Diuretic Strategies in Acute Heart Failure Patients At High Risk for Diuretic Resistance (P-Value-AHF)

Diuretic Strategies in Acute Heart Failure Patients At High Risk for Diuretic Resistance (P-Value-AHF): a Multicentre, Randomized, Parallel-group, Open-label Trial

The P-VALUE-AHF trial is a multicenter, randomized, open-label, parallel-group trial on the diuretic and decongestive effects of different diuretic escalation strategies in patients with acute heart failure and diuretic resistance.

The main aims are

• to compare the diuretic efficacy of three therapeutic strategies in patients with acute heart failure and diuretic resistance.
• to assess the improvement in clinical congestion and to compare the symptom-relief among the different treatment regimens

Study Overview

• Status: Terminated
• Conditions: Acute Heart Failure; Diuretic Resistance
• Intervention / Treatment: Drug: Furosemide; Drug: Metolazone; Drug: Acetazolamide

Detailed Description

The P-VALUE-AHF trial is a multicenter, randomized, open-label, parallel-group trial on the diuretic and decongestive effects of different diuretic escalation strategies in patients with acute heart failure (AHF) and diuretic resistance (DR).

Consenting patients with AHF and DR will be will be randomized towards 3 diuretic regimens. Two to five hours after the initial standard dose Furosemide i.v,

• the first group will receive a doubled dose Furosemide (group FF)
• the second group will receive a combination of standard dose Furosemide and Metolazone (group FM)
• the third group will receive a combination of standard dose Furosemide and Acetazolamide (group FA)

Objectives

• The primary objective is to compare the diuretic efficacy (measured as natriuresis and urine volume) of three therapeutic strategies in patients with acute heart failure and diuretic resistance.
• The secondary objective is to assess the improvement in clinical congestion (EVEREST congestion score) and to compare the symptom-relief (improvement of dyspnoea (VAS)) among the different treatment regimens (FF vs. FM vs. FA).

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 4

Contacts and Locations

Study Locations

• Switzerland
  • Zürich, Switzerland, 8063
    • Stadtspital Zürich

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Elective or emergency hospital admission with clinical diagnosis of acute heart failure
• One or more clinical signs of volume overload (i.e., peripheral edema, pleural effusion, jugular venous distension)
• Low diuretic efficacy in the first 2 hours after the standard screening dose Furosemide i.v. (i.e., urine volume < 300 ml and urine sodium concentration < 70 mmol/L)
• Plasma N terminal-proBNP level at enrolment > 1000 ng/L
• Signed Informed Consent form

Exclusion Criteria:

• Maintenance treatment with Acetazolamide or Metolazone
• Use of any non-protocol defined diuretic agent that cannot be stopped upon study inclusion except for sodium-glucose co-transporter-2 inhibitors (e.g., dapagliflozin, empagliflozin, canagliflozin) and mineralocorticoid receptor antagonists (e.g., spironolactone, eplerenone)
• Systolic blood pressure < 90 mmHg
• Expected use of intravenous vasopressors (e.g., noradrenaline, adrenaline), inotropes (e.g., dobutamine, milrinone, levosimendan) at any time point during the study
• Severe chronic kidney disease (estimated glomerular filtration rate < 15 ml/min/1.73 m2) or use of renal replacement therapy at any time before study inclusion
• Severe liver dysfunction or cirrhosis at risk of hepatic encephalopathy
• Severe electrolyte disturbances or metabolic acidosis requiring specific intravenous treatment
• Concurrent diagnosis of acute coronary syndrome requiring urgent revascularization
• History of cardiac transplantation or ventricular assist device
• Allergy, intolerance or other contraindication against one of the study drugs
• Pregnancy or breastfeeding
• Age below 18 years.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: group FF; Group FF will receive a doubled dose Furosemide i.v. The first standard dose Furosemide i.v. should be administered according to the current guidelines: (i) diuretic-naïve patients should receive Furosemide 40 mg i.v.; (ii) patients on a maintenance oral diuretic treatment should receive the equivalent dose i.v. Study medications will be used according to the prescribing information: Furosemide will be administered as an intravenous injection.	Drug: Furosemide; Two to five hours after the initial standard dose Furosemide i.v, the patients are randomized towards 3 study-specific diuretic regimens: the first group will receive a doubled dose Furosemide i.v. (group FF), the second group will receive a combination of standard dose Furosemide i.v. and Metolazone 5 mg p.o. (group FM), the third group will receive a combination of standard dose Furosemide i.v. and Acetazolamide 500 mg i.v. (group FA).; Other Names: Furosemide, doubled dose
Active Comparator: group FM; Group FM will receive a combination of standard dose Furosemide i.v. and Metolazone 5 mg p.o. The first standard dose Furosemide i.v. should be administered according to the current guidelines: (i) diuretic-naïve patients should receive Furosemide 40 mg i.v.; (ii) patients on a maintenance oral diuretic treatment should receive the equivalent dose i.v. Study medications will be used according to the prescribing information: Furosemide will be administered as an intravenous injection. Metolazone will be administered orally.	Drug: Furosemide; Two to five hours after the initial standard dose Furosemide i.v, the patients are randomized towards 3 study-specific diuretic regimens: the first group will receive a doubled dose Furosemide i.v. (group FF), the second group will receive a combination of standard dose Furosemide i.v. and Metolazone 5 mg p.o. (group FM), the third group will receive a combination of standard dose Furosemide i.v. and Acetazolamide 500 mg i.v. (group FA).; Other Names: Furosemide, doubled dose; Drug: Metolazone; Two to five hours after the initial standard dose Furosemide i.v, the patients are randomized towards 3 study-specific diuretic regimens: the first group will receive a doubled dose Furosemide i.v. (group FF), the second group will receive a combination of standard dose Furosemide i.v. and Metolazone 5 mg p.o. (group FM), the third group will receive a combination of standard dose Furosemide i.v. and Acetazolamide 500 mg i.v. (group FA).; Other Names: Furosemide + Metolazone
Active Comparator: group FA; Group FA will receive a combination of standard dose Furosemide i.v. and Acetazolamide 500 mg i.v. The first standard dose Furosemide i.v. should be administered according to the current guidelines: (i) diuretic-naïve patients should receive Furosemide 40 mg i.v.; (ii) patients on a maintenance oral diuretic treatment should receive the equivalent dose i.v. Study medications will be used according to the prescribing information: Furosemide will be administered as an intravenous injection. Acetazolamide (500mg) will be administered intravenously as a short infusion.	Drug: Furosemide; Two to five hours after the initial standard dose Furosemide i.v, the patients are randomized towards 3 study-specific diuretic regimens: the first group will receive a doubled dose Furosemide i.v. (group FF), the second group will receive a combination of standard dose Furosemide i.v. and Metolazone 5 mg p.o. (group FM), the third group will receive a combination of standard dose Furosemide i.v. and Acetazolamide 500 mg i.v. (group FA).; Other Names: Furosemide, doubled dose; Drug: Acetazolamide; Two to five hours after the initial standard dose Furosemide i.v, the patients are randomized towards 3 study-specific diuretic regimens: the first group will receive a doubled dose Furosemide i.v. (group FF), the second group will receive a combination of standard dose Furosemide i.v. and Metolazone 5 mg p.o. (group FM), the third group will receive a combination of standard dose Furosemide i.v. and Acetazolamide 500 mg i.v. (group FA).; Other Names: Furosemide + Acetazolamide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diuretic efficacy after 6h	urine- natrium concentration (mmol/L)	6 hours after administration of the study-specific diuretic regimen

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diuretic efficacy after 2h	urine- natrium concentration (mmol/L)	2 hours after administration of the study-specific diuretic regimen
Diuretic efficacy after 24h	urine- natrium concentration (mmol/L)	24 hours after administration of the study-specific diuretic regimen
Change in clinical congestion	EVEREST congestion score	0 and 24 hours after administration of the study-specific diuretic regimen
Change in dyspnea severity	numeric rating scale	0 and 24 hours after administration of the study-specific diuretic regimen.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Outcomes 1	Hypotension (SBP< 90 mmHg) with symptoms or requiring therapeutic intervention	0-24 hours after administration of the study-specific diuretic regimen
Safety Outcomes 2	Increase in serum creatinine >50% from baseline	0-24 hours after administration of the study-specific diuretic regimen
Safety Outcomes 3	New electrolyte disturbances (sodium < 130mmol/l or > 150mmol/l, potassium < 3.0mmol/l or > 5.5 mmol/l)	0-24 hours after administration of the study-specific diuretic regimen

Collaborators and Investigators

• Sponsor: Stadtspital Zürich
• Collaborators: Ospedale Regionale di Lugano
• Investigators: Principal Investigator: Mattia Arrigo, PD, Dr. med., City Hospital Zürich Triemli, Birmensdorferstr. 497, 8063 Zürich, Switzerland

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2023
• Primary Completion (Actual): December 31, 2024
• Study Completion (Actual): December 31, 2024

Study Registration Dates

• First Submitted: April 27, 2023
• First Submitted That Met QC Criteria: August 8, 2023
• First Posted (Actual): August 14, 2023

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 12, 2025
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Diuretic therapy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Failure; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Membrane Transport Modulators; Diuretics; Natriuretic Agents; Anticonvulsants; Carbonic Anhydrase Inhibitors; Sodium Potassium Chloride Symporter Inhibitors; Antihypertensive Agents; Sodium Chloride Symporter Inhibitors; Acetazolamide; Furosemide; Metolazone
• Other Study ID Numbers: P-Value-AHF

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No