TY - JOUR
T1 - Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension study
AU - Damy, Thibaud
AU - Garcia-Pavia, Pablo
AU - Hanna, Mazen
AU - Judge, Daniel P.
AU - Merlini, Giampaolo
AU - Gundapaneni, Balarama
AU - Patterson, Terrell A.
AU - Riley, Steven
AU - Schwartz, Jeffrey H.
AU - Sultan, Marla B.
AU - Witteles, Ronald
N1 - Funding Information:
This study was sponsored by Pfizer. We thank all patients and their families, and all study investigators, for their participation in this study. We thank Michelle Casey (Pfizer) for her suggestions and guidance on these analyses and Ben Ebede (Pfizer) for his contribution to the long-term extension study. Medical writing support was provided by Joshua Fink, PhD, of Engage Scientific Solutions, and was funded by Pfizer. This study was sponsored by Pfizer. Upon request, and subject to certain criteria, conditions and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programmes that have been terminated (i.e. development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer. Conflict of interest: T.D. has served on a scientific advisory board for Pfizer; received funding from Pfizer for scientific meeting expenses; and his institution has received grant support from Pfizer. P.G.P. has served as a speaker in scientific meetings for Pfizer, Eidos, Akcea, and Alnylam; received funding from Pfizer and Alnylam for scientific meeting expenses; received consultancy fees from Pfizer, Alnylam, Eidos, Akcea, and Neuroimmune; and his institution has received grant/educational support from Pfizer, Eidos, Alnylam, Akcea, and Prothena. M.H. has received honoraria for advisory board participation from Pfizer, Alnylam, Akcea, and Eidos; and served as a speaker for a scientific meeting session funded by Alnylam. D.P.J. has received grants and funding for the trial, for travel expenses, and consultancy fees from Pfizer; received consultancy fees from Alnylam, Blade Therapeutics, and GSK; received clinical trial funding from Array Biopharma and Eidos. G.M. has no conflicts to disclose. B.G., T.A.P., S.R., and M.B.S. are full-time employees of Pfizer and hold stock and/or stock options. At the time of this analysis J.H.S. was an employee of Pfizer; he holds stock and stock options with Pfizer and is now retired. R.W. has received honoraria for advisory board participation from Pfizer and Alnylam, and funding for clinical trials from Pfizer, Alnylam, and Eidos.
Publisher Copyright:
© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
PY - 2021/2
Y1 - 2021/2
N2 - 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.
AB - 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.
KW - Biomarkers
KW - Clinical trial
KW - Mortality
KW - Transthyretin amyloid cardiomyopathy
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U2 - 10.1002/ejhf.2027
DO - 10.1002/ejhf.2027
M3 - Article
C2 - 33070419
AN - SCOPUS:85096688433
VL - 23
SP - 277
EP - 285
JO - European Journal of Heart Failure
JF - European Journal of Heart Failure
SN - 1388-9842
IS - 2
ER -