Abstract
Fluid restriction is frequently recommended to patients with chronic heart failure, but randomized clinical trials assessing the effects of fluid restriction remain scarce. In this multicenter open-label trial, outpatients with chronic heart failure were randomized to receiving advice for liberal fluid intake versus receiving advice for fluid restriction, up to 1,500 ml per day of fluid intake. The primary outcome of the trial was health status after 3 months, as assessed by the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS). Secondary outcomes included thirst distress and safety events. Among 504 randomized patients (67.3% male), the KCCQ-OSS after 3 months was 74.0 in the liberal fluid intake group versus 72.2 in the fluid restriction group, with a mean difference after adjustment for baseline scores of 2.17 (95% confidence interval −0.06 to 4.39; P = 0.06), indicating that the primary outcome was not met. Thirst distress was higher in the fluid restriction group and no differences were observed for safety events between the two groups. These findings question the benefit of fluid restriction in chronic heart failure. ClinicalTrials.gov registration: NCT04551729.
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Data availability
Anonymized participant data can be made available upon requests directed to the corresponding author. Data requests will be reviewed on the basis of scientific merit, ethical review, available resources and regulatory requirements, and a response can be expected within two weeks. Following approvals, unidentified patient data and a data dictionary will be provided. The steering committee will have the right to review and comment on any draft papers based on these data before publication.
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Acknowledgements
We thank the Netherlands Heart Institute for their logistical support, and both the Dutch Heart Foundation (grant no. 2019T100 to R.R.J.v.K.) as well as the Academic Alliance Fund of the Radboud University Medical Center, Nijmegen and Maastricht University Medical Center (grant R0005106) for their financial support (H.-P.B.-L.R., F.B.-W., D.H.F.G., R.R.J.v.K.). The funder of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report.
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H.-P.B.-L.R., T.J., F.B.-W., L.B., D.H.F.G. and R.R.J.v.K. wrote the study protocol. All authors approved the protocol. L.E.H.J.M.B., F.B.-W., M.H.I.V., D.H.F.G. and R.R.J.v.K. acquired funding for the project. L.R. and D.H.F.G. planned the statistical analysis, which was executed by J.J.H. and L.R. J.J.H. and L.R. accessed and verified the underlying study data. J.J.H., H.-P.B.-L.R., L.E.H.J.M.B., F.B.-W., S.C.A.M.B., L.B., J.W.M.v.E., H.C.H., G.C.M.L., R.P., S.S.-v.W. and M.H.I.V. participated in patient enrollment and carried out the trial. J.J.H. drafted the initial version of the manuscript with input from D.H.F.G. and R.R.J.v.K. All authors reviewed the data analyses, data interpretation and writing of the report. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. All authors have seen and approved of the manuscript before submission.
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H.-P.B.-L.R. has received research grants from Innovative Health Initiative Joint Undertaking and Roche Diagnostics, received consulting fees from Astra Zeneca, Boehringer Ingelheim, Novartis, Roche Diagnostics and Vifor Pharma, received honoraria from Roche Diagnostics and participated on an Advisory Board of CeleCor Therapeutics. S.S.-v.W. has received research grants from Boehringer Ingelheim, CRL funds and ZonMW, received honoraria from Astra Zeneca, Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, Roche Diagnostics and Pfizer, and is a member of the board of the Werkgroep Cardiologisch Centra Nederland and Stichting Perfusie. P.v.d.M. has received research grants from Astra Zeneca, Pfizer, Pharma Nord, Novo Nordisk, Ionis and Vifor Pharma, honoraria from Astra Zeneca, Boehringer Ingelheim, BridgeBio, Daiichi Sankyo, Ionis, Novartis, Novo Nordisk, Pfizer, Pharma Nord, Pharmacosmos and Vifor Pharma, and participated on an Advisory Board for CorHeart. J.L.J. has received research grants from Abbott, Applied Therapeutics, Astra Zeneca, HeartFlow and Novartis, received consulting fees from Abbott, Applied Therapeutics, Astra Zeneca, Beckman, Boehringer Ingelheim, Bristol Myers, Intellia, Jana Care, Novartis, Pfizer, Merck, Roche Diagnostics and Siemens, participated on an Advisory Board for Abbott, AbbVie, Bayer, CVRx, Roche Diagnostics and Takeda, is a member of the board of American College of Cardiology and Imbria Pharmaceuticals, and has stock (options) in Imbria Pharmaceuticals and Jana Care. A.B.-G. has lectured and/or participated in advisory boards for Abbott, Astra Zeneca, Bayer, Boehringer Ingelheim, Medtronic, Novartis, Novo Nordisk, Roche Diagnostics and Vifor Pharma. D.H.F.G. received a speaker’s fee from Novartis and travel support from Astra Zeneca. R.R.J.v.K. received consulting fees from Novo Nordisk and Roche Diagnostics, honoraria from Hippocrates Academy and is a fiduciary member of the ESC working group on Peripheral Artery and Aortic Disease. The other authors declare no competing interests.
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Extended data
Extended Data Fig. 1 Win ratio.
The win ratio for safety outcomes during the six months follow-up.
Extended Data Fig. 2 Primary outcome, according to pre-specified subgroup: study site.
The primary outcome of the trial, adjusted mean difference in the KCCQ Overall Summary, tested two-sided with ANCOVA analysis using baseline KCCQ Overall Summary Score as covariate, according to the pre-specified subgroup: study site.
Supplementary information
Supplementary Information
Supplementary Table 1 and Supplementary Information (steering committee members, data safety and monitoring board members, independent event adjudication committee members, principal investigators; inclusion and exclusion criteria; standardized lifestyle advice and Thirst Distress Scale for patients with heart failure), study protocol, summary of changes and statistical analysis plan.
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Herrmann, J.J., Brunner-La Rocca, HP., Baltussen, L.E.H.J.M. et al. Liberal fluid intake versus fluid restriction in chronic heart failure: a randomized clinical trial. Nat Med 31, 2062–2068 (2025). https://doi.org/10.1038/s41591-025-03628-4
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DOI: https://doi.org/10.1038/s41591-025-03628-4
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