Impact of Heart Failure Severity on Vutrisiran Efficacy in Transthyretin Amyloidosis with Cardiomyopathy
Publication Details
Journal of the American College of Cardiology
March 2025
Author(s)
Mathew S Maurer1, Ronald M Witteles2, Pablo Garcia-Pavia3, Farooq H Sheikh4, Caroline Morbach5, Daniel Rodriguez Duque6, Emre Aldinc6, Satish A Eraly6, Julian D Gillmore7
Affiliations
1Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA; 2Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA; Stanford Amyloid Center, Stanford, California, USA; 3Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Health Research Institute of the Puerta de Hierro Majadahonda-Segovia, Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBER-CV), Madrid, Spain; Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; 4MedStar Heart and Vascular Institute, Georgetown University School of Medicine, Washington DC, USA; 5Department of Clinical Research and Epidemiology, Comprehensive Heart Failure Center, Würzburg, Germany; Department of Medicine I, University Hospital Würzburg, Würzburg, Germany; 6Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA; 7National Amyloidosis Centre, UCL, Division of Medicine, Royal Free Hospital, London, United Kingdom
Abstract
Background:
Vutrisiran reduced the risk of all-cause mortality (ACM) and recurrent cardiovascular (CV) events in patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM) in HELIOS-B (A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy; NCT04153149).
Objectives:
This study sought to assess the effect of vutrisiran in HELIOS-B patients with different heart failure severities.
Methods:
HELIOS-B randomized patients with ATTR-CM with NYHA functional class I-III (functional class IV or functional class III with National Amyloidosis Centre [NAC] stage 3 were excluded) 1:1 to vutrisiran 25 mg or placebo every 3 months for up to 36 months. This exploratory subgroup analysis assessed the primary composite endpoint of ACM and recurrent CV events, ACM, and additional functional and biomarker endpoints.
Results:
Of 654 patients, 84 (13%), 508 (78%), and 62 (9%) were in NYHA functional class I, II, and III, respectively. Median baseline N-terminal pro–B-type natriuretic peptide (NT-proBNP) level was 1,920 ng/L. Lower risk of ACM and recurrent CV events was observed with vutrisiran vs placebo across baseline severity subgroups: respective HRs were 0.54 (95% CI: 0.27-1.10), 0.77 (95% CI: 0.57-1.03), and 0.68 (95% CI: 0.33-1.41) in NYHA functional classes I, II, and III, respectively; 0.52 (95% CI: 0.30-0.88), 0.61 (95% CI: 0.37-1.00), and 0.93 (95% CI: 0.64-1.35) in NT-proBNP tertiles <1,368 ng/L, ≥1,368 and <2,691 ng/L, and ≥2,691 ng/L; 0.49 (95% CI: 0.34-0.72) and 1.08 (95% CI: 0.74-1.56) in NAC stages 1 and 2/3, respectively; and 0.69 (95% CI: 0.45-1.07) and 0.74 (95% CI: 0.53-1.02) in Columbia early and intermediate/late stages, respectively. Similar effects were observed in the monotherapy population (patients not on tafamidis at baseline) and across the additional endpoints evaluated.
Conclusions:
Vutrisiran demonstrated evidence of benefit across the range of baseline disease severities in HELIOS-B, with the greatest benefit in earlier, less severe disease. (A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy [HELIOS-B]; NCT04153149)
PMID
40099776
DOI
10.1016/j.jacc.2025.03.477
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