Concomitant use of tafamidis or heart failure (HF) therapies did not modify the treatment benefit of vutrisiran on all-cause mortality and recurrent cardiovascular events, according to a HELIOS-B analysis recently published in JACC.

Arielle Abovich, MD, MPH, et al., included 654 randomized patients with transthyretin amyloid cardiomyopathy (ATTR-CM) who received either vutrisiran or placebo – 40% were receiving tafamidis and 77% at least one HF medication at baseline. The authors evaluated treatment effect modification on the trial's primary composite endpoint: all-cause mortality and recurrent cardiovascular events.

There was no statistically significant change in treatment effect by baseline or time-updated use of tafamidis, SGLT2 inhibitors, MRAs, beta-blockers or ARBs (p-interaction = 0.95, 0.59, 0.92, 0.75 and 0.82, respectively).

Abovich and colleagues note that their findings "support the consistency of vutrisiran's treatment effect across the spectrum of contemporary ATTR-CM pharmacotherapy and provide evidence for its use alongside other disease-modifying and guideline-directed HF therapies in clinical practice."

In an accompanying editorial comment, Joshua A. Rushakoff, MD, MPP, et al., highlight questions spurred by this HELIOS-B analysis requiring further research: "Will growing background stabilizer use diminish treatment effects of add-on silencer therapy? Can HF therapies impact the natural history of ATTR-CM, and will they modify the demonstrated benefits of targeted therapies?"

In addition, a Special Communication article published recently in JACC proposes a new biological framework for thinking about disease progression in ATTR-CM. Marianna Fontana, MD, PhD, et al., outline three domains that align disease progression with therapeutic mechanism and biomarker development: 1) precursor protein biology, 2) amyloid burden and 3) downstream organ response.

"The future of disease monitoring in cardiac amyloidosis lies not in measuring disease severity more precisely, but in defining disease biology more accurately," they write. "As therapeutic options expand, the central question will no longer be whether a patient is progressing, but which biological process is driving the progression and whether it is being adequately targeted by therapy."