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. 2025 Aug 29:S0140-6736(25)01665-4.
doi: 10.1016/S0140-6736(25)01665-4. Online ahead of print.

Vericiguat in patients with chronic heart failure and reduced ejection fraction (VICTOR): a double-blind, placebo-controlled, randomised, phase 3 trial

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

Vericiguat in patients with chronic heart failure and reduced ejection fraction (VICTOR): a double-blind, placebo-controlled, randomised, phase 3 trial

Javed Butler et al. Lancet. .

Abstract

Background: Vericiguat is indicated to reduce the risk of cardiovascular death and hospitalisation for heart failure in patients with heart failure and reduced ejection fraction (HFrEF) following a recent worsening event. The aim of the VICTOR trial was to assess the effect of vericiguat in patients with HFrEF without recent heart failure worsening.

Methods: In this double-blind, placebo-controlled, phase 3 trial, conducted at 482 sites across 36 countries, patients aged 18 years or older with HFrEF (left ventricular ejection fraction of ≤40%) without heart failure hospitalisation within 6 months or outpatient intravenous diuretic use within 3 months before randomisation were randomly assigned (1:1) using an intervention randomisation system with interactive response technology to oral vericiguat (target 10 mg dose) or matching placebo. The primary composite endpoint was time to cardiovascular death or heart failure hospitalisation. Efficacy endpoints were assessed in the intention-to-treat population. Adverse events were assessed in all randomly assigned patients who received at least one dose of study drug (safety population). This trial is registered with ClinicalTrials.gov, NCT05093933, and is complete.

Findings: Between Nov 2, 2021, and Dec 21, 2023, 10 921 patients were screened and 6105 were randomly assigned: 3053 to vericiguat and 3052 to placebo. The median age was 68·0 years (IQR 61·0-75·0), 1440 (23·6%) patients were women, 4665 (76·4%) were men, 3934 (64·4%) were White, and 2899 (47·5%) had no previous hospitalisation for heart failure. During a median follow-up of 18·5 months (IQR 13·6-24·7), primary outcome events occurred in 549 (18·0%) patients in the vericiguat group and 584 (19·1%) patients in the placebo group (hazard ratio [HR] 0·93 [95% CI 0·83-1·04]; p=0·22). As prespecified in the protocol, because the primary endpoint was not statistically significant, all analyses of secondary and exploratory endpoints are considered nominal. Cardiovascular death occurred in 292 (9·6%) patients in the vericiguat group and 346 (11·3%) patients in the placebo group (HR 0·83 [95% CI 0·71-0·97]). Hospitalisation for heart failure occurred in 348 (11·4%) patients in the vericiguat group and in 362 (11·9%) patients in the placebo group (HR 0·95 [95% CI 0·82-1·10]). Serious adverse events occurred in 717 (23·5%) of 3049 patients in the vericiguat group and 751 (24·6%) of 3049 patients in the placebo group. The most common adverse event was symptomatic hypotension (345 [11·3%] patients in the vericiguat group and 281 [9·2%] in the placebo group). All-cause death occurred in 377 (12·3%) patients in the vericiguat group and 440 (14·4%) patients in the placebo group (HR 0·84 [95% CI 0·74-0·97]).

Interpretation: Among patients with HFrEF and no recent worsening, vericiguat did not reduce the risk of a composite endpoint of time to cardiovascular death or heart failure hospitalisation. Fewer cardiovascular deaths were observed in the vericiguat group than in the placebo group.

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

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Conflict of interest statement

Declaration of interests JB reports 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 honoraria from Boehringer Ingelheim-Lilly, Impulse Dynamics, and Merck. CJM, IB, DG, AU, AX, and MJP are employees of Merck, Sharp & Dohme. KJA reports institutional research funding from Merck, Bayer, and the US National Institutes of Health; and participation on data safety monitoring boards for the US National Institutes of Health. MPB reports institutional grant or consulting funding 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 Biopharma, Cardiol Therapeutics, CellResearch, Cleerly, Cook Regentec, CSL Behring, Eidos Therapeutics, EP Trading, Epizon Pharma, Esperion Therapeutics, Everly Well, 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, VarmX, and Virta Health; participation on data safety monitoring board or advisory board for Nectero East; and serving on the board of trustees for the Society of Vascular Medicine. MB, SC, PPT, and VV are employees of Bayer. JAE reports research grants and personal fees from Amgen, Bayer, American Regent, Merck, Otsuka, Novo Nordisk, Applied Therapeutics, Cardurion, CSL-Vifor, AstraZeneca, BI-Lilly, and US2.ai. GMF reports institutional research grants from Merck, the US National Institutes of Health, Bayer, Novartis, Cytokinetics, Otsuka, CSL-Behring, and Bristol Myers Squibb; consulting fees from Novartis, Bristol Myers Squibb, Cytokinetics, Boehringer Ingelheim, River2Renal, Roche Diagnostics, and Whiteswell; participation on a data safety monitoring board or advisory board for Rocket Pharma, V Wave, the US National Institutes of Health; and leadership roles with the Heart Failure Society of America. CSPL reports research grants from the National Medical Research Council of Singapore, NovoNordisk, and Roche Diagnostics; consulting fees from Alleviant Medical, Allysta Pharma, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development, Medscape/WebMD Global, Merck, Novartis, Novo Nordisk, Prosciento, Quidel Corporation, Radcliffe Group, Recardio, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; a pending patent (PCT/SG2016/050217. US Patent No. 10,702, 247); and a leadership role and stock and stock options with Us2.ai. EFL reports the following support for the present manuscript from Merck, AstraZeneca, Intellia, Dal-Cor, Akebia, and the American Heart Association; grants or contracts from Merck, Dal-Cor, and the American Heart Association; consulting fees from Merck, AstraZeneca, Intellia, Dal-Cor, and Akebia; participation on a data safety monitoring board or advisory board for the US NHLBI; and leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for the American Heart Association. JL reports consulting fees from Abbott, Adona, Alleviant, Axon, Boston Scientifi, CVRx, Edwards Lifesciences, Intershunt, Inoventric, Medtronic, Merck, Orchestra Biomed, Pulnova, Whiteswell, VWave, and Vascular Dynamics. RJM reports research support from Merck, Bayer, BI-Lilly, AstraZeneca, and Novartis; consulting fees from Merck, Bayer, BI-Lilly, AstraZeneca, and Novartis; honoraria from Merck and Bayer; participation on a data safety monitoring board for Reprieve and Rocket; and other research support and honoraria from Abbott, Alleviant Medical, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, CVRx, Cytokinetics, Daiichi Sankyo, Fast BioMedical, Gilead, Innolife, Eli Lilly, Endotronix, Lexicon, Medtronic, Medable, Merck, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Relypsa, Reprieve Cardiovascular, Respicardia, Roche, Rocket Pharmaceuticals, Sanofi, Verily, Vifor, Windtree Therapeutics, and Zoll. CMO'C reports consulting fees from Merck, Abiomed, and Zealcare. PP reports research support, consulting fees, and honoraria from, and participation on a data safety monitoring board or advisory board for, Abbott Vascular, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, NovoNordisk, Pharmacosmos, Radcliffe Cardiology, Reprieve Cardiovascular, and Vifor. YNVR reports institutional research grants from the US National Heart, Lung, and Blood Institute, Merck, United Pharmaceuticals, Sleep Number, and Bayer. GMCR reports funding for the study provided by Merck Sharp & Dohme (a subsidiary of Merck) and Bayer; consulting fees from Anlylam, AstraZeneca, Servier, and Vifor Pharma; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events, and support for attending meetings or travel from Anlylam, AstraZeneca, Boehringer Ingelheim, Medtronic, Servier, Viatris, and Vifor Pharma. CS reports honoraria from Merck, Servier, AstraZeneca, Boehringer Ingelheim, Novartis, Medtronic, Bayer, and Eli Lilly; and consulting fees from Bayer, Merck, and NovoNordisk. LS reports institutional research grant from Merck. JU reports honoraria from Merck; research grants from Cardurion, Alleviant, FIRE1, and Reprieve Cardiovascular; payment for expert testimony from Boston Medical Center; and participation on a data safety monitoring board for Cytokinetics and Medtronic. AAV reports institutional research grants and consulting fees from Bayer, Merck, Adrenomed, Anacardio, Armgo, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Cardurion, Corteria, Eli Lilly, Moderna, Novartis, NovoNordisk, and SalubrisBio. FZ reports honoraria from Applied Therapeutics, Bayer, Biopeutics, Boehringer Ingelheim, CVRx, Cereno Pharmaceutical, Cellprothera, Merck, Owkin, and Ribocure; participation on a data safety monitoring board or advisory board for Merck; leadership role with CVCT; and stock or stock options with G3Pharmaceutical and Cereno Pharmaceutical. MS declares no competing interests.

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