Consistent Efficacy of Vutrisiran Across Sexes in Transthyretin Cardiac Amyloidosis: Evidence from the HELIOS-B Trial.
Vutrisiran appears to have consistent efficacy in reducing mortality and cardiovascular events in both men and women with ATTR-CM, though findings in women are less precise due to a smaller sample size.
Where it sits
this study against the rest of the cardiogen (aedr) corpusSummary and findings
This study evaluated sex differences in baseline characteristics and outcomes in patients with transthyretin cardiac amyloidosis (ATTR-CM) receiving vutrisiran. The trial involved 654 participants, with 25 mg of vutrisiran administered subcutaneously every 12 weeks. Results indicated that vutrisiran reduced the primary composite endpoint of all-cause mortality and recurrent cardiovascular events in both sexes.
Abstract
<h4>Aims</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.
Background
This paper addresses the underrepresentation of women in clinical trials for transthyretin cardiac amyloidosis (ATTR-CM) and the need to understand sex-specific treatment effects. Prior studies have shown that sex differences exist in the phenotype and outcomes of ATTR-CM, yet the implications for treatment response have not been fully explored. This study is significant as it aims to evaluate the efficacy of vutrisiran across sexes in a large cohort.
Methods
The HELIOS-B trial was a phase 3, randomised, double-blind, placebo-controlled study involving 654 patients with wild-type or variant ATTR-CM. Participants were randomised 1:1 to receive subcutaneous vutrisiran (25 mg every 12 weeks) or placebo. The prespecified analysis focused on baseline characteristics, efficacy, and safety according to sex.
Results
Among the 654 participants, 49 (7.5%) were women. Vutrisiran reduced the primary composite endpoint of all-cause mortality and recurrent cardiovascular events in women (HR 0.59, 95% CI 0.26-1.30) and men (HR 0.71, 95% CI 0.54-0.94; p-interaction = 0.66). Mortality reduction was observed in women (HR 0.56, 95% CI 0.14-2.34) and men (HR 0.65, 95% CI 0.46-0.90, p-interaction = 0.91) at 42 months.
Interpretation
The findings suggest that vutrisiran has a consistent efficacy across sexes, although the effect size in women is less precise due to the small sample size. The mortality reduction observed in both sexes is noteworthy, but the wide confidence intervals in women indicate a need for caution in interpreting these results. The lack of statistically detectable interaction by sex suggests that the treatment may be beneficial across the phenotypic spectrum of ATTR-CM, but further studies are needed to confirm these findings.
Key findings
- 49 (7.5%) were women among 654 participants.
- Variant ATTR-CM was more prevalent in women (42.9% vs 9.1%, p < 0.001).
- Vutrisiran reduced the primary composite endpoint in women (HR 0.59, 95% CI 0.26-1.30) and men (HR 0.71, 95% CI 0.54-0.94; p-interaction = 0.66).
- Mortality reduction was observed in women (HR 0.56, 95% CI 0.14-2.34) and men (HR 0.65, 95% CI 0.46-0.90, p-interaction = 0.91) at 42 months.
Limitations
- small n=654 with only 49 women
- wide confidence intervals in women reflect limited precision
- no statistically detectable sex-specific interaction