Long-term Survival Benefit of Tafamidis in Patients with Transthyretin Amyloid Cardiomyopathy

Abstract

Introduction In the pivotal ATTR-ACT study, tafamidis was associated with a 30% lower mortality risk than placebo (PBO) in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) over 30 months. Because patients receiving PBO in ATTR-ACT switched to tafamidis in the ongoing, open-label long-term extension (LTE), the long-term efficacy of tafamidis cannot be directly compared with PBO. A statistical extrapolation method has been used to estimate between-group differences in survival beyond the 30-month trial duration. Hypothesis Comparing observed long-term survival with tafamidis in the LTE with estimated survival with PBO extrapolated from ATTR-ACT will allow fuller assessment of tafamidis survival benefits. Methods In ATTR-ACT, patients with ATTR-CM received tafamidis (80 or 20 mg) or PBO for 30 months. In the LTE, patients previously receiving tafamidis continued on the same tafamidis dose, and those previously receiving PBO were randomized to tafamidis 80 mg or 20 mg. Based on a protocol amendment (July 20, 2018), all patients in the LTE transitioned to tafamidis free acid 61 mg (bioequivalent to tafamidis 80 mg). All-cause mortality was assessed using a Cox proportional hazards model for tafamidis 80/61 mg or PBO/tafamidis in ATTR-ACT/LTE. A gamma model based on patient-level data for the PBO group in ATTR-ACT and best model fitting criteria (AIC, BIC) was used to extrapolate survival beyond 30 months. Results In this interim analysis of all-cause mortality, 75/176 (42.6%) and 108/177 (61.0%) patients in the tafamidis 80/61 mg and PBO/tafamidis groups, respectively, died (median follow-up: 51.9 and 51.4 months). Long-term continuous tafamidis treatment was superior to PBO/tafamidis treatment (Figure). Mortality risk was reduced by 41.1% with tafamidis 80/61 mg (n = 176) vs PBO/tafamidis (n = 177) (hazard ratio, 0.5888 [95% CI: 0.4370-0.7931]; P = 0.0004). In the extrapolated PBO group, the estimated median overall survival was 35.2 months, vs 35.8 months in the observed PBO/tafamidis group. The curves for PBO/tafamidis and estimated PBO diverged after ∼44 months in favor of tafamidis. Conclusions Extrapolation of PBO data from ATTR-ACT was a valuable tool allowing comparison of potential outcomes with and without tafamidis treatment. Although these extrapolated data suggest that delayed initiation of tafamidis may provide some survival benefit, early continuous treatment with tafamidis results in significantly better survival outcomes in patients with ATTR-CM.