Efficacy of Tafamidis by Baseline 6-minute Walk Test Distance in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT)

Abstract

Introduction Tafamidis significantly reduced all-cause mortality and cardiovascular (CV)-related hospitalizations in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). The effect of tafamidis treatment was more pronounced in patients who were NYHA class I or II at baseline than in patients who were NYHA class III. However, NYHA class can be an imperfect measure of disease severity. The 6-minute walk test (6MWT), a measure of functional capacity, was identified as a predictor of overall survival in patients with ATTR-CM. Hypothesis Understanding the effect of tafamidis treatment in patients by functional capacity, as assessed by baseline 6MWT distance, will provide new data on measures of baseline disease severity and the efficacy of tafamidis. Methods In ATTR-ACT, adult patients with ATTR-CM were randomized to tafamidis (n=264) or placebo (n=177) for 30 months. Patients with 6MWT distance Results The improvement with tafamidis in the primary outcome (win ratio [95% CI]) was more pronounced in patients with a greater baseline 6MWT distance: Q1, 1.15 (0.71, 1.87); Q2, 1.48 (0.88, 2.49); Q3, 1.78 (0.95, 3.31); Q4, 2.56 (1.36, 4.84). Overall, all-cause mortality was higher in the shorter baseline 6MWT quartiles. Tafamidis significantly reduced the decline in 6MWT distance (LS mean difference [95% CI] from placebo) with minimal difference between quartiles: Q1, 73.4 (23.9, 122.9); Q2, 58.3 (0.4, 116.2); Q3, 78.2 (41.2, 115.2); Q4, 92.0 (49.2, 134.8). The reduction in the overall decline in KCCQ-OS score with tafamidis (vs placebo) was more pronounced in patients with greater baseline 6MWT distance (LS mean difference [95% CI]): Q1, 8.5 (-0.7, 17.7); Q2, 11.3 (-1.4, 24.0); Q3, 19.9 (10.7, 29.1); Q4, 15.1 (8.6, 21.6). Conclusions Tafamidis reduces all-cause mortality and CV-related hospitalizations, and the decline in functional capacity and health-related quality of life, in all patients with ATTR-CM. The reduction in disease progression with tafamidis was observed across all quartiles; however, it was more pronounced in patients with a greater baseline 6MWT distance. These data highlight the importance of early diagnosis and treatment.