Impact of Tafamidis on Transthyretin Concentration and Its Relation to All-Cause Mortality in Patients with Transthyretin Amyloid Cardiomyopathy: An Analysis from ATTR-ACT

INTRODUCTION: Tafamidis is approved to treat transthyretin amyloid cardiomyopathy (ATTR-CM) on the basis of results of the phase 3 study ATTR-ACT. This post hoc analysis from ATTR-ACT evaluated the effect of tafamidis on transthyretin (TTR) concentration and explored the potential relationship between changes in TTR concentration at month 1 (early ΔTTR) and all-cause mortality (ACM). METHODS: Patients with ATTR-CM treated with tafamidis 80 mg or placebo in ATTR-ACT who survived until month 1 were included. The independent association between early ΔTTR and ACM at month 30 was evaluated using univariate analyses, including a logistic model for ACM incidence and a Cox model for time to ACM. Baseline variables significantly influencing this relationship were identified using backward selection and included as covariates (baseline TTR concentration and National Amyloidosis Centre stage) in a multivariable Cox model. RESULTS: Tafamidis 80 mg produced a 36.3% mean increase in TTR concentration by month 1 (mean [SD] change 7.3 [3.9] mg/dL) that was sustained through month 30, whereas placebo showed minimal change at month 1 (mean change [SD] - 0.02 [2.9] mg/dL) and throughout the study period. Logistic regression showed early ΔTTR was associated with reduced odds of ACM by month 30 only in patients treated with tafamidis; every 5 mg/dL increase correlated with a 45.0% reduction in odds of ACM (p = 0.0193). In univariate analysis, every 1 mg/dL increase in TTR concentration at month 1 in patients treated with tafamidis was associated with a 9.3% hazard reduction in ACM (hazard ratio 0.907; 95% CI 0.837-0.983, p = 0.0174). Multivariable analysis showed an 8.7% reduction in hazard of ACM for each 1 mg/dL increase. CONCLUSIONS: Tafamidis was associated with an early increase in TTR concentration that was sustained through month 30, and early increases correlated with reduced ACM. However, mechanisms underlying TTR concentration increases and their clinical significance remain unclear. Graphical abstract available for this article. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01994889.