Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension study

Abstract

Aims: Tafamidis is an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM) in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). While ATTR-ACT was not designed for a dose-specific assessment, further analysis from ATTR-ACT and its long-term extension study (LTE) can guide determination of the optimal dose.

Methods and results: In ATTR-ACT, patients were randomized (2:1:2) to tafamidis 80 mg, 20 mg, or placebo for 30 months. Patients completing ATTR-ACT could enrol in the LTE (with placebo-treated patients randomized to tafamidis 80 or 20 mg; 2:1) and all patients were subsequently switched to high-dose tafamidis. All-cause mortality was assessed in ATTR-ACT combined with the LTE (median follow-up 51 months). In ATTR-ACT, the combination of all-cause mortality and cardiovascular-related hospitalizations over 30 months was significantly reduced with tafamidis 80 mg (P = 0.0030) and 20 mg (P = 0.0048) vs. placebo. All-cause mortality vs. placebo was reduced with tafamidis 80 mg [Cox hazards model (95% confidence interval): 0.690 (0.487-0.979), P = 0.0378] and 20 mg [0.715 (0.450-1.137), P = 0.1564]. The mean (standard error) change in N-terminal pro-B-type natriuretic peptide from baseline to Month 30 was -1170.51 (587.31) (P = 0.0468) with tafamidis 80 vs. 20 mg. In ATTR-ACT combined with the LTE there was a significantly greater survival benefit with tafamidis 80 vs. 20 mg [0.700 (0.501-0.979), P = 0.0374]. Incidence of adverse events in both tafamidis doses were comparable to placebo.

Conclusion: Tafamidis, both 80 and 20 mg, effectively reduced mortality and cardiovascular-related hospitalizations in patients with ATTR-CM. The longer-term survival data and the lack of dose-related safety concerns support tafamidis 80 mg as the optimal dose.

Clinical trial registration: ClinicalTrials.gov NCT01994889; NCT02791230.

Keywords: Biomarkers; Clinical trial; Mortality; Transthyretin amyloid cardiomyopathy.

Figure 1

Change from baseline with tafamidis 80 mg, tafamidis 20 mg, and placebo in (A) 6‐min walk test (6MWT) distance and (B) Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ‐OS) in ATTR‐ACT. P‐values are for the treatment difference vs. placebo for tafamidis 80 mg (shown above the curve) and tafamidis 20 mg (shown below the curve). LS, least squares; SE, standard error.

Figure 2

Forest plot of covariate‐adjusted all‐cause mortality in ATTR‐ACT and ATTR‐ACT combined with the long‐term extension study (LTE). Hazard ratios are for: patients in ATTR‐ACT (30 months follow‐up), tafamidis 80 mg (n = 176) compared with 20 mg (n = 88); patients in ATTR‐ACT combined with the LTE and treatment with tafamidis free acid 61 mg (51 months follow‐up), tafamidis 80 mg/tafamidis free acid 61 mg (n = 230) compared with tafamidis 20 mg/tafamidis free acid 61 mg (n = 116). The unadjusted row was based on the prespecified Cox proportional hazards model with treatment, New York Heart Association baseline classification, and genotype in the model. The single covariate‐adjusted rows were generated by adding age, N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) (log transformed), and 6‐min walk test (6MWT) distance separately as covariates to the pre‐specified model. The all‐covariate‐adjusted row was generated by adding all covariates to the pre‐specified model. Patients who discontinued due to heart or combined heart and liver transplantation, or due to implantation of a cardiac mechanical assist device, were counted as death for these analyses. *P‐values for ATTR‐ACT combined with the LTE (51 months of follow‐up) were: unadjusted, P = 0.0374; age‐adjusted, P = 0.0054; NT‐proBNP‐adjusted, P = 0.0099; 6MWT‐adjusted, P = 0.0444; age/NT‐proBNP/6MWT‐adjusted, P = 0.0030. CI, confidence interval.

Figure 3

Least squares (LS) mean (standard error, SE) change in (A) N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and (B) troponin I from baseline to Month 30 in ATTR‐ACT. The differences from placebo at Month 30 in NT‐proBNP and troponin I were significant for tafamidis 80 mg but not tafamidis 20 mg. (C) Cumulative distribution of percent change from baseline in NT‐proBNP at Month 30 with tafamidis 80 mg, tafamidis 20 mg, and placebo in ATTR‐ACT.