Abstract Body (Do not enter title and authors here): Background: Atrial fibrillation/flutter (AF/AFL) is a common complication of transthyretin amyloid cardiomyopathy (ATTR-CM) that can impact quality of life even in early-stage disease. ATTR-CM is caused by the destabilization of transthyretin (TTR) and aggregation of amyloid fibrils in the heart, leading to progressive heart failure (HF). Acoramidis achieves near-complete (≥90%) TTR stabilization and is approved in the USA, UK, EU and Japan for the treatment of ATTR-CM in adults. In the placebo-controlled phase 3 ATTRibute-CM study (NCT03860935), acoramidis lowered the risk of all-cause mortality (ACM) or first cardiovascular hospitalization (CVH) in participants who had early-stage HF, defined as New York Heart Association (NYHA) class I or II functional classification at study entry.

Research Question: Does acoramidis lower the risk of ACM or CVH in patients with early-stage HF, with or without an AF/AFL diagnosis at baseline?

Methods: Participants in ATTRibute-CM received acoramidis or placebo (2:1). All participants in the open-label extension study (OLE) received acoramidis. This post hoc analysis was conducted in the modified intention-to-treat population participants who had early-stage HF (NYHA class I/II). Participants were grouped by presence or absence of an AF/AFL diagnosis at baseline (defined as AF medical history or the presence of AF or AFL on ECG at enrollment). Outcomes assessed were ACM or first CVH at Month 30, first CVH at Month 30, and ACM at Month 42 (ATTRibute-CM 30 months + 12 months OLE). Time-to-event analyses were conducted using a stratified Cox proportional hazards model.

Results: Overall, 512/611 (83.8%) participants were classified as NYHA class I or II, of whom 315 (61.5%) had an AF/AFL diagnosis at baseline and 197 (38.5%) did not. In participants with early-stage HF, lower risk of ACM or first CVH, as well as first CVH, was observed with acoramidis versus placebo regardless of AF/AFL diagnosis at baseline through Month 30 (Figure). Similar findings were demonstrated through Month 42; continuous acoramidis lowered the observed risk of ACM versus placebo to acoramidis regardless of AF/AFL diagnosis at baseline (Figure).

Conclusions: Lower risk of clinical outcomes (ACM and CVH) was observed with acoramidis in patients with early-stage HF, regardless of the presence or absence of an AF/AFL diagnosis at baseline.