Diuretic Strategies in Acute Heart Failure Patients at High Risk for Diuretic Resistance

Study Overview
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Brief Summary
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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

Detailed Description
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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).

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

Conditions
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Acute Heart Failure, Diuretic Resistance

Intervention / Treatment
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* Drug: Furosemide
* Drug: Metolazone
* Drug: Acetazolamide


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: group FF<br>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<br>* 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).<br>* Other names: Furosemide, doubled dose;|
| Active Comparator: group FM<br>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<br>* 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).<br>* Other names: Furosemide, doubled dose;Drug: Metolazone<br>* 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).<br>* Other names: Furosemide + Metolazone;|
| Active Comparator: group FA<br>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<br>* 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).<br>* Other names: Furosemide, doubled dose;Drug: Acetazolamide<br>* 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).<br>* Other names: Furosemide + Acetazolamide;|

What is the study measuring?
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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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diuretic therapy