The drug reduced CV mortality but not HF hospitalizations, a disconnect that left some experts scratching their heads.
MADRID, Spain—Vericiguat (Verquvo; Merck Sharp & Dohme/Bayer) failed to provide an overall benefit for patients who have heart failure with reduced ejection fraction (HFrEF) but without signs or symptoms of clinical worsening over roughly 18 months of follow-up, results from the VICTOR trial show.
Even though the study missed its primary endpoint—a composite of cardiovascular mortality or hospitalization for heart failure—making sense of the findings is no straightforward task, however.
The trial was powered for cardiovascular mortality, and a prespecified analysis focused on the individual components of the composite endpoint showed that vericiguat reduced the risk of that outcome. Somewhat surprisingly, there was no accompanying reduction in the risk of HF hospitalization.
Presenting the data Saturday during a Hot Line session at the European Society of Cardiology (ESC) Congress 2025, co-principal investigator Faiez Zannad, MD, PhD (Université de Lorraine/INSERM, Nancy, France), said the group was “intrigued” by the disconnect between the two endpoints.
“It’s kind of unique in heart failure trials because [cardiovascular] death usually goes hand in hand with heart failure hospitalizations,” said Zannad.
John McMurray, MD, PhD (University of Glasgow/Queen Elizabeth University Hospital, Scotland), the discussant following the presentation, also was puzzled by the results, adding that the disconnect between mortality and HF hospitalizations has not been seen in other trials of HF drugs. In PARADIGM-HF, for example, treatment with an angiotensin receptor-neprilysin inhibitor (ARNI) lowered the risk of cardiovascular mortality and HF hospitalizations by 20%, with both endpoints driving the effect.
“When I first saw [VICTOR], I thought, ‘Oh my goodness, this looks like an ICD trial,’ because the only treatment I can think of that reduces death but doesn’t reduce heart failure hospitalizations is an ICD,” he commented.
Akshay Desai, MD (Brigham and Women’s Hospital, Boston, MA), who wasn’t involved in VICTOR, was equally perplexed.
“The cardiovascular mortality benefit is a little hard for me to unpack,” Desai told TCTMD. “In almost every heart failure trial of a heart failure drug that we’ve seen, the effects are often the opposite—you see an effect on a composite endpoint that’s driven mostly by worsening heart failure and then there’s an effect on mortality. To see no effect on the conventional heart failure hospitalization endpoint, but to see an effect on mortality, is a little hard to reconcile.”
The VICTOR trial was published in the Lancet, while a deep dive into the effect of vericiguat on various HF outcomes was published in JACC.
VICTORIA Meets VICTOR
Vericiguat, a drug that targets cyclic guanosine monophosphate (cGMP), was first shown to be effective in the VICTORIA trial of more than 5,000 patients with chronic HFrEF. All patients had a recent worsening event, such as hospitalization for HF/intravenous diuretic use or elevated natriuretic peptides (BNP or NT-proBNP).
On the basis of VICTORIA, vericiguat was approved for the treatment of worsening HF in HFrEF patients and awarded a class IIb recommendation to reduce HF hospitalizations and cardiovascular death in both the ESC and American College of Cardiology/American Heart Association guidelines.
The VICTOR trial, on the other hand, tested vericiguat in 6,105 ambulatory HFrEF patients (median age 68 years; 23.6% women) without recent HF worsening. Patients were well treated with guideline-directed medical therapy (GDMT): 95% were on beta-blockers, 56% taking an ARNI, roughly 60% taking a sodium-glucose cotransporter 2 inhibitor, and nearly 80% on a mineralocorticoid receptor antagonist.
“They had the best possible guideline-directed medical therapy so far compared to any HFrEF trial,” said Zannad. Nearly half of the randomized VICTOR patients did not have a prior hospitalization for heart failure.
During a median follow-up of 18.5 months, the primary composite endpoint of cardiovascular death or hospitalization for HF did not significantly differ between those treated with vericiguat versus placebo (HR 0.93; 95% CI 0.83-1.04). There was a significant 17% relative reduction in the risk of cardiovascular death but no difference in the risk of first hospitalization for HF.
Sudden cardiac and HF-related deaths each were significantly lower in those treated with vericiguat, although the absolute reductions were relatively modest (0.9% and 1.1%, respectively).
With the “puzzling” disparity between deaths and hospitalizations, Zannad said the researchers suspected that worsening heart failure might not necessarily mean hospitalization. When patients without a prior hospital admission develop symptoms, it’s unlikely their doctor will rush them to hospital, said Zannad. With that in mind, they conducted an exploratory analysis focused on an expanded definition of worsening HF that encompassed urgent visits to outpatient clinics or additional oral diuretic therapy.
Using this definition, there was a borderline significant 10% lower risk of worsening HF events in patients treated with vericiguat (HR 0.90; 95% CI 0.81-1.00).
McMurray urged caution with these types of analyses. When a trial misses the primary endpoint, all other findings should be considered exploratory, he said. “We have to be cautious about interpreting [VICTOR], but I personally don’t agree that you live or die by your primary endpoint,” he said. “I think it’s entirely appropriate to dig deeper into such a large and important dataset.”
He pointed out that there were just 690 HF hospitalizations during follow-up in VICTOR, which made it difficult to show a treatment effect with vericiguat. When using the expanded definition to include worsening HF, the number of events more than doubled. Clinically, the expanded definition makes sense, said McMurray.
“Heart failure matters wherever it occurs,” he said. “It doesn’t have to be in the hospital if it occurs in the community. That is an important event.”
Desai agreed that the expanded HF endpoint is a reasonable approach to assess outcomes, but it still didn’t make the VICTOR results any clearer.
“In VICTORIA, you got a reduction in heart failure hospitalizations in a sicker heart failure population, but no impact on mortality,” said Desai. “[In VICTOR], you have a mortality reduction without a heart-failure-hospitalization reduction in a healthier population. That’s where I think this expanded composite endpoint is a little interesting because it captures worsening heart failure events, mostly ambulatory events, in a well-treated, more stable heart failure population. If that’s the case, I’m still struggling with the leap to the cardiovascular mortality reduction.”
Combining VICTOR and VICTORIA
Javed Butler, MD (University of Mississippi Medical Center, Jackson), one of the co-principal investigators, presented data from a combined patient-level analysis of the VICTOR and VICTORIA trials during the same Hot Line session.
In 11,155 patients, the primary endpoint of cardiovascular death or hospitalization for HF was 9% lower in those treated with vericiguat (P = 0.009). Analyzed individually, there was an 11% relative reduction in the risk of cardiovascular death (P = 0.020) and an 8% lower risk of first hospitalization for HF (P = 0.043). All-cause mortality was also 10% lower in the vericiguat-treated patients (P = 0.025).
“The heart failure hospitalization benefit appeared around 4 months and all-cause death at around 8 months,” said Butler.
Butler said the VICTORIA trial informed the design of VICTOR because data from that first trial showed that HFrEF patients with increased NT-proBNP levels did not benefit from treatment, leading the VICTOR investigators to exclude those with NT-proBNP > 6,000 pg/mL. The median NT-proBNP concentration in the combined analysis was 1,864 pg/mL, with most patients having concentrations less than 3,000 ng/mL.
In the pooled analysis, the only subgroup with a significant and consistent interaction with the treatment benefit was in patients with NT-proBNP levels of 6,000 pg/mL or less. These patients had a larger reduction in the risk of cardiovascular death or hospitalization for HF.
To TCTMD, Desai said he believes that there is a clinical benefit with vericiguat in both the VICTOR- and VICTORIA-like patients, albeit with fewer question marks surrounding the latter group.
“To be honest, in my practice, utilization of vericiguat has been very low after VICTORIA,” he said. “Not because I don’t think the drug is effective, but the opportunity to utilize it is really relegated to second-line therapy in patients who are progressing despite standard medications. If we’re able to get four-drug GDMT on board, heart failure hospitalization rates are not that high. The symptom burden is not that high, even if there is a residual event rate.”
The ambition to add a fifth medication to a patient doing reasonably well on four-pillar HF therapy is a difficult sell, he added. For the VICTOR-like patient who has not experienced clinical worsening, Desai is uncertain exactly how he will use vericiguat in clinical practice, although he believes that it could play a role.
“I think there’s a treatment benefit, but the question really is which patients in clinical practice,” said Desai. “Given the already robust data for four drugs, are we going to add a fifth? I think it gives us one more tool to consider in that population, but uptake in practice is going to be driven heavily by some of the questions around cost and the willingness of patients to take a fifth medication.”
To TCTMD, Zannad acknowledged the challenges of polypharmacy in the HFrEF patient but emphasized that vericiguat is a “lifesaving medication with proven survival [benefits]” and that he “would recommend this drug in all heart failure patients.” He hopes that the development of polypills for HF care will ease some of the burdens around taking so many medications.