Abstract Body (Do not enter title and authors here): Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, life-threatening disorder caused by transthyretin deposition in cardiac tissue. Tafamidis, Acoramidis, and Vutrisiran are FDA-approved agents targeting different disease mechanisms. In the absence of head-to-head trials, this network meta-analysis compares their efficacy and safety.

Methods: A systematic search across five databases identified relevant randomized controlled trials (RCTs). Network meta-analysis was conducted using the Netmeta package in R, with visualization in Stata 18.0. Study quality was assessed using the ROB 2.0 tool.

Results: Thirty-five RCTs (n = 5,721) included: Vutrisiran (n = 1,132), Acoramidis (n = 1,056), Tafamidis (n = 1,036), Patisiran (n = 254) (Used as Placebo in some RCTs), and placebo (n = 1,958). Vutrisiran showed the best survival benefit (ORs: 0.20 [0.03–1.27] to 0.53 [0.26–1.05]), followed by Acoramidis (ORs: 0.34 [0.13–0.90] to 0.75 [0.50–1.14]) and Tafamidis (ORs: 0.18 [0.03–1.15] to 7.26 [3.54–14.90]). Patisiran outperformed Tafamidis (OR 1.79 [1.21–2.67]) but not Vutrisiran (OR 2.43 [0.40–14.90]). SUCRA ranked Tafamidis highest, placebo, Acoramidis, and Vutrisiran. Mortality risk reduction was greatest with Vutrisiran (RR 0.04 [0.02–0.06]), followed by Acoramidis (RR 0.13 [0.05–0.31]) and Tafamidis (RR 0.27 [0.01–0.54]). In the 6-minute walk test, Acoramidis improved most (mean 9.55 [1.33–20.43]), followed by Vutrisiran (mean 2.51 [2.13–2.89]) and Tafamidis (mean 1.45 [1.00–3.90]). Vutrisiran had the lowest rehospitalization rate (mean −2.12 [−2.44 to −1.79]), then Tafamidis (mean −0.85 [−1.03 to −0.66]), while Acoramidis increased risk (RR 1.23 [0.79–1.68]). Vutrisiran reduced NT-proBNP most (mean 0.98 [0.73–1.07]), followed by Tafamidis (mean 0.68 [−1.58 to 3.25]) and Acoramidis (mean 0.41 [−2.72 to 3.50]). Stroke volume improved most with Vutrisiran (mean 2.90 [2.70–3.10]), followed by Acoramidis (mean 1.67 [1.49–1.85]) and Tafamidis (mean 1.20 [0.11–2.51]). HRQOL changes were modest for Acoramidis (mean −6.43 [−15.11 to 2.25]) and Tafamidis (mean −6.69 [−17.01 to 30.39]), with no data for Vutrisiran. Risk of bias was low across studies.

Conclusion: Vutrisiran demonstrated the most consistent survival and biomarker benefits, while Patisiran ranked highest in overall efficacy. Acoramidis showed strong improvement in functional capacity but varied across domains.