Table of Contents
- Key Points
- Background: Why This Research Matters
- What Is Vericiguat and What Is HFrEF?
- How the Research Was Conducted
- Who Was Studied
- Key Findings: What the Analysis Showed
- The Role of NT-proBNP Levels
- Results Across Patient Subgroups
- Safety and Tolerability
- What This Means for Patients
- Limitations of the Study
- Recommendations and Next Steps
- Frequently Asked Questions
- Source Information
Key Points
- In a combined analysis of 11,155 patients with HFrEF, vericiguat reduced the risk of cardiovascular death or hospitalization for heart failure by 9% versus placebo.
- The primary endpoint occurred in 25.9% of patients taking vericiguat compared with 27.9% taking placebo, a statistically significant difference (hazard ratio 0.91, p=0.0088).
- Both individual components—cardiovascular death and heart failure hospitalization—were also reduced with vericiguat.
- The benefit appeared greater in patients with an NT-proBNP concentration of 6,000 pg/mL or lower.
- Vericiguat was generally well tolerated, with similar discontinuation rates between vericiguat and placebo groups.
Background: Why This Research Matters
Heart failure is a condition in which the heart cannot pump enough blood to meet the body's needs. When the heart's pumping ability is reduced, it is called heart failure with reduced ejection fraction, or HFrEF. Ejection fraction is a measurement of how much blood the heart pumps out with each beat.
Patients with HFrEF face a high risk of hospitalization and death. Over the past decade, treatment has improved significantly. Doctors now recommend "quadruple therapy" for most patients with HFrEF. This four-drug combination includes:
- A beta blocker (a drug that slows the heart rate and lowers blood pressure)
- A mineralocorticoid receptor antagonist (a drug that helps remove excess fluid and protects the heart)
- An angiotensin receptor–neprilysin inhibitor (ARNI, a drug that relaxes blood vessels and helps the heart pump better)
- A sodium–glucose cotransporter 2 (SGLT2) inhibitor (a drug originally developed for diabetes that also protects the heart)
Despite these advances, many patients still experience worsening heart failure. This is where vericiguat comes in.
The first major trial of vericiguat, called VICTORIA, studied patients with recent worsening of heart failure. Based on the VICTORIA results, vericiguat was approved in 2021 by the US Food and Drug Administration and the European Medicines Agency. It also received a class IIb recommendation in European and North American treatment guidelines. A class IIb recommendation means the treatment may be considered for some patients, based on weaker evidence.
A second trial, called VICTOR, studied vericiguat in patients with HFrEF who had not recently experienced worsening heart failure. The VICTOR trial enrolled patients from 2021 to 2023, a time when more patients were receiving the newer quadruple therapy.
The researchers combined data from both trials to understand how vericiguat works across the full spectrum of HFrEF severity. This type of analysis is called a pooled individual participant-level analysis, which means the researchers combined the raw data from every patient in both trials.
What Is Vericiguat and What Is HFrEF?
Vericiguat is a soluble guanylate cyclase stimulator. This type of drug works by stimulating an enzyme in the body called soluble guanylate cyclase. When this enzyme is stimulated, it helps blood vessels relax and improves blood flow. In heart failure, the signaling pathway involving this enzyme does not work properly, and vericiguat helps restore it.
Vericiguat is taken as an oral tablet once daily. Patients start at a low dose of 2.5 mg. The dose is increased to 5 mg after 14 days and to 10 mg after 28 days, as long as blood pressure and symptoms allow. The target dose is 10 mg once daily.
HFrEF occurs when the left ventricle (the main pumping chamber of the heart) is weakened and cannot pump enough blood. Doctors measure how well the heart pumps using the left ventricular ejection fraction. In the VICTORIA trial, patients needed an ejection fraction below 45% to participate. In the VICTOR trial, patients needed an ejection fraction of 40% or lower.
Doctors also measure a substance in the blood called NT-proBNP (N-terminal pro-B-type natriuretic peptide). NT-proBNP is a hormone that the heart releases when it is under stress or not pumping well. Higher NT-proBNP levels generally indicate more severe heart failure.
How the Research Was Conducted
This pooled analysis combined patient-level data from two large, randomized, double-blind, placebo-controlled phase 3 trials. A randomized trial means patients were assigned by chance to receive either the study drug or a placebo. A double-blind design means neither the patients nor their doctors knew which treatment they received. A placebo is an inactive tablet that looks identical to the study drug.
The VICTORIA trial ran from September 25, 2016, to September 2, 2019. It enrolled 5,050 patients at 616 sites in 42 countries. The VICTOR trial ran from November 2, 2021, to February 5, 2025. It enrolled 6,105 patients at 482 sites in 36 countries.
Both trials enrolled adults aged 18 years or older with specific criteria:
- VICTORIA trial: Patients had HFrEF with recent worsening, defined as either a hospitalization for heart failure within the previous 6 months or outpatient use of intravenous diuretics within the previous 3 months. They also had elevated NT-proBNP levels (at least 1,000 pg/mL for patients in sinus rhythm or at least 1,600 pg/mL for those with atrial fibrillation).
- VICTOR trial: Patients had HFrEF with no recent worsening. Their NT-proBNP levels were between 600 and 6,000 pg/mL for patients in sinus rhythm, or between 900 and 6,000 pg/mL for those with atrial fibrillation.
Both trials required patients to have an estimated glomerular filtration rate (eGFR) of at least 15 mL/min per 1.73 m². The eGFR is a measure of kidney function.
In both trials, patients were randomly assigned in a 1:1 ratio to receive either vericiguat or a matching placebo. The dose titration schedule was identical in both trials. Patients continued study treatment until the end of the trial unless they needed to stop due to side effects, chose to withdraw, or had another reason to discontinue.
The primary endpoint for this pooled analysis was a composite of cardiovascular death or first hospitalization for heart failure. The researchers also assessed each component individually. Other outcomes included:
- First hospitalization for heart failure
- Total hospitalizations for heart failure (including repeat hospitalizations)
- Death from any cause
An independent clinical events committee at Duke Clinical Research Institute in Durham, North Carolina, reviewed and classified all events. The committee members did not know which treatment group each patient was in. The same standardized definitions were used for both trials.
The researchers used statistical methods including Kaplan–Meier survival curves and Cox proportional hazards regression to analyze the data. They also tested whether the treatment effect differed between the two trials. The analysis plan was registered with PROSPERO (registration number CRD420251065636) before the analysis began.
Who Was Studied
A total of 17,778 patients were screened for the two trials, and 11,155 were enrolled. Of these, 5,050 patients were in the VICTORIA trial and 6,105 were in the VICTOR trial. A total of 5,579 patients were randomly assigned to vericiguat and 5,576 to placebo.
The median age of patients was 68.0 years (interquartile range 60.0–75.0). An interquartile range means the middle 50% of patients fell within that age range. Of the 11,155 patients, 2,648 (23.7%) were female and 8,507 (76.3%) were male.
The median NT-proBNP concentration at baseline was 1,864 pg/mL (interquartile range 1,036–3,537). Of the 10,790 patients with baseline measurements, 9,566 (88.7%) had an NT-proBNP concentration of 6,000 pg/mL or lower.
At the time of randomization, 7,797 (69.9%) of 11,151 patients with data on this measure were classified as New York Heart Association functional class II, and 3,352 (30.1%) were classified as class III–IV. The New York Heart Association classification describes how much heart failure limits a patient's daily activities. Class II means slight limitation, while class III–IV means more significant limitation.
The mean left ventricular ejection fraction at screening was 29.8% (standard deviation 7.7). The mean baseline eGFR was 66.6 mL/min per 1.73 m² (standard deviation 25.9).
Of the 11,155 patients, 8,256 (74.0%) had previously been hospitalized for heart failure or had received intravenous diuretics before enrolling. The remaining 2,899 (26.0%) patients, who had no previous worsening of heart failure, came from the VICTOR trial.
The use of guideline-directed medical therapy was strong in both trials. However, the specific drugs used differed between the trials because treatment guidelines changed over time:
- Sacubitril–valsartan (an ARNI) was used by 731 (14.5%) of 5,050 patients in the VICTORIA trial and 3,416 (56.0%) of 6,105 patients in the VICTOR trial.
- SGLT2 inhibitors were used by 212 (4.2%) of 5,050 patients in the VICTORIA trial and 3,610 (59.1%) of 6,105 patients in the VICTOR trial.
Of the 11,155 patients in the pooled population, 3,408 (30.6%) had an implantable cardioverter-defibrillator. 1,643 (14.7%) had cardiac resynchronization therapy. 1,200 (10.8%) had a cardiac resynchronization therapy-defibrillator or had both cardiac resynchronization therapy and an implantable cardioverter-defibrillator.
The median follow-up duration for the primary endpoint was 10.8 months in the VICTORIA trial and 18.5 months in the VICTOR trial. In the pooled population, the median follow-up for the primary endpoint was 15.6 months (interquartile range 9.2–22.6), with 99.4% ascertainment achieved. The median follow-up time for death endpoints was 17.6 months (interquartile range 12.0–24.2), with 99.9% completeness.
Study treatment discontinuations were balanced between groups. A total of 1,794 (32.2%) of 5,568 patients who received vericiguat and 1,831 (32.9%) of 5,564 patients who received placebo did not complete the trial regimen. The main reasons for discontinuation were death (519 [9.3%] in the vericiguat group and 587 [10.5%] in the placebo group) and adverse events (432 [7.8%] in the vericiguat group and 384 [6.9%] in the placebo group).
At about 1 year, 6,863 (89.2%) of 7,691 pooled patients in the trials were tolerating the 10 mg dose.
Only 39 (0.3%) of the 11,155 patients were lost to follow-up over the two trials.
Key Findings: What the Analysis Showed
The primary endpoint of cardiovascular death or first hospitalization for heart failure occurred in 1,446 (25.9%) of 5,579 patients in the vericiguat group and 1,556 (27.9%) of 5,576 patients in the placebo group. This represents a hazard ratio of 0.91 with a 95% confidence interval of 0.85–0.98 and a p value of 0.0088.
To understand these numbers: a hazard ratio of 0.91 means that patients taking vericiguat had a 9% lower risk of experiencing the primary endpoint compared with patients taking placebo. The 95% confidence interval of 0.85–0.98 means that the true effect is likely between a 2% and 15% reduction in risk. The p value of 0.0088 means there is less than a 1% chance that this result occurred by random chance alone.
The individual components of the primary endpoint were also reduced:
- Cardiovascular death: Hazard ratio 0.89 (95% confidence interval 0.80–0.98; p=0.020). This means patients taking vericiguat had an 11% lower risk of dying from cardiovascular causes.
- Hospitalization for heart failure as a first event: Hazard ratio 0.92 (95% confidence interval 0.84–1.00; p=0.043). This means patients taking vericiguat had an 8% lower risk of being hospitalized for heart failure for the first time.
The researchers also found that vericiguat reduced all-cause death. The benefit of vericiguat appeared greater in the large group of patients with an NT-proBNP concentration of 6,000 pg/mL or lower.
There was no evidence that the treatment effect differed between the two trials. This means vericiguat worked similarly in patients with recent worsening of heart failure (VICTORIA trial) and in patients without recent worsening (VICTOR trial).
The Role of NT-proBNP Levels
The VICTORIA trial had previously found that vericiguat provided less benefit to patients with baseline NT-proBNP concentrations in the upper quartile (above 5,314 pg/mL). This was compared with patients in the lower three quartiles. A quartile divides a group into four equal parts. The upper quartile represents the 25% of patients with the highest NT-proBNP levels.
Because of this finding, the researchers in this pooled analysis specifically planned to assess the relationship between baseline NT-proBNP concentrations and clinical outcomes. They used a statistical method called a restricted cubic spline model to examine this relationship.
The pooled analysis confirmed that patients with lower NT-proBNP levels (6,000 pg/mL or lower) appeared to receive greater benefit from vericiguat. This finding is important because it suggests that NT-proBNP levels may help doctors identify which patients are most likely to benefit from vericiguat treatment.
Results Across Patient Subgroups
The researchers assessed treatment effects across prespecified subgroups. A subgroup is a smaller group of patients within the overall study population who share certain characteristics, such as age, sex, or baseline health status.
The researchers tested whether the treatment effect was consistent across different subgroups. They also tested whether the treatment effect differed between the two trials by fitting a statistical model that included trial, treatment, and a treatment-by-trial interaction term.
The proportional hazard assumption was tested using the weighted Schoenfeld residuals test across all time-to-first-event outcomes. This is a statistical check to make sure the analysis method was appropriate for the data.
The researchers calculated numbers needed to treat for efficacy endpoints based on the absolute risk reduction at 1 year. The number needed to treat is the number of patients who need to receive a treatment for one additional patient to benefit. A lower number needed to treat means the treatment is more effective.
For patients who died or were censored before 1 year, follow-up was truncated at the time of censoring. For recurrent event endpoints, between-treatment differences in annualized event rates were used to calculate absolute risk reductions.
Safety and Tolerability
Vericiguat was generally well tolerated. The rate of treatment discontinuation was similar between the vericiguat and placebo groups. As noted earlier, 32.2% of patients taking vericiguat and 32.9% of patients taking placebo did not complete the trial regimen.
The most common reasons for discontinuation were:
- Death: 519 (9.3%) in the vericiguat group and 587 (10.5%) in the placebo group
- Adverse events: 432 (7.8%) in the vericiguat group and 384 (6.9%) in the placebo group
- Patient decision: 355 in the vericiguat group and 366 in the placebo group
- Physician decision: 335 in the vericiguat group and 345 in the placebo group
The once-daily administration and favorable tolerability and safety profile of vericiguat support its consideration as an additional therapeutic option for patients with HFrEF.
What This Means for Patients
This pooled analysis provides strong evidence that vericiguat reduces the risk of cardiovascular death and hospitalization for heart failure in patients with HFrEF across a broad range of clinical severity. This includes patients receiving contemporary guideline-directed medical therapy.
The findings suggest that vericiguat might be suitable as an additional treatment option for selected patients with HFrEF. The benefit appeared greater in patients with an NT-proBNP concentration of 6,000 pg/mL or lower.
For patients with recent worsening of heart failure, the VICTORIA trial demonstrated clear benefit. For stable ambulatory patients with HFrEF and no recent worsening, the VICTOR trial did not reduce the risk of the primary composite endpoint. However, vericiguat was associated with a reduction in cardiovascular and all-cause mortality in these stable patients.
These findings suggest that vericiguat might offer clinical benefit in selected patient populations across the spectrum of HFrEF. The results support considering vericiguat as part of a comprehensive treatment plan for appropriate patients.
The use of guideline-directed medical therapy was robust in both trials. However, the specific drugs used differed between trials because treatment guidelines evolved over the 7-year interval between the start of VICTORIA enrollment in 2016 and the completion of VICTOR enrollment in 2023. During this time, quadruple therapy became the recommended standard for all patients with HFrEF.
Limitations of the Study
This analysis has several limitations that patients and doctors should consider.
First, the VICTORIA and VICTOR trials enrolled different patient populations. The VICTORIA trial enrolled patients at high risk with recent worsening of heart failure. The VICTOR trial enrolled patients at lower risk without recent worsening. The pooled population represents individuals across a broad range of HFrEF severity, but the treatment effect may differ in important ways between these groups.
Second, the background medical therapy differed between the two trials. In the VICTORIA trial, only 14.5% of patients were taking sacubitril–valsartan and only 4.2% were taking SGLT2 inhibitors. In the VICTOR trial, 56.0% were taking sacubitril–valsartan and 59.1% were taking SGLT2 inhibitors. This means the VICTORIA trial results may not fully reflect the effects of vericiguat when added to contemporary quadruple therapy.
Third, the median follow-up duration differed between trials: 10.8 months in VICTORIA and 18.5 months in VICTOR. The shorter follow-up in VICTORIA limited the ability to assess the effects of longer-term exposure to vericiguat on cardiovascular death.
Fourth, the p values presented are descriptive rather than formal tests of statistical inference. This means they should be interpreted with caution.
Fifth, missing data were not imputed, and analyses were based on available data.
Finally, the VICTOR trial did not reduce the risk of the primary composite endpoint of cardiovascular death or hospitalization for heart failure. However, vericiguat was associated with a reduction in cardiovascular and all-cause mortality in stable ambulatory patients with HFrEF. Further research is warranted to clarify the optimal role of vericiguat in the management of ambulatory patients.
Recommendations and Next Steps
Based on these findings, vericiguat may be considered as an additional treatment option for selected patients with HFrEF. The once-daily dosing and favorable tolerability profile support its use.
Patients who may benefit most from vericiguat include:
- Patients with HFrEF and recent worsening of heart failure (hospitalization within the previous 6 months or need for outpatient intravenous diuretics within the previous 3 months)
- Patients with an NT-proBNP concentration of 6,000 pg/mL or lower
- Patients who are tolerating guideline-directed medical therapy
Patients should discuss with their healthcare provider whether vericiguat is appropriate for their individual situation. The decision should consider the patient's overall health, kidney function, blood pressure, and other medications.
Further research is needed to clarify the optimal role of vericiguat in the management of ambulatory patients with HFrEF. Researchers continue to study how best to use this medication across the spectrum of heart failure severity.
Frequently Asked Questions
What is vericiguat and how does it work?
Vericiguat is a soluble guanylate cyclase stimulator taken as an oral tablet once daily. It works by stimulating an enzyme that helps blood vessels relax and improves blood flow. In heart failure, this signaling pathway does not work properly, and vericiguat helps restore it. It is used in patients with heart failure with reduced ejection fraction (HFrEF).
Who was studied in the combined analysis of vericiguat?
The analysis included 11,155 adults with heart failure and reduced ejection fraction from two large trials. Their median age was 68 years, and about 24% were female. Some had recent worsening of heart failure, while others did not. All had reduced ejection fraction and elevated NT-proBNP levels, and most were taking guideline-directed medical therapy.
What did the combined analysis show about vericiguat?
The primary endpoint of cardiovascular death or first hospitalization for heart failure occurred in 25.9% of patients taking vericiguat versus 27.9% taking placebo. This was a statistically significant 9% lower risk (hazard ratio 0.91). Both cardiovascular death and heart failure hospitalization were also reduced. The benefit appeared greater in patients with NT-proBNP of 6,000 pg/mL or lower.
What does a hazard ratio of 0.91 mean for patients?
A hazard ratio of 0.91 means patients taking vericiguat had a 9% lower risk of experiencing the primary endpoint—cardiovascular death or first hospitalization for heart failure—compared with placebo. The 95% confidence interval was 0.85 to 0.98, meaning the true effect is likely between a 2% and 15% reduction in risk.
What are the side effects and how well is vericiguat tolerated?
Vericiguat was generally well tolerated. Treatment discontinuation rates were similar between vericiguat and placebo groups: 32.2% versus 32.9%. The most common reasons for stopping were death and adverse events. At about one year, 89.2% of patients were tolerating the 10 mg dose. The once-daily administration and favorable tolerability profile support its consideration as an additional option.
How is vericiguat dosed?
Vericiguat is taken as an oral tablet once daily. Patients start at a low dose of 2.5 mg. The dose is increased to 5 mg after 14 days and to 10 mg after 28 days, as long as blood pressure and symptoms allow. The target dose is 10 mg once daily. Dose changes depend on your blood pressure and how you feel.
Which patients might benefit most from vericiguat?
Patients who may benefit most include those with HFrEF and recent worsening of heart failure (hospitalization within the previous 6 months or need for outpatient intravenous diuretics within the previous 3 months), those with an NT-proBNP concentration of 6,000 pg/mL or lower, and those tolerating guideline-directed medical therapy. Discuss with your healthcare provider whether vericiguat is appropriate for your situation.
When should a patient with heart failure and reduced ejection fraction (HFrEF) seek a second opinion about adding vericiguat?
A second opinion can help when vericiguat is being considered for HFrEF. The benefit appears greater in patients with an NT-proBNP concentration of 6,000 pg/mL or lower, and in those with recent worsening of heart failure. The VICTOR trial did not reduce the primary composite endpoint in stable ambulatory patients, though it was associated with lower cardiovascular and all-cause mortality. Because background therapy and patient populations differed between trials, an independent review can clarify whether vericiguat fits your situation. Diagnostic Detectives Network provides independent expert second opinions.
Source Information
Original article title: Vericiguat-for-patients-with-heart-failure-and-red
Authors: Faiez Zannad, Christopher M O'Connor, Javed Butler, Ciaran J McMullan, Kevin J Anstrom, Irina Barash, Marc P Bonaca, Maria Borentain, Stefano Corda, Davis Gates, Justin A Ezekowitz, Adrian F Hernandez, Carolyn S P Lam, Eldrin F Lewis, JoAnn Lindenfeld, Robert J Mentz, Piotr Ponikowski, Yogesh N V Reddy, Giuseppe M C Rosano, Clara Saldarriaga, Michele Senni, Pedro P Teixeira, James Udelson, Alessia Urbinati, Vanja Vlajnic, Adriaan A Voors, Aiwen Xing, Mahesh J Patel, Paul W Armstrong, for the VICTORIA and VICTOR Study Groups
Publication: The Lancet, Volume 406, pages 1351–1362, September 27, 2025. Published online August 30, 2025.
DOI: https://doi.org/10.1016/S0140-6736(25)01682-4
Funding: Merck Sharp & Dohme (a subsidiary of Merck) and Bayer.
Clinical trial registrations: VICTORIA (NCT02861534) and VICTOR (NCT05093933). This pooled analysis is registered with PROSPERO, CRD420251065636.
This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and should not replace consultation with a qualified healthcare provider. Patients should discuss any treatment decisions with their doctor.
