Stage-dependent timing of relative and absolute treatment benefit in transthyretin amyloid cardiomyopathy
- 1Cardiovascular Medicine, Saga University Faculty of Medicine Graduate School of Medical Sciences, Saga, Japan
- 2Saga University Faculty of Medicine Graduate School of Medical Sciences, Saga, Japan
- 3Department of Cardiovascular Medicine, Tobata General Hospital, Kitakyushu, Fukuoka Prefecture, Japan
Abstract
Background: In transthyretin amyloid cardiomyopathy (ATTR-CM), treatment effects are often delayed and stage-dependent, which complicates interpretation of a single HR. The timing of relative and absolute benefit at each stage is unclear. We examined stage-specific treatment effects of tafamidis using complementary time-to-event analyses.
Methods: Individual patient-level data were reconstructed from published Kaplan-Meier curves of the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial long-term extension and analysed by National Amyloidosis Centre (NAC) stage. Time to benefit (TTB) was estimated from flexible parametric (Royston-Parmar) models with time-varying treatment effects, providing time-varying HRs and absolute risk reduction and was cross-checked with truncated Cox and restricted mean survival time (RMST) trajectory analyses.
Results: Effects differed by NAC stage. Tafamidis reduced mortality in NAC1 (HR 0.45, 95% CI 0.27 to 0.73) and NAC2 (HR 0.55, 95% CI 0.35 to 0.86); no effect was seen in NAC3. Hazard reduction was early and consistent in NAC1 but delayed in NAC2. HR-based TTB was 36 months in NAC1 and 50 months in NAC2 and was not reached in NAC3. RMST-based TTB occurred later (38 and 61 months). At maximum follow-up, RMST gain was 17 months in NAC1, 13 months in NAC2 and 1 month in NAC3.
Conclusions: Survival benefit from tafamidis is stage-dependent, appearing earlier and lasting longer in less advanced disease. In intermediate-stage disease, relative effects preceded—and at times diverged from—absolute survival gains. These data support early initiation of therapy and the use of complementary analytical approaches alongside the conventional HR.
Related
- Eplontersen for Transthyretin Amyloid Cardiomyopathy
- Wild-Type Transthyretin Amyloid Cardiomyopathy With Positive 18F-FDG/13N-Ammonia Cardiac Positron Emission Tomography
- Impact of Tafamidis on Transthyretin Concentration and Its Relation to All-Cause Mortality in Patients with Transthyretin Amyloid Cardiomyopathy: An Analysis from ATTR-ACT
- Stage-Specific Cost-Effectiveness of Early vs. Delayed Tafamidis for Transthyretin Amyloid Cardiomyopathy in Japan
- Case Report: Gastrointestinal-onset hereditary transthyretin amyloidosis with cardiomyopathy and equivocal 99mTc-PYP scintigraphy: diagnosis by florbetapir PET-guided skeletal muscle biopsy and genetic testing
BibTeX
@article{nabeshima2026stagedependent,
title = {{Stage-dependent timing of relative and absolute treatment benefit in transthyretin amyloid cardiomyopathy}},
author = {Yosuke Nabeshima and Tetsuya Kaneko and Ayumu Yajima and Koichi Node and Masaaki Takeuchi},
journal = {Open Heart},
year = {2026},
month = oct,
doi = {10.1136/openhrt-2026-004295},
url = {https://doi.org/10.1136/openhrt-2026-004295},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Stage-dependent timing of relative and absolute treatment benefit in transthyretin amyloid cardiomyopathy
AU - Yosuke Nabeshima
AU - Tetsuya Kaneko
AU - Ayumu Yajima
AU - Koichi Node
AU - Masaaki Takeuchi
PY - 2026
DA - 2026/10/26
JO - Open Heart
DO - 10.1136/openhrt-2026-004295
UR - https://doi.org/10.1136/openhrt-2026-004295
AB - Background: In transthyretin amyloid cardiomyopathy (ATTR-CM), treatment effects are often delayed and stage-dependent, which complicates interpretation of a single HR. The timing of relative and absolute benefit at each stage is unclear. We examined stage-specific treatment effects of tafamidis using complementary time-to-event analyses. Methods: Individual patient-level data were reconstructed from published Kaplan-Meier curves of the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial long-term extension and analysed by National Amyloidosis Centre (NAC) stage. Time to benefit (TTB) was estimated from flexible parametric (Royston-Parmar) models with time-varying treatment effects, providing time-varying HRs and absolute risk reduction and was cross-checked with truncated Cox and restricted mean survival time (RMST) trajectory analyses. Results: Effects differed by NAC stage. Tafamidis reduced mortality in NAC1 (HR 0.45, 95% CI 0.27 to 0.73) and NAC2 (HR 0.55, 95% CI 0.35 to 0.86); no effect was seen in NAC3. Hazard reduction was early and consistent in NAC1 but delayed in NAC2. HR-based TTB was 36 months in NAC1 and 50 months in NAC2 and was not reached in NAC3. RMST-based TTB occurred later (38 and 61 months). At maximum follow-up, RMST gain was 17 months in NAC1, 13 months in NAC2 and 1 month in NAC3. Conclusions: Survival benefit from tafamidis is stage-dependent, appearing earlier and lasting longer in less advanced disease. In intermediate-stage disease, relative effects preceded—and at times diverged from—absolute survival gains. These data support early initiation of therapy and the use of complementary analytical approaches alongside the conventional HR.
SN - 2053-3624
ER -