Witteles, Ronald MGarcia-Pavia, PabloDamy, ThibaudGrogan, MarthaSheikh, Farooq HMorbach, CarolineBender, ShaunExter, JasonEraly, Satish AFontana, Marianna2025-07-232025-07-232025-04-30J Am Coll Cardiol. 2025 Apr 30:S0735-1097(25)06170-4.https://hdl.handle.net/20.500.12105/26845Patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM) have high mortality and morbidity. Vutrisiran, a subcutaneous RNA interference therapeutic, reduced the composite of all-cause mortality (ACM) and cardiovascular (CV) events (CV hospitalizations and urgent heart failure [HF] visits) in HELIOS-B (A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy) in patients with ATTR-CM. Here we present data from HELIOS-B evaluating the impact of vutrisiran on ACM and CV mortality with additional patient follow-up through 42 months, and CV events such as CV hospitalizations, HF hospitalizations, and urgent HF visits. The HELIOS-B trial randomized 655 patients to vutrisiran 25 mg or placebo once every 3 months for up to 33 to 36 months in the double-blind (DB) period, followed by an open-label extension. Prespecified mortality and CV mortality analyses used data through 39 to 42 months of follow-up (DB period and up to 6 months of the open-label extension). CV hospitalizations and HF events were evaluated over the DB period of 33 to 36 months. Differences between vutrisiran and placebo were evaluated in the overall population, and in those stratified by baseline tafamidis use. In the overall population, vutrisiran reduced the risk of ACM (HR: 0.64; 95% CI: 0.46-0.88) and CV mortality (HR: 0.67; 95% CI: 0.47-0.96) vs placebo. Vutrisiran also reduced the risk of a composite of CV mortality and CV events (HR: 0.72; 95% CI: 0.55-0.94), and lowered rates of CV hospitalizations (rate ratio [RR]: 0.75; 95% CI: 0.62-0.91), urgent HF visits (RR: 0.54; 95% CI: 0.30-0.98), and HF hospitalizations (RR: 0.67; 95% CI: 0.52-0.86) vs placebo. Consistent trends were seen regardless of baseline tafamidis use. Consistent with the primary trial results, vutrisiran reliably reduced the risk of ACM, CV mortality, CV hospitalizations, HF hospitalizations, and urgent HF visits vs placebo in patients with ATTR-CM. (HELIOS-B: A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy; NCT04153149).This study was funded by Alnylam Pharmaceuticals Inc. The funder collaborated with the authors during the study design, data collection, data analysis, data interpretation, and writing of the report. All authors had full access to all the data in the study and took final responsibility for the decision to submit the manuscript for publication. Prof Witteles has received personal fees from Alexion, Alnylam Pharmaceuticals, AstraZeneca, BridgeBio, Novo Nordisk, and Pfizer. Dr Garcia-Pavia has received speaker fees from Alnylam Pharmaceuticals, AstraZeneca, Bayer, BridgeBio, Intellia, Ionis Pharmaceuticals, Novo Nordisk, and Pfizer; has received consulting fees from Alexion, Alnylam Pharmaceuticals, AstraZeneca, Attralus, Bayer, BridgeBio, Intellia, Ionis Pharmaceuticals, Neurimmune, Novo Nordisk, and Pfizer; and has received research/educational support to his institution from Alnylam Pharmaceuticals, AstraZeneca, BridgeBio, Intellia, Novo Nordisk, and Pfizer. Dr Damy has received honoraria from Akcea, Alexion, Alnylam Pharmaceuticals, BridgeBio, Ionis Pharmaceuticals, Neurimmune, Novo Nordisk, and Pfizer. Dr Grogan has received research grants, participated in advisory boards, and has received consultancy fees paid to her institution from Alnylam Pharmaceuticals, AstraZeneca, BridgeBio/Eidos, Intellia, Janssen, Novo Nordisk, and Pfizer. Dr Sheikh has received research support from Abbott, Alnylam Pharmaceuticals, AstraZeneca, BridgeBio, and Intellia; and has performed consulting for Abbott, Alnylam Pharmaceuticals, AstraZeneca, BridgeBio, Pfizer, Procyrion, and XVIVO. Dr Morbach has research cooperation with Tomtec Imaging Systems and the University of Würzburg funded by a research grant from the Bavarian Ministry of Economic Affairs, Regional Development and Energy, Germany (MED-1811-0011, LSM-2104-0002, and LSM-2403- 0005); is supported by the German Research Foundation (DFG) within the Comprehensive Research Center 1525 “Cardio-immune interfaces” (453989101, project C5); receives financial support from the Interdisciplinary Center for Clinical Research-IZKF Würzburg (advanced clinician-scientist program; AdvCSP 3); has received advisory and speaker honoraria as well as travel grants from Alexion, Alnylam Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, EBR Systems Edwards, Eli Lilly, Intellia, Janssen, Novo Nordisk, Pfizer, SOBI, and Tomtec; and serves as principal investigator in trials sponsored by Alnylam Pharmaceuticals, AstraZeneca, Bayer, Intellia, and Novo Nordisk. Drs Bender, Exter, and Eraly are employees of, and own shares in, Alnylam Pharmaceuticals. Dr Fontana has received consultancy or advisory board fees from Alexion/Caelum Biosciences, Alnylam Pharmaceuticals, AstraZeneca, Attralus, Bayer, BridgeBio/Eidos, Cardior, Intellia, Ionis Pharmaceuticals, Janssen, Lexeo Therapeutics, Mycardium, Novo Nordisk, Pfizer, and Prothena; has received research grants from Alnylam Pharmaceuticals, AstraZeneca, BridgeBio, and Pfizer; has received salary from the British Heart Foundation Intermediate Fellowship; and has share options in Lexeo Therapeutics and Mycardium.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/HELIOS-Bcardiovascular eventscardiovascular mortalitytransthyretin amyloidosis with cardiomyopathyvutrisiranAttribution-NonCommercial-NoDerivatives 4.0 International40380962Journal of the American College of Cardiologyopen access