Comparative efficacy and safety of tafamidis versus acoramidis in transthyretin amyloid cardiomyopathy: a matching-adjusted indirect comparison
S Perlini, B W Sperry, C Khanji, M Ines, C L Baker, P F Branquinho, J Cappelleri, H Chu, L Han, R Dey, H MoradianAbstract
Introduction
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a rare, progressive disease with significant morbidity and mortality. Tafamidis is an established once-daily oral transthyretin stabilizer which demonstrated a statistically significant reduction in mortality at 30 months in ATTR-CM patients vs placebo. Acoramidis is another stabilizer that was recently approved. In the absence of head-to-head trials, population-adjusted indirect treatment comparisons may help inform comparative effectiveness for decision making.
Purpose
Evaluate the comparative effectiveness of tafamidis and acoramidis.
Methods
Individual patient data from the Phase 3 randomized controlled ATTR-ACT trial (tafamidis vs placebo) were reweighted using matching-adjusted indirect comparison to mirror the baseline data from ATTRibute-CM (acoramidis vs placebo); a study in which patients could initiate tafamidis treatment after Month 12. To be consistent with the ATTRibute-CM trial, for the base case, efficacy endpoints were analyzed using a modified intention-to-treat population and safety endpoints were analyzed using an intention-to-treat population. Because of known differences in trial populations, the following effect modifiers were prespecified for the base case by clinical experts and included if reported in both trials: N-terminal pro-B-type natriuretic peptide, estimated glomerular filtration rate, New York Heart Association class, age, sex, genotype and for efficacy endpoints, country was also included. Efficacy endpoints feasible for comparison included all-cause mortality (ACM), cardiovascular mortality (CVM), change from baseline for 6-Minute Walk Distance, and Kansas City Cardiomyopathy Questionnaire Overall Score. Safety outcomes were also assessed, and sensitivity analyses were performed.
Results
In the base case, after adjustment (effective sample size: 121) (Table 1), tafamidis showed directional improvement in all efficacy outcomes over acoramidis and was associated with a statistically significant reduction in CVM of 63% (Hazard ratio [HR] 0.37, 95% CI: 0.14–0.97). Regarding the safety analysis (effective sample size: 207) (Table 2), no statistically significant differences were found between treatments, except for treatment-related treatment-emergent adverse events (TEAEs) where a significant reduction was found with tafamidis (Odds Ratio [OR] 0.31, 95% CI: 0.13–0.74). All sensitivity analyses showed that tafamidis was associated with improved outcomes over acoramidis.
Conclusion
These findings highlight a consistent trend toward improved efficacy and safety of tafamidis vs acoramidis in patients with ATTR-CM. Statistically significant differences favouring tafamidis were found for CVM and treatment-related TEAEs. By adjusting for population differences, these findings provide a robust basis for evidence-based decisions in a contemporary population and support the use of tafamidis as a consolidated benchmark therapy.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.