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Effect of Vutrisiran According to Baseline Tafamidis Use in Transthyretin Amyloidosis with Cardiomyopathy: Insights From HELIOS-B
Publication Details
Journal of the American College of Cardiology
August 2026
Author(s)
Yasuhiro Hamatani 1, Brian L Claggett 2, Sarah A M Cuddy 2, Nitasha Sarswat 3, Joban Vaishnav 4, Martha Grogan 5, Mathew S Maurer 6, Ronald M Witteles 7, Esther Gonzalez-Lopez 8, Pablo Garcia-Pavia 8, Farooq H Sheikh 9, Brian M Drachman 10, Alisa Kosheleff 11, Sameer Bansilal 11, Julian D Gillmore 12, Marianna Fontana 12, Scott D Solomon 13
Affiliations
1Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; National Hospital Organization Kyoto Medical Center, Kyoto, Japan; 2Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; 3Division of Cardiovascular Medicine, University of Chicago Medicine, Chicago, Illinois, USA; 4Johns Hopkins Hospital, Baltimore, Maryland, USA; 5Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA; 6Division of Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA; 7Stanford University School of Medicine, Stanford, California, USA; 8Hospital Universitario Puerta de Hierro Majadahonda, IDIPHIM, CIBERCV, and Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; 9MedStar Heart and Vascular Institute/Georgetown University School of Medicine, Washington, DC, USA; 10Penn Presbyterian Medical Center, University of Pennsylvania Health System, Philadelphia, Pennsylvania, USA; 11Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA; 12National Amyloidosis Centre, UCL, Division of Medicine, Royal Free Hospital, London, United Kingdom; 13Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Abstract
Background
Vutrisiran, an RNA interference therapeutic that suppresses hepatic transthyretin production, improved survival and cardiovascular outcomes in transthyretin amyloidosis with cardiomyopathy (ATTR-CM) in HELIOS-B (A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy). Tafamidis, a transthyretin stabilizer, also improves clinical outcomes. Although combining these therapies is mechanistically appealing, clinical evidence supporting this approach is limited.
Objective
We sought to evaluate whether the treatment effects of vutrisiran differed according to baseline tafamidis use in HELIOS-B.
Methods
In HELIOS-B, patients with ATTR-CM were randomized to vutrisiran 25 mg or placebo every 3 months for up to 36 months, with tafamidis use permitted and stratified. We assessed treatment effects according to baseline tafamidis use for the primary outcome of all-cause mortality and recurrent cardiovascular events and secondary endpoints, including individual components of the primary outcome, composite of all-cause mortality, cardiovascular events and outpatient worsening heart failure events, functional capacity (6-minute walk distance), and health status (Kansas City Cardiomyopathy Questionnaire–overall summary score [KCCQ-OSS]).
Results
Among 654 participants, 259 (40%) were receiving tafamidis at baseline. Patients on tafamidis were slightly younger and had higher baseline 6-minute walk distance and higher KCCQ-OSS, while baseline characteristics were generally balanced between randomized groups. The treatment effect estimates of vutrisiran compared with placebo for the primary outcome were directionally consistent across baseline tafamidis strata (rate ratio: 0.79 [95% CI: 0.51-1.21] with tafamidis vs 0.67 [95% CI: 0.49-0.93] without), with no statistically significant interaction (Pinteraction = 0.55). Similar patterns were observed for all-cause mortality, cardiovascular events, and outpatient worsening heart failure (all Pinteraction > 0.20), although the magnitudes of the estimated effects were numerically smaller among patients receiving tafamidis at baseline. Vutrisiran preserved 6-minute walk distance in both baseline tafamidis strata (Pinteraction = 0.24), whereas improvement in KCCQ-OSS appeared attenuated among patients receiving tafamidis at baseline.
Conclusions
Treatment effect estimates for vutrisiran on clinical outcomes were consistent across baseline tafamidis strata, with no statistically significant interaction according to baseline tafamidis use, with reduced effect size noted in those receiving baseline stabilizers in comparison to monotherapy. These data underscore the need for future prospective studies examining combination therapy in this population. (HELIOS-B: A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy; NCT04153149)
PMID
42669070
DOI
https://doi.org/10.1016/j.jacc.2026.07.022
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