Outpatient Worsening Heart Failure Predicts Mortality in Patients With ATTR-CM

Outpatient worsening heart failure (HF) may serve as an important clinical marker of disease progression and mortality in patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM), according to new findings from the HELIOS-B (NCT04153149) trial.¹

The study, published in Journal of the American College of Cardiology, also found that treatment with vutrisiran (Amvuttra; Alnylam Pharmaceuticals) significantly reduced the rate of outpatient HF worsening events over 36 months.

“Our results indicate that outpatient worsening HF is an early, sensitive indicator of increasing risk of all-cause mortality and CV [cardiovascular] events,” wrote the researchers of the study.

ATTR-CM is a progressive and potentially fatal disease caused by misfolded transthyretin proteins that accumulate as amyloid fibrils in the myocardium. These deposits lead to stiffening of the heart muscle, impaired cardiac function, and eventual heart failure. As the disease advances, patients often experience worsening functional status and increased risk of hospitalization and death.²

Among the 654 patients enrolled in the trial, outpatient worsening HF events were frequent. Nearly half of participants (49.1%) experienced at least 1 outpatient worsening HF event during follow-up. In comparison, 37.5% had at least 1 cardiovascular (CV) event, such as hospitalization or an urgent HF visit, and 18.3% died during the study period. Only 36.2% of patients experienced no events.

The study found that outpatient worsening HF was strongly associated with adverse outcomes. Patients experiencing these events had more than double the risk of the composite outcome of all-cause mortality and recurrent CV events (HR, 2.58; 95% CI, 2.04-3.27). They also faced a significantly increased risk of all-cause mortality alone (HR, 2.45; 95% CI, 1.70-3.52).

In addition to higher mortality risk, patients with outpatient HF worsening demonstrated greater clinical decline. These individuals experienced larger reductions in 6-minute walk test distance and poorer health-related quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire Overall Summary score. Biomarker changes also reflected worsening cardiac stress, with greater increases in N-terminal pro–B-type natriuretic peptide.

The investigators also assessed the effects of vutrisiran, an RNA interference therapy designed to reduce hepatic production of transthyretin protein. By lowering circulating transthyretin levels, vutrisiran helps reduce the formation of amyloid fibrils that damage cardiac tissue.³

During the double-blind phase of HELIOS-B, treatment with vutrisiran significantly reduced the rate of outpatient worsening HF compared with placebo, with a relative rate ratio of 0.66 (95% CI, 0.56-0.78).¹ The therapy also lowered the risk of a broader composite end point—including all-cause mortality, recurrent CV events, and outpatient worsening HF—by 31% compared with placebo (HR, 0.69; 95% CI, 0.57-0.83).

These findings highlight the potential clinical importance of tracking outpatient HF worsening in patients with ATTR-CM. Traditionally, studies and clinical monitoring have focused primarily on hospitalizations or mortality; however, outpatient diuretic intensification may capture earlier signs of disease progression that occur before hospitalization.

Recognition and diagnosis of ATTR-CM have improved in recent years due to advances in imaging techniques and greater awareness of the disease. Once considered rare, ATTR-CM is now increasingly recognized among older adults with HF with preserved ejection fraction and unexplained ventricular hypertrophy.²

The HELIOS-B results suggest that outpatient worsening HF could serve as a practical, real-world marker for identifying patients at higher risk of clinical deterioration. As disease-modifying therapies such as vutrisiran continue to expand treatment options, incorporating outpatient worsening HF into routine monitoring may help clinicians intervene earlier and optimize management for patients with this life-threatening cardiomyopathy.

“The data suggest that outpatient HF worsening is a prognostic and disease progression marker in patients with ATTR-CM and may be a useful endpoint in future ATTR-CM clinical trials, either alone or as part of a composite end point,” wrote the researchers.

References

1. Fontana M, Maurer MS, Gillmore JD, et al. Outpatient worsening heart failure in patients with transthyretin amyloidosis with cardiomyopathy in the HELIOS-B trial. J Am Coll Cardiol. 2025;85(7):753-761. doi:10.1016/j.jacc.2024.11.015

2. Gillmore JD, Damy T, Fontana M, et al. A new era for transthyretin amyloidosis: advances in diagnosis and treatment. Nat Rev Cardiol. 2021;18(12):743-758. doi:10.1038/s41569-021-00542-1

3. Maurer MS, Elliott P, Merlini G, et al. Design and rationale of the HELIOS-B study evaluating vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy. J Card Fail. 2021;27(9):1004-1012. doi:10.1016/j.cardfail.2021.05.011