Abstract Body (Do not enter title and authors here): Background: Atrial fibrillation/flutter (AF/AFL) is a frequent complication of heart failure in transthyretin amyloid cardiomyopathy (ATTR-CM) and its increasing incidence is a marker of disease progression. Increasing N-terminal B-type natriuretic peptide (NT-proBNP) levels are also an independent indicator of ATTR-CM progression and higher NT-proBNP levels are seen in ATTR-CM with superimposed AF. Acoramidis achieves near-complete (≥90%) TTR stabilization, and is approved in the USA, UK, Europe and Japan for the treatment of ATTR-CM in adults. Acoramidis blunts the progressive rise in NT-proBNP, compared with placebo in patients with ATTR-CM.

Research Question: How does acoramidis treatment influence ATTR-CM disease progression based on NT-proBNP levels in the presence or absence of AF/AFL?

Methods: The ATTRibute-CM (NCT03860935) study has been published. This post hoc analysis was conducted in the modified intention-to-treat population who had baseline (BL) and Month 30 NT-proBNP assessments (n=413). Categories defined were: 1) presence or absence of AF/AFL diagnosis at BL (defined as recorded AF medical history or presence of AF/AFL on ECG at enrollment), 2) incidence of AF/AFL treatment-emergent adverse event (TEAE) during the study, and 3) AF/AFL at any time (defined as [1] or [2]). Clinically meaningful improvement at Month 30 was defined as a reduction of >300 pg/mL and >30% in NT-proBNP from BL. AF/AFL TEAEs were identified using ‘atrial fibrillation’, ‘atrial flutter’ and ‘cardiac flutter’ MedDRA preferred terms.

Results: At study entry, participants with BL AF/AFL had lower 6-minute walk distances, left ventricular ejection fractions and Kansas City Cardiomyopathy Questionnaire Overall Summary scores, higher NT-proBNP levels and were more frequently categorized in higher National Amyloidosis Centre stages versus those without BL AF/AFL. Other BL characteristics were comparable between groups. At Month 30, a higher proportion of participants had improved NT-proBNP with acoramidis than with placebo, regardless of AF/AFL status at BL and/or development of AF/AFL during the study (Table).

Conclusions: In ATTRibute-CM, the proportion of participants with improved NT-proBNP at Month 30 was consistently around 15 percentage points higher with acoramidis than placebo, regardless of AF/AFL status at BL or during the study. The ongoing open-label extension study may offer insights into the durability of this effect and its long-term clinical consequences.