# Vericiguat and mortality in heart failure and reduced ejection fraction: the VICTOR trial

Javed Butler, Francesco Fioretti, Ciaran J Mcmullan, Kevin J Anstrom, Irina Barash, Marc P Bonaca, Maria Borentain, Stefano Corda, Pedro P Teixeira, Justin A Ezekowitz, et al.

► To cite this version:

Javed Butler, Francesco Fioretti, Ciaran J Mcmullan, Kevin J Anstrom, Irina Barash, et al. Vericiguat and mortality in heart failure and reduced ejection fraction: the VICTOR trial. European Heart Journal, 2025, 10.1093/eurheartj/ehaf655. hal-05240626

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1 **Vericiguat and mortality in heart failure and reduced ejection fraction: the VICTOR trial**

2 Javed Butler¹,², Francesco Fioretti², Ciaran J. McMullan³, Kevin J. Anstrom⁴, Irina Barash³,

3 Marc P. Bonaca⁵, Maria Borentain⁶, Stefano Corda⁷, Pedro P. Teixeira⁶ Justin A. Ezekowitz⁸,

4 Davis Gates³, Carolyn S.P. Lam⁹, Eldrin F. Lewis¹⁰, JoAnn Lindenfeld¹¹, Robert J. Mentz¹²,

5 Christopher M. O'Connor¹³, Piotr Ponikowski¹⁴, Yogesh N.V. Reddy¹⁵, Giuseppe M.C.

6 Rosano¹⁶,¹⁷,¹⁸, Clara Saldarriaga¹⁹, Michele Senni²⁰,²¹, James Udelson²², Alessia Urbinati³, Vanja

7 Vlajnic²³, Adriaan A. Voors²⁴, Aiwen Xing³, Mahesh J. Patel³, and Faiez Zannad²⁵, VICTOR

8 Study Group

9

10 ¹Department of Medicine, University of Mississippi, Jackson, MS, USA;

11 ²Baylor Scott and White Research Institute, Dallas, TX, USA;

12 ³Merck & Co., Inc., Rahway, NJ, USA;

13 ⁴University of North Carolina, Chapel Hill, NC, USA;

14 ⁵Department of Medicine, Colorado Prevention Center Clinical Research, University of

15 Colorado, Aurora, CO, USA;

16 ⁶Bayer AG, Berlin, Germany;

17 ⁷Bayer AG, Basel, Switzerland;

18 ⁸Canadian VIGOUR Centre, University of Alberta, Edmonton, AB, Canada;

19 ⁹National Heart Centre Singapore and Duke-National University, Singapore, Singapore;

20 ¹⁰Stanford University School of Medicine, Stanford, CA, USA;

21 ¹¹Vanderbilt University Medical Center, Nashville, TN, USA;

© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
1. 12Duke Clinical Research Institute, Durham, NC, USA;

2. 13Inova Heart and Vascular Institute, Falls Church, VA, USA;

3. 14Wroclaw Medical University, Wroclaw, Poland;

4. 15Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA;

5. 16Department of Human Sciences and Promotion of Quality of Life, San Raffaele Open

6. University of Rome, Rome, Italy;

7. 17Cardiology, San Raffaele Cassino Hospital, Cassino, Italy;

8. 18IRCCS San Raffaele Roma, Rome, Italy;

9. 19Cardio VID Clinic, Medellin, Colombia;

10. 20University of Milano-Bicocca, Milan, Italy;

11. 21Papa Giovanni XXIII Hospital, Bergamo, Italy;

12. 22Division of Cardiology and the CardioVascular Center, Tufts Medical Center, Boston, MA,

13. USA;

14. 23Bayer US LLC, Whippany, NJ, USA;

15. 24University of Groningen, Groningen, Netherlands;

16. 25CVCT and Universite de Lorraine, Nancy, France.

17.

18. **Corresponding author:** Javed Butler, MD, MPH, MBA. Baylor Scott & White Research

19. Institute, 3434 Live Oak St., Dallas, TX 75204, USA; email: butlzih@gmail.com

20.
# 1 Abstract

## 2 Background and Aims: In the VICTOR trial (NCT05093933), vericiguat was neutral for the primary composite endpoint of cardiovascular death or hospitalization for heart failure (HF).

## 4 VICTOR was powered to independently assess cardiovascular death. This study reports detailed analysis on the effects of vericiguat on mortality.

## 6 Methods: VICTOR, a double-blind, placebo-controlled, randomized trial, enrolled 6105 ambulatory patients with HF and reduced ejection fraction (HFrEF) without recent worsening and randomized them to vericiguat or placebo. The main outcome for this analysis was the prespecified secondary endpoint of cardiovascular death, All-cause death, sudden cardiac death, and death related to HF were also assessed.

## 11 Results: Over a median of 19.7 months (interquartile range 14.6–25.4), cardiovascular deaths occurred in 292 patients (5.7 deaths per 100 patient-years) and 346 patients (6.8 deaths per 100 patient-years) in the vericiguat and placebo groups, respectively (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.71–0.97; *P* = 0.020). Risk of death from any cause was lower with vericiguat vs placebo (377 [7.3 deaths per 100 patient-years] vs 440 [8.6 deaths per 100 patient-years]; HR 0.84, 95% CI 0.74–0.97; *P* = 0.015). Sudden cardiac death and HF-related deaths were lower with vericiguat vs placebo (1.6 vs 2.2 events per 100 patient-years; HR 0.75, 95% CI 0.56–0.99; *P* = 0.042 and 1.7 vs 2.4 events per 100 patient-years; HR 0.71, 95% CI 0.54–0.94; *P* = 0.016, respectively). Lower mortality rates were consistent across subgroups including baseline therapy. Consistent cardiovascular and all-cause mortality benefit was seen across baseline N-terminal pro-B-type natriuretic peptide levels.

## 22 Conclusions: In ambulatory well-treated participants with HFrEF, vericiguat was associated with clinically meaningful reductions in the key secondary outcome of cardiovascular death, as well as all-cause mortality.
1

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5

**Introduction**

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Despite contemporary treatment with beta-blockers, angiotensin receptor-neprilysin inhibitors (ARNI), mineralocorticoid receptor antagonists (MRA), sodium-glucose cotransporter 2 inhibitors (SGLT2i), and implantable devices, patients with heart failure (HF) with reduced ejection fraction (HFrEF) continue to experience high residual risk for mortality.¹ Vericiguat is approved for the treatment of worsening HFrEF based on the results of the Vericiguat Global

Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial that showed a significant reduction in the risk for cardiovascular death or hospitalization for HF in patients with HFrEF who were hospitalized for HF within 6 months or needed outpatient intravenous diuretic therapy within 3 months prior to randomization.² Due to the elevated risk profile of patients enrolled in VICTORIA and the high event rate, the overall follow-up was less than 11 months, diminishing the opportunity to assess the effect of vericiguat on mortality that may require longer follow-up to fully manifest. In a pre-specified analysis of VICTORIA based on N-terminal pro-B-type natriuretic peptide (NT-proBNP) level at baseline, patients in the lower three quartiles (<5314 pg/mL) had a more pronounced overall benefit, including cardiovascular mortality by itself showing a hazard ratio (HR) of 0.78 (95% confidence interval [CI] 0.65-0.94).³

22

23

In the Vericiguat in Adults with Chronic Heart Failure and Reduced Ejection Fraction (VICTOR) trial, the effect of vericiguat was assessed in ambulatory patients with HFrEF who
1 had not experienced recent worsening, had screening NT-proBNP levels of <6000 pg/mL, and a

2 high percentage of whom were on a background of contemporary guideline-directed medical

3 therapy (GDMT). The primary endpoint of time to cardiovascular death or hospitalization for HF

4 (HR 0.93, 95% CI 0.83-1.04; *P* = 0.219) or time to first HF hospitalizations (HR 0.95, 95% CI

5 0.82-1.10; *P* = 0.509) in VICTOR was not significantly reduced.⁴ VICTOR was designed and

6 powered, conditional on the primary endpoint success, to assess the effect of vericiguat on

7 cardiovascular mortality.⁵ The aim of this analysis was to evaluate in detail the effect of

8 vericiguat on mortality outcomes in patients enrolled in VICTOR.

9

## 10 METHODS

### 11 Study design

12 The VICTOR trial design and participant baseline characteristics have been previously

13 published.⁵,⁶ Briefly, VICTOR (NCT05093933) was a double-blind, placebo-controlled, 1:1

14 randomized, event-driven trial assessing the effects of vericiguat (target dose 10 mg daily) versus

15 placebo in ambulatory patients with HFrEF and no recent worsening. The trial was approved by

16 the ethics committee at each site and all patients provided written consent. The key entry criteria

17 included history of HF with left ventricular ejection fraction (LVEF) ≤40%, New York Heart

18 Association (NYHA) class II–IV symptoms on optimally tolerated GDMT and no hospitalization

19 for HF within 6 months or outpatient intravenous diuretic use within 3 months prior to

20 randomization. NT-proBNP levels within 30 days prior to randomization were required to be

21 600–6000 pg/mL for patients in sinus rhythm and 900–6000 pg/mL for those in atrial fibrillation.

22 Participants with estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m² were

23 excluded. The study was designed to accrue at least 590 cardiovascular deaths to provide 80%
1 power to detect a HR of 0.80 for this endpoint. Assuming a rate of six cardiovascular deaths per

2 100 patient-years, a sample size of 6000 was planned to accrue 590 events within 39.5 months

3 from the first patient randomized.

4

5 **Outcomes**

6 For this analysis the main outcome was cardiovascular death, which was the key secondary

7 endpoint in VICTOR. Sudden cardiac death and death related to HF, as components of

8 cardiovascular death, were also assessed individually. Finally, all-cause mortality including both

9 cardiovascular and non-cardiovascular mortality, was assessed. All mortality outcomes were

10 independently adjudicated by a blinded clinical events committee.

11

12 **Statistical analysis**

13 Baseline characteristics of study participants who experienced cardiovascular death and those

14 who did not were evaluated. Time-to-event endpoints were analysed using the intention-to-treat

15 principle with a stratified log-rank test. Cox-proportional hazards analyses were used to estimate

16 HR with 95% CI with unadjusted nominal *P*-values calculated. However, the proportional hazard

17 assumption was tested using the weighted Schoenfeld residuals test for the time-to-event

18 endpoints. These analyses were not part of a trial hypothesis testing. The impact of vericiguat on

19 sudden cardiac death and death related to HF was assessed individually. The earliest time to

20 death benefit was assessed by performing the stratified log-rank test successively with each

21 accrued mortality event and noting the time when the first unadjusted stratified log-rank *P*-value

22 was < 0.050. In addition, the effect of vericiguat on cardiovascular mortality in the group that

23 remained on treatment was assessed. An analysis was also performed using the investigator-
assigned cause of death. Subgroup analyses were performed to assess consistency of effect

across demographics characteristics, comorbidities, eGFR (≥15–≤30 mL/min/1.73 m² vs ≥30–

≤60 mL/min/1.73 m² vs ≥60 mL/min/1.73 m²), and mean LVEF (<31% vs ≥31%). The impact of

baseline medical therapy and implantable cardioverter-defibrillators individually, and the number

of GDMT drugs (0–2 vs 3 vs 4) on mortality outcomes were assessed. Outcomes were also

assessed based on recency of hospitalization for HF (no prior HF hospitalization, hospitalization

for HF 6–12 months and >12 months prior to randomization). The association with NT-proBNP

levels at baseline was assessed as categorical (quartiles) and continuous levels. Continuous

variables are summarized as means (standard deviations [SD]) or medians (interquartile range)

and as counts and percentages for categorical variables. All analyses were conducted using SAS

software, version 9.4 (SAS Institute, Cary, NC, USA).
# 1 RESULTS

## 2 Trial participants

Between November 2021 and December 2023, 6105 participants were enrolled, of whom 3053 were assigned to vericiguat and 3052 to placebo. The mean age was 67 years, 23.6% were women, 47.5% of participants had no prior hospitalization for HF, and 14.0% had a history of hospitalization between 6 and 12 months prior to randomization. Overall, 79% of participants had NYHA class II symptoms, and the mean LVEF was 30%. The median NT-proBNP was 1375 pg/mL. Overall, 94.4% participants were on beta-blockers, 93.9% on renin-angiotensin system modulation (including 56.0% on ARNI, 77.7% on MRA, and 59.1% on SGLT2i; 83.4% were treated with at least three medications. Furthermore, 69.8% participants were on loop diuretics at baseline. An implantable cardioverter-defibrillator was present in 32.9% of participants. The median follow-up period (and interquartile range) for the primary endpoint was 18.5 (range 13.6–24.7) months and for cardiovascular mortality was 19.7 (range 14.6–25.4) months. Detailed baseline characteristics of the study participants have been published.⁶

## 16 Characteristic of participants by survivorship

Overall, 638 participants experienced cardiovascular death. Baseline characteristics of cardiovascular death survivors and non-survivors are shown in Table 1. Non-survivors had a higher proportion of men and those with a history of atrial fibrillation and type 2 diabetes.
Median NT-proBNP levels were higher (2194 [range 1198–3683] vs 1314 [range 800–2233] pg/mL) and mean LVEF (29±8% vs 31±7%) and eGFR (66±26 vs 72±24 mL/min/1.73 m²) were lower in non-survivors. More non-survivors had an eGFR between 15–30 mL/min/1.73 m² (8% vs 4%) and 30–60 mL/min/1.73 m² (35% vs 30%). Systolic blood pressure (119±16 mmHg vs
1 121±16 mmHg) was lower in non-survivors. Non-survivors had more advanced symptoms vs
2 survivors (NYHA class III–IV 33% vs 20%), and fewer had no prior history of hospitalization
3 for HF (41% vs 48%). Beta-blockers (92.6% and 94.7%) and MRA (75.5% and 78.0%) were
4 widely used in both non-survivors and survivors, respectively. Loop diuretics were more often
5 prescribed in non-survivors (83.4% vs 68.2%). SGLT2i (50.6% vs 60.1%) and ARNI (50.5% vs
6 56.6%) use was lower in non-survivors. The proportion of patients with devices was comparable
7 (cardioverter-defibrillators 31.0% and 33.1%; and cardiac resynchronization therapy 15.7% and
8 14.7%) among non-survivors and survivors, respectively.

9

10 **Effect of vericiguat on mortality**

11 Death from cardiovascular causes occurred in 292 patients (5.7 deaths per 100 patient-years) in
12 the vericiguat group and in 346 (6.8 deaths per 100 patient-years) in the placebo group (HR 0.83,
13 95% CI 0.71–0.97; *P* = 0.020). The risk of death from any cause was also lower in the vericiguat
14 group (*N* = 377; 7.3 deaths per 100 patient-years vs *N* = 440 in the placebo group; 8.6 deaths per
15 100 patient-years; HR 0.84, 95% CI 0.74–0.97; *P* = 0.015). Both sudden cardiac death and HF-
16 related deaths were lower in the vericiguat group (HR 0.75, 95% CI 0.56–0.99; *P* = 0.042 and
17 HR 0.71, 95% CI 0.54–0.94; *P* = 0.016, respectively) (Table 2 and Figure 1). The proportional
18 hazard assumptions passed the weighted Schoenfeld residuals test for the four death outcomes (*P*
19 > 0.300).

20
1

## Time to mortality benefit

The earliest evidence of cardiovascular death benefit, defined when the two-sided *P*-value for cardiovascular death HR decreased below 0.050, was observed at 11.0 months of median follow-up after an accrual of 335 cardiovascular deaths (150 [4.9%] in the vericiguat group and 185 [6.1%] in the placebo group; HR 0.80, 95% CI 0.65–1.00; *P* = 0.047). The time to benefit was similar for death from any cause, with the earliest benefit observed at 11.1 months of median follow-up after an accrual of 432 deaths (196 [6.4%] in the vericiguat group and 236 [7.7%] in the placebo group; HR 0.82, 95% CI 0.68–0.995; *P* = 0.044). The sudden cardiac death benefit was first observed after an accrual of 21 sudden cardiac deaths (6 [0.4%] in the vericiguat group and 15 [1.1%] in the placebo group; HR 0.40, 95% CI 0.155-1.032; *P* = 0.0497), which occurred at a median follow-up of 5.4 months. The HF death benefit occurred at a median follow-up of 16.8 months after an accrual of 177 HF deaths (76 [2.5%] in the vericiguat group and 101 [3.3%] in the placebo group; HR 0.74, 95% CI 0.55–1.00; *P* = 0.046).

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## Subgroup analysis

The benefit of vericiguat on both cardiovascular mortality and all-cause mortality were generally consistent across subgroups based on demographic, region, baseline clinical characteristics and comorbidities (Supplementary Tables 1 and 2 and Figure 2 and Figure 3).

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## Prior HF hospitalization

There was no significant difference in benefits on either cardiovascular mortality (interaction *P* = 0.362) or all-cause mortality (interaction *P* = 0.562) among patients with no prior history of
1 hospitalization for HF, or prior hospitalization for HF within 6–12 months or more than 12
2 months prior to randomization (Supplementary Tables 1 and 2 and Figure 2 and Figure 3).

3
4 **Effect of vericiguat on mortality by baseline therapy**
5 There was consistent benefit with vericiguat on cardiovascular mortality and all-cause mortality
6 irrespective of baseline therapy with SGLT2i, ARNI, or implantable cardioverter-defibrillator
7 (all treatment-by-outcome interaction *P* > 0.200). The benefit across the number of GDMT drugs
8 at baseline was consistent for cardiovascular mortality (event rates per 100 patient-years 7.3 vs
9 9.2 for 0–2 drugs [HR 0.80, 95% CI 0.57–1.11], 6.2 vs 6.8 for 3 drugs [HR 0.91, 95% CI 0.72–
10 1.16], and 4.5 vs 5.9 for 4–5 drugs [HR 0.76, 95% CI 0.58–0.98] among vericiguat and placebo
11 groups, respectively; treatment-by-outcome interaction *P* = 0.579). Similar results were seen for
12 all-cause mortality. Event rates were 6.5 versus 8.3 per 100 patient-years and 3.7 versus 3.2 per
13 100 patient-years among loop-diuretic users and non-users in the vericiguat and placebo groups,
14 respectively (HR 0.77, 95% CI 0.65–0.91 for users and HR 1.17, 95% CI 0.80–1.71 for non-
15 users; treatment-by-outcome interaction *P* = 0.050). Similar results were seen for all-cause
16 mortality (Table 3 and Figure 4).

17
18 **Effect of vericiguat on mortality by baseline natriuretic peptide levels**
19 The beneficial effect of vericiguat on cardiovascular and all-cause mortality was consistent
20 across the quartiles of baseline NT-proBNP concentrations (treatment by quartile interaction *P* ≥
21 0.640). When examined as a continuous variable, vericiguat reduced cardiovascular and all-cause
22 mortality risk across the range of NT-proBNP levels (Table 2 and Figure 5).
1

## 2 On-treatment analysis

3 In the on-treatment analysis, a total of 185 cardiovascular deaths occurred in the treatment group versus 239 events in the placebo group (6.1%; 4.0 events per 100 patient-years vs 7.8%; 5.2 events per 100 patient-years; HR 0.77, 95% CI 0.63–0.93; P = 0.007).

6

## 7 Investigator-assessed cardiovascular death

8 A total of 284 investigator-reported cardiovascular deaths occurred in the treatment group versus 350 in the placebo group (9.3% vs 11.5%; HR 0.80, 95% CI 0.68–0.93).

10

## 11 DISCUSSION

12 In the VICTOR trial, vericiguat led to a 17% relative risk reduction for cardiovascular death and 13 16% relative risk reduction for all-cause death (both P < 0.050). Similarly, 25% and 29% relative 14 risk reductions were seen for sudden cardiac death and death due to HF, respectively (both P < 15 0.050) (Structured Graphical Abstract). These data are notable considering that these risk 16 reductions with vericiguat were seen in a cohort of patients receiving the most comprehensive 17 HFrEF evidence-based therapy seen in any HF clinical trial or contemporary real-world registry. 18 Importantly, both the cardiovascular and all-cause death benefits were consistent across major 19 subgroups.

20 Patients with HFrEF are at substantial risk for mortality despite advances in therapy. In 21 VICTORIA, vericiguat was shown to reduce the risk of cardiovascular death or hospitalization 22 for HF in patients with HFrEF and worsening HF.² Cardiovascular death by itself, however, was 23 not significantly reduced in VICTORIA, where the average follow-up was short, diminishing the
chances of seeing a mortality benefit. Longer-term follow-up may generally be needed to assess

the impact of HF therapy on mortality. VICTOR was designed and powered to assess the impact

of vericiguat on cardiovascular mortality, which was reduced with clinically meaningfully

relative risk reductions similar to those seen previously with ARNIs and SGLT2is. Subgroup and

sensitivity analyses further confirmed the robustness of the findings. These data underscore the

relevance of mortality risk in patients with HFrEF in the contemporary era despite ambulatory

status, no recent clinical instability, and on an appropriate baseline medical therapy.

VICTOR stands out with respect to the comprehensive baseline medical therapy in the

study population. Despite that, there was consistent benefit with vericiguat on cardiovascular

mortality and all-cause mortality irrespective of baseline therapy with SGLT2i, ARNI, MRA,

and implantable cardioverter-defibrillators. Importantly, the benefit was consistent regardless of

the number of GDMT drugs the participant was receiving at baseline. The lack of treatment

heterogeneity observed across subgroups based on baseline therapy in VICTOR reinforces the

independent benefit of vericiguat on mortality regardless of other therapies. In this respect, based

on tolerability, side-effects, accessibility, or other concerns with current standard of care for

patients with ambulatory HFrEF, vericiguat can be an option when indicated without any specific

sequencing of drugs necessary. This is further complemented by the consistent safety and

tolerability data with vericiguat seen across both VICTOR and VICTORIA.²,⁴,⁷⁻⁹

While the mortality results in VICTOR were positive but the primary composite endpoint

of time to cardiovascular death or hospitalization for HF was not statistically significantly

reduced. Cardiovascular death is arguably the most important outcome in HF trials and in

previous years was the primary outcome of interest. Subsequently the move towards composite

endpoints including hospitalization for HF was adopted, in part driven to improve upon the trial
logistics, costs, duration, and feasibility. The choice of the primary endpoint is largely arbitrary and in retrospect, we may have chosen cardiovascular mortality as a primary endpoint and the composite of cardiovascular mortality and HF hospitalization as the first key secondary. While the primary endpoint was neutral, it should be noted that VICTOR was powered to assess cardiovascular death effect and the observed cardiovascular death benefit was based on over 600 events. These results were internally consistent, showing improvements in the risk for all-cause mortality as well as specifically in both sudden cardiac death and death due to HF, along with cardiovascular death. The cardiovascular death benefit was also consistent across subgroups. Cardiovascular death is less ambiguous than other endpoints like hospitalization that may be influenced by clinical choices and regional differences.

When a clinical trial is neutral for its primary endpoint, a more nuanced interpretation of secondary endpoint is warranted based on study design, importance of the secondary outcome, statistical power, number of events, magnitude and direction of the treatment effect and confidence intervals, and mechanistic plausibility.¹⁰ The consistency of result on cardiovascular death, all-cause death, sudden death, and death related to HF, and benefit across subgroups including those on GDMT in a trial designed and powered to assess the effect of vericiguat on cardiovascular death, provide valuable information for the use of vericiguat in patients with HFrEF.

Participants who died from cardiovascular causes had markers of more advanced disease burden, including higher NT-proBNP level, lower eGFR, more advanced symptoms, higher use of loop diuretics, and higher comorbidity burden. Underutilization of GDMT among non-survivors may have contributed to the worse prognosis, however, patients with more advanced diseases are usually more intolerant to GDMT.¹¹,¹² The more common use of loop diuretic
therapy likely reflects higher baseline clinical and/or subclinical congestion or diuretic
resistance, which are predictors of worse outcomes.¹³

The benefit of vericiguat on either cardiovascular mortality or all-cause mortality did not
differ significantly among patients with no prior history of hospitalization for HF, or prior
hospitalization for HF within 6–12 months or more than 12 months prior to randomization.

These results underscore the persistent risk for adverse outcomes in patients with chronic HFrEF
irrespective of baseline medical therapy or stability status, and the need for timely interventions
to improve outcomes regardless of symptom burden or worsening HF events.

In VICTORIA, the benefit of vericiguat was influenced by baseline NT-proBNP levels.²,³,¹⁴

Vericiguat reduced the risk of cardiovascular death or hospitalization for HF in patients with NT-
proBNP levels up to ~8000 pg/mL. There was a significant interaction between NT-proBNP
levels and treatment effect, with the greatest benefit seen in patients with baseline NT-proBNP
levels in the lowest three quartiles (<5314 pg/mL). Based on these data, patients with NT-
proBNP levels above 6000 pg/mL at screening were excluded from VICTOR.⁵ Notably, the
beneficial effect of vericiguat on cardiovascular and all-cause mortality in VICTOR was
consistent regardless of baseline NT-proBNP.

This study is limited by the fact that the primary endpoint of the main trial was neutral
and therefore any significant findings in secondary endpoints must be interpreted with caution.

The exclusion of patients with NT-proBNP >6000 pg/mL at screening in VICTOR limits the
generalizability of these data. Also, the trial was not powered to assess interaction within
subgroups. The lack of treatment heterogeneity observed across subgroups based on baseline
therapy in VICTOR may suggest an independent benefit of vericiguat on mortality regardless of
1 other therapies. However, these subgroup analyses are exploratory in nature and were not
2 powered to detect interaction effects.
3
4 GDMT, there is a persistent high risk of mortality in patients with HFrEF. In VICTOR,
5 vericiguat was associated with a significant relative risk reduction for cardiovascular death and
6 all-cause death. The risk for both common causes of cardiovascular death in patients with
7 HFrEF, i.e., sudden cardiac deaths and HF-related deaths, were reduced. The observed benefit
8 was consistent across key subgroups. In combination with the known safety and tolerability
9 profile of vericiguat, these findings support the role of vericiguat as an effective addition to
10 GDMT in HFrEF.

11

12

13 FUNDING

14 Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and Bayer
15 AG.

16

17 DISCLOSURE OF INTEREST

18 JB has received consulting fees from Abbott, American Regent, Amgen, Applied Therapeutic,
19 AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers
20 Squibb, Cardiac Dimension, Cardiocell, Cardior, Cardiorem, CSL Bearing, CVRx, Cytokinetics,
21 Daxor, Edwards, Element Science, Faraday, Foundry, G3P, Innolife, Impulse Dynamics, Imbria,
22 Inventiva, Ionis, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin,
23 Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Pfizer, Prolaio, Regeneron, Renibus,
1 Roche, Salamandra, Sanofi, SC Pharma, Secretome, Sequana, SQ Innovation, Tenex, Tricog,

2 Ultromics, Vifor, and Zoll; and payment or honoraria for lectures, presentations, speakers

3 bureaus, manuscript writing, or educational events from Novartis, Boehringer Ingelheim-Lilly,

4 AstraZeneca, Impulse Dynamics, and Vifor.

5 FF has nothing to disclose.

6 CJM, IB, DG, AU, AX, and MJP are employees of Merck Sharp & Dohme LLC, a subsidiary of

7 Merck & Co., Inc., Rahway, NJ, USA, and may own stock and/or stock options in Merck & Co.,

8 Inc., Rahway, NJ, USA.

9 KJA has received research grants from Merck and the National Institutes of Health and

10 participates in several data safety monitoring boards outside of the heart failure disease area.

11 MPB is the executive director of CPC, a non-profit academic research organization affiliated

12 with the University of Colorado, that receives or has received research grant/consulting funding

13 between August 2021 and present from Abbott Laboratories, Agios Pharmaceuticals, Inc.,

14 Alexion Pharma, Alnylam Pharmaceuticals, Inc., Amgen Inc., Angionetics, Inc., Anthos

15 Therapeutics, Array BioPharma, Inc., AstraZeneca and Affiliates, Atentiv LLC, Audentes

16 Therapeutics, Inc., Bayer and Affiliates, Bristol-Myers Squibb Company, Cambrian Biopharma,

17 Inc., Cardiol Therapeutics Inc., CellResearch Corp., Cleerly Inc., Cook Regentec LLC, CSL

18 Behring LLC, Eidos Therapeutics, Inc., EP Trading Co. Ltd., Epizon Pharma, Inc., Esperion

19 Therapeutics, Inc., Everly Well, Inc., Exicon Consulting Pvt. Ltd., Faraday Pharmaceuticals,

20 Inc., Foresee Pharmaceuticals Co. Ltd., Fortress Biotech, Inc., HDL Therapeutics Inc.,

21 HeartFlow Inc., Hummingbird Bioscience, Insmed Inc., Ionis Pharmaceuticals, Janssen and

22 Affiliates, Kowa Research Institute, Inc., Lexicon Pharmaceuticals, Inc., Medimmune Ltd.,

23 Merck & Affiliates, Nectero Medical Inc., Novartis Pharmaceuticals Corp., Novo Nordisk, Inc.,
1 Osiris Therapeutics Inc., Pfizer Inc., PhaseBio Pharmaceuticals, Inc., Prairie Education and

2 Research Cooperative, Prothena Biosciences Limited, Regeneron Pharmaceuticals, Inc., Regio

3 Biosciences, Inc., Sanofi-Aventis Groupe, Silence Therapeutics PLC, Smith & Nephew plc,

4 Stealth BioTherapeutics Inc., Tourmaline, VarmX, and Virta Health Corporation.

5 MB, PPT, and SC are employees of Bayer AG.

6 JAE has received research grants and consulting fees from AstraZeneca, Bayer, Boehringer

7 Ingelheim-Lilly, Merck, Amgen, CSL-Vifor, Carduirion, American Regent, Otsuka, Novo

8 Nordisk, and Applied Therapeutics.

9 CSPL: has received research grants from the National Medical Research Council of Singapore,
10 Novo Nordisk, and Roche Diagnostic; has received consulting fees from Alleviant Medical,

11 Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Bioeutics,

12 Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical

13 Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen

14 Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo

15 Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd., Recardio Inc, ReCor

16 Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; has patent

17 PCT/SG2016/050217 pending and patent US Patent No. 10702, 247; is a co-founder and non-executive director of Us2.ai; and has received stock or stock options from Us2.ai.

18 EFL reports grants or contracts from Merck, the American Heart Association, and the National

19 Heart, Lung, and Blood Institute; consulting fees from Akebia, AstraZeneca, Dal-Cor, Intellia, and Merck; and a leadership or fiduciary role with the American Heart Association.

20 JL is receiving research support from AstraZeneca and Volumetrix and consulting fees from

21 Abbott, Adonis, Alleviant, AstraZeneca, Axon, Boston Scientific, Cordio, CVRx, Edwards
1 Lifesciences, Fire-1, Inoventic, Intershunt, Merck, Medtronic, Orchestra Biomed, Whiteswell,

2 Vascular Dynamics, and VWave.

3 RJM has received research support and honoraria from Bayer and Merck Sharp & Dohme LLC,

4 a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; and consulting fees from Abbott,

5 Alleviant Medical, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim,

6 Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Eli Lilly, Lexicon, Medtronic,

7 Medable, Merck, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Relypsa, Reprieve

8 Cardiovascular, Respicardia, Roche, Rocket Pharmaceuticals, Sanofi, Verily, Vifor, Windtree

9 Therapeutics, and Zoll.

10 CMO has received consulting fees from Abiomed, Merck, and Zealcare.

11 PP has received support for the current work from Bayer; grants or contracts from Boehringer

12 Ingelheim, AstraZeneca, Vifor Pharma, Novartis, Bayer, Abbott Vascular, Novo Nordisk,

13 Pharmacosmos, and Moderna; consulting fees from Boehringer Ingelheim, AstraZeneca, Vifor

14 Pharma, Servier, Novartis, Berlin Chemie, Bayer, Pfizer, Abbott Vascular; payment or honoraria

15 for lectures, presentations, speakers bureaus, manuscript writing or educational events from

16 Boehringer Ingelheim, AstraZeneca, Vifor Pharma, Servier, Novartis, Berlin Chemie, Bayer,

17 Pfizer, and Abbott Vascular; support for attending meetings and/or travel from Boehringer

18 Ingelheim, Vifor Pharma; and has participated in a data safety monitoring board or advisory

19 board for Boehringer Ingelheim, Vifor Pharma, Novo Nordisk, Pharmacosmos, and Moderna.

20 YNVR is supported by grants from NHLBI (K23HL164901), Sleep Number, Bayer, Merck,

21 United Pharmaceuticals and the Earl Wood Career Development Award from Mayo Clinic; and

22 reports consulting fees from Edwards Life Sciences.
1 GMCR reports consulting fees from Anlylam, 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, AstraZeneca, Boehringer Ingelheim, Medtronic, Servier, Viatris, and Vifor Pharma.

5 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; travel support for attending meetings from Bayer, Servier, Pfizer, Novartis, and Boehringer Ingelheim.

10 MS reports consultancy fees, support for attending meetings and/or travel, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Merck.

13 JU reports support for the current work from Merck; is a member of the steering and executive committees for the VICTOR trial; consulting fees from FIRE-1 and Reprieve CV; and participation in data safety monitoring boards or advisory boards for Merck, Medtronic, Cytokinetics, and Alleviant.

17 VV is an employee of Bayer US LLC.

18 The employer of AAV received consultancy fees and/or research support from Adrenomed, Anacardio, AstraZeneca, Bayer AG, BMS, Boehringer Ingelheim, Cardurion, Corteria, EliLilly, Merck, Moderna, Novartis, Novo Nordisk, Rycarma, SalubrisBio

21 FZ reports personal fees from 89bio, Applied Therapeutics, Bayer, Betagenon, Bioeutics, Boehringer, BMS, CVRx, Cardior, Cambrian, Cereno pharmaceutical, Cellprothera, CEVA, Merck, Northsea, Novartis, Novo Nordisk, Otsuka, Owkin, and Salubri; payment or honoraria
1 for lectures, presentations, speakers bureaus, manuscript writing, or educational events from
2 Bayer, Boehringer, CVRx, Cellprothera, CEVA, and Merck; participates in a data safety
3 monitoring board or advisory board for Merck/Acceleron; has equities at G3Pharmaceutical,
4 Cereno, Cardiorenal, and Eshmoun Clinical Research; and is founder of Global CardioVascular
5 Clinical Trialists.

6
7 **Data availability statement**
8 The data sharing policy, including restrictions, of Merck Sharp & Dohme LLC, a subsidiary of
9 Merck & Co., Inc., Rahway, NJ, USA (MSD), is available
10 at https://trialstransparency.msdclinicaltrials.com/policies-perspectives.aspx. Requests for access
11 to the clinical study data can be submitted via email to the Data Access mailbox
12 (mailto-dataaccess@msd.com).

13
# 1 REFERENCES

2. Murphy SP, Ibrahim NE, Januzzi JL, Jr. Heart Failure With Reduced Ejection Fraction: A Review. JAMA 2020;324:488-504.

4. Armstrong PW, Pieske B, Anstrom KJ et al. Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med 2020;382:1883-1893.

6. Senni M, Lopez-Sendon J, Cohen-Solal A et al. Vericiguat and NT-proBNP in patients with heart failure with reduced ejection fraction: analyses from the VICTORIA trial. ESC Heart Fail 2022;9:3791-3803.

9. Butler J, McMullan C J, Anstrom K J et al. Vericiguat in Patients with Chronic Heart Failure and Reduced Ejection Fraction. Submitted and in review.

11. Reddy YNV, Butler J, Anstrom KJ et al. Vericiguat Global Study in Participants with Chronic Heart Failure: Design of the VICTOR trial. Eur J Heart Fail 2025;27:209-218.

13. Saldarriaga CI, Zannad F, McMullan CJ et al. Baseline characteristics of contemporary trial participants with heart failure and reduced ejection fraction: The VICTOR trial. Eur J Heart Fail 2025.

16. Lam CSP, Mulder H, Lopatin Y et al. Blood Pressure and Safety Events With Vericiguat in the VICTORIA Trial. J Am Heart Assoc 2021;10:e021094.

18. Voors AA, Mulder H, Reyes E et al. Renal function and the effects of vericiguat in patients with worsening heart failure with reduced ejection fraction: insights from the VICTORIA (Vericiguat Global Study in Subjects with HFrEF) trial. Eur J Heart Fail 2021;23:1313-1321.

21. Ezekowitz JA, McMullan CJ, Westerhout CM et al. Background Medical Therapy and Clinical Outcomes From the VICTORIA Trial. Circ Heart Fail 2023;16:e010599.
10. Pocock SJ, Stone GW. The Primary Outcome Fails-What Next? N Engl J Med 2016;375:861-870

11. Greene SJ, Butler J, Albert NM et al. Medical Therapy for Heart Failure With Reduced Ejection Fraction: The CHAMP-HF Registry. J Am Coll Cardiol 2018;72:351-366.

12. D'Amario D, Rodolico D, Rosano GMC et al. Association between dosing and combination use of medications and outcomes in heart failure with reduced ejection fraction: data from the Swedish Heart Failure Registry. Eur J Heart Fail 2022;24:871-884.

13. Kristjánsdóttir I, Thorvaldsen T, Lund LH. Congestion and Diuretic Resistance in Acute or Worsening Heart Failure. Card Fail Rev 2020;6:e25.

14. Ezekowitz JA, O'Connor CM, Troughton RW et al. N-Terminal Pro-B-Type Natriuretic Peptide and Clinical Outcomes: Vericiguat Heart Failure With Reduced Ejection Fraction
# FIGURE LEGENDS

## Graphical Abstract

LVEF, left ventricular ejection fraction; HF, heart failure; HFrEF, heart failure with reduced ejection fraction;

HR, hazard ratio; QD, once daily

**Figure 1.** Estimates of the cumulative incidence of the mortality outcomes in the VICTOR trial. Shown are the cumulative incidences of cardiovascular death (A), all-cause death (B), sudden cardiac death (C), and HF-related death (D).

HF, heart failure.

subgroups for cardiovascular death.

CI indicates confidence interval; eGFR, estimated glomerular filtration rate; FU, follow-up; HF, heart failure;

HFH, heart failure hospitalization; HR, hazard ratio; LVEF, left ventricular ejection fraction; NT-proBNP, N-

terminal pro-B type natriuretic peptide; NYHA, New York Heart Association.

**Figure 3.** All-cause death across subgroups. Shown are the number of events, HRs, and 95% CI across

subgroups for all-cause death.

CI indicates confidence interval; eGFR, estimated glomerular filtration rate; FU, follow-up; HF, heart failure;

HFH, heart failure hospitalization; HR, hazard ratio; LVEF, left ventricular ejection fraction; NT-proBNP, N-

terminal pro-B type natriuretic peptide; NYHA, New York Heart Association.

**Figure 4.** Mortality outcomes based on heart failure therapy at baseline. Shown are the number of events, HRs,

and 95% CIs across subgroups for cardiovascular death (A) and all-cause death (B).
1 ACEi indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CI, confidence interval; GDMT, guideline-directed medical therapy; HR, hazard ratio; ICD, implantable cardioverter-defibrillator; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium-glucose cotransporter 2 inhibitor.

4

5 **Figure 5.** Treatment effect of vericiguat compared with placebo across the range of NT-proBNP. Shown are
6
7 cardiovascular death (A) and all-cause death (B). Left axis indicates the treatment effect expressed as HR (blue
8 line) with 95% CIs (blue shaded area). Vertical shaded bars indicate the number of patients within each NT-
9 proBNP measurement bracket, expressed as a percentage on the right vertical axis.

9 CI indicates confidence interval; HR, hazard ratio; NT-proBNP, N-terminal pro-B type natriuretic peptide.

10
11
<table><caption>1 Table 1. Baseline characteristics of cardiovascular death survivor and non-survivors</caption><thead><tr><th>Characteristic</th><th>Survivors<br>(N = 5467)</th><th>Non-Survivors<br>(N = 638)</th></tr></thead><tbody><tr><td>Age, years, mean (SD)</td><td>66.9 (10.9)</td><td>67.9 (11.9)</td></tr><tr><td>Women, n (%)</td><td>1307 (23.9)</td><td>133 (20.8)</td></tr><tr><td>Race, n (%)</td><td></td><td></td></tr><tr><td>White</td><td>3526 (64.5)</td><td>408 (63.9)</td></tr><tr><td>Black/African American<sup>a</sup></td><td>575 (10.5)</td><td>81 (12.7)</td></tr><tr><td>American Indian or Alaskan</td><td>277 (5.1)</td><td>24 (3.8)</td></tr><tr><td>Native Hawaiian or Pacific Islander</td><td>8 (0.1)</td><td>3 (0.5)</td></tr><tr><td>Asian</td><td>663 (12.1)</td><td>83 (13.0)</td></tr><tr><td>Multiracial</td><td>580 (10.6)</td><td>63 (9.9)</td></tr><tr><td>Not reported</td><td>1 (0.0)</td><td>0</td></tr><tr><td>Geographic region, n (%)</td><td></td><td></td></tr><tr><td>North America</td><td>573 (10.5)</td><td>76 (11.9)</td></tr><tr><td>Latin and South America</td><td>1599 (29.2)</td><td>176 (27.6)</td></tr><tr><td>Europe</td><td></td><td></td></tr><tr><td>Eastern Europe</td><td>1494 (27.3)</td><td>206 (32.3)</td></tr><tr><td>Western Europe</td><td>1035 (18.9)</td><td>92 (14.4)</td></tr><tr><td>Asia Pacific</td><td>766 (14.0)</td><td>88 (13.8)</td></tr><tr><td>Comorbidities, n (%)</td><td></td><td></td></tr><tr><td>Diabetes</td><td>2288 (41.9)</td><td>297 (46.6)</td></tr><tr><td>Atrial fibrillation</td><td>2045 (37.4)</td><td>272 (42.6)</td></tr><tr><td>Systolic blood pressure, mmHg, mean (SD)</td><td>121.3 (16.1)</td><td>118.9 (15.6)</td></tr><tr><td>Haemoglobin, g/dL, mean (SD)</td><td>14.3 (2.6)</td><td>13.8 (1.9)</td></tr><tr><td>Body mass index, kg/m<sup>2</sup>, mean (SD)</td><td>28.4 (5.6)</td><td>28.3 (5.8)</td></tr><tr><td>NT-proBNP at randomization, pg/mL, median (IQR)</td><td>1314.0<br>(800.0–2233.0)</td><td>2193.5<br>(1197.5–3683.0)</td></tr><tr><td>No prior hospitalization for heart failure, n (%)</td><td>2635 (48.2)</td><td>264 (41.4)</td></tr><tr><td>New York Heart Association class, n (%)</td><td></td><td></td></tr><tr><td>II</td><td>4393 (80.4)</td><td>429 (67.2)</td></tr><tr><td>III</td><td>1062 (19.4)</td><td>206 (32.3)</td></tr><tr><td>IV</td><td>12 (0.2)</td><td>3 (0.5)</td></tr></tbody></table>
<table><tbody><tr><td>Left ventricular ejection fraction, %, mean (SD)</td><td>30.6 (6.9)</td><td>28.6 (7.7)</td></tr><tr><td>eGFR, mL/min/1.73 m², mean (SD)</td><td>71.5 (23.8)</td><td>65.8 (25.5)</td></tr><tr><td>eGFR categories at randomization, n (%)</td><td></td><td></td></tr><tr><td>&lt;15 mL/min/1.73 m²</td><td>5 (0.1)</td><td>2 (0.3)</td></tr><tr><td>≥15–&lt;30 mL/min/1.73 m²</td><td>193 (3.5)</td><td>50 (7.8)</td></tr><tr><td>≥30 to &lt;60 mL/min/1.73 m²</td><td>1640 (30.0)</td><td>221 (34.6)</td></tr><tr><td>≥60 mL/min/1.73 m²</td><td>3522 (64.4)</td><td>353 (55.3)</td></tr><tr><td>Medical therapy, n (%)</td><td></td><td></td></tr><tr><td>Loop diuretics</td><td>3728 (68.2)</td><td>532 (83.4)</td></tr><tr><td>Beta-blockers</td><td>5175 (94.7)</td><td>591 (92.6)</td></tr><tr><td>Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker</td><td>2070 (37.9)</td><td>268 (42.0)</td></tr><tr><td>Angiotensin receptor-neprilysin inhibitor</td><td>3094 (56.6)</td><td>322 (50.5)</td></tr><tr><td>Mineralocorticoid receptor antagonist</td><td>4266 (78.0)</td><td>482 (75.5)</td></tr><tr><td>Sodium-glucose cotransporter-2 inhibitor</td><td>3287 (60.1)</td><td>323 (50.6)</td></tr><tr><td>Device therapy, n (%)</td><td></td><td></td></tr><tr><td>Implantable cardioverter-defibrillator</td><td>1811 (33.1)</td><td>198 (31.0)</td></tr><tr><td>Cardiac resynchronization therapy</td><td>804 (14.7)</td><td>100 (15.7)</td></tr></tbody></table>

ªIncludes participants who self-identified as Black, or multiracial including Black.

eGFR, estimated glomerular filtration rate; IQR, interquartile range; NT-proBNP, N-terminal pro-B-type

natriuretic peptide; SD, standard deviation.

1

2

3

4
<table><caption>1 Table 2. Mortality outcomes</caption><thead><tr><th rowspan="2">Variable</th><th colspan="2">Vericiguat<br>(N = 3053)</th><th colspan="2">Placebo<br>(N = 3052)</th><th rowspan="2">Hazard ratio (95%<br>confidence<br>interval)</th><th rowspan="2">P-value</th></tr><tr><th>No (%) of<br>events</th><th>Events/<br>100 patient-yr</th><th>No (%) of<br>events</th><th>Events/<br>100 patient-yr</th></tr></thead><tbody><tr><td>Cardiovascular death</td><td>292 (9.6)</td><td>5.7</td><td>346 (11.3)</td><td>6.8</td><td>0.83<br>(0.71–0.97)</td><td>0.020</td></tr><tr><td>All-cause mortality</td><td>377 (12.3)</td><td>7.3</td><td>440 (14.4)</td><td>8.6</td><td>0.84<br>(0.74–0.97)</td><td>0.015</td></tr><tr><td>Sudden cardiac death</td><td>83 (2.7)</td><td>1.6</td><td>110 (3.6)</td><td>2.2</td><td>0.75<br>(0.56–0.99)</td><td>0.042</td></tr><tr><td>Heart failure related<br>death</td><td>88(2.9)</td><td>1.7</td><td>121 (4.0)</td><td>2.4</td><td>0.71<br>(0.54–0.94)</td><td>0.016</td></tr></tbody></table>

2

3
<table><caption>1 Table 3. Cardiovascular mortality and all-cause mortality by baseline medical and device therapy</caption><thead><tr><th rowspan="2"></th><th colspan="3">Vericiguat (N = 3053)</th><th colspan="3">Placebo (N = 3052)</th><th colspan="2">Treatment comparison</th></tr><tr><th>n/N (%)</th><th>Events/ 100-person year</th><th>Events, % (95% confidence interval)</th><th>n/N (%)</th><th>Events/ 100-person year</th><th>Events, % (95% confidence interval)</th><th>Hazard ratio (95% CI)</th><th>Treatment by subgroup P-value</th></tr></thead><tbody><tr><td colspan="9">Cardiovascular mortality</td></tr><tr><td colspan="9">Angiotensin receptor neprilysin inhibitor</td></tr><tr><td>Yes</td><td>142/1734 (8.2)</td><td>4.9</td><td>12.0 (9.8–14.7)</td><td>180/1682 (10.7)</td><td>6.4</td><td>15.9 (13.4–18.8)</td><td>0.75 (0.61–0.94)</td><td>0.208</td></tr><tr><td>No</td><td>150/1319 (11.4)</td><td>6.7</td><td>16.6 (13.9–19.8)</td><td>166/1370 (12.1)</td><td>7.3</td><td>18.1 (15.4–21.3)</td><td>0.92 (0.74–1.15)</td><td></td></tr><tr><td colspan="9">Sodium-glucose cotransporter-2 inhibitor</td></tr><tr><td>Yes</td><td>144/1812 (7.9)</td><td>4.9</td><td>11.6 (9.5–14.2)</td><td>179/1798 (10.0)</td><td>6.1</td><td>15.4 (12.9–18.2)</td><td>0.79 (0.63–0.98)</td><td>0.525</td></tr><tr><td>No</td><td>148/1241 (11.9)</td><td>6.8</td><td>16.6 (13.9–19.8)</td><td>167/1254 (13.3)</td><td>7.7</td><td>18.6 (15.9–21.8)</td><td>0.87 (0.70–1.09)</td><td></td></tr><tr><td colspan="9">Loop diuretic</td></tr><tr><td>Yes</td><td>236/2131 (11.1)</td><td>6.5</td><td>15.5 (13.5–17.9)</td><td>296/2129 (13.9)</td><td>8.3</td><td>20.0 (17.7–22.6)</td><td>0.77 (0.65–0.91)</td><td>0.050</td></tr><tr><td>No</td><td>56/922 (6.1)</td><td>3.7</td><td>10.5 (7.3–15.0)</td><td>50/923 (5.4)</td><td>3.2</td><td>9.1 (6.4–12.8)</td><td>1.17 (0.80–1.71)</td><td></td></tr><tr><td colspan="9">Implantable cardioverter defibrillator</td></tr><tr><td>Yes</td><td>88/993 (8.9)</td><td>5.1</td><td>13.0 (10.2–16.4)</td><td>110/1016 (10.8)</td><td>6.2</td><td>15.2 (12.5–18.4)</td><td>0.81 (0.61–1.07)</td><td>0.810</td></tr></tbody></table>
<table><tbody><tr><td>No</td><td>204/2060 (9.9)</td><td>6.0</td><td>14.6 (12.4-17.1)</td><td>236/2036 (11.6)</td><td>7.1</td><td>18.0 (15.5-20.9)</td><td>0.84 (0.70-1.01)</td></tr><tr><td colspan="8">Number of baseline guideline-directed medical therapies</td></tr><tr><td>0-2</td><td>65/506 (12.8)</td><td>7.3</td><td>17.1 (13.1-22.1)</td><td>76/501 (15.2)</td><td>9.2</td><td>21.4 (16.8-27.0)</td><td>0.80 (0.57-1.11)</td></tr><tr><td>3</td><td>127/1183 (10.7)</td><td>6.2</td><td>15.6 (12.9-18.9)</td><td>140/1203 (11.6)</td><td>6.8</td><td>16.4 (13.7-19.6)</td><td>0.91 (0.72-1.16)</td></tr><tr><td>4</td><td>100/1364 (7.3)</td><td>4.5</td><td>11.0 (8.6-14.2)</td><td>130/1348 (9.6)</td><td>5.9</td><td>15.6 (12.7-19.1)</td><td>0.76 (0.58-0.98)</td></tr><tr><td colspan="8">Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker</td></tr><tr><td>Yes</td><td>131/1150 (11.4)</td><td>6.8</td><td>16.9 (13.9-20.4)</td><td>137/1188 (11.5)</td><td>6.9</td><td>17.4 (14.5-20.8)</td><td>0.99 (0.78-1.25)</td></tr><tr><td>No</td><td>161/1903 (8.5)</td><td>5.0</td><td>12.3 (10.2-14.8)</td><td>209/1864 (11.2)</td><td>6.7</td><td>16.5 (14.1-19.2)</td><td>0.74 (0.60-0.90)</td></tr><tr><td colspan="8">Beta-blockers</td></tr><tr><td>Yes</td><td>270/2886 (9.4)</td><td>5.5</td><td>13.8 (12.0-15.8)</td><td>321/2880 (11.1)</td><td>6.7</td><td>16.7 (14.7-18.8)</td><td>0.83 (0.71-0.98)</td></tr><tr><td>No</td><td>22/167 (13.2)</td><td>7.7</td><td>18.3 (11.4-28.7)</td><td>25/172 (14.5)</td><td>9.2</td><td>20.8 (12.5-33.5)</td><td>0.80 (0.45-1.41)</td></tr><tr><td colspan="8">Mineralocorticoid receptor antagonist</td></tr><tr><td>Yes</td><td>216/2358 (9.2)</td><td>5.4</td><td>13.8 (11.7-16.1)</td><td>266/2390 (11.1)</td><td>6.7</td><td>16.8 (14.7-19.2)</td><td>0.81 (0.68-0.97)</td></tr></tbody></table>
<table><tbody><tr><td>No</td><td>76/695 (10.9)</td><td>6.4</td><td>15.0 (11.7–19.2)</td><td>80/662 (12.1)</td><td>7.2</td><td>17.2 (13.5–21.9)</td><td>0.89 (0.65–1.22)</td></tr><tr><td colspan="9">All-cause mortality</td></tr><tr><td colspan="9">Angiotensin receptor neprilysin inhibitor</td></tr><tr><td>Yes</td><td>190/1734 (11.0)</td><td>6.5</td><td>16.3 (13.7–19.2)</td><td>224/1682 (13.3)</td><td>8.0</td><td>19.0 (16.4–21.9)</td><td>0.81 (0.67–0.98)</td><td>0.549</td></tr><tr><td>No</td><td>187/1319 (14.2)</td><td>8.4</td><td>20.8 (17.8–24.2)</td><td>216/1370 (15.8)</td><td>9.5</td><td>22.6 (19.6–25.9)</td><td>0.88 (0.73–1.07)</td><td></td></tr><tr><td colspan="9">Sodium-glucose cotransporter-2 inhibitor</td></tr><tr><td>Yes</td><td>194/1812 (10.7)</td><td>6.5</td><td>16.6 (14.0–19.7)</td><td>226/1798 (12.6)</td><td>7.7</td><td>18.6 (16.0–21.4)</td><td>0.84 (0.70–1.02)</td><td>1.000</td></tr><tr><td>No</td><td>183/1241 (14.7)</td><td>8.4</td><td>20.2 (17.3–23.5)</td><td>214/1254 (17.1)</td><td>9.9</td><td>22.9 (20.0–26.3)</td><td>0.84 (0.69–1.03)</td><td></td></tr><tr><td colspan="9">Loop diuretics</td></tr><tr><td>Yes</td><td>300/2131 (14.1)</td><td>8.3</td><td>20.0 (17.7–22.6)</td><td>370/2129 (17.4)</td><td>10.4</td><td>24.0 (21.5–26.6)</td><td>0.78 (0.67–0.91)</td><td>0.037</td></tr><tr><td>No</td><td>77/922 (8.4)</td><td>5.1</td><td>13.9 (10.3–18.6)</td><td>70/923 (7.6)</td><td>4.5</td><td>12.2 (9.2–16.1)</td><td>1.14 (0.83–1.58)</td><td></td></tr><tr><td colspan="9">Implantable cardioverter defibrillator</td></tr><tr><td>Yes</td><td>125/993 (12.6)</td><td>7.2</td><td>18.6 (15.3–22.6)</td><td>143/1016 (14.1)</td><td>8.0</td><td>18.9 (16.0–22.3)</td><td>0.88 (0.70–1.12)</td><td>0.639</td></tr><tr><td>No</td><td>252/2060 (12.2)</td><td>7.4</td><td>18.0 (15.6–20.6)</td><td>297/2036 (14.6)</td><td>9.0</td><td>21.8 (19.1–24.8)</td><td>0.82 (0.70–0.97)</td><td></td></tr></tbody></table>

Number of Baseline Guideline-Directed Medical Therapies
<table><tbody><tr><td>0-2</td><td>88/506<br>(17.4)</td><td>9.9</td><td>22.3<br>(18.0-27.5)</td><td>101/501<br>(20.2)</td><td>12.2</td><td>26.5<br>(21.7-32.1)</td><td>0.81<br>(0.61-1.08)</td><td>0.950</td></tr><tr><td>3</td><td>149/1183<br>(12.6)</td><td>7.3</td><td>18.1<br>(15.2-21.5)</td><td>174/1203<br>(14.5)</td><td>8.4</td><td>20.0<br>(17.1-23.3)</td><td>0.86<br>(0.69-1.07)</td><td></td></tr><tr><td>4</td><td>140/1364<br>(10.3)</td><td>6.3</td><td>17.0<br>(13.8-21.0)</td><td>165/1348<br>(12.2)</td><td>7.5</td><td>18.8<br>(15.8-22.3)</td><td>0.84<br>(0.67-1.05)</td><td></td></tr><tr><td colspan="9">Angiotensin Converting Enzyme Inhibitor/Angiotensin Receptor Blocker</td></tr><tr><td>Yes</td><td>158/1150<br>(13.7)</td><td>8.2</td><td>20.9<br>(17.6-24.7)</td><td>174/1188<br>(14.6)</td><td>8.7</td><td>21.5<br>(18.4-25.1)</td><td>0.94<br>(0.76-1.16)</td><td>0.224</td></tr><tr><td>No</td><td>219/1903<br>(11.5)</td><td>6.8</td><td>16.7<br>(14.3-19.4)</td><td>266/1864<br>(14.3)</td><td>8.6</td><td>19.9<br>(17.5-22.7)</td><td>0.79<br>(0.66-0.94)</td><td></td></tr><tr><td colspan="9">Beta-blockers</td></tr><tr><td>Yes</td><td>347/2886<br>(12.0)</td><td>7.1</td><td>18.0<br>(15.9-20.2)</td><td>406/2880<br>(14.1)</td><td>8.4</td><td>20.2<br>(18.2-22.4)</td><td>0.85<br>(0.73-0.98)</td><td>0.841</td></tr><tr><td>No</td><td>30/167<br>(18.0)</td><td>10.5</td><td>23.5<br>(16.1-33.6)</td><td>34/172<br>(19.8)</td><td>12.5</td><td>28.3<br>(19.0-40.8)</td><td>0.80<br>(0.49-1.31)</td><td></td></tr><tr><td colspan="9">Mineralocorticoid receptor antagonist</td></tr><tr><td>Yes</td><td>279/2358<br>(11.8)</td><td>7.0</td><td>18.1<br>(15.8-20.7)</td><td>337/2390<br>(14.1)</td><td>8.5</td><td>20.6<br>(18.3-23.1)</td><td>0.83<br>(0.71-0.97)</td><td>0.638</td></tr><tr><td>No</td><td>98/695<br>(14.1)</td><td>8.3</td><td>19.0<br>(15.4-23.3)</td><td>103/662<br>(15.6)</td><td>9.3</td><td>20.8<br>(16.9-25.5)</td><td>0.89<br>(0.68-1.18)</td><td></td></tr></tbody></table>
Kaplan-Meier Plot for Cumulative Event Rate
Secondary Endpoint: Time to CEC Confirmed Cardiovascular Death
ITT Population

<figure><img src="image_2.png" /></figure>

Number of participants at risk

<table><tr><td>Vericiguat</td><td>3053</td><td>3000</td><td>2928</td><td>2752</td><td>2092</td><td>1516</td><td>968</td><td>536</td></tr><tr><td>Placebo</td><td>3052</td><td>3003</td><td>2910</td><td>2728</td><td>2050</td><td>1456</td><td>940</td><td>514</td></tr></table>

Cumulative number of events up to the time point

<table><tr><td>Vericiguat</td><td>0</td><td>37</td><td>99</td><td>156</td><td>201</td><td>234</td><td>263</td><td>279</td></tr><tr><td>Placebo</td><td>0</td><td>40</td><td>111</td><td>177</td><td>243</td><td>287</td><td>314</td><td>340</td></tr></table>

Based on data up to the primary completion date (20Nov2024).

Source: [P035MK1242: adam-adsl; adttec]
Kaplan-Meier Plot for Cumulative Event Rate
Secondary Endpoint: Time to CEC Confirmed All-cause Mortality
ITT Population

<figure><img src="image_3.png" /></figure>

**Number of participants at risk**

<table><tr><td>Vericiguat</td><td>3053</td><td>3000</td><td>2928</td><td>2752</td><td>2092</td><td>1516</td><td>968</td><td>536</td></tr><tr><td>Placebo</td><td>3052</td><td>3003</td><td>2910</td><td>2728</td><td>2050</td><td>1456</td><td>940</td><td>514</td></tr></table>

**Cumulative number of events up to the time point**

<table><tr><td>Vericiguat</td><td>0</td><td>51</td><td>123</td><td>197</td><td>254</td><td>292</td><td>335</td><td>361</td></tr><tr><td>Placebo</td><td>0</td><td>47</td><td>140</td><td>223</td><td>307</td><td>368</td><td>402</td><td>432</td></tr></table>

Based on data up to the primary completion date (20Nov2024).

Source: [P035MK1242: adam-adsl; adttec]
Kaplan-Meier Plot for Cumulative Event Rate
Time to Sudden Cardiac Death
ITT Population

<figure><img src="image_4.png" /></figure>

Number of participants at risk

<table><tr><td>Vericiguat</td><td>3053</td><td>3000</td><td>2928</td><td>2752</td><td>2092</td><td>1516</td><td>968</td><td>536</td></tr><tr><td>Placebo</td><td>3052</td><td>3003</td><td>2910</td><td>2728</td><td>2050</td><td>1456</td><td>940</td><td>514</td></tr></table>

Cumulative number of events up to the time point

<table><tr><td>Vericiguat</td><td>0</td><td>18</td><td>31</td><td>44</td><td>62</td><td>70</td><td>73</td><td>78</td></tr><tr><td>Placebo</td><td>0</td><td>22</td><td>47</td><td>64</td><td>84</td><td>92</td><td>98</td><td>107</td></tr></table>
Kaplan-Meier Plot for Cumulative Event Rate
Time to Heart Failure Death
ITT Population

<figure><img src="image_5.png" /></figure>

Number of participants at risk

<table><tr><td>Vericiguat</td><td>3053</td><td>3000</td><td>2928</td><td>2752</td><td>2092</td><td>1516</td><td>968</td><td>536</td></tr><tr><td>Placebo</td><td>3052</td><td>3003</td><td>2910</td><td>2728</td><td>2050</td><td>1456</td><td>940</td><td>514</td></tr></table>

Cumulative number of events up to the time point

<table><tr><td>Vericiguat</td><td>0</td><td>7</td><td>30</td><td>46</td><td>59</td><td>73</td><td>81</td><td>85</td></tr><tr><td>Placebo</td><td>0</td><td>9</td><td>30</td><td>53</td><td>81</td><td>103</td><td>114</td><td>120</td></tr></table>
<figure><img src="image_6.png" /><figcaption>Figure 2
167x188 mm (DPI)</figcaption></figure>
<figure><img src="image_7.png" /><figcaption>Figure 3
167x188 mm (DPI)</figcaption></figure>
A

<figure><img src="image_8.png" /></figure>

B

<figure><img src="image_9.png" /><figcaption>Figure 4
167x208 mm (DPI)</figcaption></figure>
<figure><img src="image_10.png" /><figcaption>B</figcaption></figure>

<figure><img src="image_11.png" /></figure>

Figure 5
169x185 mm (DPI)
# Graphical abstract

## Key Question

How does vericiguat affect mortality in ambulatory adults with a history of heart failure and reduced ejection fraction (HFrEF)?

## Key Finding

In this analysis of the VICTOR trial of the prespecified secondary endpoint of cardiovascular death, risks of cardiovascular, all-cause, sudden cardiac and HF-related death were lower with vericiguat versus placebo. These benefits were observed in the overall study population and in prespecified subgroups, including participants with different baseline medical therapies.

## Take Home Message

In patients with HFrEF, vericiguat significantly reduces cardiovascular and all-cause mortality compared with placebo.

<figure><img src="image_12.png" /><figcaption>Structured Graphical Abstract
159x244 mm (DPI)</figcaption></figure>