Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy

TLDR

Transthyretin amyloid cardiomyopathy results from deposition of transthyretin amyloid fibrils in the myocardium when wild‑type or variant transthyretin misfolds, and tafamidis binds transthyretin to prevent tetramer dissociation and amyloidogenesis. In a multicenter, double‑blind, placebo‑controlled phase 3 trial, 441 patients were randomized 2:1:2 to receive 80 mg, 20 mg, or placebo tafamidis for 30 months, with primary analysis hierarchically assessing all‑cause mortality and cardiovascular‑related hospitalizations via the Finkelstein‑Schoenfeld method and secondary endpoints including changes in the 6‑minute walk test and KCCQ‑OS scores. Tafamidis reduced all‑cause mortality (29.5 % vs. 42.9 %, HR 0.70) and cardiovascular‑related hospitalizations (RR 0.68), slowed decline in 6‑minute walk distance and KCCQ‑OS scores, and had a similar adverse‑event profile compared with placebo.

Abstract

Transthyretin amyloid cardiomyopathy is caused by the deposition of transthyretin amyloid fibrils in the myocardium. The deposition occurs when wild-type or variant transthyretin becomes unstable and misfolds. Tafamidis binds to transthyretin, preventing tetramer dissociation and amyloidogenesis.In a multicenter, international, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 441 patients with transthyretin amyloid cardiomyopathy in a 2:1:2 ratio to receive 80 mg of tafamidis, 20 mg of tafamidis, or placebo for 30 months. In the primary analysis, we hierarchically assessed all-cause mortality, followed by frequency of cardiovascular-related hospitalizations according to the Finkelstein-Schoenfeld method. Key secondary end points were the change from baseline to month 30 for the 6-minute walk test and the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS), in which higher scores indicate better health status.In the primary analysis, all-cause mortality and rates of cardiovascular-related hospitalizations were lower among the 264 patients who received tafamidis than among the 177 patients who received placebo (P<0.001). Tafamidis was associated with lower all-cause mortality than placebo (78 of 264 [29.5%] vs. 76 of 177 [42.9%]; hazard ratio, 0.70; 95% confidence interval [CI], 0.51 to 0.96) and a lower rate of cardiovascular-related hospitalizations, with a relative risk ratio of 0.68 (0.48 per year vs. 0.70 per year; 95% CI, 0.56 to 0.81). At month 30, tafamidis was also associated with a lower rate of decline in distance for the 6-minute walk test (P<0.001) and a lower rate of decline in KCCQ-OS score (P<0.001). The incidence and types of adverse events were similar in the two groups.In patients with transthyretin amyloid cardiomyopathy, tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo. (Funded by Pfizer; ATTR-ACT ClinicalTrials.gov number, NCT01994889 . ).