• Marianna Fontana, John L Berk, Julian D Gillmore, Ronald M Witteles, Martha Grogan, Brian Drachman, Thibaud Damy, Pablo Garcia-Pavia, Jorg Taubel, Scott D Solomon, Farooq H Sheikh, Nobuhiro Tahara, José González-Costello, Kenichi Tsujita, Caroline Morbach, Zoltán Pozsonyi, Mark C Petrie, Diego Delgado, Peter Van der Meer, Andrew Jabbour, Antoine Bondue, Darae Kim, Olga Azevedo, Steen Hvitfeldt Poulsen, Ali Yilmaz, Ewa A Jankowska, Vincent Algalarrondo, Andrew Slugg, Pushkal P Garg, Katherine L Boyle, Elena Yureneva, Nancy Silliman, Lilli Yang, Jihong Chen, Satish A Eraly, John Vest, Mathew S Maurer, and HELIOS-B Trial Investigators.
• From the National Amyloidosis Centre, Division of Medicine, University College London, Royal Free Hospital (M.F., J.D.G.), and Richmond Pharmacology (J.T.), London, and the Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, Glasgow (M.C.P.) - all in the United Kingdom; Boston University School of Medicine (J.L.B.) and the Cardiovascular Division, Brigham and Women's Hospital (S.D.S.) - both in Boston; the Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA (R.M.W.); the Department of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, MN (M.G.); the Division of Cardiology, Penn Presbyterian Medical Center, University of Pennsylvania Health System, Philadelphia (B.D.); the Cardiology Department and French National Reference Centre for Cardiac Amyloidosis, GRC Amyloid Research Institute and Clinical Investigation Centre 1430 at Hôpitaux Universitaires Henri-Mondor, Assistance Publique-Hôpitaux de Paris (AP-HP), and Institut Mondor de Recherche Biomédicale, INSERM, Université Paris Est Creteil, Creteil (T.D.), and the Department of Cardiology, French National Reference Center for Cardiac Amyloidosis, Bichat University Hospital, AP-HP, Paris (V.A.) - all in France; the Department 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), and Centro Nacional de Investigaciones Cardiovasculares (P.G.-P.), and CIBER-CV (J.G.-C.), Madrid, and the Department of Cardiology, Hospital Universitari de Bellvitge, Instituto de Investigación Biomédica de Bellvitge, and Universitat de Barcelona, Barcelona (J.G.-C.) - all in Spain; MedStar Heart and Vascular Institute, MedStar Health, and Georgetown University School of Medicine - both in Washington, DC (F.H.S.); the Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume (N.T.), and the Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto (K.T.) - both in Japan; the Department of Clinical Research and Epidemiology, Comprehensive Heart Failure Center, University Hospital Würzburg, and the Department of Medicine I, University Hospital Würzburg, Würzburg (C.M.), and the Division of Cardiovascular Imaging, University Hospital Münster, Münster (A.Y.) - both in Germany; the Department of Internal Medicine and Hematology, Semmelweis University, Budapest, Hungary (Z.P.); the Department of Cardiology, University Health Network of Toronto, Toronto (D.D.); University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (P.V.M.); the Victor Chang Cardiac Research Institute, the Cardiology Department, St. Vincent's Hospital, and the School of Clinical Medicine, University of New South Wales - all in Sydney (A.J.); the Department of Cardiology, Hôpital Universitaire de Bruxelles-Hôpital Erasme, Université Libre de Bruxelles, Brussels (A.B.); the Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (D.K.); the Cardiology Department, Hospital Senhora da Oliveira-Guimarães, Guimarães, and the School of Medicine, University of Minho, Braga - both in Portugal (O.A.); the Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark (S.H.P.); the Division of Translational Cardiology and Clinical Registries, Institute of Heart Diseases, Wrocław Medical University, Wrocław, Poland (E.A.J.); Alnylam Pharmaceuticals, Cambridge, MA (A.S., P.P.G., K.L.B., E.Y., N.S., L.Y., J.C., S.A.E., J.V.); and Columbia University Irving Medical Center, New York (M.S.M.).
• N. Engl. J. Med. 2024 Aug 30.

BackgroundTransthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, fatal disease. Vutrisiran, a subcutaneously administered RNA interference therapeutic agent, inhibits the production of hepatic transthyretin.MethodsIn this double-blind, randomized trial, we assigned patients with ATTR-CM in a 1:1 ratio to receive vutrisiran (25 mg) or placebo every 12 weeks for up to 36 months. The primary end point was a composite of death from any cause and recurrent cardiovascular events. Secondary end points included death from any cause, the change from baseline in the distance covered on the 6-minute walk test, and the change from baseline in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score. The efficacy end points were assessed in the overall population and in the monotherapy population (the patients who were not receiving tafamidis at baseline) and were tested hierarchically.ResultsA total of 655 patients underwent randomization; 326 were assigned to receive vutrisiran and 329 to receive placebo. Vutrisiran treatment led to a lower risk of death from any cause and recurrent cardiovascular events than placebo (hazard ratio in the overall population, 0.72; 95% confidence interval [CI], 0.56 to 0.93; P = 0.01; hazard ratio in the monotherapy population, 0.67; 95% CI, 0.49 to 0.93; P = 0.02) and a lower risk of death from any cause through 42 months (hazard ratio in the overall population, 0.65; 95% CI, 0.46 to 0.90; P = 0.01). Among the patients in the overall population, 125 in the vutrisiran group and 159 in the placebo group had at least one primary end-point event. In the overall population, treatment with vutrisiran resulted in less of a decline in the distance covered on the 6-minute walk test than placebo (least-squares mean difference, 26.5 m; 95% CI, 13.4 to 39.6; P<0.001) and less of a decline in the KCCQ-OS score (least-squares mean difference, 5.8 points; 95% CI, 2.4 to 9.2; P<0.001). Similar benefits were observed in the monotherapy population. The incidence of adverse events was similar in the two groups (99% in the vutrisiran group and 98% in the placebo group); serious adverse events occurred in 62% of the patients in the vutrisiran group and in 67% of those in the placebo group.ConclusionsAmong patients with ATTR-CM, treatment with vutrisiran led to a lower risk of death from any cause and cardiovascular events than placebo and preserved functional capacity and quality of life. (Funded by Alnylam Pharmaceuticals; HELIOS-B ClinicalTrials.gov number, NCT04153149.).Copyright © 2024 Massachusetts Medical Society.

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