Abstract
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.
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 primary results of this trial were further supported through the application of pre-specified sensitivity analyses.
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. 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.
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 CVrelated hospitalizations (P<0.001). Tafamidis also significantly reduced the decline in both the six-minute walk distance (by 75.68 m [standard error, 9.24]; P<0.001]), and KCCQ overall score (by 13.65 [2.13]; P<0.001) as compared with placebo. Sensitivity analyses consistently confirmed the efficacy of tafamidis in patients with ATTR-CM: there was a 30% reduction in risk of all-cause mortality (heart transplant and implantation of a cardiac mechanical assist device treated as death) with tafamidis compared with placebo (P=0.0259); and when heart transplant and implantation of a cardiac mechanical assist device were not treated as death, there was a 33% reduction in risk of all-cause mortality with tafamidis compared with placebo (P=0.018). Tafamidis was safe and well tolerated in this population.
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.