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. 2025 Aug 29:S0140-6736(25)01682-4.
doi: 10.1016/S0140-6736(25)01682-4. Online ahead of print.

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

Faiez Zannad  1 , Christopher M O'Connor  2 , Javed Butler  3 , Ciaran J McMullan  4 , Kevin J Anstrom  5 , Irina Barash  4 , Marc P Bonaca  6 , Maria Borentain  7 , Stefano Corda  8 , Davis Gates  4 , Justin A Ezekowitz  9 , Adrian F Hernandez  10 , Carolyn S P Lam  11 , Eldrin F Lewis  12 , JoAnn Lindenfeld  13 , Robert J Mentz  10 , Piotr Ponikowski  14 , Yogesh N V Reddy  15 , Giuseppe M C Rosano  16 , Clara Saldarriaga  17 , Michele Senni  18 , Pedro P Teixeira  19 , James Udelson  20 , Alessia Urbinati  4 , Vanja Vlajnic  7 , Adriaan A Voors  21 , Aiwen Xing  4 , Mahesh J Patel  4 , Paul W Armstrong  9 ; VICTORIA and VICTOR Study Groups
Collaborators, Affiliations

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

Faiez Zannad et al. Lancet. .

Abstract

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

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

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

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

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

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Conflict of interest statement

Declaration of interests FZ reports personal fees from Alnylam Pharmaceuticals, Bayer, Biopeutics, Boehringer Ingelheim, CellProthera, Cereno Scientific, Corteria, CVRx, Merck, Owkin, Ribocure Pharmaceuticals, and Roche; reports payment or honoraria for lectures, presentations, speakers bureaus, or educational events from Bayer, Boehringer Ingelheim, Centrix, CVRx, Lupin, Opalia Recordati, Merck, Novo Nordisk, and Viatris; participates in a data safety monitoring board or advisory board for Merck/Acceleron; has equities at G3Pharmaceutical, Cereno Scientific, and Eshmoun Clinical Research; and is the founder of Global CardioVascular Clinical Trialists. CMO has received consulting fees from Abiomed, Merck, and ZealCare. JB has received consulting fees from Abbott Laboratories, American Regent, Amgen, Applied Therapeutics, AskBio, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, CardioCell, Cardior, Cardiorem, CSL Behring, CVRx, Cytokinetics, Daxor, Edwards Lifesciences, Element Science, Faraday Pharmaceuticals, The Foundry, G3P, Innolife, Impulse Dynamics, Imbria Pharmaceuticals, Inventiva Pharma, Ionis Pharmaceuticals, Lexicon Pharmaceuticals, Lilly, LivaNova, Janssen Pharmaceuticals, Medtronic, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, PharmaIN, Prolaio, Regeneron Pharmaceuticals, Renibus Therapeutics, Roche, Salamandra, Sanofi, scPharmaceuticals, Secretome Therapeutics, Sequana Medical, SQ Innovation, Tenex Therapeutics, Tricog Health, Ultromics, Vifor Pharma, and ZOLL Medical; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novartis, Boehringer Ingelheim-Lilly, AstraZeneca, Impulse Dynamics, and Vifor Pharma. CJM, IB, DG, AU, AX, and MJP are employees of Merck Sharp & Dohme (a subsidiary of Merck) and hold stock options in Merck. KJA has received research grants from Merck and the National Institutes of Health and participates in several data safety monitoring boards outside of the heart failure disease area. MPB is the executive director of CPC, a non-profit academic research organisation affiliated with the University of Colorado, that receives or has received research grant and/or consulting funding between August, 2021, and the present from Abbott Laboratories, Agios Pharmaceuticals, Alexion Pharma, Alnylam Pharmaceuticals, Amgen, Angionetics, Anthos Therapeutics, Array BioPharma, AstraZeneca and Affiliates, Atentiv, Audentes Therapeutics, Bayer and Affiliates, Bristol Myers Squibb, Cambrian Bio, Cardiol Therapeutics, CellResearch, Cleerly, Cook Regentec, CSL Behring, Eidos Therapeutics, EP Trading, Epizon Pharma, Esperion Therapeutics, Everlywell, Exicon Consulting, Faraday Pharmaceuticals, Foresee Pharmaceuticals, Fortress Biotech, HDL Therapeutics, HeartFlow, Hummingbird Bioscience, Insmed, Ionis Pharmaceuticals, Janssen and Affiliates, Kowa Research Institute, Lexicon Pharmaceuticals, Medimmune, Merck & Affiliates, Nectero Medical, Novartis Pharmaceuticals, Novo Nordisk, Osiris Therapeutics, Pfizer, PhaseBio Pharmaceuticals, Prairie Education and Research Cooperative, Prothena Biosciences, Regeneron Pharmaceuticals, Regio Biosciences, Sanofi-Aventis Groupe, Silence Therapeutics, Smith & Nephew, Stealth BioTherapeutics, Tourmaline Bio, VarmX, and Virta Health Corporation. MB, PPT, and SC are employees of Bayer. JAE has received research grants and consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim-Lilly, Merck, Amgen, CSL-Vifor, Cardurion Pharmaceuticals, American Regent, Otsuka Pharmaceutical, Novo Nordisk, and Applied Therapeutics. AFH reports research grants from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Merck, Novartis, and Verily; and consulting fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, MyoKardia, and Novartis. CSPL has received research grants from the National Medical Research Council of Singapore, Novo Nordisk, and Roche Diagnostic; has received consulting fees from Alnylam Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Corteria, CPC Clinical Research, Cytokinetics, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Janssen Research & Development, Medscape/WebMD Global, Merck, Novartis, Novo Nordisk, Quidel Corporation, Radcliffe Group, Roche, and Us2.ai; has patent PCT/SG2016/050217 pending and US Patent numbers 10,631,828 B1, US 10,702,247 B2, US 11,301,996 B2, US 11,446,009 B2, US 11,931,207 B2, and US 12,001,939; is a co-founder and non-executive director of Us2.ai; and has received stock or stock options from Us2.ai. EFL reports grants or contracts from Merck, the American Heart Association, and the National Heart, Lung, and Blood Institute; consulting fees from Akebia Therapeutics, AstraZeneca, DalCor Pharmaceuticals, Intellia Therapeutics, and Merck; and a leadership role with the American Heart Association. JL is receiving research support from AstraZeneca and VoluMetrix and consulting fees from Abbott Laboratories, Adonis, Alleviant Medical, AstraZeneca, Axon Therapies, Boston Scientific, Cordio Medical, CVRx, Edwards Lifesciences, FIRE1, Innoventric, InterShunt, Merck, Medtronic, Orchestra BioMed, WhiteSwell, Vascular Dynamics, and V-Wave. RJM has received research support and honoraria from Bayer and Merck Sharp & Dohme (a subsidiary of Merck); and consulting fees from Abbott Laboratories, Alleviant Medical, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead Sciences, Innolife, Eli Lilly, Lexicon Pharmaceuticals, Medtronic, Medable, Merck, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Relypsa, Reprieve Cardiovascular, Respicardia, Roche, Rocket Pharmaceuticals, Sanofi, Verily, Vifor Pharma, Windtree Therapeutics, and ZOLL Medical. PP has received support for the current work from Bayer; grants or contracts from Boehringer Ingelheim, AstraZeneca, Vifor Pharma, Novartis, Bayer, Abbott Vascular, Novo Nordisk, Pharmacosmos, and Moderna; consulting fees from Boehringer Ingelheim, AstraZeneca, Vifor Pharma, Servier, Novartis, Berlin Chemie, Bayer, Pfizer, and Abbott Vascular; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim, AstraZeneca, Vifor Pharma, Servier, Novartis, Berlin Chemie, Bayer, Pfizer, and Abbott Vascular; support for attending meetings and/or travel from Boehringer Ingelheim and Vifor Pharma; and has participated in a data safety monitoring board or advisory board for Boehringer Ingelheim, Vifor Pharma, Novo Nordisk, Pharmacosmos, and Moderna. YNVR is supported by grants from the National Heart, Lung, and Blood Institute, Sleep Number, Bayer, Merck, United Pharmaceuticals, and the Earl Wood Career Development Award from Mayo Clinic; and reports consulting fees from Edwards Lifesciences. GMCR reports consulting fees from Anlylam Pharmaceuticals, AstraZeneca, Servier, and Vifor Pharma; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, educational events, and support for attending meetings and/or travel from Anlylam Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Medtronic, Servier, Viatris, and Vifor Pharma. CS reports consulting fees from Bayer, Merck, and Novo Nordisk; payment or honoraria for lectures, presentations, speakers bureaus, or educational events from Novartis, AstraZeneca, Boehringer Ingelheim, Bayer, Merck, Servier, Sanofi, Pfizer, Novo Nordisk, Eli Lilly, Viatris, and Medtronic; and travel support for attending meetings from Bayer, Servier, Pfizer, Novartis, and Boehringer Ingelheim. MS reports consultancy agreements with Novo Nordisk, Bayer, Cardurion Pharmaceuticals, Boehinger Ingelheim, Amgen, AstraZeneca, Merck, MSD, Reprieve Cardiovascular, and CPC Clinical Research; reports serving on advisory boards for AstraZeneca, Novo Nordisk, Bayer, Merck, Boehringer Ingelheim, Cardurion Pharmaceuticals, and Amgen; and reports receiving speaker fees from Merck, MSD, Bayer, Novo Nordisk, AstraZeneca, Cardurion Pharmaceuticals, and Amgen. JU reports support for the current work from Merck; is a member of the steering and executive committees for the VICTOR trial; reports consulting fees from FIRE1 and Reprieve Cardiovascular; and reports participation in data safety monitoring boards or advisory boards for Merck, Cardurion Pharmaceuticals, Medtronic, Cytokinetics, and Alleviant Medical. VV is an employee of Bayer US. The employer of AAV received consultancy fees and/or research support from Adrenomed, AnaCardio, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Cardurion Pharmaceuticals, Corteria Pharmaceuticals, Eli Lilly, Merck, Moderna, Novartis, Novo Nordisk, RyCarma Therapeutics, and SalubrisBio. PWA has received consulting fees from Merck, Bayer, Boehringer Ingelheim and Novo Nordisk; and research grants from Merck, Bayer, Boehringer Ingelheim/Eli Lilly and CSL.

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