Eplontersen and Vutrisiran Improve ATTR-CM Outcomes

Transthyretin (TTR) gene-silencing therapies reduced a composite of all-cause death and recurrent cardiovascular (CV) events among patients with transthyretin amyloid cardiomyopathy (ATTR-CM), according to a meta-analysis published in JAMA.

The prespecified, trial-level meta-analysis combined 2 randomized, placebo-controlled phase 3 outcome trials: CARDIO-TTRansform, which evaluated eplontersen in 1432 participants, and HELIOS-B, which evaluated vutrisiran in 654 participants. The pooled population included 2086 patients with a median age of 77 years; 1902 were men. Median follow-up was 2.7 years in CARDIO-TTRansform and 3.0 years in HELIOS-B.

Gene-silencing therapy reduced the rate of the primary composite outcome by 20% compared with placebo (rate ratio [RR], 0.80; 95% CI, 0.69-0.94; P = .006), without evidence of heterogeneity between trials. Treatment also reduced the risk of all-cause death (hazard ratio [HR], 0.74; 95% CI, 0.61-0.91) and of the time-to-first-event composite of all-cause death or CV events (HR, 0.77; 95% CI, 0.67-0.89).

Compared with placebo, gene silencers preserved 6-minute walk distance by a placebo-corrected 22.2 m and Kansas City Cardiomyopathy Questionnaire–Overall Summary Score by 4.5 points. Effects on the primary outcome differed according to baseline TTR stabilizer use: the RR was 0.69 among patients not receiving a stabilizer and 0.97 among those receiving one, with significant subgroup heterogeneity. All baseline stabilizer therapy in the trials was tafamidis.

Safety outcomes were assessed descriptively because event ascertainment and reporting differed between trials. Serious adverse-event and treatment-discontinuation rates were similar between groups, and no new safety signals were identified. The authors cautioned that the analysis used aggregate trial-level data and that neither trial was powered to determine the incremental benefit of combining a gene silencer with a TTR stabilizer.

Source: Gillmore JD, Hamatani Y, Fontana M, et al. Gene silencer therapy in transthyretin amyloid cardiomyopathy: a meta-analysis of outcomes trials. JAMA. Published online August 30, 2026. doi:10.1001/jama.2026.17246