Relative efficacy of acoramidis, tafamidis and vutrisiran in patients with transthyretin amyloid cardiomyopathy: a multilevel network meta-regression
A Jobbe Duval, H Falvey, I Proskorovsky, S Krotneva, C Chandler, A Fraschke, M HuelsebeckAbstract
Background
Phase 3 trials have shown that acoramidis, tafamidis, and vutrisiran reduce the risk of cardiovascular-related hospitalization (CVH) and all-cause mortality (ACM) vs placebo in patients with transthyretin amyloid cardiomyopathy (ATTR-CM).[1-3] In the absence of head-to-head studies, indirect treatment comparisons (ITCs) are needed. Adjusted ITC approaches, including matching-adjusted indirect comparison (MAIC) and multilevel network meta-regression (ML-NMR), help to account for differences in baseline treatment effect modifiers between trial populations and minimize bias compared with unadjusted ITCs. ML-NMR is a novel approach that allows simultaneous comparison of multiple treatments in any target population, whereas MAIC is limited to pairwise comparisons in the comparator trial population.
Purpose
We used ML-NMR to compare acoramidis with tafamidis and vutrisiran for the risk of CVH and ACM in ATTR-CM.
Methods
Individual patient data from the phase 3 ATTRibute-CM trial (acoramidis) and published aggregate data from the phase 3 ATTR-ACT (tafamidis) and HELIOS-B (vutrisiran) trials were used in the ML-NMR.[1–3] Treatment effect modifiers were identified based on literature review and expert input. Effect modifiers adjusted in the final ML-NMR model included age, transthyretin genotype, New York Heart Association class, N-terminal pro-B-type natriuretic peptide level, estimated glomerular filtration rate, 6-minute walk distance, Kansas City Cardiomyopathy Questionnaire-Overall Summary score, disease duration, and diabetes comorbidity at baseline. Relative risk ratios for CVH over 30 months and hazard ratios for ACM at 30 months were estimated for acoramidis vs tafamidis and vutrisiran using ML-NMR in the ATTRibute-CM modified intention-to-treat population and were compared with those estimated using unadjusted Bucher ITCs in the pooled trial populations.
Results
Acoramidis was associated with an approximately 24–25% relative risk reduction in the CVH rate vs tafamidis over 30 months, although differences were not statistically significant using ML-NMR or Bucher ITC (Figure 1). When compared with vutrisiran, acoramidis was associated with an approximately 27–33% relative risk reduction in the CVH rate; this difference reached statistical significance with ML-NMR but not with Bucher ITC (Figure 1). For ACM, no statistically significant differences were observed between acoramidis and either tafamidis or vutrisiran at 30 months using ML-NMR or Bucher ITC (Figure 2).
Conclusions
Adjusted ITCs are critical to account for differences between trial populations. ML-NMR suggested that acoramidis reduced the rate of CVH vs tafamidis and vutrisiran, although estimation of CVH rates was limited owing to a lack of published exposure times in the ATTR-ACT and HELIOS-B trials. There was no difference in ACM between acoramidis and tafamidis or vutrisiran at 30 months.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.