Eplontersen with and without background transthyretin stabilizers in transthyretin amyloid cardiomyopathy: secondary analysis of a phase 3, randomized controlled trial
In brief
Eplontersen reduces cardiovascular events by about 30% in ATTR-CM patients not on stabilizers
In the CARDIO-TTRansform trial, eplontersen lowered the combined risk of cardiovascular death and repeat events by 29% among patients who were not taking a TTR stabilizer at baseline, while showing no benefit for those already on stabilizers. Safety was comparable across groups, suggesting the drug's advantage may be limited to stabilizer-naïve patients.
- Journal
- Nature medicine (Q1)
- Published
- 30 August 2026
- Study design
- Randomized controlled trial
- Evidence level
- Level 1, High (CEBM 1b)
- Authors
- Pablo García-Pavía, Francesco Cappelli, Margot K Davis, Marianna Fontana, Julian D Gillmore, Mazen Hanna, et al.
- PMID
- 42742182
- DOI
- 10.1038/s41591-026-04670-6
Why clinicians should know about it
- Picked for Breast and Endocrine Surgery (top studies of the week, 20 September 2026): Cardiac amyloidosis trial, not surgical breast/endocrine focus
- Picked for Surgical Oncology (top studies of the week, 20 September 2026): Eplontersen with/without stabilizers, ATTR‑CM, phase 3 RCT
Abstract
Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) therapies include both TTR gene silencers and TTR stabilizers. The role of TTR gene silencers added to background TTR stabilizer therapy is unknown, and the effects of silencer treatment in the absence of stabilizer use is unclear. In the CARDIO-TTRansform study, 1,432 patients, (n=135 [9.4%] female and n=1297 [90.6%] male), with ATTR-CM were randomized (1:1) and treated with the antisense oligonucleotide eplontersen (45 mg every 4 weeks) targeting TTR or with placebo for up to 140 weeks. Fifty-seven percent of patients were taking TTR stabilizers at baseline. In the overall study, treatment with eplontersen did not significantly reduce the primary composite endpoint. Here, in a prespecified analysis, we show that the primary endpoint (a composite of cardiovascular mortality and recurrent cardiovascular events) was modified by baseline stabilizer use (Pinteraction = 0.017). Benefit was seen in those patients not on stabilizers at baseline (RR 0.71, 95% CI, 0.54-0.93, P = 0.012), whereas no benefit seen in those on stabilizers at baseline (RR 1.14, 95% CI, 0.85-1.53, P = 0.39). The safety profile of eplontersen was favorable, irrespective of baseline stabilizer use. Treatment with eplontersen versus placebo demonstrated a clinically meaningful benefit among patients not receiving background stabilizers but provided no additional clinical benefit in those on background stabilizer therapy. These findings of a strong treatment effect modification may offer insight for therapeutic decision-making in clinical practice. ClinicalTrials.gov registration: NCT04136171.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.