Timing of Mortality Benefit in Outcomes Trials in Transthyretin Amyloidosis.

Abstract

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. 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. 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. 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. 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]).