Outpatient worsening heart failure in transthyretin amyloid cardiomyopathy: findings from ATTRibute-CM

Background: Acoramidis, an oral transthyretin stabilizer that achieves near-complete (≥90%) transthyretin stabilization, demonstrated significant clinical benefit over placebo in participants with transthyretin amyloid cardiomyopathy (ATTR-CM) in the phase 3 ATTRibute-CM trial (NCT03860935). Methods: Post-hoc exploratory analyses of ATTRibute-CM were performed to evaluate associations between outpatient worsening heart failure (HF) (initiation/escalation of oral loop diuretics) and clinical outcomes, the impact of acoramidis on outpatient worsening HF, and the effect of acoramidis on clinical outcomes adjusting for time-dependent first outpatient worsening HF. Results: In the modified-intention-to-treat population, 287/611 participants (46.97%) experienced outpatient worsening HF, which was associated with an increased risk of all-cause mortality (ACM)/recurrent cardiovascular hospitalization (CVH) (hazard ratio [HR] 1.95, 95% confidence interval [CI] 1.51-2.51), first CVH (HR 2.78, 95% CI 1.95-3.95), ACM (HR 1.64, 95% CI 1.14-2.36), and cardiovascular mortality (HR 1.63, 95% CI 1.08-2.46) through month 30. Acoramidis was associated with a 41% risk reduction of first outpatient worsening HF versus placebo (HR 0.59, 95% CI 0.46-0.75); Kaplan-Meier curves separated early, nominal statistical significance was first reached at day 30 (HR 0.562, 95% CI 0.317-0.998; p = 0.0492), and sustained nominal statistical significance was achieved at day 134 through month 30. When adjusting for time-dependent first outpatient worsening HF over 30 months, acoramidis reduced the risk of ACM/recurrent CVH and first CVH versus placebo. Conclusions: Outpatient worsening HF was associated with clinical outcomes in ATTR-CM. Acoramidis reduced the risk of outpatient worsening HF; effects emerged early and persisted throughout follow-up.