A trial emulation study indirectly comparing tafamidis and acoramidis in transthyretin amyloid cardiomyopathy: the ReplicATTR study
Publication: Journal of Comparative Effectiveness Research
Abstract
Aim: Tafamidis and acoramidis are transthyretin stabilizers approved for the treatment of transthyretin amyloid cardiomyopathy. We compared the effectiveness of acoramidis versus tafamidis regarding all-cause mortality (ACM). Materials & methods: This study used a hybrid design to compare 42-month ACM with acoramidis versus tafamidis using trial emulation, calibration, and indirect treatment comparison. Two real-world cohorts of participants initiating tafamidis were identified from TriNetX (2019–2024) using observational analogues to emulate ATTR-ACT and ATTRibute-CM trial eligibility criteria and baseline characteristics. A calibration factor was derived by comparing 42-month ACM in the ATTR-ACT tafamidis arm with the ATTR-ACT emulation cohort to quantify the net effect of systematic differences between the populations. This factor was applied to the ATTRibute-CM emulation tafamidis cohort and compared with the ATTRibute-CM acoramidis arm. Using these values and corresponding variance, Monte Carlo simulation (MCS)-estimated medians and percentile-based 95% CIs were derived. Results: In the ATTRibute-CM emulation tafamidis cohort (n = 617), 42-month ACM risk was 35.4% (95% CI: 29.6–42.0), and decreased to a MCS-estimated median of 31.2% (95% CI: 25.3–39.0) after application of the calibration factor (MCS-estimated median: 1.14 [95% CI: 0.91–1.43]). Comparison with 42-month ACM risk observed in the ATTRibute-CM acoramidis arm (24.0%, 95% CI: 20.0–28.7) yielded a relative risk of 0.78 (95% CI: 0.60–0.99), consistent with lower observed ACM risk in the acoramidis arm. Conclusion: Acoramidis was linked to a lower estimated ACM risk in this emulated comparative analysis. These findings should be considered as hypothesis-generating, requiring confirmation in head-to-head studies.
Plain language summary
What is this article about?
Transthyretin amyloid cardiomyopathy is a serious condition caused by abnormal protein buildup in the heart. This buildup can make the heart stiff and less able to pump blood properly. Tafamidis and acoramidis are approved treatments that stabilize this protein and may slow the disease, but they have not been compared directly in a randomized trial.
This study indirectly compared the 42-month risk of death from any cause with acoramidis versus tafamidis. We combined clinical trial findings with real-world data from patients receiving tafamidis. The real-world results were adjusted to make the groups more comparable and account for differences between patients treated in routine practice and clinical trial participants.
What were the results?
Before adjustment, the estimated 42-month risk of death from any cause with tafamidis was 35.4%. After adjustment, the estimated risk was 31.2%, compared with 24.0% among participants receiving acoramidis in the ATTRibute-CM trial. The indirect comparison estimated an 22% lower relative risk of death from any cause with acoramidis, corresponding to a difference of about 7 percentage points.
What do the results mean? Why is this important?
The findings suggest that, in this indirect comparison, acoramidis may be linked with a lower 42-month risk of death from any cause than tafamidis. This provides useful preliminary evidence for patients and clinicians considering these treatments. However, this was an adjusted indirect comparison, not a head-to-head randomized trial. The findings should therefore be interpreted cautiously and confirmed in additional comparative studies.
Graphical abstract
Supplementary Material
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References
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© 2026 The authors. This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License
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Received: 4 June 2026
Accepted: 2 September 2026
Published online: 14 September 2026
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A trial emulation study indirectly comparing tafamidis and acoramidis in transthyretin amyloid cardiomyopathy: the ReplicATTR study. (2026) Journal of Comparative Effectiveness Research. DOI: 10.57264/cer-2026-0114
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