Vutrisiran: Echocardiographic Assessments in HELIOS-B

Vutrisiran: Echocardiographic Assessments in HELIOS-B

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 Summary

Index

Study Design – Patient Demographics & Baseline Characteristics – 30-Month Echocardiographic Analyses – 18‑Month Echocardiographic Analyses – Safety Results – Abbreviations – References

 Study Design

HELIOS-B was a phase 3, global, randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of vutrisiran in patients with ATTR-CM, including both hATTR and wtATTR. Patients were randomized (1:1) to receive either vutrisiran 25 mg (n=326) or placebo (n=329) every 3 months by subcutaneous injection for up to 36 months. The primary endpoint was the composite endpoint of all-cause mortality and recurrent CV events (CV hospitalizations and urgent heart failure visits) at the end of the double-blind period in the overall population and in the monotherapy population (patients not receiving tafamidis at baseline).1

Echocardiograms were performed at baseline and at 12, 18, 24, and 30 months by certified sonographers at each site. The changes from baseline in echocardiographic parameters over time were analyzed with MMRM with the corresponding baseline echocardiographic parameter included as a covariate and treatment group, visit, treatment-by-visit interaction, baseline tafamidis use, treatment‑by-baseline tafamidis use interaction, ATTR disease type, and age group (<75 vs ≥75 years) included as fixed-effect terms in the overall population.2,5

 Patient Demographics & Baseline Characteristics

Select baseline characteristics of echocardiographic measures in the overall population and the monotherapy population are presented in Table 1.2 The median age of study participants was 77 years, 93% were male, and 88% had wtATTR. The monotherapy population was defined as patients who did not receive tafamidis at baseline and comprised a total of 395 patients (196 patients [60%] in the vutrisiran arm and 199 patients [60%] in the placebo arm).1

In the overall population, baseline use of SGLT2 inhibitors was 3% in both treatment arms. Baseline use of diuretics was 80% and 79% in the vutrisiran and placebo arms, respectively.6

Table 1. Select Baseline Echocardiographic Parameters in HELIOS-B.2

 30-Month Echocardiographic Analyses

The changes from baseline in mean LV wall thickness and GLS at 30 months were prespecified as exploratory endpoints in the HELIOS-B study. Changes in other echocardiographic parameters were not prespecified and are considered exploratory. Missing data were not imputed.2

The changes from baseline in select echocardiographic parameters at 30 months in the overall and monotherapy populations are summarized in Tables 2 and 3, respectively. The changes from baseline in echocardiographic parameters over time in the vutrisiran group compared with the placebo group in the overall population are presented in Figure 1.2

Table 2. LS Mean Changes from Baseline in Select Echocardiographic Parameters at 30 Months in the Overall Population.2

Table 3. LS Mean Changes from Baseline in Select Echocardiographic Parameters at 30 Months in the Monotherapy Population.2

Figure 1. Change from Baseline in Echocardiographic Parameters Over Time in the Overall Population.2

Additional post-hoc analyses of the HELIOS-B study were conducted to assess the changes from baseline in measures of right ventricular and left atrial function with vutrisiran treatment.3,4

Right Ventricular Free Wall Strain

Among 548 patients who had available baseline RVFWS, the absolute mean RVFWS was 14.4 ± 5.1%. RV dysfunction, defined as RVFWS <20%, was present in 85% of patients. Lower RVFWS at baseline was non-linearly associated with an increased risk of all-cause mortality and recurrent CV events, independent of age, sex, ATTR disease type, NAC disease stage, atrial fibrillation/flutter, baseline tafamidis use, and LV GLS (Figure 2).3

Figure 2. Association of Baseline RVFWS with Subsequent Clinical Outcomes.3

At 30 months, the between-group difference in mean change from baseline in RVFWS between the vutrisiran and placebo groups was 1.6% (95% CI 0.7, 2.5) (Figure 3).3

Figure 3. Mean Change from Baseline in RVFWS at 30 Months.3

Left Atrial Strain

Among 644 patients with available baseline LAS, lower LAS at baseline was associated with an increased risk of all-cause mortality and recurrent CV events, independent of LV systolic function and E/e’ (Figure 4).4

Figure 4. Association of Baseline LAS with Subsequent Clinical Outcomes.4

The mean change from baseline in LAS at 30 months in the vutrisiran and placebo groups are presented in Figure 5.4

Figure 5. Mean Change from Baseline in LAS at 30 Months.4

 18-Month echocardiographic Analyses 

A post-hoc analysis of the HELIOS-B study was conducted to evaluate the associations between baseline echocardiographic parameters with clinical outcomes and to assess how changes in echocardiographic parameters at 18 months related to subsequent clinical outcomes.5

Association of Baseline Echocardiographic Parameters with Clinical Outcomes

Over a median follow-up period of 35.7 months, 125 patients in the vutrisiran group and 159 patients in the placebo group experienced the primary composite outcome of all-cause mortality and recurrent CV events. Sixty patients (18%) in the vutrisiran group and 85 patients (26%) in the placebo group died during the double-blind and 6-month OLE period.5

The association of select baseline echocardiographic parameters with the primary composite outcome and with the secondary outcome of all-cause mortality are presented in Tables 4 and 5, respectively.5

Table 4. Association of Select Baseline Echocardiographic Parameters with the Primary Composite Outcome.5

Table 5. Association of Select Baseline Echocardiographic Parameters with All-Cause Mortality.5

Change from Baseline in Echocardiographic Parameters at 18 Months

In the overall population, the LS mean (±SEM) change from baseline in LVEF at 18 months was ‑3.1% (0.6) in the vutrisiran group and -4.7% (0.6) in the placebo group, resulting in a LS mean difference (95% CI) of 1.6% (0.1, 3.2).7

The LS mean (±SEM) change from baseline in absolute GLS at 18 months was -0.4% (0.2) in the vutrisiran group and ‑1.1% (0.2) in the placebo group, resulting in a LS mean difference (95% CI) of 0.7% (0.3, 1.2).7

The LS mean (±SEM) change from baseline in RV S’ at 18 months was 0.1 cm/s (0.2) in the vutrisiran group and -0.4 cm/s (0.1) in the placebo group, resulting in a LS mean difference (95% CI) of 0.5 cm/s (0.1, 0.9).7

The LS mean (±SEM) change from baseline in lateral E/e’ at 18 months was -0.6 (0.3) in the vutrisiran group and 0.7 (0.3) in the placebo group, resulting in a LS mean difference (95% CI) of -1.4 (-2.2, ‑0.6).7

Association of Change from Baseline to 18 Months in Echocardiographic Parameters and Subsequent Clinical Outcomes

The associations of the changes in echocardiographic parameters from baseline to 18 months were assessed in landmark analyses using modified Andersen-Gill and Cox proportional hazards regression models, respectively.5

The association of changes in select echocardiographic parameters from baseline to 18 months with the subsequent primary composite outcome is presented in Table 6.5

Table 6. Association of Changes in Select Echocardiographic Parameters from Baseline to 18 Months with the Subsequent Primary Composite Outcome.5

The association of changes in select echocardiographic parameters from baseline to 18 months with subsequent all-cause mortality are presented in Table 7 and Figure 6. A 1% point worsening in absolute GLS, a 5% decline in LVEF, and a 1 cm/s decline in RV S’ were associated with a 9%, 15%, and 18% increased risk of subsequent all-cause mortality, respectively, independent of age, sex, ATTR disease type, NAC disease stage, baseline tafamidis use, and treatment assignment.5

Table 7. Association of Changes in Select Echocardiographic Parameters from Baseline to 18 Months with Subsequent All-Cause Mortality.5

Figure 6. Association of Changes from Baseline to Month 18 in Select Echocardiographic Parameters with Subsequent All-Cause Mortality.5

 Safety Results

In the overall population, the incidence of AEs and cardiac AEs were similar between the treatment groups. A summary of the safety results during the double-blind period are presented in Table 8.1,6

Table 8. HELIOS-B Safety Summary.6

There were no clinically relevant changes in laboratory measures (including hematologic measures, blood chemistry measures, liver function tests, and renal function tests), vital signs, or electrocardiograms in either treatment group.1

 Abbreviations

ACM = all-cause mortality; AE = adverse event; AF = atrial fibrillation; AFl = atrial flutter; ATTR = transthyretin amyloidosis; ATTR-CM = transthyretin amyloidosis with cardiomyopathy; CI = confidence interval; CV = cardiovascular; E/A = ratio of early to late diastolic transmitral inflow velocities; E/e’ = ratio of peak early diastolic transmitral flow velocity to peak early diastolic mitral annular tissue velocity; GLS = global longitudinal strain; hATTR = hereditary transthyretin amyloidosis; HF = heart failure; HR = hazard ratio; LAS = left atrial strain; LAVi = left atrial volume index; LS = least squares; LV = left ventricular; LVEF = left ventricular ejection fraction; MMRM = mixed models for repeated measures; NAC = National Amyloidosis Centre; RV = right ventricular; RV S’ = right ventricular systolic myocardial velocity; RVFWS = right ventricular free wall strain; SAE = serious adverse event; SD = standard deviation; SEM = standard error of the mean; SGLT2 = sodium‑glucose cotransporter-2; TDI lateral e’ = lateral peak early diastolic mitral annular tissue velocity; wtATTR = wild-type transthyretin amyloidosis.

Updated 21 January 2026

References

1.  Fontana M, Berk JL, Gillmore JD, et al. Vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy. N Engl J Med. 2025;392(1):33-44. doi:10.1056/NEJMoa2409134

2.  Jering KS, Fontana M, Lairez O, et al. Effects of vutrisiran on cardiac structure and function in patients with transthyretin amyloidosis with cardiomyopathy: secondary outcomes of the HELIOS-B trial. Nat Med. 2025;31(10):3560-3568. doi:10.1038/s41591-025-03851-z

3.  Manafi A, Jering K, Fontana M, et al. Right ventricular free wall strain and clinical outcomes in transthyretin amyloid cardiomyopathy and effect of vutrisiran: The HELIOS-B study. Presented at: American Heart Association (AHA) Scientific Sessions; November 7-10, 2025; New Orleans, LA, USA.

4.  Jering K, Manafi A, Bart N, et al. Left atrial strain and clinical outcomes in transthyretin amyloidosis with cardiomyopathy: Insights from the HELIOS-B trial on vutrisiran efficacy. Presented at: American Heart Association (AHA) Scientific Sessions; November 7-10, 2025; New Orleans, LA, USA.

5.  Jering KS, Fontana M, Skali H, et al. Effects of vutrisiran on cardiac function and outcomes in patients with transthyretin amyloidosis with cardiomyopathy. J Am Coll Cardiol. 2025;86(6):444-455. doi:10.1016/j.jacc.2025.06.022

6.  Supplement to: Fontana M, Berk JL, Gillmore JD, et al. Vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy. N Engl J Med. 2025;392(1):33-44. doi:10.1056/NEJMoa2409134

7.  Supplement to: Jering KS, Fontana M, Skali H, et al. Effects of vutrisiran on cardiac function and outcomes in patients with transthyretin amyloidosis with cardiomyopathy. J Am Coll Cardiol. 2025;86(6):444-455. doi:10.1016/j.jacc.2025.06.022