Vutrisiran preserves or even improves daily functioning and QoL in ATTR-CM

In a post-hoc analysis of HELIOS-B among patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM), more vutrisiran-treated participants maintained or improved functional capacity, health status, and QoL over 30 months than placebo-treated participants.

This summary is based on the publication of Sheikh FH, Habib G, Tang WHW, et al. - Impact of Vutrisiran on Functional Capacity and Quality of Life in Transthyretin Amyloidosis With Cardiomyopathy. J Am Coll Cardiol. 2025 Mar 17:S0735-1097(25)05796-1 [Online ahead of print]. doi: 10.1016/j.jacc.2025.03.454.

Introduction and methods

Background

Transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal disease characterized by the deposition of amyloid fibrils, which consist of misfolded transthyretin (TTR) aggregates, in the myocardium. Progression of the disease and associated HF greatly affect these patients’ functional capacity, health status, and quality of life (QOL) [1-3].

Recently, the HELIOS-B (A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy) trial demonstrated that vutrisiran, an siRNA that inhibits the production of amyloidogenic TTR protein, reduced the risk of all-cause mortality or recurrent CV events compared with placebo in ATTR-CM patients [4]. In addition, it improved functional capacity and QoL and prevented or delayed worsening of HF symptoms.

Aim of the study

In a post-hoc analysis of the HELIOS-B trial, the authors examined the effects of vutrisiran on the maintenance or improvement of functional capacity, health status, and QoL according to clinically important cutoff values in ATTR-CM patients.

Methods

The HELIOS-B trial was a global, placebo-controlled, double-blind, phase 3 RCT in which 654 patients with variant or wild-type ATTR-CM and a history of HF were randomized to subcutaneous vutrisiran 25 mg or placebo every 12 weeks up to 36 months. A total of 247 (75.1%) placebo-treated and 263 (80.7%) vutrisiran-treated patients completed the visit at 30 months. Treatment with tafamidis (either at baseline or initiated during the trial) was permitted.

Functional capacity was assessed with the 6-minute walk distance (6MWD), and health status and health-related QoL were assessed with the KCCQ – Overall Summary Score (OSS). Cutoff values for worsening 6MWD were decreases from baseline >7 m, >15 m, and >35 m, whereas cutoff values for worsening KCCQ-OSS were decreases from baseline >5 and >10 points.

Outcomes

The outcome measures were the percentages of patients who maintained or improved their 6MWD and KCCQ-OSS between baseline and 30 months (i.e., they did not show a decrease larger than the respective cutoff value) and the changes in these parameters from baseline to 30 months in prespecified subgroups and KCCQ subdomains.

Main results

Functional capacity

• In the overall population, greater proportions of patients treated with vutrisiran (n=228) showed maintenance or improvement of their 6MWD at 30 months compared with those treated with placebo (n=223) (cutoff used: >7 m: 49.6% vs. 33.2%; >15 m: 55.5% vs. 38.6%; >35 m: 68.5% vs. 51.6%; all P<0.001).
• Similar results were observed in the monotherapy population (i.e., all patients who received any dose of the study drug and were not treated with tafamidis at baseline; n=254) (all P<0.01).
• The least-squares mean difference in 6MWD change from baseline to 30 months also favored vutrisiran over placebo, in the overall population and in subgroups stratified by, among others, age, baseline tafamidis use, or NYHA class.

Health status and quality of life

• In the overall population, more vutrisiran-treated patients maintained or improved their KCCQ-OSS between baseline and 30 months than placebo-treated patients (cutoff used: >5 points: 63.5% vs. 46.6%; P<0.001; >10 points: 74.6% vs. 60.7%; P<0.01). Once more, similar findings were seen in the monotherapy population (both P<0.001).
• The beneficial effects of vutrisiran over placebo were also apparent for changes from baseline to 30 months in the KCCQ-OSS, its 4 subdomains (physical limitations, Total Symptom Score, QoL, and social limitations), and the KCCQ – Clinical Symptom Score.

Conclusion

In this post-hoc analysis of the HELIOS-B trial among patients with ATTR-CM and HF, more participants treated with vutrisiran showed maintenance or improvement of their functional capacity, health status, and QoL according to clinically important cutoff values over 30 months than placebo-treated participants. The authors note that “although the cutoff values assessed have been used in prior research, there are no widely used values validated specifically for the ATTR-CM population. [We] aimed to address this limitation by using multiple cutoffs, all of which led to consistent results.”

Find this article online at J Am Coll Cardiol.

References

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2. Ruberg FL, Maurer MS, Judge DP, Zeldenrust S, Skinner M, Kim AY, et al. Prospective evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy: the Transthyretin Amyloidosis Cardiac Study (TRACS). Am Heart J. 2012;164(2):222–8 e1.
3. Lane T, Fontana M, Martinez-Naharro A, Quarta CC, Whelan CJ, Petrie A, et al. Natural history, quality of life, and outcome in cardiac transthyretin amyloidosis. Circulation. 2019;140(1):16–26.
4. Fontana M, Berk JL, Gillmore JD, Witteles RM, Grogan M, Drachman B, et al. Vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy. N Engl J Med. 2025;392(1):33–44.