Repositioning Vericiguat after VICTOR: Towards a Risk- and Timing-Based Framework in Contemporary HFrEF

Abstract Vericiguat, an oral soluble guanylate cyclase stimulator, provides a mechanistically distinct approach to reducing residual risk in heart failure with reduced ejection fraction (HFrEF). The VICTORIA trial demonstrated a reduction in cardiovascular death or heart failure hospitalisation among patients with recent worsening heart failure, whereas vericiguat did not significantly reduce the primary endpoint in the subsequent VICTOR trial in a more stable HFrEF population. Nevertheless, the prespecified pooled analysis of VICTORIA and VICTOR showed a significant reduction in cardiovascular death or first heart failure hospitalisation across the combined HFrEF population, without significant heterogeneity between the trials. Together, these findings shift the focus from efficacy alone to clinical prioritisation according to baseline risk and timing, while recognising that validated treatment-selection criteria and an optimal timing strategy remain undefined. Contemporary observational studies have identified associations between blood pressure, disease severity, prior heart failure hospitalisation, and clinical or biomarker outcomes during vericiguat treatment; however, these characteristics have not been validated as predictors of vericiguat-specific treatment benefit. This review integrates evidence from VICTORIA, VICTOR, pooled analyses, and contemporary real-world studies and proposes a hypothesis-generating, risk- and timing-based framework for vericiguat use. Clinically meaningful worsening heart failure may represent a period of increased absolute risk in which consideration of vericiguat may be particularly relevant after clinical stabilisation, but neither an optimal therapeutic window nor a validated responder phenotype has been established. Prospective studies specifically evaluating treatment-by-risk and treatment-by-timing interactions are required to validate this framework.