An exploratory analysis of the VICTOR trial suggests that in compensated patients with heart failure and reduced ejection fraction (HFrEF), vericiguat may reduce the overall burden of worsening heart failure (HF) when outpatient events are included alongside hospitalisations.¹

Vericiguat is an oral soluble guanylate cyclase stimulator that enhances the cyclic guanosine monophosphate pathway, leading to smooth muscle relaxation and vasodilation.

VICTOR (Vericiguat Global Study in Participants With Chronic Heart Failure) was a phase 3, double-blind, placebo-controlled trial that randomised 6,105 ambulatory patients with symptomatic HFrEF (left ventricular ejection fraction ≤40%).² Participants were required to have no recent worsening HF, defined as no hospitalisation for heart failure (HHF) within 6 months or outpatient intravenous diuretic use within 3 months.

Patients received either vericiguat (target dose 10 mg once daily) or placebo, on a background of contemporary guideline-directed medical therapy. The primary endpoint was a composite of cardiovascular death or first HHF. This post-hoc analysis evaluated an exploratory endpoint of overall worsening HF, which included HHF, urgent HF visits requiring intravenous diuretics, or outpatient oral diuretic initiation or intensification.¹

The primary endpoint of the trial was not statistically significantly reduced with vericiguat. In this analysis, outpatient worsening HF was the most common first worsening event (59.3%), compared with HHF (35.4%). Outpatient oral diuretic initiation or intensification was associated with a subsequent increased risk of mortality (RR: 1.69; 95% CI: 1.47-1.94; P<0.001).

The exploratory endpoint of overall worsening HF occurred in 686 participants (22.5%) in the vericiguat group versus 748 (24.8%) in the placebo group (HR: 0.90; 95% CI: 0.81-1.00; P=0.047). The composite of all-cause death and overall worsening HF was also lower in the vericiguat group, occurring in 917 participants (30.0%) compared to 1,004 (32.9%) in the placebo group (HR: 0.90; 95% CI: 0.82-0.98; P=0.016).¹

This analysis of the VICTOR trial highlights the significant burden of outpatient worsening HF in a contemporary, well-treated, and stable HFrEF population. These outpatient events, often marked by the need for diuretic intensification, are prognostically important and more frequent than HHF. While the trial's primary endpoint was not met, these exploratory findings suggest that vericiguat may mitigate the progression of HF when the full spectrum of clinical worsening, including both inpatient and outpatient events, is considered. The authors suggest that future clinical trials in ambulatory HF should consider including outpatient diuretic intensification in composite endpoints to better capture the total burden of disease and overall treatment effects.

This study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, and Bayer AG.

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References

1. Zannad F, Reddy YNV, Barash I, et al. Effect of Vericiguat on Total Heart Failure Events in Compensated Outpatients With HFrEF: Insights From VICTOR. J Am Coll Cardiol. 2025;86(24):2471-2491. https://doi.org/10.1016/j.jacc.2025.08.051

2. Reddy YNV, Butler J, Anstrom KJ, et al. Vericiguat global study in participants with chronic heart failure: design of the VICTOR trial. Eur J Heart Fail. 2025;27:209-218. https://doi.org/10.1002/ejhf.3501