The VICTOR trial, investigating vericiguat in patients with ambulatory heart failure with reduced ejection fraction (HFrEF) who had received contemporary background therapy, failed to achieve its primary endpoint of reduction in cardiovascular mortality and heart failure hospitalizations. However, it did display fewer cardiovascular and all-cause deaths. Investigators suggested vericiguat may prove beneficial in ambulatory patients with HFrEF on top of optimal background therapy.1
At the European Society of Cardiology Congress 2025 in Madrid, hosts Steve Greene, MD, and Muthiah Vaduganathan, MD, MPH, sat down with Javed Butler, MD, to review the results of the highly anticipated VICTOR trial, a companion study to the pivotal VICTORIA trial evaluating vericiguat in heart failure with reduced ejection fraction (HFrEF). While VICTORIA focused on patients recently hospitalized or otherwise destabilized, VICTOR deliberately enrolled the opposite population—ambulatory, stable patients, systematically excluding anyone with a recent hospitalization or outpatient IV diuretic use. As Butler noted, this created one of the most stable trial cohorts in HFrEF to date, with nearly 90% of participants free from hospitalization for over a year at baseline.
The rationale, Butler explained, stemmed from post-hoc signals in VICTORIA suggesting a cardiovascular mortality benefit in patients with lower NT-proBNP levels, as well as a trend toward curve separation late in follow-up. VICTOR was thus powered specifically for cardiovascular mortality while retaining the same primary composite endpoint of CV death or HF hospitalization. With a longer median follow-up of more than two years and excellent baseline therapy - including >50% use of SGLT2 inhibitors, >50% on ARNIs, and nearly half on quadruple therapy - the trial provided a rigorous test of vericiguat in a contemporary, optimally treated HFrEF population.
The results, presented by Butler, were mixed but thought-provoking. The trial did not meet its primary composite endpoint, with only a 7% nonsignificant relative reduction (p=0.22). Yet vericiguat achieved consistent, statistically significant reductions in multiple mortality endpoints: CV mortality, all-cause mortality, sudden cardiac death, and HF-related death. With over 600 mortality events accrued, the findings were robust, matching the predicted event rates despite the cohort’s stability.
Discussion turned to interpreting this unusual pattern of mortality benefit without a reduction in HF hospitalizations. Butler argued that VICTOR and VICTORIA should not be viewed as contradictory, but rather as capturing different phases of the HF trajectory. In VICTORIA’s higher-risk post-hospital population, reductions in hospitalization predominated. In VICTOR’s stable cohort, early worsening often manifests as outpatient oral diuretic intensification, a marker strongly associated with subsequent mortality. Indeed, over half of the first worsening events in VICTOR were oral intensifications rather than hospitalizations, suggesting vericiguat may exert benefits earlier in the decompensation continuum.
The conversation also addressed the broader implications. Butler emphasized that vericiguat’s effects appear additive to guideline-directed therapy, with no differences in outcomes based on ARNI or device use. Pooled analyses of VICTORIA and VICTOR demonstrate consistent benefit across the spectrum of HFrEF, particularly in patients with NT-proBNP <6000 pg/mL, where relative risk reductions for mortality approach 15–17%. The group noted that while VICTOR was technically neutral, its mortality signal challenges conventional thinking. While many therapies reduce HF hospitalizations without a robust mortality benefit, vericiguat may represent the reverse. This raises the possibility that its mechanism, through the stimulation of soluble guanylate cyclase and nitric oxide signaling, exerts systemic benefits beyond traditional congestion pathways.
The episode closed with a reflection on the clinical and guideline implications. Although VICTOR did not meet its composite primary endpoint, the magnitude and consistency of mortality reduction may argue for serious consideration of vericiguat as a mortality-reducing therapy in HFrEF, potentially forming part of an emerging “quintuple therapy” standard. As Butler concluded, mortality remains the “true north” in heart failure management, and these results underscore the persistent residual risk even in optimally treated patients and the potential for novel therapies like vericiguat to address it.
References
European Society of Cardiology. Vericiguat did not meet its primary endpoint but lowered the risk of cardiovascular death in patients with heart failure. News Release. August 30, 2025. Accessed August 30, 2025.
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
