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Clinical Trial
. 2024 Jan 1;9(1):25-34.
doi: 10.1001/jamacardio.2023.4147.

Effect of Tafamidis on Cardiac Function in Patients With Transthyretin Amyloid Cardiomyopathy: A Post Hoc Analysis of the ATTR-ACT Randomized Clinical Trial

Sanjiv J Shah  1 , Nowell Fine  2 , Pablo Garcia-Pavia  3 , Allan L Klein  4 , Fabio Fernandes  5 , Neil J Weissman  6 , Mathew S Maurer  7 , Kurt Boman  8 , Balarama Gundapaneni  9 , Marla B Sultan  10 , Perry Elliott  11
Affiliations
Clinical Trial

Effect of Tafamidis on Cardiac Function in Patients With Transthyretin Amyloid Cardiomyopathy: A Post Hoc Analysis of the ATTR-ACT Randomized Clinical Trial

Sanjiv J Shah et al. JAMA Cardiol. .

Abstract

Importance: Tafamidis has been shown to improve survival in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) compared with placebo. However, its effect on cardiac function has not been fully characterized.

Objective: To examine the effect of tafamidis on cardiac function in patients with ATTR-CM.

Design, setting, and participants: This was an exploratory, post hoc analysis of the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), a multicenter, international, double-blind, placebo-controlled phase 3 randomized clinical trial conducted from December 2013 to February 2018. The ATTR-ACT included 48 sites in 13 counties and enrolled patients aged 18 to 90 years with ATTR-CM. Data were analyzed from July 2018 to September 2023.

Intervention: Patients were randomized to tafamidis meglumine, 80 mg or 20 mg, or placebo for 30 months.

Main outcomes and measures: Patients were categorized based on left ventricular (LV) ejection fraction at enrollment as having heart failure with preserved ejection fraction (≥50%), mildly reduced ejection fraction (41% to 49%), or reduced ejection fraction (≤40%). Changes from baseline to month 30 in LV ejection fraction, LV stroke volume, LV global longitudinal strain, and the ratio of early mitral inflow velocity to septal and lateral early diastolic mitral annular velocity (E/e') were compared in patients receiving tafamidis, 80 mg, vs placebo.

Results: A total of 441 patients were randomized in ATTR-ACT, and 436 patients had available echocardiographic data. Of 436 included patients, 393 (90.1%) were male, and the mean (SD) age was 74 (7) years. A total of 220 (50.5%), 119 (27.3%), and 97 (22.2%) had heart failure with preserved, mildly reduced, and reduced LV ejection fraction, respectively. Over 30 months, there was less pronounced worsening in 4 of the echocardiographic measures in patients receiving tafamidis, 80 mg (n = 176), vs placebo (n = 177) (least squares mean difference: LV stroke volume, 7.02 mL; 95% CI, 2.55-11.49; P = .002; LV global longitudinal strain, -1.02%; 95% CI, -1.73 to -0.31; P = .005; septal E/e', -3.11; 95% CI, -5.50 to -0.72; P = .01; lateral E/e', -2.35; 95% CI, -4.01 to -0.69; P = .006).

Conclusions and relevance: Compared with placebo, tafamidis, 80 mg, attenuated the decline of LV systolic and diastolic function over 30 months in patients with ATTR-CM. Approximately half of patients had mildly reduced or reduced LV ejection fraction at enrollment, suggesting that ATTR-CM should be considered as a possible diagnosis in patients with heart failure regardless of underlying LV ejection fraction.

Trial registration: ClinicalTrials.gov Identifier: NCT01994889.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Shah reported grants from Pfizer and personal fees from Pfizer during the conduct of the study as well as personal fees from Intellia, Novo Nordisk, Ionis, AstraZeneca, and Eidos outside the submitted work. Dr Fine reported personal fees from Pfizer during the conduct of the study as well as personal fees from Alynylam outside the submitted work. Dr Garcia-Pavia reported payments from Pfizer during the conduct of the study; grants from Pfizer and Alnylam; and personal fees from Pfizer, Neuroimmune, Alnylam, NovoNordisk, BridgeBio, AstraZeneca, Ionis, and Attralus outside the submitted work. Dr Klein reported grants and personal fees from Pfizer outside the submitted work. Dr Fernandes reported grants from Heart Institute during the conduct of the study. Dr Weissman reported grants from Pfizer during the conduct of the study. Dr Maurer reported grants from Pfizer, Alnylam, Ionis, and Eidos during the conduct of the study as well as personal fees from Intellia and Novo-Nordisk outside the submitted work. Dr Boman reported personal fees from Pfizer AB Sweden during the conduct of the study. Dr Elliott reported personal fees from Pfizer during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Least Squares (LS) Mean Changes From Baseline to Month 30 With Tafamidis, 80 mg, vs Placebo
Data are shown for left ventricular ejection fraction (LVEF), left ventricular stroke volume (LVSV), left ventricular (LV) global longitudinal strain (GLS), early mitral inflow velocity to septal/early diastolic mitral annular velocity (E/e′), and lateral E/e′. LS mean differences represent tafamidis, 80 mg, minus placebo. LV GLS is expressed as a negative number; therefore, a change in the positive direction indicates worsening of this measure.
Figure 2.
Figure 2.. Least Squares (LS) Mean Changes From Baseline Over Time With Tafamidis, 80 mg, vs Placebo
Data are shown for left ventricular ejection fraction (LVEF), left ventricular stroke volume (LVSV), left ventricular (LV) global longitudinal strain (GLS), early mitral inflow velocity to septal/early diastolic mitral annular velocity (E/e′), and lateral E/e′. LS mean differences represent tafamidis, 80 mg, minus placebo. LV GLS is expressed as a negative number; therefore, a change in the positive direction indicates worsening of this measure.
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