JAMA. 2026 Aug 30. doi: 10.1001/jama.2026.17246. Online ahead of print.
ABSTRACT
IMPORTANCE: Gene-silencing therapies reduce hepatic transthyretin (TTR) production and have been evaluated in phase 3 trials in TTR amyloid cardiomyopathy (ATTR-CM). However, differences in trial design and background therapies have limited assessment of the overall treatment effect and its consistency according to baseline TTR stabilizer use.
OBJECTIVE: To assess the effect of TTR gene-silencing therapies in patients with ATTR-CM.
DATA SOURCES AND STUDY SELECTION: PubMed was searched through June 15, 2026, for randomized, placebo-controlled, phase 3 outcome trials of gene-silencing therapies in ATTR-CM.
DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted data, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Fixed-effects meta-analysis estimated rate ratios (RRs) or hazard ratios (HRs) with 95% CIs.
MAIN OUTCOMES AND MEASURES: The prespecified primary outcome was the composite of all-cause mortality and recurrent cardiovascular events. Secondary outcomes included all-cause mortality, cardiovascular death, time to first primary outcome, functional capacity (6-minute walk distance), and health status (Kansas City Cardiomyopathy Questionnaire-Overall Summary Score).
RESULTS: A total of 2 studies (HELIOS-B and CARDIO-TTRansform) met the inclusion criteria and included 2086 patients with ATTR-CM. The studies included 1902 men with a median age of 77 years (range for HELIOS-B, 45-85 years; for CARDIO-TTRansform, 41-91 years). Gene-silencing therapy reduced the primary end point by 20% (RR, 0.80; 95% CI, 0.69-0.94; P = .006), with no heterogeneity between trials (P for heterogeneity = .28). Gene-silencing therapy also reduced the risk of all-cause death (HR, 0.74; 95% CI, 0.61-0.91) and time to first all-cause death or cardiovascular events (HR, 0.77; 95% CI, 0.67-0.89) compared with placebo. Gene silencers preserved 6-minute walk distance (placebo-corrected difference, +22.2 m; 95% CI, 14.3-30.0) and Kansas City Cardiomyopathy Questionnaire-Overall Summary Score (+4.5; 95% CI, 2.7-6.2), with no evidence of between-trial heterogeneity. Treatment effects on primary end points differed according to baseline stabilizer use, with significant benefits observed among patients not receiving background stabilizer therapy (RR, 0.69; 95% CI, 0.57-0.85) and no significant incremental benefit observed for those receiving concomitant stabilizer at baseline (RR, 0.97; 95% CI, 0.77-1.23; P for heterogeneity = .03). Similar heterogeneity was observed for functional capacity and health status.
CONCLUSIONS AND RELEVANCE: The findings from this meta-analysis support TTR gene silencing for ATTR-CM. The attenuated benefit observed for patients receiving concomitant TTR stabilizer therapy may reflect residual differences in case mix, disease duration, or magnitude of TTR suppression or a true ceiling on additional benefit of gene silencing in the setting of background TTR stabilization.
TRIAL REGISTRATION: PROSPERO registration: CRD420261421656. ClinicalTrials.gov Identifier: HELIOS-B, NCT04153149; and CARDIO-TTRansform, NCT04136171.
PMID:42669065 | DOI:10.1001/jama.2026.17246