status, 33.3% required HF hospitalization, and 12.5% died within 12 months.
Conclusion
Nearly half of the patients met criteria for non-response at 12 months, underscoring the need for improved patient selection and closer follow-up strategies. Tafamidis non-responders showed an adverse profile characterized by advanced age, high comorbidity burden, and high rates of short-term events. Further studies are warranted to clarify the clinical impact of delayed treatment initiation.For image description, please refer to the figure legend and surrounding text.