Vericiguat did not reduce the risk of a composite endpoint of time to cardiovascular death or heart failure (HF) hospitalization among patients with HF and reduced ejection fraction (HFrEF) without recent HF worsening, based on findings from the VICTOR trial presented at ESC Congress 2025 and simultaneously published in The Lancet. However, study investigators said there were fewer cardiovascular deaths with vericiguat compared with placebo.

VICTOR, which was conducted at 482 sites across 36 countries, randomized 6,105 patients with HFrEF but without HF hospitalization within six months or outpatient intravenous diuretic use within three months to either oral vericiguat (target 10 mg dose) or matching placebo. The median participant age was 68 years, 23.6% were women, 64.4% were White and 47.5% had no previous hospitalization for HF. The primary composite endpoint was time to cardiovascular death or HF hospitalization.

Results showed primary outcome events occurred in 549 (18%) of patients assigned to vericiguat compared with 584 (19%) assigned to placebo over a median follow-up of 18.5 months. Broken out by event, cardiovascular death occurred in 292 (9.6%) patients in the vericiguat group compared with 346 (11.3%) patients in the placebo group, while HF hospitalization occurred in 348 (11.4%) vs. 362 (11.9%), respectively. Serious adverse events, of which symptomatic hypotension was the most common, occurred in 717 (23.5%) of 3,049 patients in the vericiguat group and 751 (24.6%) of the 3,049 patients in the placebo group. All-cause death occurred in approximately 12% of patients receiving vericiguat group compared with 14% receiving placebo. Because the primary endpoint was not statistically significant, study investigators said these analyses of secondary and exploratory endpoints should be considered nominal.

"Although vericiguat did not improve the primary composite of cardiovascular death or hospitalization for HF, there were fewer cardiovascular deaths with vericiguat and this translated into fewer all-cause deaths," said Faiez Zannad, MD, PhD, in presenting the findings. "The risk of HF hospitalization was not reduced, which may be due, at least in part, to the high use of contemporary HF therapies and the low proportion of recent hospitalizations in this population. Overall, these findings support the use of vericiguat in ambulatory patients with HFrEF on top of contemporary therapies."

In a secondary analysis of VICTOR data published in JACC, vericiguat did appear to reduce the overall risk of worsening HF considering both outpatient and inpatient events. "Combined with the observed reduction in mortality, these exploratory analyses suggest potential reduction in [HF] events among compensated outpatients with [HFrEF]," said Zannad, et al.

Meanwhile, a pooled analysis using data from more than 11,000 participants in the VICTOR trial, as well as the earlier VICTORIA trial that assessed patients with HFrEF and recent worsening HF, suggests vericiguat may be a useful option in treating a broad range of patients with HFrEF.

The analysis, also presented at ESC Congress 2025 and published in The Lancet, showed vericiguat significantly reduced the composite endpoint of cardiovascular mortality or HF hospitalization compared with placebo. Similar reductions were also observed in cardiovascular mortality and HF hospitalization, as well as all-cause mortality. Of note, the benefits of vericiguat were most pronounced among the 88.7% of participants with a baseline NT-proBNP of ≤6,000 pg/ml, according to study investigators.

"The cumulative evidence from pooling the VICTOR and VICTORIA trials affirms that vericiguat improved outcomes, including mortality, across the broad range of well-treated patients with HFrEF, with the clearest benefit observed in those with NT-proBNP ≤6,000 pg/ml," said Javed Butler, MBBS, FACC. "With once-a-day administration and a favourable safety profile, vericiguat may provide a valuable option for patients across the spectrum of HFrEF severity."

In a related editorial comment, Shun Kohsaka, MD, FACC, and Paul A. Heidenreich, MD, FACC, note that "next, we should move beyond a binary distinction of recent worsening versus stable disease. Priorities are to establish the durability and timing of mortality effects, and to conduct pragmatic effectiveness studies within a background of fully implemented quadruple therapy that incorporate patient-reported outcomes and health economics."

In a related JACC simultaneous publication, researchers updated a meta-analysis from 2022 to include large randomized controlled trials like VICTOR and noted their findings "reinforce the substantial mortality and morbidity benefit associated with the currently recommended quadruple therapy regimen – ARNis, β-blockers, MRAs, and SGLT2is – in patients with HFrEF." They write: "The addition of vericiguat may provide an incremental survival gain of approximately 0.7 years beyond that achieved with quadruple therapy. However, these results should be regarded as exploratory, as they are derived from a secondary endpoint of a single trial."