Use of vericiguat in the VICTOR trial: a study that is difficult to interpret

Abstract

Vericiguat is a soluble guanylate cyclase stimulator that acts by restoring the nitric oxide–cyclic guanosine monophosphate pathway, which is markedly impaired in heart failure with reduced ejection fraction (HFrEF). The VICTORIA trial demonstrated that treatment with vericiguat leads to a significant reduction in mortality and morbidity in patients with HFrEF and a recent episode of clinical decompensation. However, the role of vericiguat in clinically stable patients had remained unexplored until the recent publication of the VICTOR trial. In a population receiving optimal medical therapy and characterized by a lower risk of events, vericiguat did not demonstrate a significant reduction in the primary composite endpoint of cardiovascular death and hospitalization for heart failure. When analysing the individual components of the primary endpoint, no benefit was observed with respect to hospitalizations, whereas significant reductions in both cardiovascular and all-cause mortality were reported. This finding, which is highly unusual in the context of recent clinical trials in patients with HFrEF, warrants further consideration when interpreting the results of the study.

Introduction

Vericiguat is a soluble guanylate cyclase (sGC) stimulator developed to target one of the pathophysiological pathways most frequently impaired in patients with heart failure with reduced ejection fraction (HFrEF): the nitric oxide (NO)–soluble guanylate cyclase–cyclic guanosine monophosphate (cGMP) axis.¹ Under physiological conditions, this pathway regulates vasodilation, endothelial function, and the balance between haemodynamic load and ventricular response. Oxidative stress and endothelial dysfunction reduce NO bioavailability, leading to sGC deficiency and, consequently, decreased cGMP synthesis, thereby contributing to the progression of HFrEF.

Vericiguat directly stimulates sGC independently of NO, restoring the NO–sGC–cGMP pathway and thereby reducing myocardial stiffness and hypertrophy, adverse ventricular remodelling, fibrosis, and vasoconstriction, while simultaneously improving renal blood flow and endothelial function.¹

In the VICTORIA trial (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction),² vericiguat was shown to reduce the composite endpoint of cardiovascular (CV) death and heart failure hospitalizations (HHF) by 10% in a high-risk population, namely patients with chronic HFrEF (left ventricular ejection fraction <45%) and a recent episode of worsening heart failure (84% with HHF within the previous six months and 16% with an urgent visit requiring intravenous diuretic therapy within the previous three months). On the basis of these findings, vericiguat received a Class IIb recommendation, level of evidence B, in the most recent European Society of Cardiology guidelines on heart failure.³

The VICTOR trial (Vericiguat in Adults with Chronic Heart Failure and Reduced Ejection Fraction) was therefore designed to test the hypothesis that vericiguat could represent a potential new pillar of pharmacological therapy for HFrEF in clinically stable outpatients, that is, patients with characteristics more closely resembling those enrolled in recent trials of sacubitril/valsartan and sodium–glucose cotransporter 2 inhibitors.⁴

The VICTOR trial

VICTOR is an international, randomized, double-blind, placebo-controlled, phase 3 clinical trial that enrolled 6105 patients with HFrEF between November 2021 and December 2023.⁵ Eligible patients were in a condition of clinical stability, defined as the absence of recent HHF or the need for outpatient intravenous diuretic therapy within the six and three months prior to randomization, respectively. Patients were randomized in a 1:1 ratio to receive vericiguat or placebo, with the aim of demonstrating a reduction in the primary composite endpoint of CV death and HHF.

Inclusion criteria comprised age >18 years, an estimated glomerular filtration rate (eGFR) ≥ 15 mL/min/1.73 m², and NT-proBNP levels between 600 and 6000 pg/mL (900–6000 pg/mL in patients with atrial fibrillation at the time of randomization). This latter criterion was based on a post hoc analysis of the VICTORIA trial, which had shown a loss of efficacy of vericiguat in patients with NT-proBNP levels >6000 pg/mL.⁶

Table 1 compares the clinical characteristics of patients enrolled in the VICTOR trial with those of patients included in the intervention arms of the most recent HFrEF trials. As shown, the VICTOR population exhibited the highest degree of clinical stability. Compared with patients enrolled in PARADIGM-HF (Angiotensin–Neprilysin Inhibition vs. Enalapril in Heart Failure),⁷ DAPA-HF (Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction),⁸ and EMPEROR-Reduced (Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure),⁹ and especially compared with the high-risk, recently destabilized population of VICTORIA,² patients in VICTOR were slightly older (mean age 68 years) and had a comparable proportion of male participants (76%). Mean left ventricular ejection fraction (approximately 30%) was consistent with other trials, whereas NT-proBNP levels were substantially lower (median 1375 pg/mL vs. 2816 pg/mL in VICTORIA), reflecting less severe disease. Nearly 80% of patients were in New York Heart Association class II, and up to 48% had never experienced an HHF episode. In addition, mean eGFR was higher (approximately 71 mL/min/1.73 m²), suggesting better renal function than in other trials.

Table 1.

Comparison of baseline characteristics and primary endpoint results in major trials of heart failure with reduced ejection fraction

Comparison of major randomized trials in HFrEF
	PARADIGM-HF (7)	DAPA-HF (8)	EMPEROR-Reduced (9)	VICTORIA (2)	VICTOR (5)
Patients, n	8399	4744	3730	5050	6105
Mean age, years	64	66	67	67.3	68.0
Male sex, %	78	67	76	76	76.4
Mean LVEF, %	≈30	≈31	≈27	28.9	30.4
NT-proBNP, median (pg/mL)	1608	1437	1906	2816	1375 (827–2393)
NYHA class III–IV, %	25	32	25	41	21
HF hospitalization <6 months, %	31	16	NA	84	0a
eGFR <60 mL/min/1.73 m², %	37	41	48	53	≈30
eGFR inclusion criterion (mL/min/1.73 m²)	≥30	≥30	≥20	≥15	≥15
Median follow-up, months	27	18.2	16	10.8	18.5
Primary endpoint	First HF hospitalization or CV death	Worsening HF or CV death	First HF hospitalization or CV death	First HF hospitalization or CV death	CV death or first HF hospitalization
Annualized event rate (intervention vs. control), %	10.5 vs. 13.2	11.6 vs. 15.6	15.8 vs. 21.0	33.6 vs. 37.8	11.7 vs. 12.4

Hazard Ratios (HR) and 95% Confidence Intervals
Outcome	PARADIGM-HF	DAPA-HF	EMPEROR-Reduced	VICTORIA	VICTOR
Primary endpoint	0.80 (0.73–0.87)	0.74 (0.65–0.85)	0.75 (0.65–0.86)	0.90 (0.82–0.98)	0.93 (0.83–1.04)
CV death	0.80 (0.71–0.89)	0.82 (0.69–0.98)	0.92 (0.75–1.12)	0.93 (0.81–1.06)	0.83 (0.71–0.97)
First HF hospitalization	0.79 (0.71–0.89)	0.70 (0.59–0.83)	0.69 (0.59–0.81)	0.90 (0.81–1.00)	0.95 (0.82–1.10)

Abbreviations: LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; HF, heart failure; HFH, heart failure hospitalization; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HR, hazard ratio.

^aNo patients with heart failure hospitalization within 6 months prior to randomization.

As shown in Table 2, beyond a more favourable clinical profile in terms of stability, patients enrolled in the VICTOR trial were very well treated, with a high uptake of guideline-recommended therapies (sacubitril/valsartan 56%, sodium–glucose cotransporter 2 inhibitors 59%, mineralocorticoid receptor antagonists 70%, and beta-blockers 88%), a level of background therapy not previously observed in earlier clinical trials.

Table 2.

Comparison of guideline-recommended heart failure therapy at the time of randomization in major trials of heart failure with reduced ejection fraction

Baseline Therapy
	PARADIGM-HF (7)	DAPA-HF (8)	EMPEROR-Reduced (9)	VICTORIA (2)	VICTOR (5)
ACEi/ARB/ARNi	100% (enalapril vs. ARNi)	94% (10.7% ARNi)	70% (19% ARNi)	87.6% (14.3% ARNi)	94% (56% ARNi)
Beta-blockers	93%	96%	95%	93.2%	88.4%
MRAs	54%	71%	71%	69.3%	70.2%
SGLT2 inhibitors	0%a	100% (randomized therapy)	100% (randomized therapy)	4.2%	59.1%
Loop diuretics	74%	75%	80%	NR	≈70%

Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor–neprilysin inhibitor; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium–glucose cotransporter 2 inhibitor.

^aSGLT2 inhibitors were not recommended therapy at the time the PARADIGM-HF trial was conducted.

Over a median follow-up of 18.5 months, vericiguat did not significantly reduce the primary endpoint, which occurred in 18.0% of patients in the vericiguat group and in 19.1% of those receiving placebo [hazard ratio (HR) 0.93; 95% confidence interval (CI) 0.83–1.04; P = 0.22]. However, analysis of the individual components of the primary endpoint revealed a significant reduction in CV mortality (6.8% vs. 9.6%; HR 0.83; 95% CI 0.71–0.97). Similarly, the secondary endpoint of all-cause mortality occurred less frequently in the vericiguat group than in the placebo group (12.3% vs. 14.4%; HR 0.84; 95% CI 0.74–0.97). Vericiguat was well tolerated, with a similar incidence of adverse events in the two treatment groups.

Critical interpretation of the VICTOR trial

Although, from a formal standpoint, the VICTOR trial must be considered neutral—given that vericiguat did not demonstrate a statistically significant reduction in the primary endpoint compared with placebo—labelling vericiguat as a therapeutic ‘failure’ would represent an overly simplistic and potentially misleading interpretation. The first element to consider is the context of pre-existing evidence. In the VICTORIA trial, conducted in patients with HFrEF who were recently destabilized and at high risk, vericiguat demonstrated a significant 10% relative reduction in the composite endpoint of cardiovascular death or first hospitalization for heart failure, despite a population already treated according to the best available evidence at that time.² VICTOR should therefore be interpreted as an extension of this research programme rather than as a contradiction of its findings.

Moreover, in a clinically stable outpatient population characterized by a substantially lower risk profile and a much higher level of background therapy optimization than in previous trials, VICTOR confirmed the favourable safety profile of vericiguat and provided encouraging signals, with consistent and statistically significant reductions in cardiovascular mortality, all-cause mortality, sudden cardiac death, and death due to heart failure. It must, however, be acknowledged that the trial was not powered or designed to assess these individual endpoints, and these findings should therefore be regarded as hypothesis-generating, suggesting a potential association between vericiguat and these outcomes in stable patients with HFrEF.

It is also evident that, in a setting in which the margin for further prognostic improvement has progressively narrowed over time, the ability to demonstrate benefit in such a well-treated population is considerably reduced. Even the observation of a plausible survival benefit therefore represents a non-negligible signal, particularly when the association appears consistent across multiple subgroups, including those receiving other guideline-recommended therapies for HFrEF.

In addition, the choice of heart failure hospitalization (HHF) as a component of the primary endpoint may not have been optimal for several reasons. In a context of baseline clinical stability and extensive implementation of background therapy, the risk of hospitalization is already markedly reduced. Indeed, the placebo arm of VICTOR exhibited an event rate for the primary outcome (12.2 events per 100 patient-years) comparable to that observed in the treatment arm of DAPA-HF (11.6 events per 100 patient-years) and substantially lower than that of the placebo arm in DAPA-HF (15.6 events per 100 patient-years). Furthermore, in the post–COVID-19 pandemic era, hospitalization thresholds may have shifted, favouring alternative management strategies such as day-hospital care or outpatient therapeutic clinics, which allow clinical stabilization without formal hospital admission.

In an exploratory analysis of the VICTOR trial,¹⁰ which evaluated a worsening heart failure endpoint—defined as a composite of hospitalizations, urgent visits requiring intravenous diuretic therapy, or intensification of oral diuretic therapy in the outpatient setting—vericiguat was associated with a significant reduction in both worsening HF events (22.5% vs. 24.5%, P = 0.04) and in a composite endpoint of cardiovascular death and worsening HF (30% vs. 33%, P = 0.016).

Finally, a pooled analysis combining individual patient-level data from the VICTOR and VICTORIA trials¹¹ demonstrated, after a median follow-up of 15 months, a significant reduction in the composite endpoint of cardiovascular death and HHF [HR 0.91; 95% CI 0.85–0.98; P = 0.0088; absolute risk difference (ARD) 2%; number needed to treat (NNT) 50], as well as in the individual components of cardiovascular death (HR 0.89; 95% CI 0.80–0.98; P = 0.02; ARD 0.7%; NNT 143) and HHF (HR 0.92; 95% CI 0.84–1.00; P = 0.04; ARD 1.3%; NNT 77). These data help to contextualize the role of vericiguat within the therapeutic landscape of HFrEF, highlighting a higher NNT—and therefore a lower overall efficacy—compared with dapagliflozin (NNT 20), empagliflozin (NNT 19), or sacubitril/valsartan (NNT 21).

In summary, the results of the VICTOR trial, supported by the pooled analysis, do not allow vericiguat to be considered a fifth pillar of HFrEF therapy. However, they certainly do not justify discarding the drug. Rather, they support its continued positioning as a key add-on therapy in recently destabilized patients, particularly those at high residual risk and with NT-proBNP levels within the range in which benefit appears greatest, and they encourage consideration of its use in selected stable outpatients who may derive the greatest advantage. Ignoring these data and relying solely on a dichotomous interpretation based on the lack of statistical significance of the primary endpoint in VICTOR would mean forgoing a therapeutic option capable—albeit incrementally—of contributing to reductions in morbidity and mortality in a population that, despite recent advances, continues to face a substantial residual risk.

Funding

None.

Data availability

No new data were generated or analysed in support of this research.

Disclaimer

This paper was originally published in the Italian language as ‘Impiego del Vericiguat nel VICTOR, trial di difficile interpretazione’, in the Volume degli Atti del Congresso “Conoscere e Cuare il Cuore 2026”, published by Centro per la Lotta contro l'Infarto for distribution at the CCC Conference. This paper was translated by Dr. Mario Albertucci, representative of the CLI Foundation, and republished with permission.