1169Interim analysis of data from a long-term, extension trial of tafamidis meglumine in patients with transthyretin amyloid cardiomyopathy

Abstract

Background Transthyretin amyloid cardiomyopathy (ATTR-CM), is an underdiagnosed, fatal disease caused by the deposition of transthyretin amyloid fibrils in the heart leading to heart failure. The Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), an international, multi-center, double-blind, placebo-controlled, randomized study, demonstrated the efficacy and safety of tafamidis treatment for patients with ATTR-CM due to variant (ATTRm) or wild-type (ATTRwt) TTR. Purpose This is a pooled analysis of data from ATTR-ACT and interim data from the ongoing, long-term, extension study to evaluate longer term data on the efficacy of tafamidis in patients with ATTR-CM. Methods Patients who completed ATTR-ACT (which had a duration of 30 months) were eligible to be enrolled in a long-term, extension study in which patients either continued to receive tafamidis meglumine at the same dose (the tafamidis/tafamidis [T/T] group) or, for patients previously treated with placebo, were randomised (in a 1:2 ratio) to tafamidis meglumine 20 mg or 80 mg (the placebo/tafamidis [P/T] group) for up to 60 months. The primary efficacy outcome was all-cause mortality. This analysis combined data from the completed ATTR-ACT with interim data from the extension study (cut-off date: 15 Feb, 2018), and included patients treated with tafamidis meglumine across the two studies with a median follow up of 36 months. Results All-cause mortality was significantly lower in the T/T group (n=264; 88 events, 33.3%) compared with the P/T group (n=177; 88 events, 50.3%); hazard ratio (95% CI), 0.64 (0.47, 0.85); P=0.001. In the subgroup of ATTRwt patients, all-cause mortality was significantly reduced in the T/T group (55/201; 27.4%) compared with the P/T group (60/134; 44.8%); 0.64 (0.44, 0.92); P=0.002. In the 106 (24.0%) ATTRm patients, there was a trend towards a reduction in all-cause mortality in the T/T group (33/63; 52.4%) compared with the P/T group (29/43; 67.4%); 0.66 (0.39, 1.09); P=0.17. In patients who were NYHA Class I or II at baseline, all-cause mortality was significantly reduced in the T/T group (38/186; 20.4%) compared with the P/T group (45/114; 39.5%); 0.49 (0.32, 0.75); P=0.001. In those patients with more severe symptoms at baseline (NYHA Class III), there were fewer deaths in the T/T group (50/78; 64.1%) compared with the P/T group (44/63; 69.8%); 0.80 (0.53, 1.21), but this difference was not statistically significant (P=0.50). Conclusions In ATTR-ACT, tafamidis was shown to significantly improve survival, functional capacity, and quality of life in patients with ATTR-CM. This pooled analysis with data from the ongoing extension study further supports the efficacy of tafamidis in patients over a longer period of time and the importance of early diagnosis and treatment. Acknowledgement/Funding This study was sponsored by Pfizer.

Prevalence, characteristics, and mortality of patients with transthyretin amyloid cardiomyopathy in the Nordic countries

“…Aggregated country-level median survival time for patients with ATTR-CM was 31 months which is in line with previous estimates 26,27 but less than half of the median survival of the matched HF cohort. Survival in the ATTR-CM cohort was significantly shorter in all included countries.…”

Extrapolation of Survival Benefits in Patients with Transthyretin Amyloid Cardiomyopathy Receiving Tafamidis: Analysis of the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial

“…Interestingly, our extrapolated results appear to be consistent with the recently presented findings of a combined analysis of data from ATTR-ACT [ 7 ] and interim data from an ongoing, open-label, long-term extension study of ATTR-ACT (ClinicalTrials.gov number NCT02791230; data cutoff: February 2018) [ 10 ]. In the latter extension study, patients who received tafamidis meglumine during ATTR-ACT continued to receive the agent at the same dose, whereas patients who received placebo were randomized to receive either tafamidis meglumine 20 mg or 80 mg. (Data from the two tafamidis dose groups were pooled, as in the primary analysis [ 7 ].)…”

“…In the latter extension study, patients who received tafamidis meglumine during ATTR-ACT continued to receive the agent at the same dose, whereas patients who received placebo were randomized to receive either tafamidis meglumine 20 mg or 80 mg. (Data from the two tafamidis dose groups were pooled, as in the primary analysis [ 7 ].) Across the two studies, after a median follow-up of 36 months, the risk of all-cause mortality was significantly lower in the tafamidis/tafamidis group than in the placebo/tafamidis group [ 10 ], and the survival curves for each group over time approximated those obtained in the current extrapolation analysis.…”

Health impact of tafamidis in transthyretin amyloid cardiomyopathy patients: an analysis from the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and the open-label long-term extension studies

“… 13 After 30 months, all trial participants were allowed to continue or start tafamidis in an open-label extension study. 14 …”

“… 13–15 To examine the potential long-term outcomes associated with tafamidis treatment, we used a disease simulation model that was informed by patient-level data from ATTR-ACT and the open-label extension study to estimate the impact of tafamidis treatment (mean difference from SoC) over a patient's lifetime. 13 , 14 …”