Which therapy performs best across clinical domains in transthyretin amyloid cardiomyopathy? a frequentist network meta-analysis

Background Disease-modifying therapies for transthyretin amyloid cardiomyopathy include transthyretin stabilisers and gene silencers, but whether any single treatment provides consistent benefit across clinically relevant domains remains uncertain. We performed a network meta-analysis to compare outcome-specific treatment effects across survival, functional capacity, cardiac biomarkers, and patient-reported health status. Purpose To determine which therapy performs best across clinical domains in transthyretin amyloid cardiomyopathy using a frequentist network meta-analysis. Methods PubMed, Embase, and Cochrane CENTRAL were searched through August 2025 for randomised controlled trials enrolling patients with transthyretin amyloid cardiomyopathy. A frequentist network meta-analysis estimated standardised mean differences (SMD) or risk ratios (RR) with 95% confidence intervals (CI) versus placebo. Prespecified domains were functional capacity (6-minute walk distance), health status (Kansas City Cardiomyopathy Questionnaire overall summary score), biomarkers (N-terminal pro-B-type natriuretic peptide and troponin I), and survival (all-cause death). Transthyretin reduction and additional clinical events were assessed as exploratory outcomes. Treatment ranking was evaluated across domains to identify whether any therapy consistently outperformed the others. Results Seven trials, including 2,494 patients, were analysed. No therapy consistently led all endpoints, supporting domain-specific heterogeneity. Vutrisiran showed the strongest biomarker and functional profile, with greater reductions in troponin I (SMD -3.65, 95% CI -3.90 to -3.40) and N-terminal pro-B-type natriuretic peptide (SMD -0.55, 95% CI -0.71 to -0.39), together with the largest improvement in 6-minute walk distance (SMD 0.53, 95% CI 0.24 to 0.82). Tafamidis showed the greatest improvement in health status, measured by Kansas City Cardiomyopathy Questionnaire overall summary score (SMD 0.62, 95% CI 0.43 to 0.82), and was the only therapy associated with a significant reduction in all-cause death versus placebo (RR 0.70, 95% CI 0.54 to 0.90). Patisiran showed favourable but less consistent signals across domains. Exploratory analyses of transthyretin reduction and non-fatal clinical events reinforced treatment heterogeneity and did not identify a universal winner. Conclusion(s) In transthyretin amyloid cardiomyopathy, treatment benefit appears domain-specific rather than uniform. Vutrisiran preferentially improves biomarker burden and functional capacity, whereas tafamidis provides the clearest benefit for patient-reported health status and survival. These findings support phenotype- and goal-directed treatment selection according to therapeutic priority, rather than assuming universal superiority of any single therapy.