A trial emulation study comparing tafamidis and acoramidis in transthyretin amyloid cardiomyopathy using calibration and indirect treatment comparison methods: the ReplicATTR Study
P Zwetsloot, P Debonnaire, R Pfister, P Llacer, A Cipriani, P Milani, D Bonderman, C Ohlmeier, T Evers, R Wyss, E Patorno, R Doshi, C I Coleman, C Aguiar, T Ripoll VeraAbstract
Background
Tafamidis and acoramidis are both approved transthyretin stabilizers for managing transthyretin amyloid cardiomyopathy (ATTR-CM). However, there has been no randomized controlled trial directly comparing these two therapies.
Purpose
This study aims to evaluate the comparative effectiveness of acoramidis versus tafamidis in terms of the risk of all-cause mortality (ACM) in patients with ATTR-CM.
Methods
We conducted a comparative effectiveness analysis utilizing a hybrid design to assess the 42-month ACM risk associated with acoramidis versus tafamidis. This involved trial emulation, calibration, and indirect treatment comparison techniques. Using US electronic medical records from TriNetX, we identified two cohorts of patients who initiated tafamidis treatment between 2019 and 2024, aligning with the eligibility criteria of the ATTR-ACT and ATTRibute-CM trials. Additionally, these cohorts were reweighted to reflect key baseline characteristics from the trials. The observed 42-month ACM risk in the tafamidis group from the ATTR-ACT trial and the emulated cohort of real-world tafamidis users was utilized to establish a calibration factor, which addressed the net effect of systematic differences between the populations. This calibration factor allowed for a comparison of the 42-month ACM risk between the acoramidis arm in the ATTRibute-CM trial and the emulated cohort of tafamidis users. Using these values and corresponding variance, Monte Carlo simulation (MCS)-estimated medians and percentile-based 95% confidence intervals (CIs) were derived.
Results
Our analysis identified 624 tafamidis initiators who met the ATTR-ACT eligibility criteria and 617 who met the ATTRibute-CM criteria. In the emulated tafamidis cohort for the ATTRibute-CM trial, the 42-month ACM risk was observed to be 35.4%. After applying the calibration factor, this risk adjusted to a MCS-estimated median value of 31.2% (95%CI: 25.3-39.0%). When compared to the 42-month ACM risk in the acoramidis arm of the ATTRibute-CM trial (24.0%, 95%CI: 22.0-28.7%) the MCS-estimated median relative risk was calculated at 0.78 (95%CI 0.60-0.99), suggesting a significant benefit for acoramidis.
Conclusions
The findings indicate that acoramidis is associated with a meaningful reduction in ACM risk compared to tafamidis. In the absence of direct comparative trials, these results may assist clinicians in making informed treatment decisions, despite the inherent limitations of a non-randomized design and the assumptions involved in indirect comparisons.For image description, please refer to the figure legend and surrounding text.