Vericiguat is a candidate for inclusion in guideline-directed medical therapy for heart failure with reduced ejection fraction, based on a meta-analysis showing an all-cause death reduction on top of the current treatment. 

“The totality of evidence indicated that this is a lifesaving medicine [and] should be considered part of standard treatment in heart failure with reduced ejection fraction (HFrEF),” said first author Faiez Zannad, MD, PhD, head of the Division of Heart Failure at Radcliffe Cardiology in Oxford, United Kingdom.

Although Zannad was referring to all patients with HFrEF, vericiguat, a soluble guanylate cyclase stimulator (sGC) already approved for this indication, missed its primary endpoint in a new trial in an ambulatory population. 

That study found a reduction in a secondary endpoint, all-cause death relative to placebo on top of guideline-directed medical therapy (GDMT). However, secondary endpoints are considered only hypothesis-generating when the primary endpoint is not reached, according to traditional interpretations of randomized trials. 

Pooled Data Show Efficacy Across HFrEF Spectrum

Yet, when this trial was pooled with the previously published VICTORIA trial, the benefit was consistent across multiple endpoints, including the missed primary endpoint in the VICTOR study. The pooling of the data for VICTOR and VICTORIA was prespecified. 

The VICTOR trial and meta-analysis of VICTOR with VICTORIA were presented August 30 at the 2025 annual congress of the European Society of Cardiology, and published in The Lancet. 

VICTOR and VICTORIA were nearly identically designed but differed in their entry criteria. The VICTORIA trial, published in 2020, enrolled patients with heart failure who had been hospitalized in the last 6 months or received an intravenous diuretic in the last 3 months for the condition. In VICTOR, recent hospitalization (< 6 months) or IV diuretic (< 3 months) were exclusion criteria, so this study tested the effects of the drug in earlier stages of heart failure.

VICTOR was designed to assess the effect of vericiguat “in ambulatory patients with HFrEF without recent worsening,” said Zannad, who presented the findings at ESC. Nearly half of the patients enrolled in VICTOR had never been hospitalized for heart failure and 30% had not yet been started on a diuretic.

Patients in VICTOR and VICTORIA were randomly assigned to vericiguat or placebo on top of optimized contemporary GDMT. The proportion of patients in VICTOR on each of the components of this regimen, defined as beta-blockers (94.4%), mineralocorticoid receptor antagonists (70.2%), sacubitril-valsartan (56%), and SGLT2 inhibitors (59.1%), was “the best ever” of heart failure trials, Zannad said.

On the shared primary composite endpoint of cardiovascular death or hospitalization for worsening heart failure, the 10% risk reduction by hazard ratio (HR) reached statistical significance in VICTORIA (HR, 0.90; P =.02) after a median follow-up of 10.8 months, but fell short of significance in VICTOR after a median follow-up of 18.3 months (HR, 0.93; P =.22). 

All-Cause Mortality Is Reduced in VICTOR

The lack of benefit in VICTOR can be attributed to an absence of protection from worsening heart failure in a population with relatively stable disease, according to the breakdown of data presented by Zannad at ESC. 

In contrast to VICTORIA, where risk reductions did not reach statistical significance for either of the primary composite endpoints when considered in isolation, the reduction in cardiovascular death did achieve statistical significance in VICTOR (HR, 0.83; P = .02). Yet, the event curves for hospitalization that Zannad showed, although slightly in favor of vericiguat toward the end of follow-up (HR, 0.95; P = .509), were mostly superimposable.

Based on a similar trend for benefit from vericiguat across VICTOR and VICTORIA, the meta-analysis was conducted to pool data “across the spectrum of HFrEF severity,” explained Javed Butler, MD, chair of the Department of Medicine at the University of Mississippi Medical Center in Jackson. 

“The cumulative evidence from the pooled data shows that vericiguat reduced the risk of all-cause death, cardiovascular death, and hospitalization for heart failure across a broad range of HFrEF on top of current GDMT,” said Butler, who presented the meta-analysis data at the ESC meeting.

In the meta-analysis, vericiguat was associated with a significant reduction in all-cause mortality relative to placebo on top of GDMT (HR, 0.90; P = .025), a finding that was consistent with the 16% reduction (HR, 0.84; P = .02) observed in the VICTOR trial. 

In both studies, vericiguat was well tolerated. In VICTORIA, hypotension, the most common adverse event in both studies, occurred in 9.1% of patients who took vericiguat and 7.9% of those in the placebo group (P = .12). Zannad said the same favorable safety profile was observed in VICTOR.

In VICTOR, an NT-proBNP greater than 6000 pg/mL was a trial exclusion based on prior VICTORIA analyses, which indicated a diminishing benefit above this level, according to Zannad. When the effect of NT-proBNP was evaluated in the meta-analysis, the reduced effect of vericiguat at high levels was corroborated. He said that the reason for a reduced response at higher concentration is still unclear.

John J.V. McMurray, MD, director of the Institute of Cardiovascular and Medical Sciences at the University of Glasgow, in Scotland, called the loss of benefit at high levels of NT-proBNP “puzzling.” One cause might be an interaction between cyclic guanylate cyclase stimulation and NT-proBNP, McMurray said, but such a link must be confirmed.

McMurray said he was impressed by the evidence that vericiguat appears to improve outcomes across the range of HFrEF severity, and the fact that its benefits, including the reduction in all-cause mortality, were achieved on top of GDMT. So far, a mortality benefit has been shown for each agent that has been added to GDMT for HFrEF, he noted. 

However, unlike Zannad, neither McMurray nor Butler said the new data were sufficient to prompt an immediate change in the standard treatment of HFrEF. Each indicated that further studies are needed to address unanswered questions regarding efficacy across subgroups and practical issues — including cost — that might be relevant to a new standard of care.

Zannad reports financial relationships with more than 10 pharmaceutical companies that include Merck, which provided funding for the VICTOR and VICTORIA trials. Butler reports financial relationships with more than 50 pharmaceutical companies, which also includes Merck. McMurray has financial relationships with more than 20 pharmaceutical companies, but not with Merck.