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

• ClinicalTrials.gov Identifier: NCT05986773
• Recruitment Status: Recruiting
• First Posted: August 14, 2023
• Last Update Posted: November 28, 2023
• Sponsor: Stadtspital Zürich
• Collaborator: Ospedale Regionale di Lugano
• Information provided by (Responsible Party): Stadtspital Zürich

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Acute Heart Failure; Diuretic Resistance	Drug: Furosemide; Drug: Metolazone; Drug: Acetazolamide	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 75 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Diuretic Strategies in Acute Heart Failure Patients at High Risk for Diuretic Resistance (P-Value-AHF): A Multicentre, Randomized, Parallel-group, Open-label Trial
• Actual Study Start Date: October 10, 2023
• Estimated Primary Completion Date: August 1, 2025
• Estimated Study Completion Date: December 31, 2025

Arms and Interventions

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 Name: 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 Name: 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 Name: 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 Name: 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 Name: Furosemide + Acetazolamide

Outcome Measures

Primary Outcome Measures :

1. Diuretic efficacy after 6h [ Time Frame: 6 hours after administration of the study-specific diuretic regimen ]
   urine- natrium concentration (mmol/L)

Secondary Outcome Measures :

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

Other Outcome Measures:

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 100 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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 first standard dose Furosemide i.v. (i.e., urine volume < 300 ml and urine sodium concentration < 70 mmol/L)
• Plasma N terminal-proBNP level at admission > 1000 ng/L
• Signed Informed Consent form

Exclusion Criteria:

• Previous use of intravenous diuretics during the index hospitalization (exception first standard dose Furosemide i.v.)
• 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.

Contacts and Locations

Contacts

Contact: Mattia Arrigo, PD, Dr. med.; +41 44 416 30 03; mattia.arrigo@stadtspital.ch

Contact: Melina Stüssi-Helbling, Dr.med.; +41 44 416 31 13; melina.stuessi-helbling@stadtspital.ch

Locations

Switzerland

Stadtspital Zürich; Recruiting

Zürich, Switzerland, 8063

Contact: Mattia Arrigo, PD Dr. med. +41 44 416 30 03 mattia.arrigo@stadtspital.ch

Contact: Melina Stüssi-Helbling, Dr. med. +41 44 416 31 13 melina.stuessi-helbling@stadtspital.ch

Principal Investigator: Mattia Arrigo, PD Dr. med.

Sub-Investigator: Melina Stüssi-Helbling, Dr. med.

Sponsors and Collaborators

Stadtspital Zürich

Ospedale Regionale di Lugano

Investigators

• Principal Investigator: Mattia Arrigo, PD, Dr. med.; City Hospital Zürich Triemli, Birmensdorferstr. 497, 8063 Zürich, Switzerland

More Information

• Responsible Party: Stadtspital Zürich
• ClinicalTrials.gov Identifier: NCT05986773
• Other Study ID Numbers: P-Value-AHF
• First Posted: August 14, 2023
• Last Update Posted: November 28, 2023
• Last Verified: August 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Stadtspital Zürich:

Diuretic therapy

Additional relevant MeSH terms:

Heart Failure; Heart Diseases; Cardiovascular Diseases; Metolazone; Furosemide; Acetazolamide; Diuretics; Natriuretic Agents; Physiological Effects of Drugs; Sodium Potassium Chloride Symporter Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Anticonvulsants; Carbonic Anhydrase Inhibitors; Enzyme Inhibitors; Antihypertensive Agents; Sodium Chloride Symporter Inhibitors