Beyond the Four Pillars: A Risk-Targeted Framework for Vericiguat—A Narrative Review

Heart failure (HF) remains a major global health burden despite substantial therapeutic advances. Vericiguat, an oral soluble guanylate cyclase (sGC) stimulator, represents a distinct pharmacological strategy targeting impaired nitric oxide–sGC–cyclic guanosine monophosphate (NO–sGC–cGMP) signaling, a pathway closely linked to endothelial dysfunction, vascular stiffness, myocardial fibrosis, and adverse remodeling. This narrative review synthesizes the current evidence on the efficacy, safety, and clinical positioning of vericiguat across the heart failure spectrum, with a particular focus on worsening heart failure with reduced ejection fraction (HFrEF), while integrating recent trial data, updated guideline recommendations, and emerging real-world evidence to define its contemporary role in clinical practice. Randomized trials, subgroup analyses, and contemporary meta-analyses indicate that vericiguat provides a modest but clinically relevant reduction in HF-related outcomes, especially in high-risk patients with recent decompensation. However, its overall effect appears smaller than that of foundational therapies such as angiotensin receptor–neprilysin inhibitors and sodium–glucose cotransporter 2 inhibitors. Recently published data from the VICTOR program further refine the role of vericiguat in compensated outpatients with chronic HFrEF, showing a neutral primary outcome but providing supportive hypothesis-generating signals across a broader risk continuum while confirming a favorable safety profile. Overall, vericiguat should be regarded not as a replacement for cornerstone therapy but as a mechanistically complementary, risk-targeted adjunct for selected patients with persistent residual risk despite guideline-directed medical therapy.