Vutrisiran shows consistent clinical benefits and safety in ATTR-CM across age spectrum

In a prespecified analysis of HELIOS-B, vutrisiran reduced the risk of death or CV events and maintained functional capacity and QoL compared with placebo in all patients with transthyretin amyloid cardiomyopathy (ATTR-CM), including those aged ≥80 years.

This summary is based on the publication of Sheikh A, Miao ZM, Claggett B, et al. - Efficacy and safety of vutrisiran in transthyretin amyloid cardiomyopathy across the age spectrum: The HELIOS-B trial. Eur J Heart Fail. 2025 Dec;27(12):2971-2978. doi: 10.1002/ejhf.70084

Introduction and methods

Background

Transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal disease characterized by the deposition of amyloid fibrils, which consist of misfolded transthyretin (TTR) aggregates, in the myocardium. Wild-type ATTR-CM affects mostly elderly patients, with a median age of onset of ~75 years [1]. If left untreated, the median survival time following diagnosis is 2–6 years [1]. Physicians may be concerned about attenuated treatment effects and safety issues in older ATTR-CM patients, for example, due to the higher likelihood of comorbidities and polypharmacy.

Vutrisiran, an siRNA that inhibits the production of amyloidogenic TTR protein, reduced the risk of death or CV events compared with placebo in ATTR-CM patients, as shown in the HELIOS-B (A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy) trial [2]. In addition, the treatment preserved their functional capacity and quality of life.

Aim of the study

In a prespecified analysis of the HELIOS-B trial, the efficacy and safety were investigated in ATTR-CM patients across the age spectrum.

Methods

The HELIOS-B trial was a global, multicenter, placebo-controlled, double-blind, phase 3 RCT in which 654 patients with a confirmed diagnosis of ATTR-CM (wild-type or hereditary) aged 18–85 years were randomized to subcutaneous vutrisiran 25 mg or placebo every 3 months for up to 36 months. Treatment with tafamidis (either at baseline or initiated during the trial) was permitted. Patients with significant frailty or advanced comorbidities (including NYHA class IV HF symptoms) were excluded.

Of the study patients, 257 (39.3%) were <75 years old, 201 (30.7%) were aged 75–79 years, and 196 (30.0%) were ≥80 years of age.

Outcomes

The primary endpoint was a composite outcome of all-cause mortality or recurrent CV events (i.e., CV hospitalizations and urgent HF visits). Secondary endpoints included all-cause mortality up to 42 months and changes from baseline to 30 months in the 6-minute walk distance (6MWD) and KCCQ – Overall Summary Score (OSS).

Safety assessment included the frequencies of treatment-emergent adverse events, serious adverse events, and adverse events leading to discontinuation of the study drug.

Main results

Efficacy

• Vutrisiran reduced the risk of the primary composite endpoint compared with placebo in patients aged <75 years (rate ratio (RR): 0.58; 95%CI: 0.36–0.92), those aged 75–79 years (RR: 0.92; 95%CI: 0.59–1.44), and those aged ≥80 years (RR: 0.71; 95%CI: 0.45–1.12). Although the risk reductions in the latter 2 age categories were not statistically significant, there was no interaction between treatment and age group (P for interaction=0.56).
• When age was analyzed as a continuous variable, the treatment effect of vutrisiran versus placebo for the primary endpoint was also consistent across the age spectrum (P for interaction=0.63).
• Furthermore, consistent clinical benefits of vutrisiran over placebo with no significant interaction between treatment and age were observed for all-cause mortality at 42 months (P for interaction=0.87) and the changes in 6MWD (P for interaction=1.00) and KCCQ-OSS (P for interaction=0.35).

Safety

• Across all age categories, comparable incidence rates of treatment-emergent adverse events (P for interaction=0.86), serious adverse events (P for interaction=0.53), and adverse events leading to study drug discontinuation (P for interaction=0.19) were found.

Conclusion

In this prespecified analysis of the HELIOS-B trial, vutrisiran treatment reduced the risk of all-cause mortality or recurrent CV events and maintained functional capacity and quality of life compared with placebo in ATTR-CM patients across the age spectrum, including those aged ≥80 years. The safety profile of vutrisiran was also consistent across age groups. According to the authors, their findings “reinforce that age alone should not be a barrier to offering effective disease-modifying therapies for ATTR-CM and support the use of vutrisiran in elderly patients, who represent a substantial and growing proportion of the affected population.”

Find this article online at Eur J Heart Fail.

References

1. Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol 2019;73:2872–2891. https://doi.org/10.1016/j.jacc.2019.04.003
2. Fontana M, Berk JL, Gillmore JD, Witteles RM, Grogan M, Drachman B, et al.; HELIOS-B Trial Investigators. Vutrisiran in patients with transthyretin cardiac amyloidosis. N Engl J Med 2024;390:211–222. https://doi.org/10.1056/NEJMoa2409134