# Effect of Vericiguat on Worsening Heart Failure in Compensated Outpatients with HFrEF: Insights from VICTOR

Faiez Zannad, Yogesh N.V. Reddy, Irina Barash, Kevin J Anstrom, Marc P

Bonaca, Maria Borentain, Stefano Corda, Pedro P Teixeira, Justin A

Ezekowitz, Davis Gates, et al.

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## To cite this version:

Faiez Zannad, Yogesh N.V. Reddy, Irina Barash, Kevin J Anstrom, Marc P Bonaca, et al. Effect of Vericiguat on Worsening Heart Failure in Compensated Outpatients with HFrEF: Insights from VICTOR. JACC. Advances, 2025, 10.1016/j.jacc.2025.08.051. hal-05240489

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Effect of Vericiguat on Worsening Heart Failure in Compensated Outpatients with HFrEF: Insights from VICTOR

Faiez Zannad, MD, PhD, Yogesh N.V. Reddy, MBBS, Irina Barash, MD, MS, MD, Kevin J. Anstrom, PhD, Marc P. Bonaca, MD, MPH, Maria Borentain, MD, Stefano Corda, MD, PhD, Pedro P. Teixeira, MD, Justin A. Ezekowitz, MBBCH, MSC, Davis Gates, PhD, Carolyn S.P. Lam, MBBS, PhD, Eldrin F. Lewis, MD, MPH, JoAnn Lindenfeld, MD, Ciaran J. McMullan, MBBCh MSc, Robert J. Mentz, MD, Christopher M. O'Connor, MD, Piotr Ponikowski, MD, PhD, Giuseppe M.C. Rosano, MD, PhD, Clara Saldarriaga, MD, Michele Senni, MD, James Udelson, MD, Alessia Urbinati, MD, Vanja Vlajnic, PhD, MBA, MAS, MS, Adriaan A. Voors, MD, PhD, Aiwen Xing, PhD, Mahesh J. Patel, MD, Javed Butler, MD, MPH, MBA, for the VICTOR Study Group

PII: S0735-1097(25)07559-X

DOI: https://doi.org/10.1016/j.jacc.2025.08.051

Reference: JACC 32225

To appear in: JACC

Received Date: 28 July 2025

Revised Date: 19 August 2025

Accepted Date: 20 August 2025

Please cite this article as: Zannad F, Reddy YNV, Barash I, Anstrom KJ, Bonaca MP, Borentain M, Corda S, Teixeira PP, Ezekowitz JA, Gates D, Lam CSP, Lewis EF, Lindenfeld J, McMullan CJ, Mentz RJ, O'Connor CM, Ponikowski P, Rosano GMC, Saldarriaga C, Senni M, Udelson J, Urbinati A, Vlajnic V, Voors AA, Xing A, Patel MJ, Butler J, for the VICTOR Study Group, Effect of Vericiguat on Worsening Heart Failure in Compensated Outpatients with HFrEF: Insights from VICTOR, JACC (2025), doi: https://doi.org/10.1016/j.jacc.2025.08.051.

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# Effect of Vericiguat on Total Heart Failure Events in Compensated Outpatients with HFrEF: Insights from VICTOR

Faiez Zannad, MD, PhD,<fnref n="1" /> Yogesh N.V. Reddy, MBBS,<fnref n="2" /> Irina Barash, MD, MS, MD,<fnref n="3" /> Kevin J. Anstrom, PhD,<fnref n="4" /> Marc P. Bonaca, MD, MPH,<fnref n="5" /> Maria Borentain, MD,<fnref n="6" /> Stefano Corda, MD, PhD,<fnref n="7" /> Pedro P. Teixeira, MD,<fnref n="6" /> Justin A. Ezekowitz, MBBCH, MSC,<fnref n="8" /> Davis Gates, PhD,<fnref n="3" /> Carolyn S.P. Lam, MBBS, PhD,<fnref n="9" /> Eldrin F. Lewis,¹⁰ MD, MPH, JoAnn Lindenfeld, MD,¹¹ Ciaran J. McMullan MBBCh MSc,<fnref n="3" /> Robert J. Mentz,¹² MD, Christopher M. O'Connor,¹³ MD, Piotr Ponikowski, MD, PhD,¹⁴ Giuseppe M.C. Rosano, MD, PhD,¹⁵,¹⁶,¹⁷ Clara Saldarriaga, MD,¹⁸ Michele Senni, MD,¹⁹,²⁰ James Udelson, MD,²¹ Alessia Urbinati, MD,<fnref n="3" /> Vanja Vlajnic, PhD, MBA, MAS, MS,²² Adriaan A. Voors, MD, PhD,²³ Aiwen Xing, PhD,<fnref n="3" /> Mahesh J. Patel, MD,<fnref n="3" /> Javed Butler, MD, MPH, MBA,²⁴,²⁵ for the VICTOR Study Group

<footnote n="1">¹CVCT and Université de Lorraine, Nancy, France;</footnote>

<footnote n="2">²Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA;</footnote>

<footnote n="3">³Merck & Co., Inc., Rahway, NJ, USA;</footnote>

<footnote n="4">⁴University of North Carolina, Chapel Hill, NC, USA;</footnote>

<footnote n="5">⁵Department of Medicine, Colorado Prevention Center Clinical Research, University of Colorado, Aurora, CO, USA;</footnote>

<footnote n="6">⁶Bayer AG, Berlin, Germany;</footnote>

<footnote n="7">⁷Bayer AG, Basel, Switzerland;</footnote>

<footnote n="8">⁸Canadian VIGOUR Centre, University of Alberta, Edmonton, AB, Canada;</footnote>

<footnote n="9">⁹National Heart Centre Singapore and Duke-National University, Singapore, Singapore;</footnote>
¹⁰Stanford University School of Medicine, Stanford, CA, USA;

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

¹²Duke Clinical Research Institute, Durham, NC, USA;

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

¹⁴Wroclaw Medical University, Wroclaw, Poland;

¹⁵Department of Human Sciences and Promotion of Quality of Life, San Raffaele
Open University of Rome, Rome, Italy;

¹⁶Cardiology, San Raffaele Cassino Hospital, Cassino, Italy;

¹⁷IRCCS San Raffaele Roma, Rome, Italy;

¹⁸Cardio VID Clinic, Medellín, Colombia;

¹⁹University of Milano-Bicocca, Milan, Italy;

²⁰Papa Giovanni XXIII Hospital, Bergamo, Italy;

²¹Division of Cardiology and the CardioVascular Center, Tufts Medical Center,
Boston, MA, USA;

²²Bayer US LLC, Whippany, NJ, USA;

²³University of Groningen, Groningen, Netherlands;

²⁴Department of Medicine, University of Mississippi, Jackson, MS, USA;

²⁵Baylor Scott and White Research Institute, Dallas, TX, USA

Funding: Funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.,
Rahway, NJ, USA (MSD) and Bayer AG.

**Address for correspondence:** Faiez Zannad, 3 rue de l'éperon, 75006 Paris,
France; Telephone: +33607656260; email: f.zannad@chru-nancy.fr
Disclosures

FZ reports personal fees from Alnylam, Bayer, Bioeutics, Boehringer, Cellprothera, Cereno, Corteria, CVRx, Merck, Owkin, Ribocure, and Roche; payment or honoraria for lectures, presentations, speakers bureaus, or educational events from Bayer, Boehringer, Centrix, CVRx, Lupin, Opalia Recordati, Merck, NovoNordisk, and Viatris; participates in a data safety monitoring board or advisory board for Merck/Acceleron; has equities at G3Pharmaceutical, Cereno, and Eshmoun Clinical Research; and is founder of Global CardioVascular Clinical Trialists.

YNVR is supported by grants from NHLBI (K23HL164901), Sleep Number, Bayer, Merck, United Pharmaceuticals and the Earl Wood Career Development Award from Mayo Clinic; and reports consulting fees from Edwards Life Sciences.

CJM, IB, DG, AU, AX, and MJP are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may own stock and/or stock options in Merck & Co., Inc., Rahway, NJ, USA.

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 organization affiliated with the University of Colorado, that receives or has received research grant/consulting funding between August 2021 and present from Abbott Laboratories, Agios Pharmaceuticals, Inc., Alexion Pharma, Alnylam Pharmaceuticals, Inc., Amgen Inc., Angionetics, Inc., Anthos Therapeutics, Array BioPharma, Inc., AstraZeneca and Affiliates, Atentiv LLC, Audentes Therapeutics, Inc., Bayer and Affiliates, Bristol-Myers Squibb Company, Cambrian Biopharma, Inc.,
Cardiol Therapeutics Inc., CellResearch Corp., Cleerly Inc., Cook Regentec LLC, CSL Behring LLC, Eidos Therapeutics, Inc., EP Trading Co. Ltd., Epizon Pharma, Inc., Esperion Therapeutics, Inc., Everly Well, Inc., Exicon Consulting Pvt. Ltd., Faraday Pharmaceuticals, Inc., Foresee Pharmaceuticals Co. Ltd., Fortress Biotech, Inc., HDL Therapeutics Inc., HeartFlow Inc., Hummingbird Bioscience, Insmed Inc., Ionis Pharmaceuticals, Janssen and Affiliates, Kowa Research Institute, Inc., Lexicon Pharmaceuticals, Inc., Medimmune Ltd., Merck & Affiliates, Nectero Medical Inc., Novartis Pharmaceuticals Corp., Novo Nordisk, Inc., Osiris Therapeutics Inc., Pfizer Inc., PhaseBio Pharmaceuticals, Inc., Prairie Education and Research Cooperative, Prothena Biosciences Limited, Regeneron Pharmaceuticals, Inc., Regio Biosciences, Inc., Sanofi-Aventis Groupe, Silence Therapeutics PLC, Smith & Nephew plc, Stealth BioTherapeutics Inc., Tourmaline, VarmX, and Virta Health Corporation.

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

JAE has received research grants and consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim-Lilly, Merck, Amgen, CSL-Vifor, Carduirion, American Regent, Otsuka, Novo Nordisk, and Applied Therapeutics.

CSPL: has received research grants from the National Medical Research Council of Singapore, Novo Nordisk, and Roche Diagnostic; has received consulting fees from Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Bioeuetics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc,
Quidel Corporation, Radcliffe Group Ltd., Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; has patent 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.

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

JL is receiving research support from AstraZeneca and Volumetrix and consulting fees from Abbott, Adonis, Alleviant, AstraZeneca, Axon, Boston Scientific, Cordio, CVRx, Edwards Lifesciences, Fire-1, Inoventric, Intershunt, Merck, Medtronic, Orchestra Biomed, Whiteswell, Vascular Dynamics, and VWave.

RJM has received research support and honoraria from Bayer and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; and consulting fees from Abbott, Alleviant Medical, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Eli Lilly, Lexicon, Medtronic, Medable, Merck, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Relypsa, Reprieve Cardiovascular, Respicardia, Roche, Rocket Pharmaceuticals, Sanofi, Verily, Vifor, Windtree Therapeutics, and Zoll.

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

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, 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, Vifor Pharma; and has participated in a data safety monitoring board or advisory board for Boehringer Ingelheim, Vifor Pharma, Novo Nordisk, Pharmacosmos, and Moderna.

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.

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.

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.

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.

VV is an employee of Bayer US LLC.

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.

JB has received consulting fees from Abbott, American Regent, Amgen, Applied
Therapeutic, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston
Scientific, Bristol Myers Squibb, Cardiac Dimension, Cardiocell, Cardior, Cardiorem,
CSL Bearing, CVRx, Cytokinetics, Daxor, Edwards, Element Science, Faraday,
Foundry, G3P, Innolife, Impulse Dynamics, Imbria, Inventiva, Ionis, Lexicon, Lilly,
LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk,
Pfizer, Pharmacosmos, Pharmain, Pfizer, Prolaio, Regeneron, Renibus, Roche,
Salamandra, Sanofi, SC Pharma, Secretome, Sequana, SQ Innovation, Tenex,
Tricog, Ultromics, Vifor, and Zoll; and payment or honoraria for lectures,
presentations, speakers bureaus, manuscript writing, or educational events from
Novartis, Boehringer Ingelheim-Lilly, AstraZeneca, Impulse Dynamics, and Vifor.
FF has nothing to disclose.

Funding

Funding was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co.,
Inc., Rahway, NJ, USA and Bayer AG.
**Data Sharing**

The data sharing policy, including restrictions, of Merck Sharp & Dohme LLC, a
subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD), is available at
https://trialstransparency.msdclinicaltrials.com/policies-perspectives.aspx.

Requests for access to the clinical study data can be submitted via email to the Data
Access mailbox (mailto-dataaccess@msd.com).

**Acknowledgments**

The authors wish to thank Ms. Constance Hamlin and Dr. Martina Zilli for their
outstanding operational support during the conduct of the VICTOR trial. Editorial
assistance was provided by Melissa Ward, BA, and medical writing support was
provided by Hannah Kirton, PhD, both of Scion (a division of Prime, London, UK)
supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.,
Rahway, NJ, USA and Bayer AG, Wuppertal, Germany according to Good
Publication Practice guidelines (https://www.acpjournals.org/doi/10.7326/M22-1460).
**Word count Abstract (350 words)**

**Background:** In the VICTOR trial, in a contemporary ambulatory cohort with heart failure and reduced ejection fraction (HFrEF) and no recent hospitalization, the primary outcome of hospitalization for heart failure (HHF) and cardiovascular death was not statistically significantly reduced with vericiguat. Vericiguat reduced risk of mortality but not HHF. In this ambulatory compensated cohort, time to first HHF may underestimate the overall worsening HF burden by failing to consider the high proportion of outpatient worsening HF events.

**Objectives:** To determine the effect of vericiguat on the overall risk of worsening HF by incorporating the entire patient experience of worsening outpatient and inpatient HF episodes.

**Methods:** VICTOR, was a phase 3, double-blind, placebo-controlled trial testing the effect of vericiguat in ambulatory patients with HFrEF who had not experienced recent worsening (defined as HHF admission within 6 months or outpatient intravenous diuretic use within 3 months) and were on a background of high use of contemporary guideline therapy. The primary endpoint was a composite of cardiovascular death or HHF. The current analysis provides detailed effects of vericiguat on overall worsening HF in both the inpatient and outpatient settings, including urgent care visits for intravenous diuretics or outpatient oral diuretic initiation or intensification.

**Results:** A total of 6,105 participants were randomized. Outpatient worsening HF was more common as the first worsening HF event (n=851, 59.3%), compared to HHF (n=507, 35.4%) or urgent HF visits (n=76, 5.3%). Outpatient oral diuretic initiation or intensification was associated with increased mortality [RR 1.69 (95% CI
1.47-1.94), p<0.001]. Overall worsening heart failure occurred in 686 participants (22.5%) in the vericiguat group and 748 participants (24.8%) in the placebo group (HR 0.90; 95% CI 0.81-1.00, p=0.047). The composite of all-cause death and overall worsening HF occurred in 917 participants (30.0%) in the vericiguat group and 1004 participants (32.9%) in the placebo group (HR 0.90, 95% CI 0.82-0.98, p=0.016).

**Conclusions:** In compensated patients with HFrEF on contemporary guideline therapy, outpatient worsening HF was more common than HHF and was associated with higher mortality risk. Exploratory analyses suggested a potential reduction in overall worsening HF events when both inpatient and outpatient settings were considered.

**Key words:** Vericiguat • Heart failure with reduced ejection fraction • worsening heart failure

**Condensed Abstract (91 words)**

In stable compensated outpatients with heart failure and reduced ejection fraction on contemporary guideline therapy, approximately 1 in 6 patients per year have a worsening heart failure event either in the outpatient or inpatient setting, with outpatient events being nearly twice as common as hospitalization for heart failure and predictive of death. Vericiguat reduced the overall risk of worsening heart failure considering both outpatient and inpatient events (HR 0.90; 95%CI 0.81-1.00).

Combined with the observed reduction in mortality, these exploratory analyses suggest potential reduction in heart failure events among compensated outpatients with heart failure and reduced ejection fraction.

**Abbreviations**

HFrEF Heart Failure with Reduced Ejection Fraction
LVEF left ventricular ejection fraction

CVD cardiovascular death

HFH heart failure hospitalization

NT-proBNP N-terminal pro-B-type natriuretic peptide

VICTOR Vericiguat Global Study in Participants with Chronic Heart Failure

VICTORIA Vericiguat Global Study in Subjects with Heart Failure with Reduced
Ejection Fraction
# INTRODUCTION

Despite major advances in pharmacotherapy for heart failure (HF) with reduced ejection fraction (HFrEF)¹⁻³, patients still experience disease progression characterized by discrete episodes of clinical worsening in both the inpatient and outpatient setting.⁴ With the incremental risk reduction for hospitalization for HF (HHF) and outpatient worsening HF due to contemporary guideline directed medical therapy (GDMT) including angiotensin receptor-neprilysin inhibitors (ARNI) and sodium-glucose cotransporter 2 inhibitors (SGLT2i)⁵⁻⁷, the natural history and residual risk of worsening HF among compensated outpatients with HFrEF on the most contemporary GDMT is not well understood.

In the VICTOR (Vericiguat Global Study in Participants with Chronic Heart Failure) trial (NCT05093933), vericiguat was tested in an exclusively compensated, ambulatory HFrEF population without recent worsening HF⁸, in the context of excellent GDMT use including ARNI and SGLT2i of greater than 50% each.⁹ Vericiguat resulted in lower cardiovascular and all-cause mortality compared to placebo in VICTOR, but there was not a statistically significant reduction in time to first HHF. Given the unique characteristics of patients in VICTOR, related to the low rate of either prior or recent HHF, and the best GDMT background therapy to date as compared to all HFrEF trials, the goals of the present secondary analysis were to describe the broader natural history of progressive HF in this contemporary lower risk HFrEF cohort, and to assess the effect of vericiguat on 1) the total of outpatient and inpatient worsening HF events 2) natriuretic peptide trajectory and 3) overall HF stability.
# METHODS

## Trial design

VICTOR (NCT05093933) was a double-blind, placebo-controlled, 1:1 randomized, event-driven trial testing the effects of oral vericiguat at a target dose of 10 mg vs placebo in ambulatory patients with HFrEF and no recent worsening HF. Details of the trial design and primary results have been published.⁸ The trial was approved by the ethics committee at each site and all patients provided written consent. The trial sponsors were Merck & Co., Inc. and Bayer Pharmaceuticals.

## Patient population

In addition to having symptomatic HFrEF with left ventricular ejection fraction (LVEF) ≤40% and New York Heart Association (NYHA) class II-IV symptoms on optimally tolerated GDMT, participants were required to have no recent HF worsening (defined as no HHF within 6 months or outpatient intravenous diuretic use within 3 months prior to randomization). N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels within 30 days prior to randomization were required to be 600–6000 pg/ml for patients in sinus rhythm and 900–6000 pg/ml for those in atrial fibrillation.

Participants with estimated glomerular filtration rate (eGFR)<15 ml/min/1.73 m² were excluded. The full list of eligibility criteria is shown in **Table S1**.

## Dosing, study visits and natriuretic peptide assessment

After randomization, participants were started at 2.5 mg oral dose of blinded vericiguat or matching placebo once daily which was titrated to 5 mg and then 10 mg vericiguat as tolerated at 14 and 28 day study visits respectively. Following this 4-
week drug titration period, participants returned at week 24, and then every 24 weeks until study completion. All participants underwent N terminal pro B type natriuretic peptide (NT-proBNP) measurement at core lab at randomization, and every 24 weeks thereafter.

## Outcomes

The primary endpoint of VICTOR was the composite of time to first HHF or cardiovascular death, which has been reported¹⁰. In the original prespecified analysis only adjudicated HHF was included as a secondary endpoint. All suspected HHF or urgent HF visits requiring intravenous diuretic therapy underwent adjudication by an independent clinical endpoint committee. The adjudication criteria for an urgent HF event in the outpatient setting required administration of intravenous diuretics. Given the known clinical and prognostic importance of oral diuretic intensification in HFrEF⁵⁻⁷, we evaluated an exploratory endpoint of expanded overall worsening HF composite endpoint that included time to first HHF, first urgent HF visit requiring intravenous diuretics, or first worsening outpatient HF that required oral diuretic initiation or intensification. Oral diuretic initiation was defined as new initiation of oral loop diuretics or thiazide diuretics after randomization in patients with no baseline use. Oral diuretic intensification was defined as a dose increase after randomization compared with last dose on or before randomization. This time to first event expanded worsening HF endpoint therefore collectively captured clinical progression over the entire spectrum of worsening HF events across both the outpatient and inpatient settings, while accounting for the interdependence between individual worsening HF components by capturing only the first worsening HF event. Since
vericiguat resulted in a reduction in mortality in VICTOR, there was a higher competing risk of death in the placebo arm that could potentially bias isolated assessment of the effect of vericiguat on the expanded worsening HF endpoint alone. To formally account for this competing risk of death we additionally evaluated a composite of time to mortality or time to first HHF, first urgent HF visit requiring intravenous diuretics or first worsening outpatient HF that required oral diuretic initiation or intensification. Similar competing risk analysis was also performed using CV death instead of all-cause mortality. As an alternate complementary approach, we also evaluated the use of a win ratio on CV death, HHF, first urgent HF visit and first oral diuretic initiation or intensification in an exploratory analysis. An additional *post hoc* clinical stability analysis evaluated the time to all-cause death, first HHF, first urgent HF visit requiring intravenous diuretics, first worsening outpatient HF that required oral diuretic initiation or intensification, or first NYHA class worsening. NYHA class was assessed by the investigators at every study visit.

## Statistical analysis

All time-to-event endpoints were performed following the intention-to-treat principle using a stratified log-rank test. Cox-proportional hazards analyses were used to estimate hazard ratios with 95% confidence intervals with unadjusted two-sided nominal p-values calculated based on the log-rank test. Time to first HHF was a prespecified secondary endpoint. Analyses including oral diuretic intensification were exploratory analyses and these analyses were not part of any hierarchical hypothesis testing. The P values and 95% confidence intervals provided for these exploratory analyses therefore do not account for multiplicity of testing. The proportional hazard assumption was tested using the weighted Schoenfeld residuals
test across all time-to-first event outcomes with no statistical evidence of violation
with lowest P-value of 0.367 across tested endpoints. In addition, numbers needed
to treat and their 95% confidence interval were provided based on the inverse of the
difference in annualized absolute risk reductions (per 100-patient years). Subgroup
analyses for the HF endpoints were performed to assess consistency of treatment
effect across various demographics characteristics (i.e., age ≥65 vs <65 years;
female vs male; geographic region; baseline therapy (i.e., SGLT2i yes/no; ARNI
yes/no; baseline loop diuretic yes/no; implantable cardioverter defibrillator yes/no;
number of baseline GDMT 0-2 vs 3 vs 4-5); comorbidities (i.e., diabetes, atrial
fibrillation, chronic kidney disease, ischemic heart disease, anemia); baseline eGFR
(≥15-≤30 vs 30-≤60 vs >60 mL/min/1.73 m²); baseline mean LVEF (<31 vs ≥31%);
baseline NT-proBNP quartiles, NYHA class (II vs III/IV); and HHF recency prior to
randomization (never, 6-12 months, >12 months). The relationship between NT-
proBNP as a continuous variable and the efficacy outcome was performed using a
restricted cubic spline model as done previously for VICTORIA. Changes in NT-
proBNP over time were analysed using a longitudinal analysis of covariance model,
with the change from baseline in log transformed value as the dependent variable,
including categorical terms for stratification factor, week, treatment group, and the
week-by-treatment group interaction, with the log transformed baseline value as a
continuous covariate.
# Results

## Trial participants

Between November 2021 and December 2023, 6,105 participants were enrolled.⁹ A total of 3,053 participants were assigned to vericiguat and 3,052 to placebo. The baseline characteristics of the 6,105 participants randomized are described in **Table S2**. Consistent with outpatient stability, 47.5% had never been hospitalized for HF prior, 79% had mild symptoms (NYHA class II), and 30.2% of patients did not require loop diuretics at baseline. Background GDMT included a high utilization of beta-blockers (94.4%), mineralocorticoid receptor antagonist (77.8%), renin-angiotensin modulation use (94.3%, including 56.0% ARNI) and SGLT2i (59.1%).

## Worsening heart failure event rates in the placebo arm

Despite high use of contemporary GDMT and no recent worsening HF, participants in the placebo arm demonstrated a substantial residual risk with annualized event rates of 12.2% for the composite of CV death and first HHF. When considering worsening HF alone, annualized event rates were 7.6% for time to first HHF, with even higher annualized event rates of 17.2% for the expanded worsening HF endpoint including HHF, urgent HF visits or outpatient worsening requiring oral diuretic initiation or intensification.

In the placebo arm, oral diuretic initiation or intensification occurred in 7.1% and in 13.4% of participants, respectively (Table S3). Among all loop diuretic initiation or intensification events in the placebo arm (n=564), 28.2% underwent loop diuretic initiation, 22.0% had a dose increase that was less than a doubling of baseline dose, and 49.8% had at least a doubling of baseline dose.
## Baseline characteristics of patients who experienced worsening HF during follow up

Compared to those with no HHF event during study follow-up, those who eventually experienced a HHF event had at baseline more atrial fibrillation, type 2 diabetes, and prior history of HHF, along with lower systolic blood pressure, estimated glomerular filtration rate and LVEF, and higher NT-proBNP and loop diuretic use (Table 2).

When considering the type of first event in the expanded worsening HF endpoint, first events as inpatient HHF were more likely to be from North America or Eastern Europe, while first events as oral diuretic initiation or intensification were more likely to be from Western Europe, and in participants who have never had a prior HHF, or had lower NT-proBNP levels (Table 3). GDMT use and renal function was comparable across groups.

## Effect of vericiguat on first heart failure hospitalization (Prespecified Secondary Endpoint)

Hospitalization for HF occurred in 348 participants (11.4%) in the vericiguat group and in 362 participants (11.9%) in the placebo group. There was no significant reduction in time to first HHF with vericiguat (HR 0.95; 95%CI 0.82-1.10; p=0.509) (Figure 1A and Table 1).

## First expanded worsening heart failure event (Exploratory Analyses)

When considering the time to first expanded worsening HF event (including HHF and urgent care visits and outpatient worsening HF requiring oral diuretic intensification or initiation), there were 1434 worsening HF events that occurred in 23.5% of
participants, compared to 710 inpatient adjudicated HHF events in 11.6% of participants (Table 1). In the whole population, the first event of the expanded worsening HF composite was comprised mostly of outpatient worsening HF (n=851, 59.3%), followed by HHF (n=507, 35.4%) with fewer urgent HF visits (n=76, 5.3%). Overall worsening HF occurred in 686 participants (22.5%) in the vericiguat group and 748 participants (24.5%) in the placebo group (HR 0.90; 95% CI 0.81-1.00, p=0.047).

The composite of all-cause death and overall worsening HF (HHF, UHF with IV diuretic, oral diuretic intensification or initiation) occurred in 917 participants (30.0%) in the vericiguat group and 1004 participants (32.9%) in the placebo group (HR 0.90, 95% CI 0.82-0.98, p=0.016). The clinical stability composite of all-cause death, overall worsening HF and worsening NYHA functional class occurred in 1022 participants (33.5%) in the vericiguat group and 1113 participants (36.5%) in the placebo group (HR 0.90; 95% CI 0.83-0.98, p=0.016) (Table 1).

In an additional analysis, the composite endpoint of cardiovascular death, overall HF and worsening NYHA functional class occurred in 968 participants (31.7%) in the vericiguat group and 1055 participants (34.6%) in the placebo group (HR 0.90; 95% CI 0.83, 0.98, p=0.018).

Exploratory analysis using the win ratio on CV death, HHF, urgent HF visit and oral diuretic initiation or intensification also favoured the vericiguat group (win ratio 1.12 [95% CI 1.02-1.23], p=0.021) (Figure S2). Sensitivity analyses restricting oral diuretic intensification to larger dose increases ≥50% were consistent with the primary results (Table S4) (Figure S3). Absolute risk reductions and Number Needed to Treat to prevent worsening HF endpoints are provided in Table S5, which
should be considered descriptive and hypothesis-generating. Additional sensitivity analyses evaluating time to expanded worsening HF endpoint while accounting for all-cause mortality or cardiovascular death as competing risks were consistent with the primary results (Table S6,S7, Figure S4).

## Subgroup analyses

Subgroup interaction P values provided below were not corrected for multiplicity of testing and should be considered nominal and exploratory. The treatment estimates of vericiguat on first HHF were consistent across most subgroups, although there were potential interactions suggesting the possibility of greater difference in those <65 years (interaction p=0.005), without ischemic heart disease (interaction p=0.034) and with prior HHF within 6-12 months (interaction p=0.024) (Figure 2a) (Table 4) (Table S8). There was no significant subgroup interaction observed across the expanded worsening HF endpoint (Figure 2b) (Table 4) (Table S9). There were similarly no significant interactions across most tested subgroups for the expanded worsening HF endpoint including all-cause mortality and NYHA class worsening except for nominal significance by baseline use of sacubitril-valsartan (interaction p=0.031) (Figure 2c) (Table 6) (Table S10). Considering the lack of consistent subgroup interaction across the different worsening HF endpoints, and the lack of correction for multiplicity of testing, these results are not suggestive of a clear treatment-subgroup interaction of vericiguat on worsening HF. The treatment estimate of vericiguat on the overall clinical stability endpoint was consistent across the range of baseline NT-proBNP values (Figure 3).
## Changes in natriuretic peptide levels

NT-proBNP trajectory is provided from baseline through week 72, following which there were <30% of participants with available data. NT-proBNP increased over time in both groups among these compensated ambulatory outpatients. However, the longitudinal increase over time was significantly smaller in the vericiguat group compared to placebo (p≤0.001 across weeks 24, 48, and 72), with the geometric mean ratios of vericiguat over placebo decreasing from 0.94 (95% CI 0.91-0.97) to 0.90 (95% CI 0.87-0.94) and 0.89 (95% CI 0.84-0.93) across the Weeks (Figure 4). At 72 weeks, the geometric mean ratio (week 72/baseline) was 0.86 ± 2.29 with vericiguat compared to 1.00 ± 2.37 with placebo which was significantly lower by 11% with vericiguat.

## Relationship between oral diuretic initiation or intensification and outcomes

When examining the relationship between oral diuretic intensification or initiation and subsequent occurrence of the primary endpoint composite (HHF or CV Death), of the 1,115 participants who had an oral diuretic intensification or initiation, 245/1115 (22.0%) experienced the composite event compared to 662/4990 (13.3%) for those who did not have an oral diuretic intensification or initiation event (difference of 8.7 percentage points). This led to participants with oral diuretic intensification or initiation having a RR of 1.66 (95% CI 1.45, 1.89), P<0.001, of experiencing later HHF or CV death compared to those without increased oral diuretic dosing.

Similar results were observed for all-cause death, where 224/1115 (20.1%) who had an oral diuretic intensification or initiation eventually died, compared to
593/4990 (11.9%) who did not have on oral diuretic intensification or initiation
(difference of 8.2 percentage points), RR 1.69 (95% CI 1.47, 1.94, p<0.001).
Discussion

In this exploratory analysis of VICTOR, we provide updated estimates of the risk of worsening HF with contemporary GDMT among compensated, 'stable' outpatients with HFrEF, and determine the potential changes associate with vericiguat in overall worsening HF events across the inpatient and outpatient setting. Although the study cohort included the highest trial utilization of GDMT to date with over 50% of patients on SGLT2i and neprilysin inhibitors, nearly 80% on MRAs, and nearly 95% on beta blockers and ACEi/ARBs, there remained a high residual risk for worsening HF reflected by an annualized HHF event rate of 7.6% in the placebo arm. Notably, traditional time to first HHF endpoint underestimated true overall worsening HF burden in this ambulatory compensated cohort by failing to consider the high proportion of outpatient worsening HF events that represented nearly two-thirds of initial worsening HF events and were prognostically important with subsequent increase in mortality. With these additional outpatient events, the true annualized event rate for overall worsening HF was more than double the time to first HHF rate, at 17.2% in the placebo arm.

With more outpatient worsening HF events relative to HHF in this well-treated
ambulatory HFrEF cohort without recent worsening HF, vericiguat did not reduce
time to first HHF, the traditionally utilized clinical trial endpoint in HF trials to evaluate
worsening HF. However, when considering the totality of worsening HF episodes
across both outpatient and inpatient settings, there was a reduction in the
exploratory endpoint of overall worsening HF driven predominantly by fewer
episodes of outpatient worsening HF requiring oral diuretic augmentation.
Acknowledging the lack of correction for multiplicity of testing, when considering the
high burden of these outpatient worsening HF events which are importantly associated with an increased mortality risk, the exploratory analyses of the changes associated with vericiguat in overall worsening HF including objectively measured natriuretic peptides, and in mortality suggest that vericiguat might mitigate progression of worsening HF among compensated ambulatory outpatients with HFrEF.

## Outpatient worsening HF in contemporary patients with ambulatory HFrEF

Loop diuretics are effective treatments for episodic congestion, and their initiation or intensification generally reflects progression of underlying HF, as evident by the consistent association with poor survival in multiple observational analyses.<sup>6,11,12</sup> These data suggest that outpatient diuretic intensification in a blinded trial may serve as a reliable surrogate endpoint of worsening outpatient HF. Of note, in the current analysis of the most well-treated and compensated ambulatory cohort with HFrEF reported to date, outpatient worsening HF remained the most common worsening HF event and was mitigated by vericiguat. Consistently, vericiguat was associated with favourable changes on clinical stability and NT-proBNP trajectory.

Recognizing the limitations inherent to cross-trial comparisons, it is notable that outpatient worsening appears to be progressively increasing across modern trials of patients with HFrEF which was only 23% of first HF events in PARADIGM-HF with ARNI use, increased to 44% in DAPA-HF and EMPEROR-Reduced with SGLTi use, and was now 59% in VICTOR with both ARNI and SGLT2i use (Central Illustration).<sup>5-7</sup> While the reasons for these potential changes require further study, these may be indicative a practice shift among contemporary patients on excellent GDMT, many of whom have never experienced a prior HHF. This was the case in
the VICTOR trial participants who received the best GDMT reported in all recent HFrEF trials, with almost 30% not on diuretic therapy at baseline and where 79% were in class II NYHA at randomization. Randomized trials with hemodynamic monitoring have also proven that effective outpatient diuretic titration can prevent HHF in patients with HFrEF, effectively shifting worsening HF events from the inpatient to outpatient setting.¹³ Patients on multiple disease modifying drugs may have improved hemodynamic resiliency to paroxysms of volume overload that may allow effective treatment as an outpatient, whereas similar episodes of congestion in historical trials would have required hospitalization and counted as a HHF event. The clinical threshold for admitting a patient experiencing a worsening HF episode may be higher in patients who never experienced a prior HHF, and may vary across health care systems being highest in low- and medium-income countries, where a large proportion of participants were enrolled in VICTOR.¹⁴,¹⁵ Finally, VICTOR is also the first HFrEF trial entirely conducted after the COVID pandemic, which may have increased the clinical threshold for HHF, shifting the usual care towards more outpatient management, Regardless of the reason, this shift in worsening HF events from the inpatient to outpatient setting may result in an underestimation of true worsening HF burden in a trial setting where only HF hospitalization events are counted to quantify worsening HF. Failing to consider these prognostically important outpatient worsening HF episodes may then provide incomplete conclusions on treatment effects in blinded, randomized contemporary trials.

## Worsening HF across the spectrum of HFrEF

In the present VICTOR analysis in a compensated ambulatory HFrEF cohort without recent worsening, vericiguat did not meaningfully lower the risk of the traditional
inpatient HHF (HR 0.95; 95%CI 0.82-1.10, 710 events) with an annualized placebo HHF rate of 7.6%. In contrast, in the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, which enrolled only patients with a recent worsening HHF episode, the annualized placebo event rate of the traditional HHF outcome was 29.1%, more than three-fold higher than in VICTOR, and there was a modest 10% reduction in risk of HHF (HR 0.90; 95%CI 0.81-1.00, 1438 events)¹⁶.

With all the considerations above of a shift in worsening HF events to the outpatient setting in VICTOR, the current analysis provides a potential explanation for the apparent discordant findings on HHF in VICTOR compared to VICTORIA. These results, taken in the context of findings from VICTORIA, suggest that vericiguat may exert greater effects on HHF among those at highest short-term risk for recurrent HHF such as those with recent worsening HF and HHF as in VICTORIA, and potentially the subgroup from VICTOR who had relatively recent HHF 6-12 months prior to randomization. Among the overall cohort of well-compensated patients on excellent contemporary GDMT included in VICTOR, and where nearly half had never been hospitalized for HF, there may be a reduction in worsening HF primarily in the outpatient setting. Combined with the favourable changes in mortality and in the objectively measured NT-proBNP levels associated with vericiguat in VICTOR, these data suggest that vericiguat might have a potential role in addressing the high residual risk of worsening HF in compensated ambulatory patients with HFrEF receiving contemporary GDMT.

## Limitations
This is an analysis of exploratory endpoints in a randomized trial and with no
correction for multiplicity of testing in the individual endpoints and subgroup analyses
which should be considered in interpretation. Oral diuretic initiation or intensification
was captured on case report forms without additional information about worsening
HF and these events were not independently adjudicated. We therefore applied an
objective quantitative definition of diuretic initiation or intensification to capture likely
outpatient worsening HF while minimizing bias in this analysis. Although, there
remains potential for biased diuretic adjustment and ascertainment bias by
investigators with unintentional knowledge of group assignment, vericiguat has no
discernible electrolyte abnormalities or meaningful blood pressure lowering effect
that could result in unintentional unblinding. There may also be regional differences
in practice patterns regarding oral diuretic intensification, but by virtue of
randomization these regional differences were balanced between both treatment
groups. Therefore, in a blinded, randomized trial such as VICTOR there is low risk
for biased diuretic adjustment in the absence of true clinical worsening. Importantly,
the association of these events with adverse prognosis provides additional validity to
their clinical importance as a measure of HF progression, a finding that has been
independently validated in other HFrEF trials⁶,⁷. Consensus about the optimal
analytical approach to evaluate oral diuretic intensification while accounting for the
competing risk of HF hospitalization and death related to worsening HF is still to be
reached. We therefore explored multiple sensitivity analyses and chose to present
composite endpoints of time to first overall worsening HF with and without mortality
included to account for competing risks. We have also separately used the win ratio
method. Regardless, we observed general consistency of results supporting internal validity

## Conclusions

Despite the best existing medical therapy for HFrEF, roughly 1 in 6 patients per year with stable ambulatory HFrEF continue to experience worsening HF, with outpatient worsening events being almost twice as common as HHF events. Although vericiguat did not result in a statistically significant reduction in the per protocol traditional HHF endpoint in VICTOR, there was a reduction in the exploratory endpoint of overall worsening HF when considering the entire patient journey incorporating both outpatient and inpatient HF events. Future clinical trials among ambulatory patients with HF in the modern era of contemporary GDMT should consider outpatient diuretic intensification as part of the composite of worsening HF to better understand treatment effects on the overall patient burden of clinical HF progression.
## References

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6. Docherty KF, Jhund PS, Anand I, et al. Effect of Dapagliflozin on Outpatient Worsening of Patients With Heart Failure and Reduced Ejection Fraction: A Prespecified Analysis of DAPA-HF. *Circulation.* 2020;142:1623-1632.

7. Okumura N, Jhund PS, Gong J, et al. Importance of clinical worsening of heart failure treated in the outpatient setting: Evidence from the prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial (PARADIGM-HF). *Circulation.* 2016;133:2254–2262.
8. 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.

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**Legends**

**Figure 1.** Estimates of the Cumulative Incidence of the HHF Outcomes in the VICTOR trial. Heart Failure Hospitalization (Panel A), Worsening HF Composite: Heart Failure Hospitalization, Urgent Heart Failure Visit, or Oral Diuretic Intensification or Initiation (Panel B), All-Cause Death, HF Hospitalization, UHF Visit, Oral Intensification or Initiation (Panel C), All-Cause Death, HF Hospitalization, UHF Visit, Oral Intensification or Initiation NYHA Functional Class Worsening and Components (Panel D), Cardiovascular (CV) Death, HF Hospitalization, UHF Visit, Oral Intensification or Initiation NYHA Functional Class Worsening and Components (Panel E).

**Figure 2a.** Heart Failure Hospitalizations (HHF) and Composite of First Heart Failure Hospitalization, Urgent Heart Failure Visit (UHF), or Oral Diuretic Intensification or Initiation (ODI) Subgroups Forest Plots for Baseline Characteristics

**Figure 2b.** Heart Failure Hospitalizations and Composite of First Heart Failure Hospitalization, Urgent Heart Failure Visit, or Oral Diuretic Intensification or Initiation Subgroups Forest Plots for Baseline Medical and Device Therapy

**Figure 2c.** All-Cause Death, HF Hospitalization, UHF Visit, Oral Intensification or Initiation, or NYHA Functional Class Worsening and Components

**Figure 3.** Treatment Effect Across the Range of NT-pro-BNP at Randomization: Time-to-First All-Cause Death, HF Hospitalization, UHF Visit, Oral Intensification or Initiation, or NYHA Functional Class Worsening
This clinical endpoint was assessed using the restricted cubic spline with 4 knots and was observed to be nonlinear. Therefore, NT-proBNP was transformed into a logarithmic base 2 scale prior to analysis to achieve linearity. A Cox proportional hazard model stratified by NYHA was used, with hazard ratios (HRs) and 95% Confidence Intervals (CIs) to create the spline

**Figure 4** – Change in natriuretic peptide trajectory over time in vericiguat and placebo groups

**Central Illustration.** Shift in proportion of first HF events due to hospitalization for HF as compared to outpatient worsening or urgent HF visits

Percentage of first expanded HF events that were hospitalization for HF, outpatient worsening or urgent visits presented across PARADIGM HF, DAPA-HF, EMPEROR-Reduced and VICTOR. P values obtained by Chi-square analysis. Data from PARADIGM-HF and DAPA-HF obtained from Okumura N et al Circulation. 2016 Jun 7;133(23):2254-6 and Docherty KF et al Circulation. 2020 Oct 27;142(17):1623-1632 respectively. Data from EMPEROR-Reduced obtained from individual patient data.
<table><caption>Table 1. Primary and Composite 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<br>(95%<br>confidence<br>interval)</th><th rowspan="2">P-<br>Value</th></tr><tr><th>N (%)<br>of<br>events</th><th>Events/100<br>patient-yr</th><th>N (%)<br>of<br>events</th><th>Events/100<br>patient-yr</th></tr></thead><tbody><tr><td colspan="7"><strong>Primary Composite: Time to first Heart Failure Hospitalization or Cardiovascular Death Components</strong></td></tr><tr><td>Composite</td><td>549<br>(18.0)</td><td>11.3</td><td>584<br>(19.1)</td><td>12.2</td><td>0.93 (0.83,<br>1.04)</td><td>0.219</td></tr><tr><td>Cardiovascular<br>death</td><td>201<br>(6.6)</td><td></td><td>222<br>(7.3)</td><td></td><td></td><td></td></tr><tr><td>Heart failure<br>Hospitalization</td><td>348<br>(11.4)</td><td></td><td>362<br>(11.9)</td><td></td><td></td><td></td></tr></tbody></table>
Time to first Heart Failure Hospitalization

Heart Failure Hospitalization 348 (11.4) 7.2 362 (11.9) 7.6 0.95 (0.82, 1.10) 0.509

Expanded Overall Worsening Heart Failure Composite: Heart Failure

Hospitalization, Urgent Heart Failure Visit, Oral Diuretic Intensification or Initiation and Components

Composite 686 (22.5) 15.5 748 (24.8) 17.2 0.90 (0.81, 1.00) 0.047

Heart Failure Hospitalization 256 (8.4)

Urgent Heart Failure Visit 33 (1.1)

Oral Diuretic Intensification or Initiation 397 (13.0) 454 (14.9)
Expanded Overall Worsening Heart Failure Composite with All-cause Death: All-cause Death, Heart Failure Hospitalization, Urgent Heart Failure Visit, Oral Diuretic Intensification or Initiation and Components

<table><tr><td>Composite</td><td>917 (30.0)</td><td>20.7</td><td>1004 (32.9)</td><td>23.1</td><td>0.90 (0.82, 0.98)</td><td>0.016</td></tr><tr><td>All-cause Death</td><td>231 (7.6)</td><td></td><td>257 (8.4)</td><td></td><td></td><td></td></tr><tr><td>Heart Failure Hospitalization</td><td>256 (8.4)</td><td></td><td>251 (8.2)</td><td></td><td></td><td></td></tr><tr><td>Urgent Heart Failure Visit</td><td>33 (1.1)</td><td></td><td>42 (1.4)</td><td></td><td></td><td></td></tr><tr><td>Oral Diuretic Intensification or Initiation</td><td>397 (13.0)</td><td></td><td>454 (14.9)</td><td></td><td></td><td></td></tr></table>
Clinical Stability Composite: All-Cause Death, Heart Failure Hospitalization, Urgent Heart Failure Visit, Oral Intensification or Initiation, or NYHA Functional Class Worsening and Components

<table><tr><td>Composite</td><td>1022<br>(33.5)</td><td>23.9</td><td>1113<br>(36.5)</td><td>26.6</td><td>0.90 (0.83,<br>0.98)</td><td>0.016</td></tr><tr><td>All-Cause<br>Death</td><td>211<br>(6.9)</td><td></td><td>242<br>(7.9)</td><td></td><td></td><td></td></tr><tr><td>Heart Failure<br>Hospitalization</td><td>238<br>(7.8)</td><td></td><td>224<br>(7.3)</td><td></td><td></td><td></td></tr><tr><td>Urgent heart<br>Failure Visit</td><td>30<br>(1.0)</td><td></td><td>42<br>(1.4)</td><td></td><td></td><td></td></tr><tr><td>Oral<br>Intensification<br>or Initiation</td><td>374<br>(12.3)</td><td></td><td>417<br>(13.7)</td><td></td><td></td><td></td></tr></table>
<table><tr><td>NYHA</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Functional</td><td>169</td><td></td><td>188</td><td></td><td></td></tr><tr><td>Class</td><td>(5.5)</td><td></td><td>(6.2)</td><td></td><td></td></tr><tr><td>Worsening</td><td></td><td></td><td></td><td></td><td></td></tr></table>

Clinical Stability Composite with Cardiovascular Death, Heart Failure

Hospitalization, Urgent Heart Failure Visit, Oral Intensification or Initiation, or

NYHA Functional Class Worsening and Components

<table><tr><td>Composite</td><td>968<br>(31.7)</td><td>22.7</td><td>1055<br>(34.6)</td><td>25.2</td><td>0.90 (0.83,<br>0.98)</td><td>0.018</td></tr><tr><td>Cardiovascular<br>Death</td><td>157<br>(5.1)</td><td></td><td>184<br>(6.0)</td><td></td><td></td><td></td></tr><tr><td>Heart Failure<br>Hospitalization</td><td>238<br>(7.8)</td><td></td><td>224<br>(7.3)</td><td></td><td></td><td></td></tr><tr><td>Urgent Heart<br>Failure Visit</td><td>30<br>(1.0)</td><td></td><td>42<br>(1.4)</td><td></td><td></td><td></td></tr></table>
<table><tr><td>Oral Intensification or Initiation</td><td>374 (12.3)</td><td>417 (13.7)</td><td></td><td></td></tr><tr><td>NYHA Functional Class Worsening</td><td>169 (5.5)</td><td>188 (6.2)</td><td></td><td></td></tr></table>

Abbreviations: NYHA -New York Heart Association
<figure><img src="image_4.png" /></figure>
<table><caption>**Table 2.** Baseline characteristics of participants with and without HF Hospitalization events in the VICTOR Trial</caption><thead><tr><th>Characteristic</th><th>No HF<br>Hospitalization<br>(N=5395)</th><th>1<sup>st</sup> HF<br>Hospitalization<br>(N=710)</th></tr></thead><tbody><tr><td>Age (years), mean (SD)</td><td>67.0 (10.9)</td><td>67.0 (11.8)</td></tr><tr><td>Women - no. (%)</td><td>1,294 (24.0)</td><td>146 (20.6)</td></tr><tr><td>Race - no. (%)</td><td></td><td></td></tr><tr><td>White</td><td>3,488 (64.7)</td><td>446 (62.8)</td></tr><tr><td>Black/African American<sup>a</sup></td><td>571 (10.6)</td><td>85 (12.0)</td></tr><tr><td>American Indian or Alaskan</td><td>271 (5.0)</td><td>30 (4.2)</td></tr><tr><td>Native Hawaiian or Pacific Islander</td><td>8 (0.1)</td><td>3 (0.4)</td></tr><tr><td>Asian</td><td>623 (11.5)</td><td>123 (17.3)</td></tr><tr><td>Multiracial</td><td>599 (11.1)</td><td>44 (6.2)</td></tr><tr><td>Not reported</td><td>1 (0.0)</td><td>0</td></tr><tr><td>Geographic Region - no. (%)</td><td></td><td></td></tr></tbody></table>
<table><tr><td>North America</td><td>545 (10.1)</td><td>104 (14.6)</td></tr><tr><td>Latin and South America</td><td>1,650 (30.6)</td><td>125 (17.6)</td></tr><tr><td>Europe</td><td></td><td></td></tr><tr><td>Eastern Europe</td><td>1,492 (27.7)</td><td>208 (29.3)</td></tr><tr><td>Western Europe</td><td>988 (18.3)</td><td>139 (19.6)</td></tr><tr><td>Asia Pacific</td><td>720 (13.3)</td><td>134 (18.9)</td></tr><tr><td>Comorbidities, - no. %</td><td></td><td></td></tr><tr><td>Diabetes</td><td>2,249 (41.7)</td><td>336 (47.3)</td></tr><tr><td>Atrial Fibrillation</td><td>1,990 (36.9)</td><td>327 (46.1)</td></tr><tr><td>Systolic Blood Pressure, mm Hg, mean (SD)</td><td>121.4 (16.1)</td><td>118.6 (15.7)</td></tr><tr><td>Hemoglobin, g/dL, mean (SD)</td><td>14.2 (2.6)</td><td>14.0 (1.9)</td></tr><tr><td>Body mass index, kg/m², mean (SD)</td><td>28.3 (5.6)</td><td>28.8 (5.7)</td></tr><tr><td>NT-proBNP at randomization, pg/mL, median (IQR)</td><td>1,297.5 (793.0, 2199.0)</td><td>2,273.0 (1277.0, 3799.0)</td></tr><tr><td>No prior hospitalization for heart failure - no. (%)</td><td>2,700 (50.0)</td><td>199 (28.0)</td></tr></table>
<table><thead><tr><th></th><th></th><th></th></tr></thead><tbody><tr><td>New York Heart Association class – no. (%)</td><td></td><td></td></tr><tr><td>II</td><td>4,337 (80.4)</td><td>485 (68.3)</td></tr><tr><td>III</td><td>1,045 (19.4)</td><td>223 (31.4)</td></tr><tr><td>IV</td><td>13 (0.2)</td><td>2 (0.3)</td></tr><tr><td>Baseline LVEF, %, mean (SD)</td><td>30.7 (6.9)</td><td>28.1 (7.4)</td></tr><tr><td>eGFR, mL/min/1.73 m<sup>2</sup>, mean (SD)</td><td>71.5 (23.8)</td><td>66.2 (25.3)</td></tr><tr><td>eGFR categories at randomization<sup>b</sup> – no. (%)</td><td></td><td></td></tr><tr><td>&lt;15 mL/min/1.73 m<sup>2</sup></td><td>6 (0.1)</td><td>1 (0.1)</td></tr><tr><td>≥15–&lt;30 mL/min/1.73 m<sup>2</sup></td><td>188 (3.5)</td><td>55 (7.7)</td></tr><tr><td>≥30 to &lt;60 mL/min/1.73 m<sup>2</sup></td><td>1,610 (29.8)</td><td>251 (35.4)</td></tr><tr><td>≥60 mL/min/1.73 m<sup>2</sup></td><td>3,482 (64.5)</td><td>393 (55.4)</td></tr><tr><td>Medical therapy – no. (%)</td><td></td><td></td></tr><tr><td>Loop diuretics<sup>c</sup></td><td>3,657 (67.8)</td><td>603 (84.9)</td></tr><tr><td>Beta-blockers</td><td>5,100 (94.5)</td><td>666 (93.8)</td></tr><tr><td>Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker</td><td>2,129 (39.5)</td><td>209 (29.4)</td></tr></tbody></table>
<table><tr><td>Angiotensin receptor-neprilysin inhibitor</td><td>2,963 (54.9)</td><td>453 (63.8)</td></tr><tr><td>Mineralocorticoid receptor antagonist</td><td>4,218 (78.2)</td><td>530 (74.6)</td></tr><tr><td>Sodium-glucose cotransporter 2 inhibitor</td><td>3,181 (59.0)</td><td>429 (60.4)</td></tr><tr><td>Implantable cardioverter-defibrillator</td><td>1,702 (31.5)</td><td>307 (43.2)</td></tr><tr><td>Cardiac resynchronization therapy</td><td>763 (14.1)</td><td>141 (19.9)</td></tr></table>

a Expanded includes participants who identify as Black, or Multi-racial and Black.

b Missing values: vericiguat = 57, placebo = 62, total = 119

c Loop diuretic use includes Bumetanide, Etacrynic acid, Furosemide, Furosemide sodium, and Torsemide.
<table><caption>**Table 3.** Baseline characteristics of HF Hospitalization, UHF, or ODI as First Events versus No-Events enrolled in the VICTOR Trial</caption><thead><tr><th>Characteristic</th><th>No HF Hospitalization, UHF, or ODI (N=4,671)</th><th>1<sup>st</sup> HF Hospitalization (N=507)</th><th>1<sup>st</sup> UHF (N=76)</th><th>1<sup>st</sup> ODI (N=851)</th></tr></thead><tbody><tr><td>Age (years), mean (SD)</td><td>66.9 (10.9)</td><td>67.2 (11.9)</td><td>68.5 (11.0)</td><td>67.7 (11.1)</td></tr><tr><td>Women - no. (%)</td><td>1,140 (24.4)</td><td>117 (23.1)</td><td>15 (19.7)</td><td>168 (19.7)</td></tr><tr><td>Race - no. (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>White</td><td>2,993 (64.1)</td><td>311 (61.3)</td><td>52 (68.4)</td><td>578 (67.9)</td></tr><tr><td>Black/African American<sup>a</sup></td><td>512 (11.0)</td><td>69 (13.6)</td><td>9 (11.8)</td><td>66 (7.8)</td></tr><tr><td>American Indian or Alaskan</td><td>228 (4.9)</td><td>24 (4.7)</td><td>2 (2.6)</td><td>47 (5.5)</td></tr></tbody></table>
<table><tbody><tr><td>Native Hawaiian or Pacific Islander</td><td>7 (0.1)</td><td>1 (0.2)</td><td>0</td><td>3 (0.4)</td></tr><tr><td>Asian</td><td>534 (11.4)</td><td>88 (17.4)</td><td>8 (10.5)</td><td>116 (13.6)</td></tr><tr><td>Multiracial</td><td>552 (11.8)</td><td>30 (5.9)</td><td>7 (9.2)</td><td>54 (6.3)</td></tr><tr><td>Not reported</td><td>1 (0.0)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Geographic Region – no. (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>North America</td><td>458 (9.8)</td><td>82 (16.2)</td><td>13 (17.1)</td><td>96 (11.3)</td></tr><tr><td>Latin and South America</td><td>1,474 (31.6)</td><td>99 (19.5)</td><td>19 (25.0)</td><td>183 (21.5)</td></tr><tr><td>Europe</td><td></td><td></td><td></td><td></td></tr><tr><td>Eastern Europe</td><td>1,339 (28.7)</td><td>148 (29.2)</td><td>10 (13.2)</td><td>203 (23.9)</td></tr><tr><td>Western Europe</td><td>788 (16.9)</td><td>86 (17.0)</td><td>25 (32.9)</td><td>228 (26.8)</td></tr><tr><td>Asia Pacific</td><td>612 (13.1)</td><td>92 (18.1)</td><td>9 (11.8)</td><td>141 (16.6)</td></tr><tr><td>Hemoglobin, g/dL, mean (SD)</td><td>14.3 (2.7)</td><td>14.0 (1.9)</td><td>14.1 (1.8)</td><td>14.2 (1.95)</td></tr></tbody></table>
<table><tr><td>Time from Randomization to Oral Diuretic intensification or Initiation (days)</td><td>N/A</td><td>315.7 (218.3)</td><td>278.2 (199.1)</td><td>270.3 (222.2)</td></tr><tr><td>Time to Event (Month), mean (SD)</td><td>N/A</td><td>9.7 (7.2)</td><td>9.3 (7.3)</td><td>8.9 (7.3)</td></tr><tr><td>NT-proBNP at Randomization (pg/mL), median (Range)</td><td>1251 (35, 31,500)</td><td>2293 (150, 29,122)</td><td>2057.5 (505, 19,421)</td><td>1711 (180, 16,351)</td></tr><tr><td>No prior hospitalization for heart failure – no. (%)</td><td>2,364 (50.6)</td><td>148 (29.2)</td><td>19 (25.0)</td><td>368 (43.2)</td></tr><tr><td>New York Heart Association class – no. (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>II</td><td>3,768 (80.7)</td><td>359 (70.8)</td><td>51 (67.1)</td><td>644 (75.7)</td></tr><tr><td>III</td><td>890 (19.1)</td><td>146 (28.8)</td><td>25 (32.9)</td><td>207 (24.3)</td></tr><tr><td>IV</td><td>13 (0.3)</td><td>2 (0.4)</td><td>0</td><td>0</td></tr></table>
<table><tr><td>Baseline LVEF, %, mean (SD)</td><td>30.8 (6.9)</td><td>28.0 (7.4)</td><td>29.0 (6.9)</td><td>30.0 (6.85)</td></tr><tr><td>eGFR, mL/min/1.73 m², mean (SD)</td><td>72.2 (23.6)</td><td>66.1 (25.3)</td><td>65.0 (23.5)</td><td>67.0 (24.7)</td></tr><tr><td>eGFR categories at randomization<sup>b</sup> – no. (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;15 mL/min/1.73 m²</td><td>6 (0.1)</td><td>1 (0.2)</td><td>0</td><td>0</td></tr><tr><td>≥15–&lt;30 mL/min/1.73 m²</td><td>143 (3.1)</td><td>42 (8.3)</td><td>2 (2.6)</td><td>56 (6.6)</td></tr><tr><td>≥30 to &lt;60 mL/min/1.73 m²</td><td>1,376 (29.5)</td><td>173 (34.1)</td><td>33 (43.4)</td><td>279 (32.8)</td></tr><tr><td>≥60 mL/min/1.73 m²</td><td>3,055 (65.4)</td><td>283 (55.8)</td><td>36 (47.4)</td><td>501 (58.9)</td></tr><tr><td>Missing</td><td>91 (1.9)</td><td>8 (1.6)</td><td>5 (6.6)</td><td>15 (1.8)</td></tr><tr><td>Time of Primary Diagnosis of HF</td><td>5.8 (6.1)</td><td>7.7 (7.3)</td><td>8.1 (6.4)</td><td>6.6 (6.8)</td></tr></table>
<table><tr><td>with Reduced Election Fraction to Randomization (years), mean (SD)</td><td></td><td></td><td></td><td></td></tr><tr><td>Time of Earliest Diagnosis of HF to Randomization (with or without Reduced Election Fraction) (Years), mean (SD)</td><td>5.9 (6.2)</td><td>7.9 (7.3)</td><td>8.3 (6.6)</td><td>6.7 (6.9)</td></tr><tr><td>Medical therapy – no. (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>GDMT Classes</td><td></td><td></td><td></td><td></td></tr><tr><td>0-2</td><td>736 (15.8)</td><td>101 (19.9)</td><td>14 (18.4)</td><td>156 (18.3)</td></tr><tr><td>3</td><td>1,841 (39.4)</td><td>194 (38.3)</td><td>26 (34.2)</td><td>325 (38.2)</td></tr><tr><td>4-5</td><td>2,094 (44.8)</td><td>212 (41.8)</td><td>36 (47.4)</td><td>370 (43.5)</td></tr><tr><td>Use of GDMT at Baseline</td><td>4,668 (99.9)</td><td>506 (99.8)</td><td>76 (100.0)</td><td>849 (99.8)</td></tr><tr><td>ARNI and SGLT2i</td><td>1,842 (39.4)</td><td>200 (39.4)</td><td>38 (50.0)</td><td>383 (45.0)</td></tr></table>
<table><tr><td>ARNI or SGLT2i</td><td>3,438 (73.6)</td><td>413 (81.5)</td><td>64 (84.2)</td><td>648 (76.1)</td></tr><tr><td>Beta Blockers</td><td>4,416 (94.5)</td><td>480 (94.7)</td><td>69 (90.8)</td><td>801 (94.1)</td></tr><tr><td>Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker</td><td>1,874 (40.1)</td><td>154 (30.4)</td><td>21 (27.6)</td><td>289 (34.0)</td></tr><tr><td>Mineralocorticoid receptor antagonist</td><td>3,690 (79.0)</td><td>374 (73.8)</td><td>58 (76.3)</td><td>626 (73.6)</td></tr><tr><td>Angiotensin receptor- neprilysin inhibitor</td><td>2,540 (54.4)</td><td>315 (62.1)</td><td>54 (71.1)</td><td>507 (59.6)</td></tr><tr><td>Sodium-glucose cotransporter 2 inhibitor</td><td>2,740 (58.7)</td><td>298 (58.8)</td><td>48 (63.2)</td><td>524 (61.6)</td></tr><tr><td>Thiazide Initiation</td><td>N/A</td><td>27 (5.3)</td><td>4 (5.3)</td><td>68 (8.0)</td></tr><tr><td>Loop Diuretic Initiation or Intensification<sup>b</sup></td><td>N/A</td><td>217 (42.8)</td><td>41 (53.9)</td><td>817 (96.0)</td></tr></table>
<sup>a</sup> Expanded includes participants who identify as Black, or Multi-racial and Black.

<sup>b</sup> Loop diuretic use includes Bumetanide, Etacrynic acid, Furosemide, Furosemide sodium, and Torsemide. N/A=Not Applicable for those who had no events.

eGFR, estimated glomerular filtration rate; GDMT, guideline-directed medical therapy; IQR, interquartile range; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-B-type natriuretic peptide; SD, standard deviation
<table><caption>**Table 4.** Heart Failure Hospitalization by baseline medical and device therapy</caption><thead><tr><th rowspan="2"></th><th colspan="3">Vericiguat (n=3,053)</th><th colspan="3">Placebo (n=3,052)</th><th colspan="2">Treatment Comparison</th></tr><tr><th>n/m<br>(%)</th><th>Events/<br>100 PY</th><th>KM %<br>(95% CI)</th><th>n/m<br>(%)</th><th>Events/<br>100 PY</th><th>KM %<br>(95% CI)</th><th>HR<br>(95% CI)</th><th>Treatment by<br>Subgroup P-<br>Value</th></tr></thead><tbody><tr><td colspan="9"><strong>Sacubitril/Valsartan (ARNI)</strong></td></tr><tr><td>Yes</td><td>223/1734<br>(12.9)</td><td>8.2</td><td>17.2<br>(14.7, 20.0)</td><td>230/1682<br>(13.7)</td><td>8.8</td><td>19.2<br>(16.6, 22.2)</td><td>0.93<br>(0.78,1.12)</td><td>0.812</td></tr><tr><td>No</td><td>125/1319<br>(9.5)</td><td>5.9</td><td>14.1<br>(11.6, 17.3)</td><td>132/1370<br>(9.6)</td><td>6.1</td><td>13.9 (11.4,<br>16.8)</td><td>0.97<br>(0.76,1.24)</td><td></td></tr><tr><td colspan="9"><strong>SGLI2i</strong></td></tr><tr><td>Yes</td><td>213/1812<br>(11.8)</td><td>7.6</td><td>17.9<br>(14.9, 21.4)</td><td>216/1798<br>(12.0)</td><td>7.8</td><td>16.8<br>(14.4, 19.7)</td><td>0.98<br>(0.81,1.18)</td><td>0.674</td></tr><tr><td>No</td><td>135/1241<br>(10.9)</td><td>6.6</td><td>14.1<br>(11.8, 16.7)</td><td>146/1254<br>(11.6)</td><td>7.2</td><td>16.5<br>(13.9, 19.6)</td><td>0.91<br>(0.72,1.16)</td><td></td></tr></tbody></table>
Loop Diuretic

<table><tr><td rowspan="2">Yes</td><td>294/2131 (13.8)</td><td>8.7</td><td>19.2 (16.9, 21.8)</td><td>309/2129 (14.5)</td><td>9.4</td><td>20.0 (17.7, 22.6)</td><td>0.92 (0.79,1.08)</td><td>0.537</td></tr><tr><td>54/922 (5.9)</td><td>3.7</td><td>7.0 (5.2, 9.2)</td><td>53/923 (5.7)</td><td>3.6</td><td>9.1 (6.3, 13.1)</td><td>1.05 (0.72,1.54)</td><td></td></tr><tr><td>No</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr></table>

ICD

<table><tr><td rowspan="2">Yes</td><td>141/993 (14.2)</td><td>8.8</td><td>19.0 (15.9, 22.8)</td><td>166/1016 (16.3)</td><td>10.0</td><td>21.1 (18.0, 24.7)</td><td>0.86 (0.68,1.07)</td><td>0.212</td></tr><tr><td>207/2060 (10.0)</td><td>6.4</td><td>14.2 (12.1, 16.7)</td><td>196/2036 (9.6)</td><td>6.3</td><td>14.3 (12.2, 16.9)</td><td>1.04 (0.85,1.26)</td><td></td></tr><tr><td>No</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr></table>

Number of GDMT

<table><tr><td rowspan="2">0-2</td><td>62/506 (12.3)</td><td>7.6</td><td>14.4 (11.2, 18.5)</td><td>70/501 (14.0)</td><td>9.2</td><td>18.8 (14.7, 23.9)</td><td>0.84 (0.59,1.18)</td><td>0.721</td></tr><tr><td>135/1183 (11.4)</td><td>7.0</td><td>15.5 (12.9, 18.5)</td><td>139/1203 (11.6)</td><td>7.2</td><td>16.5 (13.7, 19.8)</td><td>0.98 (0.77,1.24)</td><td></td></tr><tr><td>3</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr></table>
<table><tbody><tr><td>4-5</td><td>151/1364 (11.1)</td><td>7.2</td><td>17.8 (14.2, 22.3)</td><td>153/1348 (11.4)</td><td>7.4</td><td>16.2 (13.4, 19.6)</td><td>0.98 (0.78,1.23)</td><td></td></tr><tr><td colspan="9">ACE-I/ARB</td></tr><tr><td>Yes</td><td>103/1150 (9.0)</td><td>5.6</td><td>14.0 (11.2, 17.5)</td><td>106/1188 (8.9)</td><td>5.6</td><td>13.3 (10.7, 16.5)</td><td>1.00 (0.77,1.32)</td><td>0.602</td></tr><tr><td>No</td><td>245/1903 (12.9)</td><td>8.2</td><td>17.0 (14.7, 19.6)</td><td>256/1864 (13.7)</td><td>8.9</td><td>19.0 (16.6, 21.9)</td><td>0.92 (0.77,1.10)</td><td></td></tr><tr><td colspan="9">Beta-Blockers</td></tr><tr><td>Yes</td><td>327/2886 (11.3)</td><td>7.1</td><td>15.9 (14.0, 18.0)</td><td>339/2880 (11.8)</td><td>7.5</td><td>16.8 (14.9, 18.9)</td><td>0.96 (0.82,1.11)</td><td>0.719</td></tr><tr><td>No</td><td>21/167 (12.6)</td><td>7.9</td><td>15.3 (9.3, 24.9)</td><td>23/172 (13.4)</td><td>8.9</td><td>16.7 (10.8, 25.4)</td><td>0.86 (0.47,1.55)</td><td></td></tr><tr><td colspan="9">MRA</td></tr><tr><td>Yes</td><td>260/2358 (11.0)</td><td>7.0</td><td>16.0 (13.8, 18.5)</td><td>270/2390 (11.3)</td><td>7.2</td><td>16.2 (14.1, 18.6)</td><td>0.97 (0.81,1.14)</td><td>0.704</td></tr></tbody></table>
<table><tr><td>No</td><td>88/695 (12.7)</td><td>8.0</td><td>15.6 (12.6, 19.3)</td><td>92/662 (13.9)</td><td>9.0</td><td>18.9 (15.2, 23.3)</td><td>0.90 (0.67,1.21)</td></tr></table>

CI = confidence interval, eGFR = estimated glomerular filtration rate, GDMT = guideline-directed medical therapy, HFH = heart failure hospitalization, HR = hazard ratio, ICD = implantable cardioverter defibrillator, KM = Kaplan Meier estimate, NE = Not Estimable, LVEF = left ventricular ejection fraction, PY = patient-year, SGLT2i = sodium-glucose cotransporter 2 inhibitor
<table><caption>**Table 5.** Heart Failure Hospitalization, Urgent Heart Failure Visit, or Oral Diuretic Intensification or Initiation by baseline medical and device therapy</caption><thead><tr><th rowspan="2"></th><th colspan="3">Vericiguat (n=3,053)</th><th colspan="3">Placebo (n=3,052)</th><th colspan="2">Treatment Comparison</th></tr><tr><th>n/m<br>(%)</th><th>Events/<br>100 PY</th><th>KM %<br>(95% CI)</th><th>n/m<br>(%)</th><th>Events/<br>100 PY</th><th>KM %<br>(95% CI)</th><th>HR<br>(95% CI)</th><th>Treatment by<br>Subgroup P-<br>Value</th></tr></thead><tbody><tr><td colspan="9"><strong>Sacubitril/Valsartan (ARNI)</strong></td></tr><tr><td>Yes</td><td>413/1734<br>(23.8)</td><td>16.6</td><td>29.4 (26.6,<br>32.4)</td><td>463/1682<br>(27.5)</td><td>19.8</td><td>37.4 (33.9,<br>41.0)</td><td>0.84<br>(0.74,0.96)</td><td rowspan="2">0.138</td></tr><tr><td>No</td><td>273/1319<br>(20.7)</td><td>14.1</td><td>27.1 (24.0,<br>30.5)</td><td>285/1370<br>(20.8)</td><td>14.3</td><td>28.4 (25.2,<br>32.0)</td><td>0.99<br>(0.84,1.17)</td></tr><tr><td colspan="9"><strong>SGLT2i</strong></td></tr><tr><td>Yes</td><td>413/1812<br>(22.8)</td><td>16.2</td><td>29.3 (26.3,<br>32.6)</td><td>457/1798<br>(25.4)</td><td>18.4</td><td>35.5 (32.0,<br>39.2)</td><td>0.89<br>(0.78,1.01)</td><td>0.705</td></tr></tbody></table>
<table><tbody><tr><td>No</td><td>273/1241<br>(22.0)</td><td>14.5</td><td>27.4 (24.4,<br>30.7)</td><td>291/1254<br>(23.2)</td><td>15.8</td><td>30.7 (27.4,<br>34.3)</td><td>0.92<br>(0.78,1.09)</td><td></td></tr><tr><td colspan="9">Loop Diuretic</td></tr><tr><td>Yes</td><td>526/2131<br>(24.7)</td><td>17.1</td><td>31.2 (28.6,<br>34.0)</td><td>567/2129<br>(26.6)</td><td>18.9</td><td>35.5 (32.7,<br>38.5)</td><td>0.90<br>(0.80,1.02)</td><td>0.892</td></tr><tr><td>No</td><td>160/922<br>(17.4)</td><td>11.9</td><td>20.9 (17.9,<br>24.4)</td><td>181/923<br>(19.6)</td><td>13.6</td><td>28.0 (23.5,<br>33.2)</td><td>0.89<br>(0.72,1.10)</td><td></td></tr><tr><td colspan="9">Presence of ICD Therapy</td></tr><tr><td>Yes</td><td>282/993<br>(28.4)</td><td>19.9</td><td>35.3 (31.5,<br>39.4)</td><td>326/1016<br>(32.1)</td><td>22.2</td><td>40.4 (36.5,<br>44.6)</td><td>0.88<br>(0.75,1.03)</td><td>0.644</td></tr><tr><td>No</td><td>404/2060<br>(19.6)</td><td>13.5</td><td>24.8 (22.3,<br>27.4)</td><td>422/2036<br>(20.7)</td><td>14.7</td><td>29.1 (26.2,<br>32.3)</td><td>0.92<br>(0.81,1.06)</td><td></td></tr><tr><td colspan="9">Number of GDMT</td></tr><tr><td>0-2</td><td>127/506<br>(25.1)</td><td>17.4</td><td>29.4 (25.0,<br>34.3)</td><td>144/501<br>(28.7)</td><td>21.4</td><td>36.7 (31.4,<br>42.6)</td><td>0.82<br>(0.65,1.04)</td><td>0.153</td></tr></tbody></table>
<table><tr><td rowspan="2">3</td><td>274/1183<br>(23.2)</td><td rowspan="2">15.6</td><td>29.0 (25.8,<br>32.5)</td><td>271/1203<br>(22.5)</td><td rowspan="2">15.2</td><td>30.9 (27.3,<br>34.8)</td><td>1.02<br>(0.87,1.21)</td></tr><tr><td>285/1364<br>(20.9)</td><td>27.9 (24.3,<br>31.9)</td><td>333/1348<br>(24.7)</td><td>34.3 (30.4,<br>38.5)</td><td>0.83<br>(0.71,0.98)</td></tr><tr><td>4-5</td><td></td><td>14.7</td><td></td><td></td><td>17.7</td><td></td><td></td></tr></table>

ACE-I/ARB

<table><tr><td rowspan="2">Yes</td><td>228/1150<br>(19.8)</td><td rowspan="2">13.5</td><td>26.4 (23.0,<br>30.1)</td><td>236/1188<br>(19.9)</td><td rowspan="2">13.4</td><td>27.8 (24.3,<br>31.7)</td><td>1.00<br>(0.84,1.20)</td><td rowspan="2">0.137</td></tr><tr><td>458/1903<br>(24.1)</td><td>29.6 (26.9,<br>32.4)</td><td>512/1864<br>(27.5)</td><td>36.9 (33.7,<br>40.3)</td><td>0.85<br>(0.75,0.96)</td></tr><tr><td>No</td><td></td><td>16.7</td><td></td><td></td><td>19.9</td><td></td><td></td></tr></table>

Beta-Blockers

<table><tr><td rowspan="2">Yes</td><td>644/2886<br>(22.3)</td><td rowspan="2">15.4</td><td>28.4 (26.2,<br>30.7)</td><td>706/2880<br>(24.5)</td><td rowspan="2">17.2</td><td>33.3 (30.8,<br>35.9)</td><td>0.90<br>(0.81,1.00)</td><td rowspan="2">0.751</td></tr><tr><td>42/167 (25.1)</td><td>28.7 (21.2,<br>38.3)</td><td>42/172<br>(24.4)</td><td>33.5 (24.2,<br>45.0)</td><td>0.96<br>(0.63,1.48)</td></tr><tr><td>No</td><td></td><td>17.7</td><td></td><td></td><td>18.0</td><td></td><td></td></tr></table>

MRA
<table><tr><td rowspan="2">Yes</td><td>503/2358</td><td rowspan="2">14.6</td><td>27.8 (25.3,</td><td>555/2390</td><td rowspan="2">16.2</td><td>31.9 (29.2,</td><td>0.90</td><td rowspan="2">0.840</td></tr><tr><td>(21.3)</td><td>30.4)</td><td>(23.2)</td><td>34.7)</td><td>(0.80,1.02)</td></tr><tr><td rowspan="2">No</td><td>183/695</td><td rowspan="2">18.8</td><td>30.5 (26.7,</td><td>193/662</td><td rowspan="2">21.3</td><td>38.3 (33.3,</td><td>0.88</td><td></td></tr><tr><td>(26.3)</td><td>34.8)</td><td>(29.2)</td><td>43.8)</td><td>(0.72,1.08)</td><td></td></tr></table>

CI = confidence interval, eGFR = estimated glomerular filtration rate, GDMT = guideline-directed medical therapy, HFH = heart failure hospitalization, HR = hazard ratio, ICD = implantable cardioverter defibrillator, KM = Kaplan Meier estimate, NE = Not Estimable, LVEF = left ventricular ejection fraction, PY = patient-year, SGLT2i = sodium-glucose cotransporter 2 inhibitor
<table><caption>**Table 6.** All-Cause Death, HF Hospitalization, UHF Visit, Oral Intensification or Initiation, or NYHA Functional Class
Worsening by baseline medical and device therapy</caption><tbody><tr><th colspan="9">Use of Sacubitril/Valsartan (ARNI)</th></tr><tr><td>Yes</td><td>578/1734<br>(33.3)</td><td>23.9</td><td>41.7 (38.4,<br>45.0)</td><td>651/1682<br>(38.7)</td><td>29.0</td><td>49.4 (45.9,<br>53.0)</td><td>0.83<br>(0.74,0.93)</td><td>0.031</td></tr><tr><td>No</td><td>444/1319<br>(33.7)</td><td>23.9</td><td>41.8 (38.3,<br>45.5)</td><td>462/1370<br>(33.7)</td><td>23.8</td><td>43.6 (40.0,<br>47.3)</td><td>1.00<br>(0.88,1.14)</td><td></td></tr><tr><th colspan="9">SGLI2i</th></tr><tr><td>Yes</td><td>582/1812<br>(32.1)</td><td>23.7</td><td>40.4 (37.1,<br>43.9)</td><td>644/1798<br>(35.8)</td><td>26.7</td><td>47.3 (43.8,<br>51.0)</td><td>0.89<br>(0.79,0.99)</td><td>0.667</td></tr><tr><td>No</td><td>440/1241<br>(35.5)</td><td>24.3</td><td>43.1 (39.7,<br>46.8)</td><td>469/1254<br>(37.4)</td><td>26.4</td><td>46.1 (42.5,<br>49.8)</td><td>0.92<br>(0.81,1.05)</td><td></td></tr><tr><th colspan="9">Loop Diuretic</th></tr><tr><td>Yes</td><td>766/2131<br>(35.9)</td><td>25.7</td><td>43.9 (41.1,<br>46.8)</td><td>865/2129<br>(40.6)</td><td>30.0</td><td>50.8 (47.8,<br>53.8)</td><td>0.86<br>(0.78,0.95)</td><td>0.055</td></tr></tbody></table>
<table><tbody><tr><td>No</td><td>256/922<br>(27.8)</td><td>19.8</td><td>36.1 (31.7,<br>40.9)</td><td>248/923<br>(26.9)</td><td>19.0</td><td>36.2 (31.6,<br>41.2)</td><td>1.04<br>(0.88,1.24)</td><td></td></tr><tr><td colspan="9">ICD Therapy</td></tr><tr><td>Yes</td><td>376/993<br>(37.9)</td><td>27.6</td><td>46.5 (42.4,<br>50.9)</td><td>427/1016<br>(42.0)</td><td>30.3</td><td>50.7 (46.8,<br>54.7)</td><td>0.90<br>(0.78,1.03)</td><td>0.930</td></tr><tr><td>No</td><td>646/2060<br>(31.4)</td><td>22.2</td><td>39.2 (36.4,<br>42.3)</td><td>686/2036<br>(33.7)</td><td>24.7</td><td>44.6 (41.4,<br>48.0)</td><td>0.91<br>(0.81,1.01)</td><td></td></tr><tr><td colspan="9">Number of GDMT</td></tr><tr><td>0-2</td><td>208/506<br>(41.1)</td><td>29.8</td><td>48.2 (42.8,<br>53.8)</td><td>217/501<br>(43.3)</td><td>33.5</td><td>52.1 (46.5,<br>58.0)</td><td>0.89<br>(0.74,1.08)</td><td>0.711</td></tr><tr><td>3</td><td>397/1183<br>(33.6)</td><td>23.3</td><td>41.3 (37.7,<br>45.1)</td><td>426/1203<br>(35.4)</td><td>24.8</td><td>44.8 (41.0,<br>48.8)</td><td>0.94<br>(0.82,1.08)</td><td></td></tr><tr><td>4-5</td><td>417/1364<br>(30.6)</td><td>22.3</td><td>39.5 (35.6,<br>43.6)</td><td>470/1348<br>(34.9)</td><td>25.8</td><td>46.4 (42.4,<br>50.6)</td><td>0.87<br>(0.76,0.99)</td><td></td></tr><tr><td colspan="9">ACE-I/ARB</td></tr></tbody></table>
<table><tbody><tr><td></td><td>379/1150<br>(33.0)</td><td>23.4</td><td>41.4 (37.6,<br>45.5)</td><td>385/1188<br>(32.4)</td><td>22.5</td><td>42.8 (39.0,<br>46.9)</td><td>1.03<br>(0.90,1.19)</td><td rowspan="2">0.015</td></tr><tr><td></td><td>643/1903<br>(33.8)</td><td>24.2</td><td>41.8 (38.8,<br>45.0)</td><td>728/1864<br>(39.1)</td><td>29.4</td><td>49.2 (46.0,<br>52.6)</td><td>0.83<br>(0.75,0.92)</td></tr><tr><td colspan="9"><strong>Beta-Blockers</strong></td></tr><tr><td></td><td>951/2886<br>(33.0)</td><td>23.5</td><td>41.1 (38.7,<br>43.6)</td><td>1045/2880<br>(36.3)</td><td>26.4</td><td>46.4 (43.8,<br>49.0)</td><td>0.89<br>(0.82,0.98)</td><td rowspan="2">0.547</td></tr><tr><td></td><td>71/167 (42.5)</td><td>30.8</td><td>50.4 (40.8,<br>60.9)</td><td>68/172<br>(39.5)</td><td>30.6</td><td>52.1 (40.6,<br>64.6)</td><td>0.99<br>(0.71,1.39)</td></tr><tr><td colspan="9"><strong>MRA</strong></td></tr><tr><td></td><td>756/2358<br>(32.1)</td><td>22.7</td><td>40.7 (37.9,<br>43.6)</td><td>838/2390<br>(35.1)</td><td>25.3</td><td>45.3 (42.5,<br>48.3)</td><td>0.90<br>(0.81,0.99)</td><td rowspan="2">0.977</td></tr><tr><td></td><td>266/695<br>(38.3)</td><td>28.4</td><td>45.0 (40.4,<br>49.9)</td><td>275/662<br>(41.5)</td><td>31.7</td><td>51.6 (46.3,<br>57.1)</td><td>0.90<br>(0.76,1.06)</td></tr></tbody></table>

CI = confidence interval, eGFR = estimated glomerular filtration rate, GDMT = guideline-directed medical therapy, HFH = heart failure hospitalization, HR = hazard ratio, ICD = implantable cardioverter defibrillator, KM = Kaplan Meier estimate,
NE = Not Estimable, LVEF = left ventricular ejection fraction, PY = patient-year, SGLT2i = sodium-glucose cotransporter 2 inhibitor

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

<figure><img src="image_6.png" /></figure>

No. of participants at risk

<table><tr><td>Vericiguat</td><td>3,053</td><td>2,926</td><td>2,796</td><td>2,581</td><td>1,917</td><td>1,352</td><td>849</td><td>459</td></tr><tr><td>Placebo</td><td>3,052</td><td>2,929</td><td>2,771</td><td>2,543</td><td>1,879</td><td>1,313</td><td>822</td><td>442</td></tr></table>

Cumulative no. of events up to the time point

<table><tr><td>Vericiguat</td><td>0</td><td>77</td><td>151</td><td>218</td><td>262</td><td>299</td><td>323</td><td>334</td></tr><tr><td>Placebo</td><td>0</td><td>72</td><td>152</td><td>223</td><td>273</td><td>319</td><td>343</td><td>356</td></tr></table>

B

<figure><img src="image_7.png" /></figure>

No. of participants at risk

<table><tr><td>Vericiguat</td><td>3,053</td><td>2,795</td><td>2,601</td><td>2,346</td><td>1,699</td><td>1,161</td><td>702</td><td>374</td></tr><tr><td>Placebo</td><td>3,052</td><td>2,796</td><td>2,545</td><td>2,280</td><td>1,644</td><td>1,111</td><td>682</td><td>358</td></tr></table>

Cumulative no. of events up to the time point

<table><tr><td>Vericiguat</td><td>0</td><td>211</td><td>356</td><td>478</td><td>556</td><td>621</td><td>661</td><td>674</td></tr><tr><td>Placebo</td><td>0</td><td>207</td><td>395</td><td>519</td><td>597</td><td>673</td><td>714</td><td>742</td></tr></table>

C

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

No. of participants at risk

<table><tr><td>Vericiguat</td><td>3,053</td><td>2,796</td><td>2,602</td><td>2,346</td><td>1,699</td><td>1,161</td><td>703</td><td>374</td></tr><tr><td>Placebo</td><td>3,052</td><td>2,796</td><td>2,545</td><td>2,280</td><td>1,644</td><td>1,112</td><td>684</td><td>359</td></tr></table>

Cumulative no. of events up to the time point

<table><tr><td>Vericiguat</td><td>0</td><td>254</td><td>444</td><td>611</td><td>727</td><td>806</td><td>870</td><td>898</td></tr><tr><td>Placebo</td><td>0</td><td>248</td><td>495</td><td>668</td><td>792</td><td>896</td><td>954</td><td>994</td></tr></table>

D

<figure><img src="image_9.png" /></figure>

No. of participants at risk

<table><tr><td>Vericiguat</td><td>3,053</td><td>2,744</td><td>2,518</td><td>2,247</td><td>1,632</td><td>1,107</td><td>656</td><td>348</td></tr><tr><td>Placebo</td><td>3,052</td><td>2,749</td><td>2,465</td><td>2,187</td><td>1,578</td><td>1,048</td><td>637</td><td>336</td></tr></table>

Cumulative no. of events up to the time point

<table><tr><td>Vericiguat</td><td>0</td><td>306</td><td>528</td><td>714</td><td>820</td><td>908</td><td>979</td><td>1,005</td></tr><tr><td>Placebo</td><td>0</td><td>295</td><td>575</td><td>764</td><td>885</td><td>1,004</td><td>1,065</td><td>1,104</td></tr></table>

E

<figure><img src="image_10.png" /></figure>

No. of participants at risk

<table><tr><td>Vericiguat</td><td>3,053</td><td>2,744</td><td>2,518</td><td>2,247</td><td>1,632</td><td>1,107</td><td>655</td><td>348</td></tr><tr><td>Placebo</td><td>3,052</td><td>2,749</td><td>2,465</td><td>2,187</td><td>1,578</td><td>1,048</td><td>636</td><td>335</td></tr></table>

Cumulative no. of events up to the time point

<table><tr><td>Vericiguat</td><td>0</td><td>294</td><td>511</td><td>687</td><td>783</td><td>866</td><td>930</td><td>951</td></tr><tr><td>Placebo</td><td>0</td><td>288</td><td>554</td><td>731</td><td>842</td><td>950</td><td>1,009</td><td>1,047</td></tr></table>
A

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

<figure><img src="image_12.png" /></figure>
B

<figure><img src="image_13.png" /></figure>

<figure><img src="image_14.png" /></figure>
C

<figure><img src="image_15.png" /></figure>

<figure><img src="image_16.png" /></figure>
<figure><img src="image_17.png" /></figure>

<figure><img src="image_18.png" /></figure>
<figure><img src="image_19.png" /></figure>

<figure><img src="image_20.png" /></figure>
<figure><img src="image_21.png" /></figure>

p<0.0001

<figure><img src="image_22.png" /></figure>

p<0.0001

<figure><img src="image_23.png" /></figure>

PARADIGM-HF
(n=1546 first HF events)

<figure><img src="image_24.png" /></figure>

DAPA-HF
(n=916 first HF events)

<figure><img src="image_25.png" /></figure>

EMPEROR
(n=813 first HF events)

<figure><img src="image_26.png" /></figure>

VICTOR
(n=1434 first HF events)

<figure><img src="image_27.png" /></figure>