Vutrisiran Associated With Slower Decline in Left Atrial Function in ATTR-CM

Left atrial (LA) dysfunction was independently associated with mortality, recurrent cardiovascular (CV) events, heart failure (HF) hospitalizations, and incident atrial fibrillation or flutter in patients with transthyretin amyloidosis cardiomyopathy (ATTR-CM), according to a secondary analysis of the HELIOS-B randomized clinical trial (NCT04153149) published in JAMA Cardiology.¹ The study also found that vutrisiran (Amvuttra; Alnylam Pharmaceuticals), an RNA interference therapy that reduces hepatic production of transthyretin, was associated with significantly less decline in LA function compared with placebo.

“In this post hoc analysis of the HELIOS-B randomized clinical trial, LA function as measured by LA strain was markedly impaired among patients with ATTR-CM and correlated with disease severity,” wrote the researchers of the study. “Measures of LA strain were independently associated with [amyloidosis cardiomyopathy] and recurrent CV events, CV death, and recurrent HF hospitalizations, while volumetric and Doppler-based measures of LA size and function were not.”

Among 644 HELIOS-B participants with measurable LA strain (median age, 77 years; 88.4% with wild-type ATTR), mean LA reservoir strain was 9.5%, LA conduit strain was 6.9%, and LA contractile strain was 4.2%. These values were substantially lower than those reported in healthy reference populations (39.4%, 23.0%, and 17.4%, respectively).

LA electromechanical dissociation also was identified in 9.5% of participants and was associated with particularly poor clinical outcomes, including mortality and recurrent cardiovascular events.

Worse LA reservoir and contractile strain were independently associated with all-cause mortality and recurrent CV events (HR, 1.37 and 1.53 per 5-percentage-point worsening, respectively), recurrent HFhospitalizations (HR, 1.66 and 2.23), and incident atrial fibrillation or flutter (HR, 1.30 and 2.02), even after adjustment for National Amyloidosis Centre disease stage, global longitudinal strain, and estimated filling pressures.

In contrast, LA volume index was not significantly associated with the evaluated clinical outcomes. The findings suggest that measures of atrial function may provide prognostic information not captured by LA size alone.

Treatment Effect on Atrial Function

At 30 months, LA strain worsened across the overall cohort, consistent with the progressive cardiac manifestations of ATTR-CM. However, patients randomized to vutrisiran experienced significantly less decline than those receiving placebo across all 3 strain measures. The between-group treatment differences were 1.2 percentage points for LA reservoir strain, 0.8 percentage points for LA conduit strain, and 0.8 percentage points for LA contractile strain.

No significant interaction was observed between baseline LA dysfunction and vutrisiran's treatment effect on mortality or CV events, suggesting that the observed clinical benefit was not significantly modified by the degree of atrial dysfunction at enrollment.

The authors noted several limitations, including the post hoc, hypothesis-generating nature of the analysis; single-view (apical 4-chamber) strain measurements; and lack of central adjudication for incident arrhythmias, which may have resulted in underestimation of atrial fibrillation rates.

Managed Care Implications

Before disease-specific therapies became available, annual US health care costs for ATTR-CM could exceed $60,000 per patient, driven largely by inpatient hospitalization.² The introduction of disease-modifying therapies has therefore increased attention to both their clinical benefits and their economic impact.

Vutrisiran is administered as a 25-mg subcutaneous injection once every 3 months. At current Medicare Part B payment rates, 4 quarterly doses represent roughly $500,000 in annual drug spending before administration and other health care costs. This high treatment cost makes the durability of CV benefit and the identification of clinically meaningful markers of disease progression important considerations for payers and health systems.²

For managed care decision makers, the new analysis suggests that LA strain could provide prognostic information that complements conventional measures of atrial size and existing ATTR-CM staging approaches. However, whether LA strain should be incorporated into treatment selection, prior authorization criteria, or monitoring protocols remains uncertain and would require prospective validation.

Importantly, the analysis did not demonstrate that patients with greater baseline LA dysfunction derive greater benefit from vutrisiran. Thus, the findings should not be interpreted as supporting the use of LA strain to restrict treatment to patients with more advanced atrial dysfunction. Rather, they add to evidence that detailed assessment of cardiac structure and function may help characterize disease severity and risk as health systems evaluate the clinical and economic impact of transthyretin-lowering therapies.

References

1. Jering KS, Manafi A, Claggett BL, et al. Left atrial structure and function, clinical outcomes, and efficacy of vutrisiran in transthyretin amyloidosis with cardiomyopathy: a secondary analysis of the HELIOS-B randomized clinical trial. JAMA Cardiol. Published online August 19, 2026. doi:10.1001/jamacardio.2026.2992
2. Nikitin D, Wasfy JH, Winn AN, et al. The effectiveness and value of disease-modifying therapies for transthyretin amyloid cardiomyopathy: a summary from the Institute for Clinical and Economic Review's Midwest Comparative Effectiveness Public Advisory Council. J Manag Care Spec Pharm. 2025;31(3):323-328. doi:10.18553/jmcp.2025.31.3.323