Vericiguat in the Post-Stabilization Phase of HFrEF: Targeting Residual Risk Across the Ischemia–Decompensation Continuum

Abstract

Vericiguat is currently indicated for patients with heart failure with reduced ejection fraction (HFrEF) following recent clinical worsening, based on evidence demonstrating a reduction in cardiovascular death or heart failure hospitalization in a high-risk population. While this positioning is clinically justified, it may underestimate the broader pathophysiological context in which soluble guanylate cyclase (sGC) stimulation may be relevant, particularly in phases of persistent biological activation following apparent clinical stabilization. In routine practice, acute coronary syndromes (ACS), acute heart failure (AHF), and chronic HFrEF are approached as distinct clinical entities. However, these conditions often represent sequential manifestations of a continuous disease trajectory driven by persistent endothelial dysfunction, impaired nitric oxide–sGC–cyclic guanosine monophosphate (NO–sGC–cGMP) signaling, and residual vascular risk. In this perspective, we revisit the mechanistic and clinical rationale for vericiguat and propose a reframing of its therapeutic role. Its greatest utility may lie in patients with recently worsening HFrEF who remain biologically vulnerable after stabilization. Extension of this concept to post-ACS populations remains hypothesis-generating and is not supported by direct clinical evidence. This “post-stabilization vulnerable state” represents a clinically recognizable yet insufficiently targeted phase, characterized by ongoing biological activation despite apparent clinical improvement. Adopting a continuum-based view of cardiovascular disease may improve alignment between pathophysiology and treatment, refine patient selection, and inform future trial design focused on this early post-event window. Importantly, this perspective is hypothesis-generating and reflects an effort to align emerging mechanistic insights with clinical trajectory, rather than to extend current indications beyond the available evidence base.