Vericiguat Improves HFrEF Regardless of Background Therapy, With Justin Ezekowitz, MD

Patients enrolled in the VICTOR trial, an investigation of the efficacy of vericiguat in patients with heart failure with reduced ejection fraction (HFrEF), exhibited excellent background therapy before initiation, which contributed significantly to the composite primary endpoint of cardiovascular mortality and heart failure (HF)-related hospitalization.1

An oral soluble guanylate cyclase stimulator, vericiguat restores impaired nitric oxide signaling in patients with HFrEF. It was approved by the US Food and Drug Administration (FDA) for the treatment of worsening heart failure (HF) based on a reduction in cardiovascular death or HF hospitalization in the 2020 VICTORIA trial.2

In an analysis presented at the Heart Failure Society of America Annual Scientific Meeting 2025 by Justin Ezekowitz, MD, professor of medicine in cardiology at the University of Alberta and co-director of the Canadian VIGOUR Center, investigators examined the quality of background therapy present in the VICTOR trial and how it was related to clinical outcomes.1

The editorial team at HCPLive sat down with Ezekowitz to discuss the analysis and its implications for patients with HFrEF.

“We had a lot of patients who were on optimal medical therapy, and that’s the first finding: that we really did have an exceptionally good and well-treated patient population in this HFrEF trial,” Ezekowitz told HCPLive. “The second thing to look at was how that was related to the clinical outcome. The primary endpoint was cardiovascular death and heart failure hospitalization, and what we wanted to look at was whether or not it was related to background medical therapy.”

The VICTOR trial was a double-blind, placebo-controlled, parallel group, 1:1 randomized, event-driven investigation of the effects of oral vericiguat 10 mg versus placebo in ambulatory patients with HFrEF and no worsening HF episode. Patients were excluded if they had experienced recent HF worsening, defined as either an HF event that required hospitalization in the last 6 months or urgent outpatient diuretic use in the last 3 months.3

Additionally, VICTOR enrolled patients already on background therapy, such as angiotensin-converting enzyme inhibitors (ACEi), angiotensin-receptor blockers (ARB), angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRA), and sodium glucose cotransporter inhibitors (SGLT2i). These therapies were then divided into categories of adequate, good, better, and best background therapies based on their individual effectiveness in reducing symptoms of HFrEF.1

Ezekowitz and colleagues examined the adherence to these background therapies according to the number of guideline-directed medical therapy (GDMT), as well as the Heart Failure Collaboratory score (mHFC). The primary endpoint was associations between the study treatment and the primary and secondary outcomes of VICTOR.1

Ezekowitz and colleagues found a consistent improvement in the composite VICTOR endpoints across all background therapies, regardless of the quality of treatment. Vericiguat improved both cardiovascular mortality risk and HF hospitalization irrespective of preexisting treatment compared to placebo.

“The effect of vericiguat versus placebo was pretty consistent across all ranges of GDMT; those patients on good, adequate, better, and best therapy saw a very consistent result that vericiguat was better than placebo for most of the outcomes we tested,” Ezekowitz said. “I think that’s the take-home message: regardless of where patients are starting, there was additional benefit for cardiovascular death and all-cause mortality from adding in vericiguat.”

Editor's Note: Ezekowitz reports disclosures with Bayer, Merck, Amgen, Sanofi, Novartis, Cytokinetics, and others.

References

1. Ezekowitz J, Butler J, Zannad F. Vericiguat efficacy and safety across baseline background therapy in contemporary ambulatory patients with HFrEF enrolled in the VICTOR trial. Presented at the Heart Failure Society of America Annual Scientific Meeting 2025. Minneapolis, MN. September 26-29, 2025.s

2. Vericiguat did not meet its primary endpoint but lowered the risk of cardiovascular death in patients with heart failure. European Society of Cardiology. August 30, 2025. Accessed October 17, 2025. https://www.escardio.org/The-ESC/Press-Office/Press-releases/Vericiguat-did-not-meet-its-primary-endpoint-but-lowered-the-risk-of-cardiovascular-death-in-patients-with-heart-failure

3. 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(2):209-218. doi:10.1002/ejhf.3501