Fluid Restriction in Heart Failure Versus Liberal Fluid Uptake (FRESH-UP)

Multi-centre open-label 1:1 randomized clinical trial in chronic heart failure patients on the effect of fluid restriction versus liberal fluid intake on quality of life.

Study Overview

• Status: Completed
• Conditions: Heart Failure
• Intervention / Treatment: Behavioral: Lifestyle advice for liberal fluid intake

• Study Type: Interventional
• Enrollment (Actual): 504
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Almelo, Netherlands
    • Hospital Group Twente
  • Arnhem, Netherlands
    • Rijnstate Hospital
  • Den Bosch, Netherlands
    • Jeroen Bosch Ziekenhuis
  • Heerlen, Netherlands
    • Zuyderland Ziekenhuis
  • Hoorn, Netherlands
    • Dijklander Ziekenhuis
  • Maastricht, Netherlands
    • Maastricht University Medical Centre
  • Uden, Netherlands
    • Bernhoven Ziekenhuis
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525GA
      • Radboud University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of chronic HF with NYHA class II/III according to the prevailing guidelines > 6 months prior to randomization (1)
• Adult (age ≥ 18 years)

Exclusion Criteria:

• Reversible cause of HF (thyroid disorders, severe anemia, vitamin deficiencies)
• Hospital admission for HF within 3 months of randomization
• Chronic HF with NYHA class IV
• Hyponatremia at baseline (sodium <130mmol/l)
• Changes in HF medical therapy in last 14 days prior to randomization
• Estimated Glomerular Filtration Rate (eGFR) of < 30ml/min/1.73 m2 at baseline
• Scheduled cardiac surgery within 3 months of randomization
• Recent (within 3 months) coronary intervention (PCI or CABG) or implantation of pacemaker device
• Comorbidity for which fluid restriction is advised by a different treating physician (e.g. nephrologist)
• Comorbidity with a life expectancy of less than 6 months
• The treating clinician believes that participation in the domain would not be in the best interests of the patient
• Inability to provide informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Fluid restriction; Patient will receive a lifestyle advice to adhere to fluid restriction of 1500cc/day for 3 months.	Behavioral: Lifestyle advice for liberal fluid intake; Lifestyle advice for liberal fluid intake for 3 months
Experimental: Liberal fluid intake; Patient will receive a lifestyle advice for liberal fluid intake for 3 months.	Behavioral: Lifestyle advice for liberal fluid intake; Lifestyle advice for liberal fluid intake for 3 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of life assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ)	KCCQ Overall Summary Score (OSS) (scores minimum-maximum 0-100, higher scores indicate better outcome)	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Thirst distress	Thirst Distress Scale for patients with Heart Failure (scores minimum-maximum 8-40, higher scores indicate worse outcome)	3 months
Quality of life assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ)	KCCQ Clinical Summary Score (CSS) and each of the KCCQ domains (scores minimum-maximum 0-100, higher scores indicate better outcome)	3 months
Quality of life assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ)	Proportion of patients with clinically meaningful changes in KCCQ-OSS and KCCQ-CSS (improved: ≥5 points increase; stable: <5 points increase or decrease; declined: ≥5 points decrease)	3 months
Quality of life assessed with EQ-5D-5L	EQ-5D-5L (First part; scores minimum-maximum 0-1. Second part; (scores minimum-maximum 0-100, higher scores indicate better outcome)	3 months
Patient reported fluid intake	Patient reported fluid intake for 1 week in a fluid intake diary	6 weeks
Safety (Death, all-cause hospitalisations, iv loop diuretic treatment)	Composite of death, hospitalisations and iv loop diuretic treatment	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety (death, all-cause or unplanned HF hospitalisation, the requirement of iv-loop diuretics)	Number of occurrences of: death, all-cause or unplanned HF hospitalisation or the requirement of iv-loop diuretics	6 months
Safety (death, all-cause or unplanned HF hospitalisation, the requirement of iv-loop diuretics)	Time to first occurrence of: death, all-cause or unplanned HF hospitalisation or the requirement of iv-loop diuretics	6 months
Safety (acute kidney injury)	Number of occurrences of acute kidney injury (defined as a 50% decline in estimated glomerular filtration rate relative to baseline, or decrease of >30 ml/min/1.73m2 and to a value below 60 ml/min/1.73m2)	6 months
Safety (acute kidney injury)	Time to first occurrence of acute kidney injury (defined as a 50% decline in estimated glomerular filtration rate relative to baseline, or decrease of >30 ml/min/1.73m2 and to a value below 60 ml/min/1.73m2)	6 months
Serum biomarkers	NT-proBNP	3 months
Serum biomarkers	Sodium	3 months
Serum biomarkers	Osmolality	3 months
Serum biomarkers	Haemoglobin	3 months
Serum biomarkers	Haematocrit	3 months
Weight	Weight	3 months
Medication	Use of concomitant medication (diuretics in particular)	6 months

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: Maastricht University Medical Center
• Investigators: Principal Investigator: Roland van Kimmenade, MD PhD, Radboud University Medical Center

Publications and helpful links

General Publications

• Herrmann JJ, Beckers-Wesche F, Baltussen LEHJM, Verdijk MHI, Bellersen L, Brunner-la Rocca HP, Jaarsma T, Pisters R, Sanders-van Wijk S, Rodwell L, Van Royen N, Gommans DHF, Van Kimmenade RRJ. Fluid REStriction in Heart Failure vs Liberal Fluid UPtake: Rationale and Design of the Randomized FRESH-UP Study. J Card Fail. 2022 Oct;28(10):1522-1530. doi: 10.1016/j.cardfail.2022.05.015. Epub 2022 Jun 13.
• Herrmann JJ, Brunner-La Rocca HP, Baltussen LEHJM, Beckers-Wesche F, Bekkers SCAM, Bellersen L, van Eck JWM, Hassing HC, Jaarsma T, Linssen GCM, Pisters R, Sanders-van Wijk S, Verdijk MHI, Handoko ML, van der Meer P, Verbrugge FH, Januzzi JL Jr, Bayes-Genis A, Nieuwlaat R, Rodwell L, Gommans DHF, van Kimmenade RRJ. Liberal fluid intake versus fluid restriction in chronic heart failure: a randomized clinical trial. Nat Med. 2025 Mar 30. doi: 10.1038/s41591-025-03628-4. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): April 21, 2021
• Primary Completion (Actual): September 23, 2024
• Study Completion (Actual): November 28, 2024

Study Registration Dates

• First Submitted: September 10, 2020
• First Submitted That Met QC Criteria: September 10, 2020
• First Posted (Actual): September 16, 2020

Study Record Updates

• Last Update Posted (Actual): April 18, 2025
• Last Update Submitted That Met QC Criteria: April 15, 2025
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Failure
• Other Study ID Numbers: 75112

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Other investigators can submit a proposal to the steering committee for the sharing of data.

This proposal will be discussed in the steering committee.

• IPD Sharing Time Frame: Weeks
• IPD Sharing Access Criteria: These will be determined by the steering committee.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No