Outpatient worsening HF as prognostic marker in ATTR-CM

In a prespecified analysis of HELIOS-B, outpatient worsening HF was associated with increased mortality risk in patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) but could be reduced by vutrisiran.

This summary is based on the publication of 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. 2024 Nov 9:S0735-1097(24)10464-0 [Online ahead of print]. doi: 10.1016/j.jacc.2024.11.015

Introduction and methods

Background

Transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal disease that is caused by the deposition of misfolded TTR proteins as amyloid fibrils in the myocardial extracellular space, leading to HF. Practical and sensitive monitoring methods are needed to help identify ATTR-CM patients at risk of disease progression early [1]. In the outpatient setting, initiation or intensification of oral diuretics is a common sign of worsening HF [2]. In ATTR-CM patients, oral diuretics are frequently intensified, which is associated with increased mortality [3-5].

Vutrisiran, an siRNA that inhibits the production of amyloidogenic TTR protein, lowered the risk of all-cause mortality or recurrent CV events compared with placebo in ATTR-CM patients, as recently shown by the HELIOS-B trial [6]. In addition, it prevented worsening of HF symptoms.

Aim of the study

In a prespecified analysis of the HELIOS-B trial, the authors assessed the clinical and prognostic significance of outpatient worsening HF as a marker of disease progression in patients with ATTR-CM and the effect of vutrisiran on outpatient worsening HF.

Methods

The HELIOS-B trial was a global, multicenter, placebo-controlled, double-blind, phase 3 RCT in which 654 ATTR-CM patients were randomized to subcutaneous vutrisiran 25 mg or placebo every 3 months for up to 36 months. Outpatient worsening HF was defined as initiation of or a sustained increase (duration ≥7 days) in the daily dose of oral loop diuretics. Recurrent outpatient worsening HF was defined as oral diuretic intensification that occurred ≥7 days after the prior oral diuretic initiation or intensification.

Outcomes

The trial’s primary endpoint was a composite outcome of all-cause mortality or recurrent CV events (i.e., CV hospitalizations or urgent HF visits). Secondary and exploratory endpoints included all-cause mortality and changes from baseline in 6-minute walk distance (6MWD), KCCQ – Overall Summary Score (OSS), and NT-proBNP levels.

For the current analysis, an expanded composite endpoint was used as well, which included all-cause mortality, recurrent CV events, or recurrent outpatient worsening HF.

Main results

Associations between outpatient worsening HF and clinical outcomes

• During follow-up, 321 patients (49.1%) had ≥1 outpatient worsening HF events, 245 (37.5%) had ≥1 CV events, and 120 (18.3%) died; 237 patients (36.2%) had no events.
• Patients with outpatient worsening HF had a greater risk of the primary endpoint of all-cause mortality or CV events than those with no outpatient worsening HF (HR: 2.58; 95%CI: 2.04–3.27).
• Outpatient worsening HF was also associated with an increased risk of all-cause mortality (HR: 2.45; 95%CI: 1.70–3.52), as well as greater declines in 6MWD and KCCQ – OSS and a greater NT-proBNP increase from baseline.

Treatment effect of vutrisiran on outpatient worsening HF

• Vutrisiran treatment (n=326) reduced the time to the first outpatient worsening HF event compared with placebo (n=328) (HR: 0.73; 95%CI: 0.59–0.91; P=0.0092).
• Furthermore, vutrisiran versus placebo reduced the rate of recurrent outpatient worsening HF events (relative rate ratio: 0.66; 95%CI: 0.56–0.78; P<0.0001).
• Vutrisiran also reduced the risk of the expanded composite endpoint of all-cause mortality, recurrent CV events, or recurrent outpatient worsening HF compared with placebo (HR: 0.69; 95%CI: 0.57–0.83; P<0.0001).

Conclusion

In this prespecified analysis of the HELIOS-B trial, the incidence of outpatient worsening HF in patients with ATTR-CM during the 36-month follow-up was substantial (49%) and was associated with a 2.6-fold increased risk of all-cause mortality or recurrent CV events and greater deterioration of functional capacity and quality of life. The authors believe their “results indicate that outpatient worsening HF is an early, sensitive indicator of increasing risk of all-cause mortality and CV events” in ATTR-CM patients. Vutrisiran reduced the risk of first and recurrent outpatient worsening HF events compared with placebo.

Find this article online at J Am Coll Cardiol.

References

1. Garcia-Pavia P, Bengel F, Brito D, et al. Expert consensus on the monitoring of transthyretin amyloid cardiomyopathy. Eur J Heart Fail. 2021;23:895–905. https://doi.org/10.1002/ejhf.2198
2. Okumura N, Jhund PS, Gong J, et al. Importance of clinical worsening of heart failure treated in the outpatient setting: evidence from the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF). Circulation. 2016;133:2254–2262. https://doi.org/10.1161/CIRCULATIONAHA.115.020729
3. Law S, Bezard M, Petrie A, et al. Characteristics and natural history of early-stage cardiac transthyretin amyloidosis. Eur Heart J. 2022;43:2622–2632. https://doi.org/10.1002/ejhf.2376
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6. Fontana M, Berk JL, Gillmore JD, et al. Vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy. N Engl J Med. 2024. https://doi.org/10.1056/NEJMoa2409134