Age-dependent sex differences and tafamidis treatment-associated outcomes in transthyretin wild-type cardiac amyloidosis: a nationwide multicenter study

Background Sex differences in transthyretin wild-type cardiac amyloidosis (ATTRwt) are increasingly recognized, yet their interaction with aging, myocardial remodeling kinetics, and therapeutic response remains incompletely defined. Objectives To characterize age-dependent sex differences in phenotype, longitudinal remodeling trajectories, and treatment-associated survival in ATTRwt. Methods We analyzed 4,049 patients with ATTRwt across 30 French referral centers. Women represented 17% of the cohort (n=687). Baseline phenotype was evaluated according to sex and age strata. Longitudinal changes in septal thickness, left ventricular ejection fraction (LVEF), and global longitudinal strain (GLS) were modeled using linear mixed-effects models including sex × age and sex × time interactions. Mortality was assessed using multivariable Cox proportional hazards models adjusted for age, cardiovascular risk factors, baseline NT-proBNP, and disease-modifying therapy (modeled as time-dependent). Absolute risk reductions (ARR) and number needed to treat (NNT) were derived from Kaplan–Meier estimates at 24 months. Results Women were older at diagnosis (+3.8 years, p<0.001) and exhibited less advanced myocardial remodeling (septal thickness −1.4 mm; GLS +1.6%; both p<0.01). Significant sex × age interactions were observed (p=0.021), indicating that phenotypic differences widened with advancing age. Longitudinally, women demonstrated slower structural progression (+0.12 mm/year vs +0.21 mm/year in men; p-interaction=0.018) and attenuated GLS decline (−0.25%/year vs −0.48%/year; p-interaction=0.024), consistent with distinct remodeling kinetics(Figure1and2). Treatment allocation differed modestly by sex (p=0.001), with women slightly less represented among treated patients. Overall, disease-modifying therapy—primarily tafamidis—was associated with reduced mortality (adjusted HR 0.72 [95% CI 0.61–0.85], p<0.001). At 24 months, mortality was 18% in untreated patients versus 13% in treated patients (ARR 5%; NNT=20). Treatment benefit was consistent in women (HR 0.69; ARR 6%; NNT=17) and men (HR 0.74; ARR 4%; NNT=25), with no significant sex × treatment interaction (p=0.41). Notably, benefit was more pronounced in patients <80 years (HR 0.63; ARR 7%; NNT=14) compared with ≥80 years (HR 0.81; ARR 3%; NNT=33; p-interaction=0.048). Conclusions Sex differences in ATTRwt are age-dependent and reflect distinct myocardial remodeling trajectories rather than intrinsic differences in treatment response. Despite underrepresentation and modest disparities in treatment allocation, women derive comparable survival benefit from disease-modifying therapy. The greater absolute benefit observed in younger patients underscores the importance of early, age-informed therapeutic initiation across sexes.