Vericiguat, a novel stimulator of soluble guanylate cyclase (sGC), has shown 
promising results in patients with heart failure and reduced ejection fraction 
(HFrEF) in the recent VICTORIA trial. The nitric oxide (NO)-sGC-cyclic guanosine 
monophosphate (cGMP) signaling pathway is disturbed in heart failure, leading to 
increased formation of reactive oxygen species and reduced NO bioavailability, 
and resultant myocardial dysfunction, adverse left ventricular remodeling, and 
cardiorenal syndrome. Restoration of sufficient NO-sGC-cGMP signaling has been 
proposed as an important treatment target in heart failure, beyond neurohormonal 
blockage and afterload reduction. Vericiguat has a dual mode of action on this 
axis, it both sensitizes sGC to low levels of NO, and can directly stimulate sGC 
in the absence of any endogenous NO. VICTORIA was a Phase 3 trial that compared 
vericiguat, at a target dose of 10 mg, with placebo in 5050 patients with HFrEF 
(ejection fraction < 45%) on top of guideline-indicated therapy. The composite 
endpoint was the first occurrence of cardiovascular death or hospitalization for 
heart failure. The median follow up was 10.8 months. The included patients had 
to have had a heart failure-related hospitalization or need of IV diuretic 
therapy in the past 6 months, making it a particularly high risk and vulnerable 
patient population. The composite endpoint occurred less frequently with 
vericiguat than with placebo (35.5% vs 38.5%, p = 0.02). Adverse events were 
common in both groups, syncope was more common with vericiguat than with placebo 
(4% vs 3.5%, p = 0.03). Compared to the other recent large trials in HFrEF, 
PARADIGM-HF and DAPA-HF, patients in VICTORIA were older, more symptomatic (up 
to 40% NYHA IIIIV class), had higher N-terminal-pro hormone B-type natriuretic 
peptide (NT-proBNP) levels, and were more vulnerable since 84% had been 
hospitalized for heart failure in the previous 6 months. While drugs involving 
the neurohormonal pathways are effective in slowing down the progression of 
disease in more stable HFrEF, vericiguat may be a drug of choice particularly in 
the highest risk patients with recent or recurrent hospitalizations despite full 
background medication. The drug has also shown safety in patients with reduced 
renal function. This article discusses the place in therapy of vericiguat in 
patients with HFrEF, which is a heterogenous group in terms of etiology, 
clinical profiles, and comorbidities.