Efficacy of Tafamidis in Transthyretin Amyloid Cardiomyopathy in the ATTR-ACT Trial: Sensitivity Analyses Further Support the Primary Results

Introduction Transthyretin cardiomyopathy (ATTR-CM) is an underdiagnosed, fatal disease caused by the deposition of transthyretin amyloid fibrils in the heart leading to heart failure (HF). It can be hereditary due to mutations in the TTR gene (ATTRm) or acquired (wild-type [ATTRwt]). Tafamidis is a selective transthyretin stabilizer which prevents tetramer dissociation and amyloidogenesis. The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) was an international, multicenter, double-blind, placebo-controlled, randomized trial of Tafamidis in patients with ATTR-CM. Hypotheses Given the limited number of patients with ATTR-CM, a novel study design was utilized to enable rigorous testing of the efficacy of tafamidis on hard cardiovascular (CV) endpoints in a study of relatively modest size compared with traditional CV trials. The positive primary results of this trial will be further supported through the application of pre-specified sensitivity analyses. Methods Patients with ATTR-CM were randomized (2:1:2) to tafamidis (80 mg or 20 mg of tafamidis meglumine), or placebo (orally, once daily), for 30 months. Enrollment was stratified by NYHA class and genotype. Inclusion criteria were: history of HF; genetic testing for amyloid; transthyretin amyloid in biopsy tissue; interventricular septal wall thickness u003e 12 mm, plasma NT‑proBNP ≥600 pg/mL and 6-minute walk test distance u003e 100 m. Key exclusion criteria included: NYHA class IV; estimated glomerular filtration rate 2 ; concurrent use of some nonsteroidal anti-inflammatory drugs; and modified body mass index 2 ·g/L. The primary efficacy analysis was a hierarchical combination of all-cause mortality and frequency of CV-related hospitalizations comparing the pooled tafamidis groups (20 mg and 80 mg) vs. the placebo group using the Finkelstein–Schoenfeld (F-S) method. The primary efficacy analysis result was examined using a series of sensitivity analyses. Key secondary endpoints were change from baseline to Month 30 in the six-minute walk test distance and the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall score. Safety assessments included adverse events, vital signs, and clinical laboratory tests. Results A total of 441 patients were randomized (tafamidis = 264, placebo = 177). Tafamidis was associated with a significant reduction in the hierarchical combination of all-cause mortality and CV-related hospitalizations (P Conclusions ATTR-ACT, the largest randomized controlled trial in ATTR-CM, showed that tafamidis is the first treatment to improve survival and quality of life in ATTR-CM. Significant and clinically meaningful improvements were observed in functional capacity as measured by the six-minute walk distance and quality of life by KCCQ overall score. Sensitivity analyses confirmed the robustness of these results. Tafamidis was safe and well tolerated. The primary trial results, along with the sensitivity analyses described here, provide strong rationale for the use of tafamidis as first-line therapy in ATTR-CM.