Fontana, Marianna; Berk, John L; Gillmore, Julian D; Witteles, Ronald M; Grogan, Martha; Drachman, Brian; Damy, Thibaud; ... HELIOS-B Trial Investigators; + view all Fontana, Marianna; Berk, John L; Gillmore, Julian D; Witteles, Ronald M; Grogan, Martha; Drachman, Brian; Damy, Thibaud; Garcia-Pavia, Pablo; Taubel, Jorg; Solomon, Scott D; Sheikh, Farooq H; Tahara, Nobuhiro; González-Costello, José; Tsujita, Kenichi; Morbach, Caroline; Pozsonyi, Zoltán; Petrie, Mark C; Delgado, Diego; Van der Meer, Peter; Jabbour, Andrew; Bondue, Antoine; Kim, Darae; Azevedo, Olga; Hvitfeldt Poulsen, Steen; Yilmaz, Ali; Jankowska, Ewa A; Algalarrondo, Vincent; Slugg, Andrew; Garg, Pushkal P; Boyle, Katherine L; Yureneva, Elena; Silliman, Nancy; Yang, Lilli; Chen, Jihong; Eraly, Satish A; Vest, John; Maurer, Mathew S; HELIOS-B Trial Investigators; - view fewer (2024) Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy. New England Journal of Medicine 10.1056/NEJMoa2409134. (In press).

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Abstract

BACKGROUND: Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, fatal disease. Vutrisiran, a subcutaneously administered RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. METHODS: In 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. RESULTS: A 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, 0.65; 95% CI, 0.46 to 0.90; P = 0.01). A primary end-point event occurred in 163 patients in the vutrisiran group and in 202 in the placebo group. 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. CONCLUSIONS: Among 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.).

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