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Transthyretin stabilizer reduces decline in cardiac function in ATTR-CM

11/29/2023

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

Background

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.

Methods

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%).

Outcomes

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).

Conclusion

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.”

References

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. https://www.fda.gov/media/126283/download

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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