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Transthyretin stabilizer reduces decline in cardiac function in ATTR-CM


This summary is based on the publication of Shah SJ et al. - Effect of Tafamidis on Cardiac Function in Patients With Transthyretin Amyloid Cardiomyopathy: A Post Hoc Analysis of the ATTR-ACT Randomized Clinical Trial. JAMA Cardiol. 2023 Nov 15:e234147. doi: 10.1001/jamacardio.2023.4147

Introduction and methods


Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal disease caused by the deposition of amyloid fibrils, which consists of misfolded TTR aggregates, in the myocardium. The ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial) study showed that tafamidis—a TTR kinetic stabilizer—reduced mortality, CV-related hospitalization and the decline in functional capacity and quality of life in these patients compared with placebo [1]. The next year, the FDA approved tafamidis meglumine 80 mg for ATTR-CM [2]. However, the effect of tafamidis on cardiac function has not been fully characterized.

Aim of the study

In an exploratory, post-hoc analysis of the ATTR-ACT trial, the authors assessed the effect of tafamidis on prognostic echocardiographic measures of cardiac function in patients with ATTR-CM.


The ATTR-ACT trial was an international, multicenter, double-blind, placebo-controlled phase 3 RCT in which 441 ATTR-CM patients (aged 18–90 years) with a medical history of HF and end-diastolic interventricular septal wall thickness ≥12 mm were included. Participants were randomized to tafamidis meglumine (80 or 20 mg) or placebo for 30 months.

For this pos-hoc analysis, echocardiographic data were available for 436 patients. Based on LVEF at enrollment, patients were categorized into: HFpEF (LVEF ≥50%) (n=220; 50.5%), HFmrEF (LVEF 41%–49%) (n=119; 27.3%), and HFrEF (LVEF ≤40%) (n=97; 22.2%).


Study outcomes were changes from baseline to 30 months in LVEF, LV stroke volume (LVSV), LV global longitudinal strain (LV GLS), ratio of early mitral inflow velocity to septal/early diastolic mitral annular velocity (E/e’), and lateral E/e′ in patients receiving tafamidis 80 mg versus placebo.

Main results

  • Over 30 months, the decline from baseline in 4 of the 5 echocardiographic measures was less pronounced in patients receiving tafamidis 80 mg (n=176) compared with those taking placebo (n=177). Least-squares (LS) mean differences were 7.02 mL (95%CI: 2.55–11.49; P=0.002) for LVSV, –1.02% (95%CI: –1.73% to –0.31%; P=0.005) for LV GLS, –3.11 (95%CI: –5.50 to –0.72; P=0.01) for septal E/e’, and –2.35 (95%CI: –4.01 to –0.69; P=0.006) for lateral E/e'.
  • For LVEF, the LS mean difference at 30 months was not significant (2.09%; 95%CI: −0.62% to 4.79%; P=0.13).
  • From 6 months onwards, the changes in LVSV and LV GLS were apparent in all patients.
  • The increases in septal and lateral E/e′ were visible from 6 through 30 months in the placebo group, but these echocardiographic measures changed only minimally at each time point after 6 months in the tafamidis group.
  • In the placebo group, the decline in LVEF became apparent at 6 months, whereas there was minimal decline with tafamidis through 30 months.
  • Baseline LVEF did not influence the treatment effect of tafamidis on all-cause mortality (P for interaction=0.40), CV-related hospitalizations (P for interaction=0.35), and changes from baseline in LVSV (P for interaction=0.23), LV GLS (P for interaction=0.66), septal E/e′ (P for interaction=0.66), and lateral E/e′ (P for interaction=0.84).


In this exploratory, post-hoc analysis of the ATTR-ACT trial, treatment with tafamidis 80 mg attenuated the decline in several LV systolic and diastolic functions over 30 months in ATTR-CM patients compared with placebo. There was no significant difference in the decline in LVEF between the 2 groups.

The authors observed that approximately half of the patients had HFmrEF or HFrEF at enrollment, suggesting that “ATTR-CM should be considered as a possible diagnosis in all patients with HF, regardless of LVEF.” Furthermore, as the 5 echocardiographic parameters studied “have been identified as independent prognostic factors for mortality in patients with ATTR-CM [3,4], [...] the effect of tafamidis on cardiac function in patients with ATTR-CM may underlie improved survival.”


1. Maurer MS, Schwartz JH, Gundapaneni B, et al; ATTR-ACT Study Investigators. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379(11):1007-1016. doi:10.1056/NEJMoa1805689

2. Pfizer. Vyndaqel (tafamidis meglumine) and Vyndamax (tafamidis) prescribing information. Accessed December 4, 2022.

3. Chacko L, Martone R, Bandera F, et al. Echocardiographic phenotype and prognosis in transthyretin cardiac amyloidosis. Eur Heart J. 2020;41(14):1439-1447. doi:10.1093/eurheartj/ehz905

4. Bukhari S, Bashir Z, Shpilsky D, Eisele YS, Soman P. Abstract 16145: reduced ejection fraction at diagnosis is an independent predictor of mortality in transthyretin amyloid cardiomyopathy. Circulation. 2020;142(suppl 3):A16145-A16145. doi:10.1161/circ.142.suppl_3.16145

Find this article online at JAMA Cardiol.

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