Therapies for transthyretin amyloidosis with cardiomyopathy (ATTR-CM), including transthyretin (TTR) stabilisers and silencers, have demonstrated a mortality benefit in randomised trials. However, the timing of this benefit has been a subject of debate. A new analysis of three major outcomes trials has evaluated this time course, revealing a consistent pattern across different treatments.¹

Methodology

This study evaluated the time course of mortality benefit by extracting time-to-event data from the published Kaplan-Meier curves of three key randomised trials in ATTR-CM. The trials included were ATTR-ACT (tafamidis), ATTRIBUTE-CM (acoramidis), and HELIOS-B (vutrisiran).¹˒²

Using flexible parametric survival models, the investigators estimated instantaneous hazard ratios (HRs) to assess the time-varying treatment effects on mortality across the different therapies.

Results

The analysis revealed that the mortality curves for the treatment and placebo groups in each trial began to diverge between approximately 12 and 18 months after therapy was initiated. The instantaneous HRs showed consistent time-varying treatment effects across all three trials (P=0.96), with no significant differences observed between the therapies.

A pooled model confirmed a delayed but progressively strengthening mortality benefit over time (P for treatment effect <0.001; P for time interaction <0.001). The investigators estimate that the treatment effect HR for mortality drops below 0.80 at around 15 months (95% CI: 10–19) after randomisation and continues to strengthen throughout the follow-up period.

In Practice

The findings demonstrate that both TTR silencers and stabilisers confer a delayed but consistent and progressively increasing mortality benefit in patients with ATTR-CM. The authors suggest that this “uniform pattern may reflect a shared mechanism of action—reducing new amyloid deposition rather than reversing established disease.”¹

These results highlight the clinical importance of early treatment initiation to slow disease progression before significant irreversible damage occurs. Furthermore, the delayed nature of the survival benefit has important implications for the design of future clinical trials in this field.

Next Steps

The study underscores the importance of ensuring adequate trial duration in future studies of ATTR-CM therapies to fully capture the delayed but significant effects on mortality.

References

1. Claggett BL, Fontana M, Vaduganathan M, et al. Timing of Mortality Benefit in Outcomes Trials in Transthyretin Amyloidosis. JACC. 2026;87(5):522-529. https://doi.org/10.1016/j.jacc.2025.09.1512

2. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379(11):1007-1016. https://doi.org/10.1056/NEJMoa1805689

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