Analyzing Outpatient Worsening Heart Failure in ATTR-CM

Outpatient worsening heart failure—defined in the HELIOS-B trial as the initiation or sustained increase (greater than or equal to seven days) in oral loop diuretic dose—has emerged as a simple yet clinically meaningful marker of disease progression in transthyretin amyloidosis with cardiomyopathy (ATTR-CM).

In a 2025 analysis published in The Journal of the American College of Cardiology, prespecified data from HELIOS-B highlight the prognostic value of outpatient worsening heart failure and the therapeutic potential of vutrisiran, an RNA interference agent targeting transthyretin. Here’s a brief look at its findings.

HELIOS-B Trial

As diagnostic awareness increases and disease-modifying therapies expand, there is a growing need for real-world, treatment-sensitive indicators of early deterioration. In HELIOS-B, 654 patients with wild-type or hereditary ATTR-CM were randomized to receive vutrisiran or placebo for 36 months. While the primary endpoint was a composite of all-cause mortality and recurrent cardiovascular (CV) events, this analysis focused on outpatient worsening heart failure as both a prognostic signal and therapeutic target.

Impact of Outpatient Worsening Heart Failure

The analysis found that nearly half of patients (49.1 percent) experienced at least one outpatient worsening heart failure event. These episodes were associated with a 2.5-fold increase in all-cause mortality (HR 2.45; 95 percent CI: 1.70–3.52) and a 2.6-fold increase in the composite of mortality and CV events (HR 2.58; 95 percent CI: 2.04–3.27). Functional decline and biomarker elevations paralleled these outcomes. Affected patients showed an average annual decrease of 10.7 meters in six-minute walk distance, a 2.4-point reduction in Kansas City Cardiomyopathy Questionnaire–Overall Summary (KCCQ-OS) scores, and significant increases in NT-proBNP.

Impact of Vutrisiran Therapy

When it comes to vutrisiran, the analysis discovered that it significantly reduced both incidence and recurrence of these heart failure events. Over the study period, 43.9 percent of vutrisiran-treated patients experienced at least one outpatient worsening heart failure event, compared to 54.3 percent in the placebo group (HR 0.73; 95 percent CI: 0.59–0.91). Recurrent event analysis showed a 34 percent reduction in total event rate (rate ratio 0.66; 95 percent CI: 0.56–0.78), with benefits observed as early as six months post-initiation.

Incorporating outpatient worsening heart failure into an expanded composite with CV events and death nearly doubled total event counts, from 583 to 1,147, and increased the proportion of affected patients from 43 percent to 64 percent. Vutrisiran reduced the risk of this expanded endpoint by 31 percent (HR 0.69; 95 percent CI: 0.57–0.83), with consistent benefit across subgroups, including those not on tafamidis at baseline.

Future Directions and Clinical Applications

These findings affirm outpatient worsening heart failure as a clinically accessible and prognostically informative measure of disease activity in ATTR-CM. It correlates with morbidity, mortality, functional decline, and biomarker changes, and responds to transthyretin-lowering therapy. As trials shift toward earlier-stage populations with fewer hard endpoints, outpatient worsening heart failure may offer a practical, sensitive, and scalable surrogate outcome.

Supportive evidence from the APOLLO-B trial of patisiran reinforces the broader applicability of this measure across transthyretin-lowering agents. Although not adjudicated in HELIOS-B, outpatient diuretic intensification consistently identified patients at elevated risk and contributed meaningfully to composite event burden, nearly doubling total event counts when included alongside CV events and mortality. These attributes position outpatient worsening heart failure as a valuable endpoint for both clinical research and real-world disease monitoring.

References

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.

Fontana M, Maurer MS, Gillmore JD, et al. Worsening of Heart Failure in Outpatients With Transthyretin Amyloidosis and Cardiomyopathy in the APOLLO-B Trial. J Am Coll Cardiol. 2025;85(7):744-752. doi:10.1016/j.jacc.2024.10.097