Cardiac presentation and treatment response by sex in patients with transthyretin amyloidosis: pooled analysis of vutrisiran and patisiran phase 3 studies

Background Transthyretin (TTR) amyloidosis (ATTR) is a progressive disease caused by misfolded TTR accumulating as amyloid deposits in the heart and nerves, leading to cardiomyopathy (CM) and polyneuropathy (PN). Cardiac involvement is associated with high morbidity, mortality and impaired quality of life. Although sex influences clinical presentation and outcomes across cardiovascular diseases, women remain underrepresented, underdiagnosed and undertreated in ATTR. The RNA interference therapeutics vutrisiran and patisiran decrease hepatic TTR synthesis, reducing formation/deposition of amyloid fibrils. Phase 3 trials have demonstrated their clinical benefit, but comprehensive sex-stratified analyses remain an unmet need. Pooling pivotal study data from female patients can advance our understanding of sex differences and inform treatment management strategies. Purpose To evaluate cardiac presentation and treatment response by sex in patients with hereditary or wild-type ATTR in pooled vutrisiran and patisiran Phase 3 studies. Methods Data were included from patients who received vutrisiran, patisiran or placebo in Phase 3 studies (ATTR-CM: HELIOS-B, APOLLO-B; hereditary ATTR-PN: HELIOS-A, APOLLO). Baseline characteristics were compared between sexes. Treatment effect of vutrisiran/patisiran vs placebo was analysed using a one-stage meta-analysis of individual patient data with a common fixed effect for treatment. Cox proportional hazards models were used in analysing all-cause mortality (ACM) and mixed models for repeated measures in analysing change from baseline in NT-proBNP and echocardiographic measures. For NT-proBNP, data were log-transformed. Results Overall, 203 females and 1199 males were included in the analysis. Females were more likely to have hereditary ATTR than males (p<0.0001); this difference may represent a significant confounding factor. At baseline, statistically significant differences were observed between sexes with females having worse Kansas City Cardiomyopathy Questionnaire Overall Score (p=0.0029), worse E/e’ (p=0.0156), and less impaired global longitudinal strain (p<0.0001) (Table 1). The benefits of vutrisiran/patisiran vs placebo on ACM, NT-proBNP, LV mean wall thickness indexed to height, peak longitudinal strain and average E/e’ were generally consistent between sexes; treatment effect on LV ejection fraction was higher in females (Figure 1). Conclusion In this pooled analysis of ATTR clinical studies, some baseline findings suggest more advanced disease in females vs males, despite relatively preserved myocardial function. Regardless of baseline differences, the pooled treatment effect of vutrisiran/patisiran versus placebo was generally consistent across sexes, supporting their potential for broad therapeutic applicability. Additional efforts are needed to improve earlier recognition of ATTR in women.