Reply to the letter regarding the article ‘Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR‐ACT) and long‐term extension study’

Dr Dobner commented on the results from the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR‐ACT) combined with its open‐label, long‐term extension trial (LTE) in which there was a significantly greater survival benefit with tafamidis 80 mg compared with tafamidis 20 mg.¹

The numbers of patients continuing in the LTE, and the baseline characteristics of each group in ATTR‐ACT combined with the LTE, were included in the online supplementary Table S2.¹ This Table was inadvertently omitted (but is now available), which has understandably led to some errors in the figure redrawn by Dr Dobner. We have reproduced the study design figure here with the correct numbers of patients in each group and timeline (Figure 1). It should be highlighted that the protocol amendment, and the data cut‐off for the analysis, were at specific dates, not after specific exposure times.

Figure 1.

ATTR‐ACT and long‐term extension (LTE) study design. In ATTR‐ACT, 441 patients with transthyretin amyloid cardiomyopathy were randomized (2:1:2) to tafamidis 80 mg, tafamidis 20 mg, or placebo once daily for 30 months. Upon completion of ATTR‐ACT, patients could enrol in the LTE and continued to receive the dose they had been randomized to in ATTR‐ACT, except for those who had been in the placebo group in the 30‐month study; these patients were re‐randomized (2:1) to 80 or 20 mg tafamidis. As of 20 July 2018, the LTE protocol was amended to transition all patients to tafamidis free acid 61 mg; a new, single‐capsule formulation bioequivalent to the tafamidis meglumine 80 mg used in ATTR‐ACT. In total, 252 patients continued in the LTE. Patients were treated with tafamidis 80 mg or 20 mg (up to the protocol amendment) for a median of 39 months. In the analysis of ATTR‐ACT combined with the LTE (as of the data cut‐off), patients were treated with tafamidis for a median follow‐up of 51 months. The LTE is ongoing.

It is inaccurate to conclude that all patients switched to tafamidis free acid 61 mg 9 months after the start of the LTE and that all patients received a high tafamidis dose for the final 12 months of the study. The timing of the patients' transition to free acid 61 mg varied due to the variable timing of the implementation of the amendment at each site. With the addition of data from the LTE at the data cut taken soon after the 20 July 2018 amendment, the overall median follow‐up across all patients was 39 months.

It should also be clarified that the analysis of ATTR‐ACT combined with the LTE compared two groups: (i) tafamidis 80 mg, from the start of treatment with tafamidis 80 mg either in ATTR‐ACT or the LTE, with remaining patients transitioning to the bioequivalent dose of tafamidis free acid 61 mg, and (ii) tafamidis 20 mg, from the start of treatment with tafamidis 20 mg either in ATTR‐ACT or the LTE, with remaining patients transitioning to tafamidis free acid 61 mg. No patients being treated with placebo were included in the analysis and only the tafamidis 20 mg group had a change in effective dose. That some patients in the tafamidis 20 mg group may have received the higher dose of tafamidis (free acid 61 mg) for up to 12 months in the LTE is a limitation of the analysis which, if it had an impact, would have reduced the ability to detect a difference between the tafamidis 80 mg and 20 mg doses.

As shown,¹ patients in the tafamidis 80 mg group tended to have more severe disease (and were older) than patients in the tafamidis 20 mg group in both the ATTR‐ACT and ATTR‐ACT + LTE populations. As earlier treatment with tafamidis results in significantly better survival,² these differences in baseline disease severity once again would have been expected to lead to, if anything, an underestimate of the difference in the risk of death between the doses. Adjusting for the differences in the baseline covariates of age, N‐terminal pro B‐type natriuretic peptide (NT‐proBNP) levels, and 6‐min walk test (6MWT) distance resulted in an even more pronounced survival benefit with tafamidis 80 mg compared with 20 mg, with a 43% reduction in the risk of death.¹

Not shown was the analysis of the same cohorts of patients in ATTR‐ACT combined with the LTE prior to the transition to tafamidis free acid 61 mg. At this time point there was a median follow‐up of 39 months and a more pronounced trend towards a greater survival benefit with tafamidis 80 mg than in the 30 months of ATTR‐ACT alone, with a 20% reduction in the risk of death with tafamidis 80 mg compared with 20 mg (hazard ratio 0.797, 95% confidence interval 0.545–1.167). This was even more pronounced when adjusted by all covariates (age, NT‐proBNP levels, and 6MWT distance), with a 33% reduction in the risk of death (hazard ratio 0.668, 95% confidence interval 0.439–1.031). The significant 30% reduction in the risk of death with tafamidis 80 mg compared with 20 mg after a median follow‐up of 51 months was a continuation of this trend.

In summary, the risk of death was consistently reduced with tafamidis 80 mg compared with 20 mg. This difference became more pronounced at each analysis, including longer follow‐up of patients, and was significant with a median follow‐up of 51 months. This analysis demonstrates that earlier treatment with tafamidis 80 mg, as compared with 20 mg, results in a significant survival benefit for patients with transthyretin amyloid cardiomyopathy.