Effect of Tafamidis on Cardiac Function in Patients With Transthyretin Amyloid Cardiomyopathy

Key Points

Question  Does tafamidis, 80 mg, affect cardiac function in patients with transthyretin amyloid cardiomyopathy?

Findings  In this post hoc analysis of the randomized Tafamidis in Transthyretin Cardiomyopathy Clinical Trial including 441 patients, over 30 months, there was less pronounced worsening of left ventricular (LV) stroke volume, LV global longitudinal strain, and LV filling pressure (estimated using septal and lateral E/e′ ratio) in patients treated with tafamidis, 80 mg, vs placebo.

Meaning  Compared with placebo, tafamidis, 80 mg, attenuated the decline of LV systolic and diastolic function in patients with transthyretin amyloid cardiomyopathy.

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: NCT01994889external link, opens in a new tab

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, fatal disease caused by the deposition of transthyretin (TTR) amyloid fibrils in the myocardium, leading to cardiomyopathy and symptoms of heart failure.¹external link, opens in a new tab^,2external link, opens in a new tab The 2 forms of the disease are hereditary (ATTRv-CM), in which a pathogenic TTR variant is present, and wild type (ATTRwt-CM), in which no variant is identified.¹external link, opens in a new tab Prognosis is poor in patients with untreated ATTR-CM, with median survival estimates of 2 to 6 years after diagnosis, depending on factors such as genotype and stage of disease.³external link, opens in a new tab

In ATTR-CM, the buildup of amyloid deposits in the myocardium leads to increased ventricular wall thickness and diastolic dysfunction.²external link, opens in a new tab ATTR-CM has been observed in relatively high proportions (ie, 6% to 13%) of older patients with heart failure with preserved ejection fraction (HFpEF) and increased left ventricular (LV) wall thickness and may be a frequently overlooked cause of HFpEF.⁴external link, opens in a new tab^,5external link, opens in a new tab However, LV ejection fraction (LVEF) tends to decrease in advanced stages of the disease.⁶external link, opens in a new tab^,7external link, opens in a new tab Echocardiographic measures of both systolic and diastolic function, including LVEF, longitudinal strain, LV stroke volume (SV), and early mitral inflow velocity to septal/early diastolic mitral annular velocity (E/e′; a marker of LV filling pressures), have been shown to be independent prognostic factors for mortality in patients with ATTR-CM.⁸external link, opens in a new tab^,9external link, opens in a new tab

Tafamidis is a TTR kinetic stabilizer that inhibits tetramer dissociation, the rate-limiting step in TTR amyloidogenesis.¹⁰external link, opens in a new tab In the randomized Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), tafamidis was shown to significantly reduce mortality and cardiovascular-related hospitalizations and to reduce decline in functional capacity and quality of life compared with placebo.¹¹external link, opens in a new tab Despite a recognized clinical benefit of tafamidis, its effect on cardiac function as measured by echocardiographic parameters has not been fully characterized. Three recent reports from single-center studies of tafamidis reported delays in cardiac structural and functional deterioration in patients with ATTR-CM treated with tafamidis compared with treatment-naive patients, thereby suggesting that tafamidis may attenuate the decline of cardiac function.¹²external link, opens in a new tab^-14external link, opens in a new tab

The primary aim of this post hoc analysis of the ATTR-ACT was to assess the effect of tafamidis, 80 mg, the approved dose for ATTR-CM,¹⁵external link, opens in a new tab vs placebo on echocardiographic measures of cardiac function that have previously been identified as prognostic factors for mortality in ATTR-CM.⁸external link, opens in a new tab^,9external link, opens in a new tab By focusing on these prognostic echocardiographic measures, we aimed to better understand the underlying basis of improved survival with tafamidis.