Claggett, Brian L; Fontana, Marianna; Vaduganathan, Muthiah; Hamatani, Yasuhiro; Maurer, Mathew S; Gillmore, Julian D; Solomon, Scott D; (2025) Timing of Mortality Benefit in Outcomes Trials in Transthyretin Amyloidosis. JACC 10.1016/j.jacc.2025.09.1512. (In press).

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Abstract

BACKGROUND: Therapies for transthyretin amyloidosis with cardiomyopathy (ATTR-CM), including transthyretin (TTR) stabilizers and silencers, have demonstrated mortality benefit in three 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 three randomized trials. METHODS: We extracted time-to-event mortality data from the published Kaplan-Meier curves of three ATTR-CM outcomes trials: ATTR-ACT (tafamidis), ATTRIBUTE-CM (acoramidis), and HELIOS-B (vutrisiran). Using flexible parametric survival models, we estimated instantaneous hazard ratios and assessed the time-varying treatment effects across trials. RESULTS: Mortality curves in each ATTR-CM trial began to diverge between approximately 12-18 months after therapy initiation (Figure 1, Panel A). Instantaneous hazard ratios 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 hazard ratios with widely overlapping confidence intervals. We estimate that the treatment effect hazard ratio for mortality drops below 0.80 around 15 months (95% CI, 10-19) after randomization and continues to strengthen throughout follow-up. CONCLUSIONS AND RELEVANCE: TTR silencers and stabilizers in ATTR-CM confer a delayed but consistent mortality benefit, with no significant differences observed between the three major trials. This uniform pattern may reflect a shared mechanism of action-reducing new amyloid deposition rather than reversing established disease, and underscore the importance of early treatment initiation and adequate trial duration to capture delayed mortality effects.

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