Journal of the American College of Cardiology最新文献

Background: Therapies for transthyretin amyloidosis with cardiomyopathy (ATTR-CM), including transthyretin (TTR) stabilizers and silencers, have demonstrated mortality benefit in 3 randomized trials. However, the timing of this benefit-often appearing delayed-has been debated and has broad implications for clinical use and trial design.

Objectives: The purpose of this study was to evaluate the time course of mortality benefit with TTR stabilizers and silencers in ATTR-CM by estimating time-varying treatment effects across 3 randomized trials.

Methods: We extracted time-to-event mortality data from the published Kaplan-Meier curves of 3 ATTR-CM outcomes trials: ATTR-ACT (tafamidis), ATTRIBUTE-CM (acoramidis), and HELIOS-B (vutrisiran). Using flexible parametric survival models, we estimated instantaneous HRs and assessed the time-varying treatment effects across trials.

Results: Mortality curves in each ATTR-CM trial began to diverge between approximately 12 to 18 months after therapy initiation. Instantaneous HRs showed consistent time-varying treatment effects across trials (P = 0.96), with a pooled model confirming a delayed but progressively strengthening benefit (P for treatment effect < 0.001; P for time interaction < 0.001). No significant differences were found between the 3 trials in the instantaneous HRs with widely overlapping CIs. We estimate that the treatment effect HR for mortality drops below 0.80 around 15 months (95% CI: 10-19) after randomization and continues to strengthen throughout follow-up.

Conclusions: TTR silencers and stabilizers in ATTR-CM confer a delayed but consistent mortality benefit with no significant differences observed between the 3 major trials. This uniform pattern may reflect a shared mechanism of action-reducing new amyloid deposition rather than reversing established disease-and may underscore the importance of early treatment initiation and adequate trial duration to capture delayed mortality effects. (ATTR-ACT [Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy; NCT01994889]; ATTRIBUTE-CM [Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy; NCT03860935]; and HELIOS-B [A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy; NCT04153149]).

Background: Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a progressive disease with a significant burden of recurrent cardiovascular (CV) events. Acoramidis, an approved oral therapy for ATTR-CM, achieves early, near-complete (≥90%) TTR stabilization. In the phase 3 ATTRibute-CM (Efficacy and Safety of Acoramidis in Participants with Transthyretin Amyloid Cardiomyopathy) study, acoramidis significantly reduced the composite of all-cause mortality or first CV-related hospitalization (CVH), with an effect observed at month 3. Its efficacy on the burden of cumulative CV outcome events has not been reported.

Objectives: This study was a post hoc exploratory recurrent-event analysis of the efficacy of acoramidis on the cumulative incidence of CV outcomes from ATTRibute-CM and its open-label extension.

Methods: Cumulative incidences of centrally adjudicated CV-related mortality (CVM) or recurrent CVH (first and, if applicable, subsequent CVH), recurrent CVH alone (month 30), and CVM (month 42) were measured in the modified intention-to-treat population (acoramidis, n = 409; placebo, n = 202). Mean cumulative events by treatment, and the difference between treatment groups were estimated by using a modified Andersen-Gill model.

Results: Acoramidis significantly reduced the cumulative risk of CVM or recurrent CVH through month 30 vs placebo (HR: 0.51; 95% CI: 0.43-0.62; P < 0.0001). A notable proportion of CV outcome events (19% of CVM or recurrent CVH events, 22% of CVH) occurred within the first 6 months. Numerically fewer cumulative events were observed with acoramidis compared with placebo at month 1, and the difference increased progressively, resulting at month 30 in 53 events avoided per 100 treated participants (95% CI: 29-79). At month 42, CVM was reduced with continuous acoramidis vs placebo-to-acoramidis (HR: 0.55; 95% CI: 0.39-0.79; P = 0.0011). The annualized frequency of recurrent CVH was significantly decreased through month 30 (relative risk ratio: 0.50; 95% CI: 0.35-0.69; P < 0.0001).

Conclusions: Acoramidis significantly reduced the cumulative burden of CV outcomes in ATTR-CM over 30 months. Numerically fewer events were observed with acoramidis vs placebo by month 1, and the difference increased progressively over time, resulting in 53 events avoided per 100 treated patients at month 30. Almost one-fourth of the cumulative CV events occurred within the first 6 months. These exploratory findings suggest that cumulative event burden may occur early, highlighting the importance of timely evaluation, diagnosis and treatment in ATTR-CM.