Building on the demonstrated functional benefit of tafamidis: association of TTR stabilisation with 6MWT outcomes in ATTR ACT
R Witteles, F Cappelli, V Marino, R Wang, M Crespo Leiro, S PerliniAbstract
Background
Functional impairment is a central manifestation of progression in transthyretin amyloid cardiomyopathy (ATTR-CM). Tafamidis has previously demonstrated a beneficial effect on functional capacity as assessed by the 6-minute walk test (6MWT) in the ATTR-ACT study. Tafamidis is a near-complete transthyretin (TTR) kinetic stabiliser approved for the treatment of ATTR-CM that is administered orally once daily. In ATTR-ACT, a statistically significant reduction in mortality at 30 months with tafamidis vs placebo has been demonstrated.
Purpose
To analyse longitudinal functional outcomes according to early TTR stabilisation status.
Methods
This post-hoc, descriptive analysis included patients from the ATTR-ACT intent-to-treat population: approximately 87% patients randomised to tafamidis meglumine 80 mg who had TTR stabilisation (Group A) and 97% patients randomised to placebo (Group B; no TTR stabilization). TTR stabilisation in ATTR-ACT was assessed at Month 1 of treatment using a validated subunit exchange assay, measuring the ability of circulating tafamidis to prevent dissociation of the TTR tetramer, the rate-limiting step in amyloidogenesis. Stabilisation was defined as absence of tetramer dissociation in plasma samples following ex vivo challenge. Functional status was assessed using the 6MWT at baseline, and Months 6, 12, 18, 24, and 30. Functional improvement was defined as a ≤35-meter decline from baseline at each assessment; a decline of >35 metres was considered functional worsening. Results were summarised descriptively as numbers and proportions of patients for each assessment and group.
Results
At Month 6, 12, 18, and 30 the percentage of patients with 6MWT improvement was 72.7%, 63.3%, 59.5%, 56.7% and 57.6%, respectively in patients treated with tafamidis and TTR stabilisation, and 58.6%, 52.3%, 41.5%, 31.7% and 29.9%, respectively in patients treated with placebo without TTR stabilisation. Across all visits, patients without TTR stabilisation consistently demonstrated lower proportions of functional improvement. These differences in proportions of functional improvement between the two groups became even larger after Month 18.
Conclusion
In this post-hoc analysis of ATTR-ACT, early TTR stabilisation with tafamidis was associated with maintenance of functional capacity over 30 months, as reflected by higher proportions of patients with TTR stabilisation achieving clinically meaningful 6MWT improvement compared with patients without TTR stabilisation. These findings extend the demonstrated functional benefit of tafamidis and support the clinical relevance of TTR stabilisation for long-term functional outcomes in ATTR-CM, within the limitations of a descriptive post-hoc analysis.Figure