VICTOR Trial Highlights Vericiguat’s Potential in Heart Failure

The recent VICTOR trial, which assessed the efficacy of vericiguat in patients with ambulatory heart failure with reduced ejection fraction (HFrEF), did not achieve its primary endpoint of reducing cardiovascular mortality and heart failure hospitalizations. Nevertheless, the trial showed promising outcomes, with fewer instances of both cardiovascular and all-cause mortality among participants receiving optimal background therapy.

At the European Society of Cardiology Congress 2025 in Madrid, a significant discussion unfolded among prominent cardiologists, including Javed Butler, MD. The VICTOR trial serves as a companion study to the earlier pivotal VICTORIA trial, which focused on patients who were recently hospitalized or otherwise unstable. In contrast, VICTOR specifically targeted a more stable cohort of ambulatory patients, effectively excluding those with a recent hospitalization or outpatient intravenous diuretic use.

Butler highlighted that this unique approach resulted in one of the most stable trial populations for HFrEF to date, with nearly 90% of participants free from hospitalization for over a year before enrollment. This selection aimed to explore post-hoc signals from VICTORIA, which suggested potential cardiovascular mortality benefits in patients with lower levels of NT-proBNP. The VICTOR trial was therefore strategically powered to focus on cardiovascular mortality while maintaining the same primary composite endpoint of cardiovascular death or heart failure hospitalization.

With a median follow-up period exceeding two years and a robust baseline therapy—over 50% of patients on SGLT2 inhibitors and ARNIs—the trial aimed to rigorously assess vericiguat’s efficacy in a well-treated HFrEF population.

The trial results, as presented by Butler, were complex yet insightful. Although VICTOR did not meet its primary composite endpoint—showing only a 7% non-significant relative reduction (p=0.22)—vericiguat demonstrated statistically significant reductions across multiple mortality endpoints, including cardiovascular mortality, all-cause mortality, sudden cardiac death, and heart failure-related death. The robustness of these findings was underscored by the accrual of over 600 mortality events, aligning closely with predicted event rates despite the stability of the cohort.

Discussions around these unexpected findings emphasized the importance of interpreting the results within the broader context of heart failure management. Butler argued that VICTOR and VICTORIA should not be viewed as contradictory; instead, they reflect different phases in the heart failure continuum. In the higher-risk post-hospital population represented by VICTORIA, reductions in hospitalizations were the primary concern. Conversely, in VICTOR’s stable cohort, early worsening was often indicated by outpatient oral diuretic intensification, a marker closely associated with subsequent mortality.

The implications of these findings extend beyond the trial itself. Butler noted that vericiguat’s effects appear to be additive to existing guideline-directed therapies, with no significant differences in outcomes based on the use of ARNIs or other devices. An analysis combining data from both VICTORIA and VICTOR suggests consistent benefits across the spectrum of HFrEF, particularly for patients with NT-proBNP levels below 6000 pg/mL, where relative risk reductions for mortality reached 15% to 17%.

Despite VICTOR’s technical neutrality regarding its primary endpoint, the trial’s mortality signal challenges conventional treatment paradigms. While many heart failure therapies effectively reduce hospitalizations without a corresponding mortality benefit, vericiguat appears to offer the opposite. This raises intriguing questions about its mechanism of action, which stimulates soluble guanylate cyclase and enhances nitric oxide signaling, potentially providing systemic benefits that extend beyond traditional congestion pathways.

In conclusion, while the VICTOR trial did not meet its primary composite endpoint, the significant and consistent reductions in mortality suggest that vericiguat deserves serious consideration as a promising therapy for reducing mortality in HFrEF. The findings indicate the persistent residual risk even among optimally treated patients and highlight the potential of novel therapies like vericiguat to address this challenge. As Butler aptly stated, mortality remains the “true north” in heart failure management, reinforcing the need for continued research and development in this critical area of healthcare.