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Influence of Disease-Modifying Therapy on the Efficacy of Vutrisiran in Transthyretin Cardiac Amyloidosis
Publication Details
Journal of the American College of Cardiology
August 2026
Author(s)
Arielle Abovich 1, Marianna Fontana 2, Brian Claggett 1, Julian D Gillmore 2, Francesco Cappelli 3, Amrut V Ambardekar 4, Caroline Morbach 5, Pablo Garcia-Pavia 6, Ronald M Witteles 7, Mathew S Maurer 8, Patrick Y Jay 9, Alisa Kosheleff 9, Sameer Bansilal 9, Scott D Solomon 10
Affiliations
1Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; 2National Amyloidosis Centre, Division of Medicine, University College London, Royal Free Hospital, London, United Kingdom; 3Bis Department of Clinical and Experimental Medicine, University of Florence, Florence, Italy; Tuscan Amyloidosis Referral Center Careggi University Hospital, Florence, Italy; 4Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; 5Department of Clinical Research and Epidemiology, Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany; Department of Medicine I, University Hospital Würzburg, Würzburg, Germany; 6Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Health Research Institute of the Puerta de Hierro Majadahonda-Segovia de Arana, Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBER-CV), and Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain; 7Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA; 8Columbia University Irving Medical Center, New York, New York, USA; 9Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA; 10Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Abstract
Background
Vutrisiran, an RNA interference therapeutic, reduced all-cause mortality and recurrent cardiovascular events in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) in the HELIOS-B trial. Whether concomitant disease-modifying or heart failure therapy modifies the efficacy of vutrisiran has not been described.
Objective
We aimed to characterize patterns of concomitant therapy use in HELIOS-B, describe medication initiation rates by treatment arm, and evaluate whether concomitant therapy modified vutrisiran’s treatment effect.
Methods
In HELIOS-B, 654 randomized patients with ATTR-CM received vutrisiran or placebo. We assessed baseline use and postrandomization initiation of tafamidis, sodium-glucose cotransporter-2 (SGLT2) inhibitors, mineralocorticoid receptor antagonists (MRA), beta-blockers, and renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors), and used time-updated Lin-Wei-Yang-Ying models to evaluate treatment effect modification on the primary composite endpoint of all-cause mortality and recurrent cardiovascular events.
Results
At baseline, 40% of participants were receiving tafamidis and 77% at least 1 heart failure medication. MRAs and SGLT2 inhibitors were the most frequently initiated therapies during follow-up, with initiation rates numerically higher across all heart failure medication classes in the placebo group. There was no statistically significant evidence that the treatment effect of vutrisiran was modified by baseline or time-updated use of any medication class (P-interaction: tafamidis 0.95, SGLT2 inhibitors 0.59, MRA 0.92, beta-blockers 0.75, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors 0.82).
Conclusions
In HELIOS-B, there was no statistically significant evidence that the treatment benefit of vutrisiran on all-cause mortality and recurrent cardiovascular events was modified by concomitant use of tafamidis or heart failure therapies. These findings support the consistency of vutrisiran’s efficacy across the spectrum of contemporary ATTR-CM pharmacotherapy. (HELIOS-B: A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy; NCT04153149)
PMID
42669069
DOI
https://doi.org/10.1016/j.jacc.2026.07.023
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