Clinical outcomes with vutrisiran in transthyretin amyloidosis: A systematic review and meta-analysis of randomized trials

Abstract

Background: Transthyretin amyloidosis (ATTR) is a progressive disease that causes a restrictive cardiomyopathy. Vutrisiran, a subcutaneous RNA interference (RNAi) therapy, is an approved treatment. This systematic review and meta-analysis evaluates its efficacy and safety with respect to transthyretin (TTR) reduction, functional capacity, quality of life, mortality, and adverse events.

Methods: We identified 1,032 records, of which three randomized controlled trials — HELIOS-A, HELIOS-B, and a Phase 1 study — comprising 976 participants (508 vutrisiran; 468 comparator) met the inclusion criteria. Comparator participants received placebo, patisiran (an active reference comparator in HELIOS-A), or external placebo from the APOLLO trial. Outcomes assessed were TTR reduction, functional capacity, quality of life, mortality, and adverse events, pooled using random-effects models reporting mean differences and risk ratios.

Results: Vutrisiran achieved a rapid, durable TTR reduction of up to 97% in healthy volunteers at the highest dose, and a sustained steady-state reduction in the HELIOS-A and HELIOS-B trials. QoL outcomes showed a protective effect of vutrisiran, with slowed deterioration in the intervention group. Functional outcomes (10-MWT, 6-MWT) suggested slower decline in mobility and functional capacity. Mortality showed a non-significant reduction (RR 0.51; p=0.29; I²=62%), with most deaths considered unrelated to treatment. The safety analysis showed fewer falls (RR 0.62; p=0.001; I²=0%) but no significant difference in overall adverse events (AEs) (RR 1.01; p=0.76) or serious AEs (RR 0.82; p=0.23). A sensitivity analysis supported the adverse-event findings.

Conclusions: Vutrisiran consistently suppressed TTR and showed signals of benefit in quality of life, function, and mortality, though most of these outcomes did not reach statistical significance. It reduced fall risk without increasing adverse events, indicating a favourable safety profile. Larger, long-term RCTs are needed to confirm survival and functional benefits.