Key Points:
- Eplontersen, an antisense oligonucleotide that inhibits hepatic transthyretin (TTR) production, did not significantly reduce cardiovascular (CV) death or recurrent CV events in the overall CARDIO-TTRansform trial population. However, clinical benefits were observed among patients not receiving background TTR stabilizers.
- This prespecified exploratory echocardiographic analysis evaluated changes in cardiac structure and function among 1,426 patients with transthyretin amyloid cardiomyopathy (ATTR-CM) randomized to eplontersen or placebo over 140 weeks.
- Eplontersen modestly attenuated deterioration in LV wall thickness, stroke volume, myocardial contraction fraction, and E/e′ compared with placebo, without significant differences in LVEF or global longitudinal strain (GLS).
- Benefits were primarily observed among patients not receiving TTR stabilizers at baseline. These exploratory findings suggest that TTR silencing may slow cardiac deterioration, although its incremental benefit in patients already receiving stabilizers remains uncertain.
Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by progressive myocardial amyloid deposition, increased ventricular wall thickness, and impaired cardiac function. Eplontersen reduces hepatic production of both wild-type and variant TTR. Although the original CARDIO-TTRansform trial did not significantly reduce CV death or recurrent CV events, whether treatment favorably affects cardiac structure and function remained uncertain.
On November 9th, 2026, results from “Effects of Eplontersen on Cardiac Structure and Function in Patients With Transthyretin Amyloidosis With Cardiomyopathy” were presented at the American Heart Association Scientific Sessions 2026 in Chicago, IL, with simultaneous publication in Circulation.
CARDIO-TTRansform was a multicenter, double-blind, placebo-controlled trial in patients with ATTR-CM randomized to eplontersen 45 mg subcutaneously every four weeks or placebo for 140 weeks. A total of 1,438 patients were randomized, of whom 1,432 received at least one dose of eplontersen or placebo. Background TTR stabilizer therapy was permitted, with 57% receiving stabilizers at baseline. The primary clinical endpoint of CV death or recurrent CV events was not significantly reduced with eplontersen (rate ratio 0.89 [95% CI: 0.73–1.09]; P=0.277). However, benefits were observed among patients not receiving stabilizers at baseline (rate ratio 0.71 [0.54–0.93]), with no significant benefit among those receiving stabilizers (P-interaction=0.017).
The present analysis included 1,426 participants with baseline echocardiograms; follow-up echocardiograms were scheduled at weeks 61, 97, and 140. Mean age was 76 years, 91% were men, and 85% had wild-type ATTR-CM. Baseline LVEF was approximately 56%, with impaired global longitudinal strain (GLS) and diastolic function. Measures of LV systolic and diastolic function and RV function were independently associated with mortality and CV events.
At 140 weeks, eplontersen modestly attenuated deterioration in several echocardiographic measures compared with placebo. Between-group differences favored eplontersen for mean LV wall thickness (-0.24 mm [-0.48 to -0.01]), LV stroke volume (+1.88 mL [0.07 to 3.69]), myocardial contraction fraction (+0.87 percentage points [0.18 to 1.57]), and average E/e′ (-0.71 [-1.36 to -0.07]). No significant differences were observed in LVEF, GLS, or left atrial volume.
Similar to the main trial, these effects were concentrated among patients not receiving TTR stabilizers at baseline. In this subgroup, eplontersen attenuated declines in LV stroke volume (+3.66 mL [0.77 to 6.55]) and myocardial contraction fraction (+1.73 percentage points [0.64 to 2.82]), as well as worsening of E/e′ (-1.50 [-2.52 to -0.48]) and RV outflow tract velocity-time integral (+1.13 cm [0.44 to 1.82]). No significant differences in these measures were observed among patients receiving background stabilizers.
There are limitations to this analysis. The echocardiographic analyses were exploratory and not adjusted for multiple comparisons. Background stabilizer use was not randomized, and an additional 24% of patients in each treatment arm started stabilizers during follow-up. Furthermore, only 1,060 participants had echocardiograms available at week 140, introducing potential selection and survivorship bias.
Karola Jering, MD, of Brigham and Women’s Hospital, concluded: “These findings provide mechanistic insights into the cardiac effects of TTR silencing, showing that eplontersen slows progression of cardiac remodeling and functional deterioration in ATTR-CM, particularly among patients not on stabilizers.” Whether adding TTR silencing to existing stabilizer therapy provides meaningful incremental clinical benefit remains uncertain.