Long-Term Survival With Tafamidis in Patients With Transthyretin Amyloid Cardiomyopathy

Abstract

Background: Tafamidis is approved in many countries for the treatment of transthyretin amyloid cardiomyopathy. This study reports data on the long-term efficacy of tafamidis from an ongoing long-term extension (LTE) to the pivotal ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial).

Methods: Patients with transthyretin amyloid cardiomyopathy who completed ATTR-ACT could enroll in an LTE, continuing with the same tafamidis dose or, if previously treated with placebo, randomized (2:1) to tafamidis meglumine 80 or 20 mg. All patients in the LTE transitioned to tafamidis free acid 61 mg (bioequivalent to tafamidis meglumine 80 mg) following a protocol amendment. In this interim analysis, all-cause mortality was assessed in patients treated with tafamidis meglumine 80 mg in ATTR-ACT continuing in the LTE, compared with those receiving placebo in ATTR-ACT transitioning to tafamidis in the LTE.

Results: Median follow-up was 58.5 months in the continuous tafamidis group (n=176) and 57.1 months in the placebo to tafamidis group (n=177). There were 79 (44.9%) deaths with continuous tafamidis and 111 (62.7%) with placebo to tafamidis (hazard ratio, 0.59 [95% CI, 0.44-0.79]; P<0.001). Mortality was also reduced in the continuous tafamidis (versus placebo to tafamidis) subgroups of: variant transthyretin amyloidosis (0.57 [0.33-0.99]; P=0.05) and wild-type transthyretin amyloidosis (0.61 [0.43-0.87]; P=0.006); and baseline New York Heart Association class I and II (0.56 [0.38-0.82]; P=0.003) and class III (0.65 [0.41-1.01]; P=0.06).

Conclusions: In the LTE, patients initially treated with tafamidis in ATTR-ACT had substantially better survival than those first treated with placebo, highlighting the importance of early diagnosis and treatment in transthyretin amyloid cardiomyopathy. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01994889 and NCT02791230.

Keywords: amyloid; cardiomyopathies; heart failure; mutation; phenotype.

Figure 1.

Patients in ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial) and the long-term extension (LTE) in this analysis. Showing the treatment groups (continuous tafamidis and placebo to tafamidis) in ATTR-ACT and the LTE included in this analysis. After 30 months of treatment in ATTR-ACT, patients treated with tafamidis 80 mg could continue in the LTE on the same dose of tafamidis, and patients treated with placebo were randomized (2:1) to tafamidis 80 or 20 mg in the LTE. A total of 110 patients treated with tafamidis 80 mg continued in the LTE. A total of 82 placebo-treated patients continued in the LTE. Following a protocol amendment on July 20, 2018, all patients transitioned to tafamidis free acid 61 mg (bioequivalent to tafamidis 80 mg). ATTR-ACT also included a treatment arm for tafamidis 20 mg, which was not included in this analysis.

Figure 2.

Kaplan–Meier plot of observed time to all-cause mortality in ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial) and the long-term extension (LTE) and compared with model-based extrapolation of time to all-cause mortality with placebo. Time to all-cause mortality (with heart transplant and implantation of a cardiac mechanical assist device treated as death) shown for all patients treated with tafamidis 80 mg in ATTR-ACT continuing with tafamidis 80 mg, then tafamidis free acid 61 mg in the LTE (continuous tafamidis) compared with patients treated with placebo in ATTR-ACT continuing with tafamidis (20, 80, or 61 mg) in the LTE (placebo to tafamidis). The extrapolated placebo curve (dotted line) is a model-based extrapolation of survival in placebo-treated patients in ATTR-ACT beyond 30 months. Data cutoff: March 20, 2020.