Influence of disease modifying therapy on the effectiveness of vutrisiran in transthyretin cardiac amyloidosis
A Abovich, M Fontana, B Claggett, J Gillmore, F Cappelli, A Ambardekar, C Morbach, P Garcia-Pavia, R Witteles, M Maurer, P Jay, A Kosheleff, S Bansilal, S SolomonAbstract
Background
The siRNA vutrisiran reduced cardiovascular events and mortality in patients with transthyretin cardiac amyloidosis (ATTR-CM) in the HELIOS-B trial. Patterns of use of concomitant disease-modifying therapies—including tafamidis, sodium–glucose cotransporter-2 inhibitors (SGLT2i), and other heart failure (HF) medications—during the study, and whether such background therapy modifies the treatment effect of vutrisiran, remain uncertain.
Purpose
To evaluate: (1) the use and initiation of HF medications and tafamidis during follow-up; (2) the pattern of change in prescription of these therapies over time in the overall trial population; and (3) whether background use of these therapies modifies the treatment effect of vutrisiran.
Methods
HELIOS-B randomized 654 participants with ATTR-CM to vutrisiran or placebo. To address Aims 1 and 2, we described baseline use and post-randomization initiation ("drop-in") of tafamidis and HF medications (SGLT2i, mineralocorticoid receptor antagonists (MRA), beta-blockers, and renin–angiotensin system inhibitors (ACE/ARB/ARNI)), and characterized prescribing patterns over time across the full cohort. To address Aim 3, we evaluated whether the effect of vutrisiran on the primary composite endpoint (all-cause mortality and recurrent cardiovascular events) was modified by baseline or post-baseline therapy (in time-updated models).
Results
Of 654 participants randomized (placebo n=328; vutrisiran n=326), concomitant therapies were common (tafamidis 40%; SGLT2i 3.2%; MRA 35%; beta-blockers 44%; ACE/ARB/ARNI 46%), and many patients initiated therapy during follow-up (tafamidis 13%; SGLT2i 33%; MRA 24%; beta-blockers 12%; ACE/ARB/ARNI 10%). Initiation rates for individual therapies are shown in Table 1. The nominal numerical rate of drop-in for all heart failure medications was higher in the placebo group vs. the vutrisiran group (183 vs. 168), and fewer patients initiated tafamidis due to disease progression in the vutrisiran group (10 vs. 15). In time-updated models accounting for drop-in therapy, the treatment effect of vutrisiran on all-cause death and recurrent cardiovascular events was not modified by baseline or subsequent use of any disease-modifying therapy.
Conclusion
In HELIOS-B, a contemporary ATTR-CM population in which many patients were receiving HF disease-modifying therapies at baseline and additional therapies were initiated during follow-up, prescribing patterns evolved over time. The effectiveness of vutrisiran on all-cause mortality and cardiovascular events was not modified by the use of tafamidis or other HF disease-modifying treatments.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.