Key Points:
- Transthyretin amyloidosis (ATTR-CM) is a fatal disease caused by the deposition of misfolded amyloid protein in the heart, leading to heart failure and poor cardiovascular outcomes.
- In the HELIOS-B trial, vutrisiran, an RNA interference therapeutic, significantly reduced all-cause mortality and cardiovascular (CV) events in patients with ATTR-CM.
- This prespecified analysis showed that worsening heart failure (HF) portends worse outcomes, including all-cause mortality and CV events, among ATTR-CM patients.
- Vutrisiran significantly reduced the risk of outpatient worsening HF and the composite of all-cause mortality and recurrent CV events compared with placebo.
Transthyretin cardiac amyloidosis (ATTR-CM) is a progressive disease caused by the deposition of misfolded transthyretin amyloid proteins in the heart, leading to worsening HF, cardiovascular mortality, and all-cause death. Results of the HELIOS-B trial (NCT04153149) were first presented at the ESC Congress earlier this year [1]. This large, multinational, randomized, double-blind trial enrolled patients aged 18–85 years with hereditary or wild-type ATTR-CM to evaluate the efficacy and safety of vutrisiran. Vutrisiran, a small interfering RNA (siRNA) therapeutic that rapidly lowers circulating amyloidogenic transthyretin levels, was administered subcutaneously at a dose of 25 mg every 3 months for up to 36 months. The trial demonstrated significant reductions in all-cause mortality and recurrent CV events (defined as CV hospitalizations or urgent HF visits) compared with placebo over a 36-month follow-up period.
During the Featured Science Session at the American Heart Association 2024 on November 11, 2024, Dr. Marianna Fontana from University College London, Royal Free Hospital, London, UK, presented results from a prespecified analysis of HELIOS-B. This analysis assessed the clinical and prognostic significance of outpatient worsening HF, defined as the initiation or intensification of oral diuretics, as a marker of disease progression. The association between outpatient worsening HF and all-cause mortality was evaluated in the entire HELIOS-B cohort, as well as the relationship between worsening HF, all-cause mortality, and recurrent CV events (defined as CV hospitalizations or urgent HF visits). The treatment effect of vutrisiran on these outcomes were also determined. Secondary endpoints, including 6-minute walk test (6-MWT) distance, Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score, and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP), were also assessed.
Of the 654 patients enrolled in HELIOS-B trial (92% men), 321 (49%) patients experienced at least one outpatient worsening HF event, which was strongly associated with increased all-cause mortality (HR: 2.45, 95% CI: 1.70–3.52) and recurrent CV events (HR: 2.58, 95% CI: 2.04–3.27). Vutrisiran treatment reduced the relative risk of outpatient worsening HF by 34% (rate ratio: 0.66, 95% CI: 0.56–0.78) and lowered the risk of the composite of all-cause mortality, recurrent CV events, and outpatient worsening HF (HR: 0.69, 95% CI: 0.57–0.83) compared with placebo.
Patients receiving vutrisiran also experienced improved functional capacity and quality of life, with slower declines in 6-MWT distance and KCCQ-OS score, along with smaller increases in NT-proBNP levels. Interestingly, while these results were consistent across the entire cohort and the vutrisiran monotherapy treatment groups, vutrisiran did not significantly reduce worsening HF events in patients receiving tafamidis at baseline. A noted limitation of the study was the lack of adjudication for worsening HF events, unlike the other endpoints in the trial.
In discussing the results, Dr. Fontana remarked: “We confirmed the strong prognostic significance of worsening heart failure in the outpatient setting, with a strong correlation with mortality and cardiovascular events. We also showed how once the patient experienced a worsening heart failure event, they’ve got a significant decline in functional capacity, quality of life, and biomarkers. But most importantly, when we assessed the effect of treatment, we saw that vutrisiran was associated with significantly lower worsening heart failure in the outpatient setting.”