Anchored matching-adjusted indirect comparison of acoramidis (ATTRibute-CM) vs tafamidis (ATTR-ACT) for risk of cardiovascular-related hospitalization, all-cause mortality and safety in ATTR-CM
E Joyce, A Masri, Z Shah, K Xiong, S Krotneva, I Proskorovsky, A Fraschke, M Huelsebeck, L Hennum, J F Tamby, H Falvey, A Jobbe-Duval, K AlexanderAbstract
Background
Acoramidis and tafamidis are transthyretin (TTR) stabilizers for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM). Both reduced the risk for cardiovascular-related hospitalization (CVH) and all-cause mortality (ACM) vs placebo in their respective phase 3 pivotal trials, ATTRibute-CM and ATTR-ACT, and had similar safety profiles. To date, no trials have directly compared acoramidis with tafamidis. In the absence of head-to-head studies, anchored matching-adjusted indirect comparison (MAIC) allows for indirect treatment comparisons (ITCs) while adjusting for cross-trial heterogeneity using placebo as the common anchor.
Purpose
We conducted an MAIC to compare acoramidis vs tafamidis 80mg for risk of CVH, ACM and safety in ATTR-CM.
Methods
Potential treatment effect modifiers (EMs) were prespecified before data analysis based on published evidence and clinical expert input. For efficacy outcomes, EMs included age, TTR genotype, New York Heart Association Class, N-terminal pro B-type natriuretic peptide level and estimated glomerular filtration rate. To adjust for imbalances in these EMs between studies, individual participant data from ATTRibute-CM were weighted to match published aggregate data for ATTR-ACT. Data after initiation of concomitant tafamidis, which was allowed after month 12 in ATTRibute-CM, were excluded to avoid potential confounding. Sensitivity analyses for CVH and ACM were conducted without censoring for concomitant tafamidis, and with matching on baseline medication and pacemaker use. For safety, no EMs were identified, so only naïve Bucher ITCs were conducted with and without censoring for concomitant tafamidis.
Results
For efficacy, matching and adjustment resolved imbalances in EMs (Table), resulting in the effective sample size (ESS) of 209 and 89 for acoramidis and placebo, respectively, in ATTRibute-CM. Adjusting for all potential EMs and excluding concomitant tafamidis use, acoramidis was associated with a statistically significant 34% relative risk reduction in the annual frequency of CVH vs tafamidis (relative risk ratio: 0.66; 95% confidence interval [CI]: 0.46, 0.95). For ACM, results showed a non-statistically significant 28% hazard reduction vs tafamidis (hazard ratio: 0.72; 95% CI: 0.41, 1.26) (Figure). Across the prespecified sensitivity analyses, findings were similar to the primary analysis. Safety, as assessed by naïve Bucher ITCs with and without censoring for concomitant tafamidis, was comparable between treatments.
Conclusions
The MAIC demonstrated improved clinical outcomes for acoramidis vs tafamidis, including a statistically significant, clinically meaningful reduction in the frequency of CVH and a trend towards risk reduction in ACM. Comparison of ACM was limited by the relatively short follow up of 30 months in the double-blind phase and wide confidence intervals. Further head-to-head evaluations are needed to confirm the findings.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.