Estimated glomerular filtration rate trajectories by transthyretin stabilisation status in ATTR-ACT
P Garcia-Pavia, S Perlini, V Marino, R Wang, A Dispenzieri, M HannaAbstract
Background
Renal impairment is often seen in patients with transthyretin amyloidosis (ATTR amyloidosis) and may result from both amyloid deposition and systemic factors that are, at least in part, dependent on heart failure. Transthyretin (TTR) is a multifunctional protein with established physiologic roles beyond amyloid pathogenesis, including interactions relevant to thyroid hormone transport and renal tubular handling. Tafamidis is the only near-complete TTR kinetic stabiliser for treating transthyretin amyloid cardiomyopathy (ATTR-CM) that is administered orally once daily and has demonstrated a statistically significant reduction in mortality at 30 months compared with placebo.
Purpose
This descriptive, post hoc analysis from the phase 3 study ATTR-ACT evaluated longitudinal estimated glomerular filtration rate (eGFR) outcomes by TTR stabilisation status and treatment group.
Methods
Patients with ATTR-CM from the ATTR-ACT intention-to-treat population were categorized by treatment and TTR stabilisation status: ~87% of patients in the tafamidis meglumine 80 mg arm achieved TTR stabilisation, and 96.5% in the placebo arm were TTR non-stabilised. TTR stabilisation was assessed at Month 1 (4 hr 30 minutes post dose) using the validated subunit exchange assay, which measures the ability of circulating tafamidis to prevent TTR tetramer dissociation. Stabilisation was defined as the absence of tetramer dissociation in plasma samples following ex vivo challenge. Renal function was assessed using eGFR at Months 6, 12, 18, 24, and 30. eGFR outcomes were classified as worsening (>20% decline from baseline) or stable/improved (≤20% decline from baseline). Patient numbers and proportions were summarized descriptively over time.
Results
Across all time points, a higher proportion of patients in the TTR-stabilised tafamidis group were categorized as having stable/improved eGFR compared with the non-stabilised placebo group (Figure). This difference was especially evident at Months 18, 24, and 30, where the rates of stable/improved eGFR in the TTR-stabilised tafamidis group were 84.3%, 83.0%, and 71.3% vs 71.3%, 73.9%, and 70.5% in the non-stabilised placebo group. As expected, the proportion of patients with worsening eGFR increased over time in both groups, but this increase was less pronounced in patients with tafamidis TTR stabilisation.
Conclusions
In this descriptive, post hoc analysis from ATTR-ACT, TTR stabilisation was associated with a higher proportion of patients maintaining stable renal function over 30 months compared with patients without TTR stabilisation. Although the mechanisms underlying renal preservation cannot be determined from this analysis, the observed association supports further investigation into the relationship between TTR stability, renal physiology, and long-term kidney outcomes in ATTR amyloidosis. These results should be interpreted within the limitations of a post hoc analysis.TTR stabilisation and eGFR