Heart failure with reduced ejection fraction (HFrEF) remains a major public health burden, with persistent morbidity and mortality despite advances in contemporary guideline-directed medical therapy (GDMT).^1,2 Soluble guanylate cyclase stimulators such as vericiguat offer a mechanistically novel approach by restoring impaired nitric oxide signaling, thereby improving myocardial and vascular function. The VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) results established vericiguat's efficacy in patients with recently worsening heart failure (HF) by reducing the incidence of death from cardiovascular (CV) causes or heart failure hospitalizations (HFH).³ However, its role in a broader, stable, ambulatory HFrEF population remained uncertain.

The VICTOR (Vericiguat in Patients With Chronic Heart Failure and Reduced Ejection Fraction) study addressed this gap.⁴ This phase 3, double-blind, multicenter, placebo-controlled trial included 6,105 ambulatory patients with HFrEF but without HFH within 6 months or intravenous diuretic use within 3 months and baseline N-terminal pro–B-type natriuretic peptide (NT-proBNP) level ≤6000 pg/mL. This cohort reflected a low-risk, well-treated HFrEF population with baseline characteristics including median age 68 years (interquartile range 61-75 years), mean left ventricular ejection fraction 30.4%, and median NT-proBNP level 1375 pg/mL. Additionally, 23.6% of patients were women, 79% of patients had New York Heart Association (NYHA) class II HF symptoms, and there were high rates of GDMT use (94% beta-blockers, 77% mineralocorticoid-receptor antagonists, 59% sodium-glucose cotransporter-2 inhibitors, and 56% angiotensin receptor–neprilysin inhibitors).

Over a median follow-up of 18.5 months, the primary composite endpoint of CV death or HFH occurred in 18% in the vericiguat arm and in 19.1% in the placebo arm (hazard ratio [HR], 0.93; p = 0.22). Although the composite outcome of time to CV death or HFH was neutral, there was a signal of mortality benefit in this population given an observed reduction in CV mortality (HR, 0.83; 95% confidence interval [CI], 0.71-0.97) and all-cause mortality (HR, 0.84; 95% CI, 0.74-0.97) with vericiguat. This mortality benefit was consistent across subgroups, including those taking contemporary GDMT, and across NT-proBNP levels up to 6000 pg/mL.

Compared with the VICTORIA, which included patients at high risk of recurrent events due to recent decompensation and elevated NT-proBNP levels, the VICTOR study represented a lower-risk, well-treated, ambulatory HFrEF population. These differences in trial populations are crucial for interpreting trial generalizability and efficacy outcomes. The neutral primary result likely reflects a relatively lower-risk population (without recent hospitalization), high background GDMT optimization, and lower absolute event rates, therefore limiting the incremental benefit that vericiguat could demonstrate. These differences underscore the importance of patient selection while considering adjunctive therapy.

Vericiguat demonstrated a favorable safety and tolerability profile in both the VICTORIA and VICTOR study data, with symptomatic hypotension and mild anemia being the most common adverse events, which rarely led to treatment discontinuation. No new safety signals were observed. A pooled patient-level analysis of the VICTOR and VICTORIA study data across >11,000 patients suggested an overall reduction in the composite endpoint and signals for mortality benefit in predefined subgroups (particularly in those with NT-proBNP level ≤6,000 pg/mL),⁵ although the divergent trial populations warrant cautious interpretation of these results.

Vericiguat remains primarily indicated for patients with HFrEF and recent decompensation. In stable, ambulatory patients with HFrEF but without recent decompensation who are taking modern GDMT, vericiguat may be considered selectively in individuals at higher risk (e.g., those with elevated NT-proBNP levels, prior HF events, and perhaps lower BP tolerance). However, its routine use in this setting is not yet supported by the primary outcome of the VICTOR study and should involve a case-by-case discussion of benefit versus risk. The survival curves for CV and all-cause mortality began to separate after 8 months, suggesting that longer-term follow-up may be necessary to fully assess the mortality benefit. The mortality benefits in the VICTOR study were nominal (secondary analyses) and were more hypothesis-generating than definitive practice-changing findings, although they may suggest a potential mortality benefit in select patients.

In summary, the VICTOR study results complement those of the VICTORIA by extending the evidence base for vericiguat in a contemporary lower-risk, well-treated ambulatory HFrEF population (Table 1). Although the primary composite endpoint remained neutral, the mortality signal and the pooled analysis support vericiguat as a mechanistically distinct adjunct therapy in HFrEF. Its benefit appears greatest in patients with recent worsening or elevated NT-proBNP levels, reinforcing the importance of background GDMT optimization and individualized patient selection.

Table 1: Summary of Key Differences Between the VICTOR and VICTORIA Study Results

^a CV death or HFH
AF = atrial fibrillation; ARNI = angiotensin receptor–neprilysin inhibitor; CV = cardiovascular; GDMT = guideline-directed medical therapy; HFH = heart failure hospitalization; HFrEF = heart failure with reduced ejection fraction; HR = hazard ratio; IV = intravenous; LVEF = left ventricular ejection fraction; NT-proBNP = N-terminal pro–B-type natriuretic peptide; SGLT2i = sodium-glucose cotransporter-2 inhibitor; SR = sinus rhythm; VICTOR = Vericiguat in Patients With Chronic Heart Failure and Reduced Ejection Fraction; VICTORIA = Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction.

References

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