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Consistent Efficacy of Vutrisiran Across Sexes in Transthyretin Cardiac Amyloidosis: Evidence from the HELIOS-B Trial

Publication Details

European Journal of Heart Failure

June 2026

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Author(s)

Josephine Mansell¹, Xiaowen Wang², Karola S Jering², Brian Claggett², Amira Zaroui³, Tomoko Ishizu⁴, Rocio Eiros⁵, Patrick Y Jay⁶, Sarah A M Cuddy², Arielle Abovich², Julian Gillmore¹, Scott D Solomon², Marianna Fontana¹

Affiliations

¹National Amyloidosis Centre, University College London, Royal Free Campus, Rowland Hill Street, NW3 2PF, London, UK; ²Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; ³Department of Cardiology, Referral Center for Cardiac Amyloidosis, Filiere Cardiogen, GRC Amyloid Research Institute all at APHP CHU Henri Mondor, Créteil, France; ⁴Department of Cardiology, Institute of Medicine, University of Tsukuba, Japan; ⁵Cardiovascular Imaging Unit, Cardiology Department, University Hospital of Salamanca, Biomedical Research Institute of Salamanca, Spain; ⁶Alnylam Pharmaceuticals, Cambridge, MA

Abstract

Background:

Sex differences in transthyretin cardiac amyloidosis (ATTR-CM) are increasingly recognised; however, women are underrepresented in trials and sex-specific treatment effects remain incompletely understood. We evaluated sex differences in baseline phenotype, outcomes and vutrisiran response in ATTR-CM.

Methods:

HELIOS-B was a phase 3, randomised, double-blind, placebo-controlled trial enrolling patients with wild-type or variant ATTR-CM, randomised 1:1 to receive subcutaneous vutrisiran (25 mg every 12 weeks) or placebo. This prespecified analysis assessed baseline characteristics, efficacy, and safety according to sex.

Results:

Among 654 participants, 49 (7.5%) were women. Variant ATTR-CM was more prevalent in women (42.9% vs 9.1%, p < 0.001). At baseline, women had smaller absolute left ventricular dimensions and wall thicknesses (p < 0.05), but when indexed to body surface area, wall thicknesses were higher. Women demonstrated better systolic function, but worse 6-minute walk distances and quality-of-life scores. Vutrisiran reduced the primary composite endpoint of all-cause mortality and recurrent cardiovascular events in both sexes (women, HR 0.59, 95% CI 0.26–1.30; men, HR 0.71, 95% CI 0.54–0.94; p-interaction = 0.66). Confidence intervals were wide in women, reflecting limited precision from small subgroup size. Mortality reduction was observed in both sexes (HR 0.56, 95% CI 0.14–2.34 in women, HR 0.65, 95% CI 0.46–0.90 in men, p-interaction = 0.91 for all-cause mortality at 42 months). Decline in 6-minute walk distance and quality-of-life scores was attenuated in both sexes, with no statistically detectable sex-specific interaction, and safety outcomes were comparable.

Conclusions:

Women with ATTR-CM demonstrated a distinct baseline phenotype in HELIOS-B. Despite this, vutrisiran showed no statistically detectable heterogeneity of treatment effect by sex within the limits of statistical power, supporting therapeutic benefit across the phenotypic spectrum of ATTR-CM.