{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T15:33:46Z","timestamp":1792683226322,"version":"4.5.0"},"reference-count":11,"publisher":"American Medical Association (AMA)","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA"],"abstract":"\n Importance<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To assess the effect of TTR gene-silencing therapies in patients with ATTR-CM.<\/jats:p>\n <\/jats:sec>\n \n Data Sources and Study Selection<\/jats:title>\n PubMed was searched through June 15, 2026, for randomized, placebo-controlled, phase 3 outcome trials of gene-silencing therapies in ATTR-CM.<\/jats:p>\n <\/jats:sec>\n \n Data Extraction and Synthesis<\/jats:title>\n \n Two reviewers independently extracted data, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (\n PRISMA<\/jats:ext-link>\n ) guideline. Fixed-effects meta-analysis estimated rate ratios (RRs) or hazard ratios (HRs) with 95% CIs.\n <\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n 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\u2013Overall Summary Score).<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n 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 19% (RR, 0.81; 95% CI, 0.69-0.94;\n P<\/jats:italic>\n \u2009=\u2009.006), with no heterogeneity between trials (\n P<\/jats:italic>\n for heterogeneity\u2009=\u2009.27). 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\u2013Overall 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;\n P<\/jats:italic>\n for heterogeneity\u2009=\u2009.03). Similar heterogeneity was observed for functional capacity and health status.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n PROSPERO registration:\n CRD420261421656<\/jats:ext-link>\n . ClinicalTrials.gov Identifier: HELIOS-B,\n NCT04153149<\/jats:ext-link>\n ; and CARDIO-TTRansform,\n NCT04136171<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jama.2026.17246","type":"journal-article","created":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T13:30:16Z","timestamp":1788096616000},"source":"Crossref","is-referenced-by-count":2,"title":["Gene Silencer Therapy in Transthyretin Amyloid Cardiomyopathy"],"prefix":"10.1001","author":[{"given":"Julian D.","family":"Gillmore","sequence":"first","affiliation":[{"name":"National Amyloidosis Centre, Division of Medicine, University College London, Royal Free Hospital, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Hamatani","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Brigham and Women\u2019s Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Fontana","sequence":"additional","affiliation":[{"name":"National Amyloidosis Centre, Division of Medicine, University College London, Royal Free Hospital, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muthiah","family":"Vaduganathan","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Brigham and Women\u2019s Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian L.","family":"Claggett","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Brigham and Women\u2019s Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Garcia-Pavia","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, IDIPHIM, CIBERCV, Madrid, Spain"},{"name":"Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Masri","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Oregon Health & Science University, Portland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Cappelli","sequence":"additional","affiliation":[{"name":"Tuscan Regional Amyloidosis Center, Department of Clinical and Experimental Medicine, Careggi University Hospital, Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha","family":"Grogan","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Morbach","sequence":"additional","affiliation":[{"name":"Department of Clinical Research and Epidemiology, Comprehensive Heart Failure Center, University Hospital of W\u00fcrzburg, W\u00fcrzburg, Germany"},{"name":"Department of Medicine I, University Hospital of W\u00fcrzburg, W\u00fcrzburg, Germany"},{"name":"Interdisciplinary Amyloidosis Center of Northern Bavaria, University Hospital of W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathew S.","family":"Maurer","sequence":"additional","affiliation":[{"name":"Columbia University Irving Medical Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott D.","family":"Solomon","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Brigham and Women\u2019s Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2026,8,30]]},"reference":[{"issue":"5","key":"joi260100r1","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1016\/j.jacc.2025.09.004","article-title":"Transthyretin cardiac amyloidosis evaluation and management: 2025 ACC concise clinical guidance.","volume":"87","author":"Kittleson","year":"2026","journal-title":"J Am Coll Cardiol"},{"issue":"16","key":"joi260100r2","doi-asserted-by":"publisher","first-page":"1554","DOI":"10.1093\/eurheartj\/ehab072","article-title":"Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases.","volume":"42","author":"Garcia-Pavia","year":"2021","journal-title":"Eur Heart J"},{"issue":"1","key":"joi260100r3","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1056\/NEJMoa2409134","article-title":"Vutrisiran in patients with transthyretin 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