Key Points:
- The VICOTRIA trial previously demonstrated that vericiguat reduced the risk of heart failure (HF) hospitalization or cardiovascular (CV) death in patients with recently decompensated HFrEF.
- The current VICTOR trial evaluated vericiguat vs placebo among those with stable, ambulatory HFrEF.
- Although there was no significant difference in the primary endpoint of CV death or HF hospitalization, vericiguat significantly reduced CV death as well as overall worsening heart failure events in prespecified secondary analyses.
- These findings suggests a positive impact of vericiguat on those with compensated, ambulatory HFrEF receiving contemporary guideline directed medical therapy (GDMT).
Based on the VICTORIA trial, the FDA approved vericiguat, an oral soluble guanylate cyclase stimulator, in 2021 to reduce the risk of CV death and HF hospitalization among adults with an ejection fraction (EF) less than 45% and a recent worsening HF event (i.e. recent HF hospitalization or need for outpatient IV diuretics).1 However, the effect of vericiguat on stable, ambulatory HFrEF patients without a worsening HF event is unknown.
On August 30th 2025, the results of “Vericiguat in patients with chronic heart failure and reduced ejection fraction (VICTOR): a double-blind, placebo-controlled, randomized, phase 3 trial” were presented at the European Society of Cardiology Congress, with simultaneous publication in the Lancet. The purpose was to assess the effect of vericiguat in patients with stable, ambulatory HFrEF without a recent worsening heart failure event.
This multinational trial randomized patients age >18 years with NYHA Class II-IV HF and EF ≤ 40%, NT-proBNP levels between 600-6000 pg/mL, and on stable background GDMT to vericiguat (titrated to a target dose of 10mg) or placebo once daily. Importantly, patients with HF hospitalization within the prior 6 months or outpatient IV diuretic use within 3 months were excluded. The primary endpoint was a composite of CV death or HF hospitalization. Hierarchically tested secondary endpoints included a powered endpoint for CV death, as well as total worsening HF events (including both outpatient and inpatient episodes).
Overall, 6105 patients were randomized. The mean age was 67 years; 23.5% were female, 64.5% were white, the mean EF was ~30%, and nearly half had never had a prior HF hospitalization. The group was well treated at baseline: 70% were on loop diuretics, one-third had an ICD, and background GDMT was robust. After a median follow up of 18.5 months, the primary outcome occurred in 18.0% in the vericiguat group vs. 19.1% in the placebo group (HR 0.93 [95% CI 0.83-1.04]; p =0.22). While there was no effect of vericiguat on HF hospitalizations alone, there was a significant reduction in overall worsening HF events (HR 0.90 [95% CI 0.81-1.00]; p =0.047). Importantly, vericiguat was also associated with a decrease in CV death (HR 0.83 [95% CU 0.71-0.97]; p=0.02), with consistent numerical reductions in all-cause death, sudden death, and death due to heart failure.
Prof Faiez Zannad, MD, PhD of Université de Lorraine, France, concluded: ”Vericiguat did not reduce the risk of the composite of CV death or heart failure hospitalization in ambulatory patients with HFrEF on a background of high use of contemporary GDMT. However in a pre-specified, powered secondary analysis vericiguat was associated with a significantly reduced risk of CV death…and although vericiguat did not achieve significant reduction in traditional heart failure hospitalizations, pre-specified exploratory analyses demonstrated a clinically meaningful reduction in the overall risk of worsening HF when considering the entire patient journey. The totality of evidence suggests favorable effects of vericiguat on compensated outpatients with HFrEF.”
- Armstrong PW, Pieske B, Anstrom KJ, et al. Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2020;382(20):1883-1893. doi:10.1056/NEJMoa1915928
