# Vericiguat for patients with heart failure and reduced ejection fraction across the risk spectrum: an individual participant data analysis of the VICTORIA and VICTOR trials

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, et al.

► To cite this version:

Faiez Zannad, Christopher M O'Connor, Javed Butler, Ciaran J Mcmullan, Kevin J Anstrom, et al. Vericiguat for patients with heart failure and reduced ejection fraction across the risk spectrum: an individual participant data analysis of the VICTORIA and VICTOR trials. The Lancet, 2025, 406 (10510), pp.1351-1362. 10.1016/S0140-6736(25)01682-4. hal-05237757

HAL Id: hal-05237757

https://hal.univ-lorraine.fr/hal-05237757v1

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# Vericiguat for patients with heart failure and reduced ejection fraction across the risk spectrum: an individual participant data analysis of the VICTORIA and VICTOR trials

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

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## Summary

**Background** Following completion of the VICTORIA trial, vericiguat was approved for the treatment of worsening heart failure with reduced ejection fraction (HFrEF) and received a class IIb recommendation in European and North American guidelines. The subsequent VICTOR trial evaluated the use of vericiguat in patients with HFrEF and no recent worsening. We aimed to assess the effect of vericiguat on clinical endpoints through pooled analyses of patient-level data from the VICTORIA and VICTOR trials.

**Methods** This prespecified, pooled individual participant-level analysis was conducted on data from two trials: VICTORIA, which was active from Sept 25, 2016, to Sept 2, 2019 in 42 countries, and VICTOR, which was active from Nov 2, 2021, to Feb 5, 2025 in 36 countries. The VICTORIA trial enrolled adult (aged ≥18 years) participants with HFrEF with recent worsening (defined as either hospitalisation for heart failure within the previous 6 months or outpatient use of intravenous diuretics within the previous 3 months) and increased NT-proBNP concentrations; the VICTOR trial had similar eligibility criteria but participants had no recent worsening of heart failure. Participants in both trials received contemporary background guideline-directed heart failure therapy as appropriate. The primary endpoint was a composite endpoint of cardiovascular death or hospitalisation for heart failure (also assessed individually). This study is registered with PROSPERO, CRD420251065636.

**Findings** Data from 11 155 patients (5050 in the VICTORIA trial and 6105 in the VICTOR trial) were included in the pooled analysis. The primary endpoint of cardiovascular death or hospitalisation for heart failure occurred in 1446 (25·9%) of 5579 patients in the vericiguat group and 1556 (27·9%) of 5576 patients in the placebo group (hazard ratio [HR] 0·91 [95% CI 0·85–0·98]; p=0·0088), with similar reductions in its individual components of cardiovascular death (0·89 [0·80–0·98]; p=0·020) and hospitalisation for heart failure (0·92 [0·84–1·00]; p=0·043) as first events.

**Interpretation** Vericiguat reduced the risk of hospitalisation for heart failure and cardiovascular death in patients with HFrEF across a broad range of clinical severity, including those receiving contemporary guideline-directed medical therapy. Vericiguat might be suitable as an additional treatment option for selected patients with HFrEF.

**Funding** Merck Sharp & Dohme (a subsidiary of Merck) and Bayer.

**Copyright** © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

## Introduction

Following the Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial, vericiguat—a soluble guanylate cyclase stimulator— was approved in 2021 by the US Food and Drug Administration and the European Medicines Agency for the treatment of worsening heart failure in patients with reduced ejection fraction (HFrEF). In VICTORIA, over a median of 10·8 months, vericiguat reduced the risk of cardiovascular death or hospitalisation for heart failure in 5050 patients with reduced left ventricular ejection fraction and recent decompensation of heart failure (defined as hospitalisation for heart failure in the

previous 6 months or the need for outpatient intravenous diuretic therapy within the previous 3 months).¹

In contrast to the VICTORIA trial, which enrolled patients with worsening HFrEF, the Vericiguat Global Study in Participants with Chronic Heart Failure (VICTOR) trial was conducted in an ambulatory population of 6105 patients with HFrEF and no recent decompensation. The objective was to evaluate the effects of vericiguat in patients receiving optimal contemporary guideline-directed therapy, with no history of recent hospitalisation for heart failure and a screening baseline concentration of N-terminal pro-B-type natriuretic peptide (NT-proBNP) of 6000 pg/mL or lower.²

Published Online
August 30, 2025
https://doi.org/10.1016/
S0140-6736(25)01682-4

See Online/Comment
https://doi.org/10.1016/
S0140-6736(25)01765-9

Université de Lorraine,
INSERM, Centre
d'Investigations Cliniques
Plurithématique 1433, CHRU,
Nancy, France

(Prof F Zannad MD PhD); Inova

Schar Heart and Vascular
Institute, Falls Church, VA, USA
(Prof C M O'Connor MD);

Department of Medicine,
University of Mississippi,
Jackson, MS, USA

(Prof J Butler MD); Baylor Scott
and White Research Institute,
Dallas, TX, USA (Prof J Butler);

Merck, Rahway, NJ, USA

(C J McMullan MBBCh,
I Barash MD, D Gates PhD,
A Urbinati MD, A Xing PhD,

M J Patel MD); University of
North Carolina, Chapel Hill, NC,
USA (Prof K J Anstrom PhD);

Department of Medicine,
Colorado Prevention Center
Clinical Research, University of
Colorado, Aurora, CO, USA

(Prof M P Bonaca MD); Bayer US,
Whippany, NJ, USA

(M Borentain MD, V Vlajnic PhD);

Bayer, Berlin, Germany
(P P Teixeira MD); Bayer, Basel,
Switzerland (S Corda MD PhD);

Canadian VIGOUR Centre,
University of Alberta,
Edmonton, AB, Canada

(Prof J A Ezekowitz MBBCh,
Prof P W Armstrong MD); Duke

Clinical Research Institute,
Durham, NC, USA

(Prof A F Hernandez MD,
R J Mentz MD); National Heart

Centre Singapore, Singapore
(Prof C S P Lam PhD MBBS);

Duke-National University of
Singapore, Singapore

(Prof C S P Lam); Stanford
University School of Medicine,
Stanford, CA, USA

(Prof E F Lewis MD); Vanderbilt
University Medical Center,
Nashville, TN, USA
(Prof J Lindenfeld MD);
Wroclaw Medical University,
Wroclaw, Poland
(Prof P Ponikowski MD PhD);
Department of Cardiovascular
Medicine, Mayo Clinic,
Rochester, MN, USA
(Y N V Reddy MD); Department
of Human Sciences and
Promotion of Quality of Life,
San Raffaele Open University of
Rome, Rome, Italy
(Prof G M C Rosano MD PhD);
Cardiology, San Raffaele
Cassino Hospital, Cassino, Italy
(Prof G M C Rosano); IRCCS San
Raffaele Roma, Rome, Italy
(Prof G M C Rosano); Cardio VID
Clinic, Medellin, Colombia
(Prof C Saldarriaga MD);
University of Milano-Bicocca,
Milan, Italy (Prof M Senni MD);
Papa Giovanni XXIII Hospital,
Bergamo, Italy (Prof M Senni);
Division of Cardiology
(Prof J Udelson MD) and
CardioVascular Center
(Prof J Udelson), Tufts Medical
Center, Boston, MA, USA;
University of Groningen,
University Medical Center
Groningen, Groningen,
Netherlands
(Prof A A Voors MD PhD)
Correspondence to:
Prof Faiez Zannad, Université de
Lorraine, INSERM, Centre
d'Investigations Cliniques
Plurithématique 1433, CHRU,
54500 Nancy, France
f.zannad@chru-nancy.fr

Research in context

Evidence before this study

We searched PubMed from database inception to July 28, 2025, using the search terms “heart failure” and “vericiguat”, for English-language publications reporting studies in humans. This search identified 237 records, one of which reported a randomised controlled trial (VICTORIA) with adjudicated endpoints in a population with heart failure and reduced ejection fraction (HFrEF). In the VICTORIA trial, vericiguat reduced the risk of cardiovascular death or hospitalisation for heart failure in patients with HFrEF with recent worsening (defined as either a hospitalisation for heart failure within the previous 6 months or outpatient use of intravenous diuretics within the previous 3 months). On the basis of this trial, vericiguat was approved for the treatment of patients with worsening HFrEF and received a class IIb recommendation in European and North American guidelines. The median mortality follow-up in VICTORIA was 13-7 months, which limited the ability to assess the effects of longer-term exposure to vericiguat on cardiovascular death. The use of angiotensin receptor-neprilysin inhibitors and sodium-glucose cotransporter 2 inhibitors was low, consistent with standard practice during the enrolment period of 2016-18. In addition, patients with baseline NT-proBNP concentrations in the upper quartile (>5314 pg/mL) accrued less benefit from vericiguat than did those with NT-proBNP concentrations in the lower three quartiles. The VICTOR trial, which enrolled patients from 2021 to 2023, was designed to complement the VICTORIA trial by assessing the efficacy of vericiguat in patients with HFrEF and no recent worsening, a more contemporary heart failure background therapy, and a baseline NT-proBNP concentration of 6000 pg/mL or lower. Vericiguat did not

reduce the primary composite endpoint of cardiovascular death or hospitalisation for heart failure. However, the trial was also powered to assess the effect of vericiguat on cardiovascular death, and significantly fewer cardiovascular deaths were observed among patients who received vericiguat than among those who received placebo.

Added value of this study

This pooled, participant-level analysis of two large outcomes trials of vericiguat included patients with HFrEF across a broad range of clinical severity. We found that treatment with vericiguat reduced the composite endpoint of cardiovascular death and hospitalisation for heart failure, the individual components alone, and all-cause death, with no evidence of intertrial heterogeneity of the treatment effect. The benefit of vericiguat appeared greater in the large cohort of patients with an NT-proBNP concentration of 6000 pg/mL or lower.

Implications of all the available evidence

The once-daily administration and favourable tolerability and safety profile of vericiguat support its consideration as an additional therapeutic option for patients with HFrEF, particularly those with recent worsening (as demonstrated in the VICTORIA trial). In the VICTOR trial, vericiguat did not reduce the risk of the primary composite endpoint of cardiovascular death or hospitalisation for heart failure; however, vericiguat was associated with a reduction in cardiovascular and all-cause mortality in stable ambulatory patients with HFrEF. These findings suggest that vericiguat might offer clinical benefit in selected patient populations across the spectrum of HFrEF. Further research is warranted to clarify its optimal role in the management of ambulatory patients.

Over the 7-year interval between the start of enrolment in the VICTORIA trial (Sept 25, 2016) and the completion of enrolment in the VICTOR trial (Dec 21, 2023), major changes were made to the background guideline-directed medical therapy for HFrEF. These changes resulted in the recommendation of quadruple therapy for all patients with HFrEF, consisting of a β blocker, a mineralocorticoid receptor antagonist, an angiotensin receptor-neprilysin inhibitor, and, most recently, a sodium-glucose cotransporter 2 (SGLT2) inhibitor.³,⁴

We herein report a pooled analysis of data from the 11155 patients included in the VICTORIA and VICTOR trials to evaluate the primary outcome of cardiovascular death or hospitalisation for heart failure, as well as each component individually, across the broad spectrum of risk in patients with HFrEF. Because the VICTORIA trial found that vericiguat had a lower benefit in patients with baseline NT-proBNP concentrations in the upper quartile (>5314 pg/mL) than in patients in the lower three quartiles of NT-proBNP concentration,⁵ we also planned to assess the relationship between baseline NT-proBNP concentrations and clinical outcomes.⁶

Methods

Study design and participants

This pooled analysis combines participant-level data from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials: VICTORIA (NCT02861534) and VICTOR (NCT05093933). The design and primary results of both trials have been published.¹,²,⁷,⁸ The statistical analysis plan for this pooled analysis is registered with PROSPERO, CRD420251065636.

The VICTORIA trial, which began on Sept 25, 2016, and was completed on Sept 2, 2019, enrolled 5050 patients at 616 sites in 42 countries. The primary objective was to establish whether vericiguat reduced the incidence of cardiovascular death or hospitalisation for heart failure in patients with HFrEF and recent worsening (defined as either hospitalisation for heart failure within the previous 6 months or outpatient use of intravenous diuretics within the previous 3 months). Eligible patients were adults (aged 18 years or older) with a left ventricular ejection fraction of less than 45%, New York Heart Association functional class II–IV, elevated NT-proBNP concentrations (≥1000 pg/mL for patients in sinus
rhythm or ≥1600 pg/mL for those in atrial fibrillation), and an estimated glomerular filtration rate (eGFR) of at least 15 mL/min per 1·73 m².⁹,¹⁰

The VICTOR trial, which enrolled patients from Nov 2, 2021, to Dec 21, 2023, and which completed follow-up on Feb 5, 2025, enrolled 6105 patients at 482 sites in 36 countries. The primary objective was to establish whether vericiguat reduced the incidence of cardiovascular deaths or hospitalisation for heart failure in patients with HFrEF with no recent worsening (as per the definition used in the VICTORIA trial). Eligible patients were adults (aged 18 years and older) with a left ventricular ejection fraction of no greater than 40%, New York Heart Association functional class II–IV, elevated NT-proBNP concentrations (600–6000 pg/mL for patients in sinus rhythm or 900–6000 pg/mL for those in atrial fibrillation), and an eGFR of at least 15 mL/min per 1·73 m².

The entry criteria for each trial were selected to create complementary, largely non-overlapping segments of the population with HFrEF: patients at high risk and with recent worsening of heart failure (VICTORIA trial) and patients at lower risk without recent worsening of heart failure (VICTOR trial). The pooled population therefore represents individuals across a broad range of HFrEF severity.¹¹

Both the VICTORIA and VICTOR trials were approved by the relevant ethics committees at each participating site, and all patients provided written informed consent. Details of ethical approval are provided in the original trial publications. The pooled analysis was conducted using de-identified data and in accordance with the Declaration of Helsinki.

## Procedures

Patients in both the VICTORIA and VICTOR trials were randomised 1:1 to receive oral vericiguat, titrated from a starting dose of 2·5 mg to a 10 mg target dose, or matching placebo. The titration schemes in each trial were identical, with dose increases to 5 mg at day 14 and to 10 mg at day 28, based on blood pressure and symptoms of hypotension. Patients continued study treatment until the end of the trial (ie, until they returned for the final study visit, which was scheduled to occur after the required number of primary endpoints had accrued), unless they required discontinuation due to adverse events, withdrew consent, or terminated study participation for other reasons. For the pooled CONSORT diagram, definitions of treatment discontinuation and on-treatment deaths were harmonised across the two trials to ensure consistency. All deaths occurring while on study drug were classified as a discontinuation of trial regimen due to death for both the VICTORIA and VICTOR trials. Median follow-up for the primary endpoint was 10·8 months in the VICTORIA trial and 18·5 months in the VICTOR trial. Endpoint collection and adjudication were identical between trials, using the same clinical report forms. Both trials were adjudicated

by an external clinical events committee at the Duke Clinical Research Institute (Durham, NC, USA), whose members were unaware of trial group assignments. The same standardised definitions were used for both trials.

For the pooled analyses, the primary outcome was a composite of cardiovascular death or first hospitalisation for heart failure; these components were also assessed individually. Cardiovascular death was a key secondary outcome. Other secondary outcomes were first hospitalisation for heart failure, total (first and recurrent) hospitalisations for heart failure, and all-cause death.

## Statistical analysis

The intention-to-treat population comprised all randomly assigned patients from the VICTORIA and VICTOR trials, and was the primary analysis population for all efficacy endpoints. All analyses followed the intention-to-treat principle. Baseline characteristics were summarised by treatment group using means (SD), medians (IQR), or counts (percentages), as appropriate, without statistical hypothesis testing.

Efficacy analyses were done with a stratified log-rank test with trial (VICTORIA or VICTOR) as the stratification factor. Kaplan–Meier survival curves and hazard ratios (HRs) with 95% CIs were derived from Cox proportional hazards regression. p values were calculated using the stratified log-rank test and are presented for each outcome, and are descriptive rather than formal tests of statistical inference. The relationship between NT-proBNP concentration as a continuous variable and efficacy outcome was assessed using a restricted cubic spline model, as done previously in the VICTORIA trial.⁶

Treatment effects on efficacy endpoints were assessed across prespecified subgroups. To test for heterogeneity of treatment effects between the two trials, a Cox proportional hazards model was fitted that included trial, treatment, and a treatment-by-trial interaction term as covariates, with time-to-event as the dependent variable. In addition, the proportional hazard assumption was tested using the weighted Schoenfeld residuals test across all time-to-first-event outcomes.

Numbers needed to treat for efficacy endpoints were calculated on the basis of the absolute risk reduction at 1 year, using Kaplan–Meier estimates. 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 annualised event rates (total number of patients with an event per 100 patient-years at risk) were used to calculate absolute risk reductions, with number needed to treat calculated as the reciprocal of the absolute risk reduction. Missing data were not imputed; analyses were based on available data. Statistical analyses were done by the sponsor under the oversight of the steering committee and were independently verified by statisticians at the Duke Clinical Research Institute. Analyses were conducted using SAS software, version 9.4.
<figure><img src="image_4.png" /><figcaption>**Figure 1: Trial profile**</figcaption></figure>

*Discontinuation reason applies only to the VICTOR trial. For the pooled CONSORT diagram, definitions of treatment discontinuation and on-treatment deaths were harmonised across the two trials to ensure consistency. All deaths occurring while on study drug are now included in the discontinued trial regimen due to death category for both the VICTORIA and VICTOR trials.

## Role of the funding source

The sponsors (Merck Sharp & Dohme and Bayer) of the VICTORIA and VICTOR trials were involved in the pooled study design, data analysis, data interpretation, writing of the report, and decision to submit the paper for publication. Both trials were conducted in collaboration between the sponsors and academic-led steering committees. The steering committees of both trials designed and supervised the study and were responsible for the results.

## Results

The VICTORIA trial was initiated on Sept 25, 2016 and completed on Sept 2, 2019, and the VICTOR trial started on Nov 2, 2021 with a completion date of Feb 5, 2025. A total of 17778 patients were screened for the two trials, of which 11155 were enrolled (5050 in VICTORIA and 6105 in VICTOR), with 5579 randomly assigned to vericiguat

and 5576 to placebo (figure 1). Two duplicate random assignments of one patient were excluded from the VICTOR trial. Study treatment was discontinued for reasons other than death in 1275 (22.9%) of 5579 patients assigned to receive vericiguat and 1244 (22.3%) of 5576 patients assigned to receive placebo. 889 (15.9%) of 5579 patients assigned to receive vericiguat and 974 (17.5%) of 5576 patients assigned to receive placebo died. Overall, only 39 (0.3%) of the 11155 patients were lost to follow-up over the two trials. The baseline characteristics of the patients were well balanced between treatments (table 1).⁹,¹⁰

The median age of the 11155 patients was 68.0 years (IQR 60.0–75.0); 2648 (23.7%) were female and 8507 (76.3%) were male. The median NT-proBNP concentration at baseline was 1864 pg/mL (IQR 1036–3537), and 9566 (88.7%) of 10790 patients with measurements at baseline had an NT-proBNP concentration of 6000 pg/mL or lower. At randomisation, 7797 (69.9%) of 11151 patients with data on this measure were categorised as New York Heart Association functional class II and 3352 (30.1%) as class III–IV. The mean left ventricular ejection fraction at screening was 29.8% (SD 7.7) and the mean baseline estimated glomerular filtration rate was 66.6 mL/min per 1.73 m² (SD 25.9). 8256 (74.0%) of 11155 patients had previously been hospitalised for heart failure or receipt of intravenous diuretics before enrolment; the 2899 (26.0%) of 11155 patients who had not had a previous worsening of heart failure were part of the VICTOR trial.

The use of guideline-directed medical therapy for heart failure was robust, with differences in the use of specific drug classes between trials reflecting the evolving framework of heart failure treatment—eg, sacubitril—valsartan was used by 731 (14.5%) of 5050 patients in the VICTORIA trial and 3416 (56.0%) of 6105 patients in the VICTOR trial, and SGLT2 inhibitors were used by 212 (4.2%) of 5050 patients in the VICTORIA trial and 3610 (59.1%) of 6105 patients in the VICTOR trial. Notably, of the 11155 patients in the pooled population, 3408 (30.6%) had an implantable cardioverter-defibrillator, 1643 (14.7%) had cardiac resynchronisation therapy, and 1200 (10.8%) had a cardiac resynchronisation therapy-defibrillator or had both cardiac resynchronisation therapy and an implantable cardioverter-defibrillator.⁹,¹⁰

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, median follow-up duration for the primary endpoint—a composite endpoint of cardiovascular death or the first event of hospitalisation for heart failure—was 15.6 months (IQR 9.2–22.6), with 99.4% ascertainment achieved. The median follow-up time for death endpoints was 17.6 months (12.0–24.2), with 99.9% completeness (data not shown). Study treatment discontinuations were balanced between groups, with 1794 (32.2%) of 5568 patients who received vericiguat and 1831 (32.9%) of 5564 patients who
received placebo not completing the trial regimen, and were primarily due to 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; figure 1). At about 1 year, 6863 (89.2%) of 7691 pooled patients in the trials

at that time were tolerating the 10 mg dose (data not shown).

The primary endpoint of cardiovascular death or first hospitalisation for heart failure (table 2) occurred in 1446 (25.9%) of 5579 patients in the vericiguat group and 1556 (27.9%) of 5576 patients in the placebo group

<table><thead><tr><th rowspan="2"></th><th colspan="3">Pooled trials (VICTOR and VICTORIA)</th><th rowspan="2">VICTOR (n=6105)</th><th rowspan="2">VICTORIA (n=5050)</th></tr><tr><th>Vericiguat (n=5579)</th><th>Placebo (n=5576)</th><th>Pooled (n=11155)</th></tr></thead><tbody><tr><td>Age (years)</td><td>68.0 (60.0-76.0)</td><td>68.0 (60.0-75.0)</td><td>68.0 (60.0-75.0)</td><td>68.0 (61.0-75.0)</td><td>69.0 (60.0-76.0)</td></tr><tr><td>Sex</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Female</td><td>1332 (23.9%)</td><td>1316 (23.6%)</td><td>2648 (23.7%)</td><td>1440 (23.6%)</td><td>1208 (23.9%)</td></tr><tr><td>Male</td><td>4247 (76.1%)</td><td>4260 (76.4%)</td><td>8507 (76.3%)</td><td>4665 (76.4%)</td><td>3842 (76.1%)</td></tr><tr><td>Race*</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>White</td><td>3563 (63.9%)</td><td>3610 (64.7%)</td><td>7173 (64.3%)</td><td>3934 (64.4%)</td><td>3239 (64.1%)</td></tr><tr><td>Black†</td><td>554 (9.9%)</td><td>520 (9.3%)</td><td>1074 (9.6%)</td><td>656 (10.7%)</td><td>418 (8.3%)</td></tr><tr><td>American Indian or Alaskan Native</td><td>183 (3.3%)</td><td>170 (3.0%)</td><td>353 (3.2%)</td><td>301 (4.9%)</td><td>52 (1.0%)</td></tr><tr><td>Native Hawaiian or Pacific Islander</td><td>7 (0.1%)</td><td>18 (0.3%)</td><td>25 (0.2%)</td><td>11 (0.2%)</td><td>14 (0.3%)</td></tr><tr><td>Asian</td><td>954 (17.1%)</td><td>924 (16.6%)</td><td>1878 (16.8%)</td><td>746 (12.2%)</td><td>1132 (22.4%)</td></tr><tr><td>Multiracial</td><td>496 (8.9%)</td><td>510 (9.1%)</td><td>1006 (9.0%)</td><td>643 (10.5%)</td><td>363 (7.2%)</td></tr><tr><td>Not reported</td><td>2 (&lt;0.1%)</td><td>0</td><td>2 (&lt;0.1%)</td><td>1 (&lt;0.1%)</td><td>1 (&lt;0.1%)</td></tr><tr><td>Geographical region</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Eastern Europe</td><td>1671 (30.0%)</td><td>1723 (30.9%)</td><td>3394 (30.4%)</td><td>1700 (27.8%)</td><td>1694 (33.5%)</td></tr><tr><td>Latin and South America</td><td>1250 (22.4%)</td><td>1249 (22.4%)</td><td>2499 (22.4%)</td><td>1775 (29.1%)</td><td>724 (14.3%)</td></tr><tr><td>Asia-Pacific</td><td>1024 (18.4%)</td><td>1013 (18.2%)</td><td>2037 (18.3%)</td><td>854 (14.0%)</td><td>1183 (23.4%)</td></tr><tr><td>Western Europe</td><td>1029 (18.4%)</td><td>987 (17.7%)</td><td>2016 (18.1%)</td><td>1127 (18.5%)</td><td>889 (17.6%)</td></tr><tr><td>North America</td><td>605 (10.8%)</td><td>604 (10.8%)</td><td>1209 (10.8%)</td><td>649 (10.6%)</td><td>560 (11.1%)</td></tr><tr><td>Comorbidities</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Ischaemic heart disease</td><td>3622 (64.9%)</td><td>3567 (64.0%)</td><td>7189 (64.4%)</td><td>3946 (64.6%)</td><td>3243 (64.2%)</td></tr><tr><td>Diabetes</td><td>2500 (44.8%)</td><td>2454 (44.0%)</td><td>4954 (44.4%)</td><td>2585 (42.3%)</td><td>2369 (46.9%)</td></tr><tr><td>Atrial fibrillation</td><td>2233 (40.0%)</td><td>2352 (42.2%)</td><td>4585 (41.1%)</td><td>2317 (38.0%)</td><td>2268 (44.9%)</td></tr><tr><td>No previous hospitalisation for heart failure</td><td>1426 (25.6%)</td><td>1473 (26.4%)</td><td>2899 (26.0%)</td><td>2899 (47.5%)</td><td>801 (15.9%)‡</td></tr><tr><td>BMI (kg/m²)</td><td>27.2 (24.0-31.1)</td><td>27.4 (24.2-31.3)</td><td>27.3 (24.1-31.2)</td><td>27.6 (24.5-31.4)</td><td>26.9 (23.7-30.9)</td></tr><tr><td>Baseline NT-proBNP concentration (pg/mL)</td><td>1847 (1042-3542)</td><td>1875 (1029-3535)</td><td>1864 (1036-3537)</td><td>1375 (827-2393)</td><td>2816 (1556-5314)</td></tr><tr><td>NT-proBNP concentration at randomisation§</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>≤6000 pg/mL</td><td>4787 (85.8%)</td><td>4779 (85.7%)</td><td>9566 (85.8%)</td><td>5784 (94.7%)</td><td>3782 (74.9%)</td></tr><tr><td>&gt;6000 pg/mL</td><td>626 (11.2%)</td><td>598 (10.7%)</td><td>1224 (11.0%)</td><td>201 (3.3%)</td><td>1023 (20.3%)</td></tr><tr><td>New York Heart Association class</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>I</td><td>0</td><td>2 (&lt;0.1%)</td><td>2 (&lt;0.1%)</td><td>0</td><td>2 (&lt;0.1%)</td></tr><tr><td>II</td><td>3889 (69.7%)</td><td>3908 (70.1%)</td><td>7797 (69.9%)</td><td>4822 (79.0%)</td><td>2975 (58.9%)</td></tr><tr><td>III-IV</td><td>1687 (30.2%)</td><td>1665 (29.9%)</td><td>3352 (30.0%)</td><td>1283 (21.0%)</td><td>2069 (41.0%)</td></tr><tr><td>Missing</td><td>3 (&lt;0.1%)</td><td>1 (&lt;0.1%)</td><td>4 (&lt;0.1%)</td><td>0</td><td>4 (&lt;0.1%)</td></tr><tr><td>Left ventricular ejection fraction at screening (%)</td><td>29.8% (7.6)</td><td>29.7% (7.7)</td><td>29.8% (7.7)</td><td>30.4% (7.0)</td><td>28.9% (8.3)</td></tr><tr><td>eGFR (mL/min per 1.73 m²)</td><td>66.6 (25.8)</td><td>66.6 (26.1)</td><td>66.6 (25.9)</td><td>70.9 (24.0)</td><td>61.5 (27.2)</td></tr><tr><td>eGFR values at randomisation</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;15 mL/min per 1.73 m²</td><td>7 (0.1%)</td><td>12 (0.2%)</td><td>19 (0.2%)</td><td>7 (0.1%)</td><td>12 (0.2%)</td></tr><tr><td>≥15 to &lt;30 mL/min per 1.73 m²</td><td>373 (6.7%)</td><td>364 (6.5%)</td><td>737 (6.6%)</td><td>243 (4.0%)</td><td>494 (9.8%)</td></tr><tr><td>≥30 to &lt;60 mL/min per 1.73 m²</td><td>1975 (35.4%)</td><td>2004 (35.9%)</td><td>3979 (35.7%)</td><td>1861 (30.5%)</td><td>2118 (41.9%)</td></tr><tr><td>≥60 mL/min per 1.73 m²</td><td>3115 (55.8%)</td><td>3095 (55.5%)</td><td>6210 (55.7%)</td><td>3875 (63.5%)</td><td>2335 (46.2%)</td></tr><tr><td>Missing</td><td>109 (2.0%)</td><td>101 (1.8%)</td><td>210 (1.9%)</td><td>119 (1.9%)</td><td>91 (1.8%)</td></tr></tbody></table>

(Table 1 continues on next page)
<table><caption>Table 1: Baseline characteristics of the VICTORIA and VICTOR trials</caption><thead><tr><th></th><th colspan="3">Pooled trials (VICTOR and VICTORIA)</th><th>VICTOR (n=6105)</th><th>VICTORIA (n=5050)</th></tr><tr><th>(Continued from previous page)</th><th>Vericiguat (n=5579)</th><th>Placebo (n=5576)</th><th>Pooled (n=11 155)</th><th></th><th></th></tr></thead><tbody><tr><td>Medical therapy</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>β blockers</td><td>5235 (93.8%)</td><td>5222 (93.7%)</td><td>10 457 (93.7%)</td><td>5766 (94.4%)</td><td>4691 (92.9%)</td></tr><tr><td>Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker</td><td>2997 (53.7%)</td><td>3041 (54.5%)</td><td>6038 (54.1%)</td><td>2338 (38.3%)</td><td>3700 (73.3%)</td></tr><tr><td>Sacubitril-valsartan</td><td>2094 (37.5%)</td><td>2053 (36.8%)</td><td>4147 (37.2%)</td><td>3416 (56.0%)</td><td>731 (14.5%)</td></tr><tr><td>Mineralocorticoid receptor antagonists</td><td>4105 (73.6%)</td><td>4188 (75.1%)</td><td>8293 (74.3%)</td><td>4748 (77.8%)</td><td>3545 (70.2%)</td></tr><tr><td>SGLT2 inhibitors</td><td>1918 (34.4%)</td><td>1904 (34.1%)</td><td>3822 (34.3%)</td><td>3610 (59.1%)</td><td>212 (4.2%)</td></tr><tr><td>Device therapy</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Implantable cardioverter-defibrillator</td><td>1689 (30.3%)</td><td>1719 (30.8%)</td><td>3408 (30.6%)</td><td>2009 (32.9%)</td><td>1399 (27.7%)</td></tr><tr><td>Cardiac resynchronisation therapy</td><td>834 (14.9%)</td><td>809 (14.5%)</td><td>1643 (14.7%)</td><td>904 (14.8%)</td><td>739 (14.6%)</td></tr><tr><td>Cardiac resynchronisation therapy-defibrillator, or both implantable cardioverter-defibrillator and cardiac resynchronisation therapy</td><td>595 (10.7%)</td><td>605 (10.9%)</td><td>1200 (10.8%)</td><td>677 (11.1%)</td><td>523 (10.4%)</td></tr></tbody><tfoot><tr><td colspan="6">Data are median (IQR), n (%), or mean (SD). eGFR=estimated glomerular filtration rate. *Numbers for each race category do not sum to the total number of participants because participants could select more than one race. †Includes participants who identify as Black or multiracial including Black. ‡801 participants without previous hospitalisation for heart failure were enrolled into the VICTORIA trial as they had previously received intravenous diuretics. These 801 participants were not included in the pooled columns. §Percentage of participants in the intention-to-treat population for whom baseline NT-proBNP concentrations were available. Data for 365 (3.3%) of 11 155 pooled participants were missing: 166 (3.0%) of 5579 participants in the vericiguat group and 199 (3.6%) of 5576 participants in the placebo group. Of the 10 790 participants with available data, 9566 (88.7%) of the pooled population had baseline NT-proBNP concentrations of 6000 pg/mL or lower.</td></tr></tfoot></table>

See Online for appendix

(HR 0.91 [95% CI 0.85–0.98]; p=0.0088). The key secondary endpoint of cardiovascular death occurred in 706 (12.7%) patients in the vericiguat group and 787 (14.1%) patients in the placebo group (0.89 [0.80–0.98]; p=0.020). Deaths from any cause, first hospitalisation for heart failure, and total (first and recurrent) hospitalisations for heart failure were all significantly lower in the vericiguat group than in the placebo group (table 2). The Kaplan–Meier curves (figure 2) show that the treatment effect on the primary endpoint and for hospitalisation for heart failure emerged at around 4 months, and the treatment effect on cardiovascular death emerged at around 8 months. Although the timing of these effects differed, the proportional hazards assumption held for all time-to-first outcomes: in the Schoenfeld residuals test of proportional hazards assumption, p values were p=0.43 for the primary composite endpoint, p=0.44 for cardiovascular death, p=0.26 for hospitalisation for heart failure, and p=0.43 for all-cause death (appendix p 17). When testing the heterogeneity of treatment effects across the two trials, no evidence of treatment-by-trial interaction was found (p=0.59 for cardiovascular death or hospitalisation for heart failure, p=0.32 for cardiovascular death, and p=0.51 for hospitalisation for heart failure; appendix p 5).

Treatment effects on the composite endpoint and each of its components were assessed in prespecified

subgroups (appendix pp 6–12). Although an apparent treatment benefit was observed in some subgroups, the only subgroup to show a significant and consistent interaction with the treatment effect across all endpoints was patients with a baseline NT-proBNP concentration of 6000 pg/mL or lower (composite endpoint of cardiovascular death and hospitalisation for heart failure HR 0.86 [95% CI 0.79–0.94], cardiovascular death 0.83 [0.74–0.94], and hospitalisation for heart failure 0.85 [0.77–0.94]). When examining NT-proBNP concentration as a continuous covariate against the treatment effect, the interaction p values were $p_{interaction}=0.038$ for the composite endpoint, $p_{interaction}=0.022$ for cardiovascular death, and $p_{interaction}=0.057$ for hospitalisation for heart failure.

Given these findings, we further evaluated outcomes in the 10 790 patients from the pooled population for whom baseline NT-proBNP concentrations were available (figure 3). Notably, patients with NT-proBNP concentrations of 6000 pg/mL or lower at baseline had a greater reduction in the risk of cardiovascular death or hospitalisation for heart failure than those with concentrations higher than 6000 pg/mL (figure 3; appendix pp 6–14). The majority of patients had NT-proBNP concentrations lower than 3000 pg/mL, which is consistent with the median value of 1864 pg/mL (IQR 1036–3537) in the overall pooled
<table><thead><tr><th rowspan="2"></th><th colspan="2">Vericiguat (n=5579)</th><th colspan="2">Placebo (n=5576)</th><th rowspan="2">Hazard ratio (95% CI)†</th><th rowspan="2">p value‡</th></tr><tr><th>Patients with event</th><th>Events per 100 patient-years*</th><th>Patients with event</th><th>Events per 100 patient-years*</th></tr></thead><tbody><tr><td colspan="7"><strong>Primary outcome</strong></td></tr><tr><td>Cardiovascular death or hospitalisation for heart failure</td><td>1446 (25.9%)</td><td>19.3</td><td>1556 (27.9%)</td><td>21.2</td><td>0.91 (0.85-0.98)</td><td>0.0088</td></tr><tr><td>Cardiovascular death§</td><td>407 (7.3%)</td><td>..</td><td>447 (8.0%)</td><td>..</td><td>..</td><td>..</td></tr><tr><td>Hospitalisation for heart failure§</td><td>1039 (18.6%)</td><td>..</td><td>1109 (19.9%)</td><td>..</td><td>..</td><td>..</td></tr><tr><td colspan="7"><strong>Secondary outcomes</strong></td></tr><tr><td>Cardiovascular death</td><td>706 (12.7%)</td><td>8.4</td><td>787 (14.1%)</td><td>9.5</td><td>0.89 (0.80-0.98)</td><td>0.020</td></tr><tr><td>First hospitalisation for heart failure</td><td>1039 (18.6%)</td><td>13.8</td><td>1109 (19.9%)</td><td>15.1</td><td>0.92 (0.84-1.00)</td><td>0.043</td></tr><tr><td>Total hospitalisations for heart failure (first and recurrent events)</td><td>1772</td><td>21.3</td><td>1933</td><td>23.6</td><td>0.91 (0.85-0.97)</td><td>0.0050</td></tr><tr><td>All-cause death</td><td>889 (15.9%)</td><td>10.6</td><td>974 (17.5%)</td><td>11.8</td><td>0.90 (0.82-0.99)</td><td>0.025</td></tr></tbody></table>

For participants with multiple events in a composite event outcome, only the first event contributing to the composite endpoint is counted. *Number of participants with an event per 100 patient-years at risk. †Calculated with a Cox proportional hazard model controlling for stratification factors defined by trial. ‡Calculated with a two-sided log-rank test stratified by the stratification factors defined by trial. §Components of the composite primary outcome as first events.

<caption>**Table 2:** Efficacy outcomes in the pooled VICTORIA and VICTOR trials population</caption>

population. When the effect of NT-proBNP concentration was examined as a continuous variable, vericiguat reduced the risk of hospitalisation for heart failure, cardiovascular death, and all-cause death across the concentration range, with a consistently robust treatment effect at concentrations of 6000 pg/mL or lower.

Serious adverse events were reported in 1543 (27.7%) of 5568 patients receiving vericiguat and 1627 (29.2%) of 5564 patients receiving placebo (appendix pp 15–16). The percentage of patients who discontinued the trial regimen owing to an adverse event was 7.8% (432 of 5568 patients) in the vericiguat group and 6.9% (384 of 5564 patients) in the placebo group (figure 1). Fewer patients discontinued the trial regimen owing to a serious adverse event in the vericiguat group (162 [2.9%] of 5568 patients) than in the placebo group (184 [3.3%] of 5564 patients). Exposure-adjusted incidences (in events per 100 patient-years) of investigator-reported anaemia were 6.7 in patients receiving vericiguat and 5.3 in patients receiving placebo, and of symptomatic hypotension were 9.6 in patients receiving vericiguat and 7.9 in patients receiving placebo (data not shown). Anaemia was reported in 471 (8.5%) of 5568 patients receiving vericiguat and 375 (6.7%) of 5564 patients receiving placebo, and symptomatic hypotension was reported in 657 (11.8%) of 5568 patients receiving vericiguat and 548 (9.8%) of 5564 patients receiving placebo (appendix pp 15–16).¹²,¹³ Beyond those reported in the individual trials, no new safety signals emerged in the pooled analysis.

Risk reduction in the composite endpoint was driven by similar reductions in both cardiovascular death and hospitalisation for heart failure events. Over 1 year of treatment, the absolute risk reductions were 2.7 per 100 patient-years for the composite of cardiovascular death or first hospitalisation for heart

failure events, 1.8 per 100 patient-years for first hospitalisation for heart failure events, and 0.9 per 100 patient-years for cardiovascular death events, leading to approximate numbers needed to treat for 1 year of 37 to prevent one composite endpoint event, 54 to prevent one hospitalisation for heart failure event, and 109 to prevent one cardiovascular death event. When evaluated in the large cohort of patients with NT-proBNP concentrations of 6000 pg/mL or lower, these risk reductions were more pronounced: 3.4 per 100 patient-years for the composite outcome, 2.7 per 100 patient-years for hospitalisation for heart failure, and 1.3 per 100 patient-years for cardiovascular death, leading to an approximate number needed to treat for 1 year of 29 to prevent one composite endpoint event, 37 to prevent one hospitalisation for heart failure event, and 79 to prevent one cardiovascular death event.

## Discussion

This pooled analysis of two large outcomes trials of vericiguat, across the spectrum of HFrEF severity, shows that treatment with vericiguat reduced the composite endpoint of cardiovascular death or hospitalisation for heart failure, as well as cardiovascular death, hospitalisation for heart failure, and all-cause death, with no evidence of intertrial heterogeneity of treatment effect (p<0.23 for all four endpoints). By design, the inclusion criteria of each trial selected for complementary populations: the VICTORIA trial enrolled patients at high to very high risk due to recent worsening of heart failure and high NT-proBNP concentrations, whereas the VICTOR trial enrolled ambulatory, clinically stable patients at low to moderate risk with lower NT-proBNP concentrations.¹,²,⁷ Pooling more than 11000 patients with HFrEF from both trials enabled us to examine the benefit of vericiguat in a large cohort with a broad range of HFrEF severity, thereby
<figure><img src="image_5.png" /><figcaption>**Figure 2:** Kaplan-Meier curves of efficacy outcomes for the pooled population</figcaption></figure>

(A) Primary composite outcome of cardiovascular death or hospitalisation for heart failure. (B) Cardiovascular death. (C) Hospitalisation for heart failure. (D) All-cause death. HR=hazard ratio.

improving both the precision in estimating the treatment effect and the generalisability of the treatment effect to patients across a broad risk spectrum.

In this population, patients treated with vericiguat had an overall moderate 8–11% relative benefit in the composite endpoint of cardiovascular death and hospitalisation for heart failure, as well as in each component and in all-cause death. Notably, the interaction of treatment effect by trial was not significant for any endpoint, indicating the consistency of the effect of vericiguat across trials (all *p*<sub>interaction</sub>>0·23). In the pooled cohort, treatment benefit appeared early—at about 4 months for the composite outcome and for hospitalisation for heart failure, and at about 8 months for mortality events. The treatment effect for all endpoints was sustained throughout follow-up.

No statistical heterogeneity in treatment effects was observed between trials in the patient-level pooled analyses. However, in the VICTORIA trial, which enrolled patients at high risk, vericiguat significantly reduced the risk of the composite endpoint and hospitalisation for heart failure, but not cardiovascular

death alone. By contrast, in the VICTOR trial, vericiguat significantly reduced cardiovascular death, but not the composite endpoint or hospitalisation for heart failure.¹⁷

Although our observations have a clinical rationale, we cannot exclude the possibility that these findings are due to chance. There were key clinical differences in the baseline characteristics of the trial populations and the relative incidences of cardiovascular disease and hospitalisation for heart failure. These differences—which include the recency of heart failure events before randomisation, the median NT-proBNP concentrations at baseline, and the differing background use of guideline-directed medical therapy—result from the inclusion criteria and enrolment periods of each trial. Enrolment for the VICTORIA trial ended in 2018, before quadruple therapy was adopted in European and North American HFrEF guidelines, whereas the VICTOR trial enrolled patients between 2021 and 2023, during the era of quadruple therapy; as a result, patients in the VICTOR trial had a much higher background use of guideline-directed medical therapy, especially angiotensin receptor-neprilysin inhibitors and
<figure><img src="image_6.png" /><figcaption>**Figure 3:** Treatment effects on efficacy outcomes by baseline NT-proBNP concentration</figcaption></figure>

Treatment effect across the range of NT-proBNP concentrations at randomisation for the primary composite outcome (A), cardiovascular death (B), hospitalisation for heart failure (C), and all-cause death (D). The left-hand y-axis shows the treatment effect, expressed as HR (blue line) with 95% CI (shaded area), adjusted for the trial effect. The right-hand y-axis indicates the percentage of patients, shown by green shaded bars, within each NT-proBNP concentration group. The vertical blue dotted line indicates an NT-proBNP concentration of 6000 pg/mL. The concentrations were obtained from a back-transformation of log-transformed NT-proBNP concentrations. The x-axis is truncated at 10 000 pg/mL for presentation purposes. The entry criteria for the VICTORIA and VICTOR trials differed in terms of baseline NT-proBNP concentrations: >1000 pg/mL for the VICTORIA trial and 600–6000 pg/mL in the VICTOR trial, with higher minimum thresholds in both trials if patients had atrial fibrillation at screening. HR=hazard ratio.

SGLT2 inhibitors, than those in the VICTORIA trial. The consistency of treatment effect on both the composite endpoint and cardiovascular death, irrespective of the recency of heart failure events or baseline use of angiotensin receptor-neprilysin inhibitors or SGLT2 inhibitors, suggests that these between-trial differences are unlikely to fully explain the variation in treatment effects between the two trials. Notably, the benefits of vericiguat were consistent across all endpoints irrespective of baseline use of angiotensin receptor-neprilysin inhibitors or SGLT2 inhibitors, suggesting that the use of vericiguat in a broad population of patients with HFrEF could provide incremental benefits to hospitalisation for heart failure and cardiovascular death beyond those provided by current conventional guideline-directed medical therapy. However, although our subgroup analyses suggest that the benefit of vericiguat is consistent

regardless of background use of angiotensin
receptor–neprilysin inhibitors or SGLT2 inhibitors,
these analyses are observational and not randomised
comparisons. The number of patients receiving full
quadruple therapy, especially in the VICTORIA trial,
was low, and the study was not powered to detect small
differences in these subgroups. Therefore, although
our findings support the potential for an incremental
benefit of vericiguat in addition to contemporary
guideline-directed medical therapy, they should be
interpreted with caution, and additional real-world data
might be needed to corroborate these results in patients
receiving quadruple therapy. However, patients in the
VICTORIA trial, most of whom had previous heart
failure events (hospitalisation for heart failure or
intravenous diuretic use), had a greater benefit from
vericiguat in terms of prevention of future
hospitalisation for heart failure events than patients in
the VICTOR trial, nearly half of whom had never been hospitalised for heart failure.¹,⁶,⁷

In the VICTORIA trial, which enrolled a population at high risk and with recent worsening heart failure, hospitalisation for heart failure was 3·4 times more common than cardiovascular death, whereas this ratio was only 1·7 in the VICTOR trial.¹,⁷ Among compensated patients, such as in those in the VICTOR trial, event rates were influenced by the recency of hospitalisation for heart failure episodes before randomisation, with the highest event rate in patients with a recent hospitalisation and the lowest event rate in patients with no history of hospitalisation for heart failure. A more in-depth description of the non-fatal heart failure events in the VICTOR trial is described elsewhere.¹⁴ The large contribution of hospitalisation for heart failure to the composite endpoint in the VICTORIA trial led to the trial being completed earlier than expected; the resulting relatively brief 10·8-month follow-up could potentially have obscured a longer-term effect on mortality. By contrast, in the VICTOR trial, although the primary composite endpoint of cardiovascular death or hospitalisation for heart failure was not achieved, the longer median follow-up of 18·5 months could have enabled the emergence of a cardiovascular death benefit, particularly considering that the survival curves seemed to only separate after 8 months of treatment with vericiguat. The high use of quadruple guideline-directed medical therapy and the low rate of recent hospitalisation among patients in the VICTOR trial could explain the lower relative risk reduction in hospitalisation for heart failure.⁹

Pooling the trial populations resulted in a broader population with HFrEF than in each of the individual trials alone, leading to a clearer representation of the treatment benefit of vericiguat across the risk spectrum of patients with HFrEF.

The benefits of vericiguat were generally consistent among all prespecified subgroups, except in subgroups based on baseline NT-proBNP concentrations. In patients with NT-proBNP concentrations of 6000 pg/mL or lower, the treatment effect on hospitalisation for heart failure and cardiovascular death outcomes was greater than in patients with higher NT-proBNP concentrations. This finding supports those from a subgroup analysis of patients in the VICTORIA trial with NT-proBNP concentrations of less than 8000 pg/mL, who were found to have a substantial reduction in both hospitalisation for heart failure events and cardiovascular death.⁶ Notably, the benefits of vericiguat were consistent across all endpoints irrespective of baseline use of angiotensin receptor-nprilysin inhibitors or SGLT2 inhibitors, suggesting that the use of vericiguat in a broad HFrEF population (including patients across a wide range of severity and background therapies) could provide incremental benefit in hospitalisation for heart failure and death beyond those provided by current conventional guideline-directed medical therapy. Taken together with

the convenient once-daily dosing, a well tolerated adverse event profile, and no requirement for laboratory monitoring, the current data support consideration of vericiguat use to mitigate risk along with current guideline-directed medical therapy for HFrEF.

A similar safety profile was seen in both the VICTOR and VICTORIA trials. Symptomatic hypotension and mild anaemia were more common in patients receiving vericiguat than in those receiving placebo.¹²,¹³ However, these adverse events were generally mild and infrequently led to treatment discontinuation, and no new safety signals emerged in the pooled analysis. These findings are consistent with the known safety profile of vericiguat and suggest that the drug is well tolerated in a broad population of patients with HFrEF.

Although this pooled analysis was prespecified and was preregistered before commencing, no hypothesis testing was done, and no multiplicity adjustments were undertaken for type I error. As such, the p values provided for all results should be considered descriptive. Furthermore, because the VICTORIA and VICTOR trials were separated in time, subgroup analysis for treatment effect across the two trials could be prone to confounding due to correlations between covariates defining the subgroups, which limits the ability to completely assess for treatment heterogeneity. Additionally, subgroup analyses were not powered for in the original trials or in the pooled analyses, so these results are hypothesis-generating. As with other new therapies and advances evaluated in clinical trials, the generalisability of our results to clinical practice might be limited.

In summary, the cumulative evidence from the pooled VICTORIA and VICTOR trials data shows that vericiguat reduced the risk of all-cause death, cardiovascular death, and hospitalisation for heart failure in patients with a broad range of HFrEF severities receiving guideline-directed medical therapy. Although we cannot rule out confounding factors, the benefit we observed was most prominent in the large cohort of patients with an NT-proBNP concentration of 6000 pg/mL or lower, which represents the majority of patients with HFrEF in contemporary registries¹⁵ and clinical trials.¹⁶⁻¹⁹ Additionally, the once-daily administration and favourable tolerability suggest that vericiguat could be a suitable additional treatment option for patients with HFrEF.

**Contributors**

FZ and PWA wrote the first draft of the manuscript. All authors contributed to the conceptualisation and design of the study. KJA, DG, VV, and AX contributed to the design of analytical methods, analysis, and writing of the statistical analysis plan. DG, AFH, and AX accessed and verified the raw data. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

**Declaration of interests**

FZ reports personal fees from Alnylam Pharmaceuticals, Bayer, Bioeutics, Boehringer Ingelheim, CellProthera, Cereno Scientific, Corteria, CVRx, Merck, Owkin, Ribocure Pharmaceuticals, and Roche; reports payment or honoraria for lectures, presentations, speakers
bureaus, or educational events from Bayer, Boehringer Ingelheim, Centrix, CVRx, Lupin, Opalia Recordati, Merck, Novo Nordisk, and Viatris; participates in a data safety monitoring board or advisory board for Merck/Acceleron; has equities at G3Pharmaceutical, Cereno Scientific, and Eshmoun Clinical Research; and is the founder of Global CardioVascular Clinical Trialists. CMO has received consulting fees from Abiomed, Merck, and ZealCare. JB has received consulting fees from Abbott Laboratories, American Regent, Amgen, Applied Therapeutics, AskBio, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, CardioCell, Cardior, Cardiorem, CSL Behring, CVRx, Cytokinetics, Daxor, Edwards Lifesciences, Element Science, Faraday Pharmaceuticals, The Foundry, G3P, Innolife, Impulse Dynamics, Imbria Pharmaceuticals, Inventiva Pharma, Ionis Pharmaceuticals, Lexicon Pharmaceuticals, Lilly, LivaNova, Janssen Pharmaceuticals, Medtronic, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, PharmaIN, Prolaio, Regeneron Pharmaceuticals, Renibus Therapeutics, Roche, Salamandra, Sanofi, scPharmaceuticals, Secretome Therapeutics, Sequana Medical, SQ Innovation, Tenex Therapeutics, Tricog Health, Ultromics, Vifor Pharma, and ZOLL Medical; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novartis, Boehringer Ingelheim-Lilly, AstraZeneca, Impulse Dynamics, and Vifor Pharma. CJM, IB, DG, AU, AX, and MJP are employees of Merck Sharp & Dohme (a subsidiary of Merck) and hold stock options in Merck. KJA has received research grants from Merck and the National Institutes of Health and participates in several data safety monitoring boards outside of the heart failure disease area. MPB is the executive director of CPC, a non-profit academic research organisation affiliated with the University of Colorado, that receives or has received research grant and/or consulting funding between August, 2021, and the present from Abbott Laboratories, Agios Pharmaceuticals, Alexion Pharma, Alnylam Pharmaceuticals, Amgen, Angionetics, Anthos Therapeutics, Array BioPharma, AstraZeneca and Affiliates, Atentiv, Audentes Therapeutics, Bayer and Affiliates, Bristol Myers Squibb, Cambrian Bio, Cardiol Therapeutics, CellResearch, Cleerly, Cook Regentec, CSL Behring, Eidos Therapeutics, EP Trading, Epizon Pharma, Esperion Therapeutics, Everlywell, Exicon Consulting, Faraday Pharmaceuticals, Foresee Pharmaceuticals, Fortress Biotech, HDL Therapeutics, HeartFlow, Hummingbird Bioscience, Insmed, Ionis Pharmaceuticals, Janssen and Affiliates, Kowa Research Institute, Lexicon Pharmaceuticals, Medimmune, Merck & Affiliates, Nectero Medical, Novartis Pharmaceuticals, Novo Nordisk, Osiris Therapeutics, Pfizer, PhaseBio Pharmaceuticals, Prairie Education and Research Cooperative, Prothena Biosciences, Regeneron Pharmaceuticals, Regio Biosciences, Sanofi-Aventis Groupe, Silence Therapeutics, Smith & Nephew, Stealth BioTherapeutics, Tourmaline Bio, VarmX, and Virta Health Corporation. MB, PPT, and SC are employees of Bayer. JAE has received research grants and consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim-Lilly, Merck, Amgen, CSL-Vifor, Cardurion Pharmaceuticals, American Regent, Otsuka Pharmaceutical, Novo Nordisk, and Applied Therapeutics. AFH reports research grants from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Merck, Novartis, and Verily; and consulting fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, MyoKardia, and Novartis. CSPL has received research grants from the National Medical Research Council of Singapore, Novo Nordisk, and Roche Diagnostic; has received consulting fees from Alnylam Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Bioethics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Corteria, CPC Clinical Research, Cytokinetics, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Janssen Research & Development, Medscape/ WebMD Global, Merck, Novartis, Novo Nordisk, Quidel Corporation, Radcliffe Group, Roche, and Us2.ai; has patent PCT/SG2016/050217 pending and US Patent numbers 10,631,828 B1, US 10,702,247 B2, US 11,301,996 B2, US 11,446,009 B2, US 11,931,207 B2, and US 12,001,939; is a co-founder and non-executive director of Us2.ai; and has received stock or stock options from Us2.ai. EFL reports grants or contracts from Merck, the American Heart Association, and the National Heart, Lung, and Blood Institute; consulting fees from Akebia Therapeutics, AstraZeneca, DalCor Pharmaceuticals, Intellia Therapeutics, and Merck;

and a leadership role with the American Heart Association. JL is receiving research support from AstraZeneca and NovuMetrix and consulting fees from Abbott Laboratories, Adonis, Alleviant Medical, AstraZeneca, Axon Therapies, Boston Scientific, Cordio Medical, CVRx, Edwards Lifesciences, FIRE1, Innoventric, InterShunt, Merck, Medtronic, Orchestra BioMed, WhiteSwell, Vascular Dynamics, and V-Wave. RJM has received research support and honoraria from Bayer and Merck Sharp & Dohme (a subsidiary of Merck); and consulting fees from Abbott Laboratories, Alleviant Medical, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead Sciences, Innolife, Eli Lilly, Lexicon Pharmaceuticals, Medtronic, Medable, Merck, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Relypsa, Reprieve Cardiovascular, Respicardia, Roche, Rocket Pharmaceuticals, Sanofi, Verily, Vifor Pharma, Windtree Therapeutics, and ZOLL Medical. PP has received support for the current work from Bayer; grants or contracts from Boehringer Ingelheim, AstraZeneca, Vifor Pharma, Novartis, Bayer, Abbott Vascular, Novo Nordisk, Pharmacosmos, and Moderna; consulting fees from Boehringer Ingelheim, AstraZeneca, Vifor Pharma, Servier, Novartis, Berlin Chemie, Bayer, Pfizer, and Abbott Vascular; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim, AstraZeneca, Vifor Pharma, Servier, Novartis, Berlin Chemie, Bayer, Pfizer, and Abbott Vascular; support for attending meetings and/or travel from Boehringer Ingelheim and Vifor Pharma; and has participated in a data safety monitoring board or advisory board for Boehringer Ingelheim, Vifor Pharma, Novo Nordisk, Pharmacosmos, and Moderna. YNVR is supported by grants from the National Heart, Lung, and Blood Institute, Sleep Number, Bayer, Merck, United Pharmaceuticals, and the Earl Wood Career Development Award from Mayo Clinic; and reports consulting fees from Edwards Lifesciences. GMCR reports consulting fees from Anlylam Pharmaceuticals, AstraZeneca, Servier, and Vifor Pharma; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, educational events, and support for attending meetings and/or travel from Anlylam Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Medtronic, Servier, Viatris, and Vifor Pharma. CS reports consulting fees from Bayer, Merck, and Novo Nordisk; payment or honoraria for lectures, presentations, speakers bureaus, or educational events from Novartis, AstraZeneca, Boehringer Ingelheim, Bayer, Merck, Servier, Sanofi, Pfizer, Novo Nordisk, Eli Lilly, Viatris, and Medtronic; and travel support for attending meetings from Bayer, Servier, Pfizer, Novartis, and Boehringer Ingelheim. MS reports consultancy agreements with Novo Nordisk, Bayer, Cardurion Pharmaceuticals, Boehinger Ingelheim, Amgen, AstraZeneca, Merck, MSD, Reprieve Cardiovascular, and CPC Clinical Research; reports serving on advisory boards for AstraZeneca, Novo Nordisk, Bayer, Merck, Boehringer Ingelheim, Cardurion Pharmaceuticals, and Amgen; and reports receiving speaker fees from Merck, MSD, Bayer, Novo Nordisk, AstraZeneca, Cardurion Pharmaceuticals, and Amgen. JU reports support for the current work from Merck; is a member of the steering and executive committees for the VICTOR trial; reports consulting fees from FIRE1 and Reprieve Cardiovascular; and reports participation in data safety monitoring boards or advisory boards for Merck, Cardurion Pharmaceuticals, Medtronic, Cytokinetics, and Alleviant Medical. VV is an employee of Bayer US. The employer of AAV received consultancy fees and/or research support from Adrenomed, AnaCardio, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Cardurion Pharmaceuticals, Corteria Pharmaceuticals, Eli Lilly, Merck, Moderna, Novartis, Novo Nordisk, RyCarma Therapeutics, and SalubrisBio. PWA has received consulting fees from Merck, Bayer, Boehringer Ingelheim and Novo Nordisk; and research grants from Merck, Bayer, Boehringer Ingelheim/Eli Lilly and CSL.

### Data sharing

The data sharing policy, including procedures and restrictions, of Merck Sharp & Dohme (a subsidiary of Merck), is available at https://externaldatasharing-msd.com/.

### Acknowledgments

Funding was provided by Merck Sharp & Dohme (a subsidiary of Merck) and Bayer. We thank Constance Hamlin for her outstanding operational support during the conduct of both trials. Statistical support was
provided by Daniel Wojdyla and Derek Cyr from Duke Clinical Research Institute (Durham, NC, USA). Editorial assistance was provided by Melissa Ward and medical writing support was provided by Hannah Kirton, both of Scion (a division of Prime, London, UK), supported by Merck Sharp & Dohme (a subsidiary of Merck) and Bayer (Wuppertal, Germany), according to Good Publication Practice guidelines.

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