The Heart Failure Diuresis Efficacy Comparison (DEA-HF) Study

Study Overview
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Brief Summary
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To investigate the effectiveness of three (3) IV diuretic regimens to increase natriuresis in volume-overloaded HF patients, allowing for better decongestion and potentially resulting in improved clinical and biochemical parameters outcome.

Detailed Description
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The study will assess the efficacy and safety of three (3) different clinically prevailing diuretic regimens. All three regimens are based on furosemide, as mentioned above- a 1st line HF GL2,3 recommended and MOH registered 7 for fluid decongestion, and the two adjuvants medications are also approved as diuretics in HF patients. Better natriuresis will lead to better decongestion in CHF patients with volume overload. It is expected that the better natriuresis will lead to better decongestion, and improvement in favorable markers parameters such as NT pro BNP. The trial will investigate treatment regimens, readily available, clinically approved (on-label in Israel), which can be very easily administered, through an IV infusion or IV and PO administration without additional extra testing or invasive monitoring. The setting is in an established dedicated HF day-care unit at the cardiology department of Rambam Health Campus (RMC)- a tertiary referral academic center. The knowledge gathered in this study, could be easily adopted by every clinic or hospital in a quick manner with considerable cost-savings with regards to health care expenditure. Importantly, this study will examine which application of existing decongestive therapies (not novel drugs), based on strong scientific reasoning, will result in a better outcome for patients. Therefore, data from the study will provide information regarding the safety and efficacy of diuretic treatment in the above-mentioned patient population. The study intends to be a real-life study, in the manner of: Conducted in an established, protocol-operated setting Essential only recruitment restrictions Without any additional testing to the day care standard of care Have minimal or no additional expected risk for the patient (comparison between standard diuretic regimens) Have very clinically meaningful endpoints. Therefore, this study should be considered a 'Low-intervention clinical trial' as: The investigational medicinal products, which are used in clinical practice and approved, have a very low-risk profile and are well-known to general cardiologists and internists worldwide. According to the protocol of the clinical trial, all investigational medicinal products will be used in accordance with EU and US marketing approval according to published guidelines. Note: from commercial and supply chain reasons oral metolazone and IV acetazolamide are imported by medical institutions in Israel by means of group 29 gimel form. Both are FDA and EU labeled for HF treatment. No additional diagnostic or monitoring procedures are asked. Hence, minimal additional risk or burden to the safety of the subjects compared to normal clinical practice.

Official Title
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Diuresis Efficacy in Ambulatory Chronic Heart Failure Patients With Volume Overload- Intra -Patient Comparison of Three Diuretics Regimens

Conditions
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Chronic Heart Failure, Diuretics Drug Reactions, Congestive Heart Failure

Intervention / Treatment
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* Drug: IV Furosemide
* Drug: IV Furosemide and PO Metolazone
* Drug: IV Furosemide and IV Acetazolamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent must be obtained before any study assessment is performed. Male or female patients 18 years of age or older Confirmed Diagnosis of Heart Failure (per ESC guidelines 20212) At least one sign of active congestion at recruitment: Jugular venous pressure(JVP)/Ascites/Edema/Pulmonary rales/Pleural effusion/ Lung ultrasound B lines >3 lines (at 6 sites). Patient is at least on two heart failure drugs including: BB, MRA, sGLT2i, ACEI/ARB/ARNI (or has a clinical reason for its absence) and on oral diuretics for the last 30 days before study inclusion. Exclusion Criteria: History of myocardial infraction in the last 14 days prior to patient randomization. History of a cardiac transplantation and/or ventricular assist device. Mean blood pressure <60 mmHg at screening Simultaneous use of intravenous inotropes, vasopressors or nitroprusside due to acute decompensated heart failure in the last 14 days. Estimated glomerular filtration rate <20ml/min/1.73m2 at screening Any circumstances where urine collection is not possible. Use of renal replacement therapy or ultrafiltration 30 days prior to patient randomization. Subjects who are pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 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: Crossover Assignment
Interventional Model Description: Single-site, single-arm, open-label, cross-over controlled study Randomization will determine the sequence of the three (3) regimens
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Diuretic comparison<br>each participant will be followed for 4 consecutive weeks. during which 3 different diuretic regimens will be given (random sequence). Last week follow up without protocol regimen. | Drug: IV Furosemide<br>* Given over 4-hour drip using IV pump, 40mg of the 250mg will be given as a bolus<br>Drug: IV Furosemide and PO Metolazone<br>* Given over 4-hour drip using IV pump, 40mg of the 250mg will be given as a bolus +5mg PO Metolazone<br>Drug: IV Furosemide and IV Acetazolamide<br>* Furosemide would be given over 4-hour drip using IV pump, 40mg of the 250mg will be given as a bolus. 500mg IV Acetazolamide would be given in 100cc of saline over half an hour<br>* Other names: Oral Magnesium citrate 600mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sodium weight | Na Weight (Spot Na * total volume of urine) | 1st week visit (time zero) | 
| Sodium weight | Na Weight (Spot Na * total volume of urine) | 1 week after 1st visit | 
| Sodium weight | Na Weight (Spot Na * total volume of urine) | 2 weeks after 1st visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urine Volume | Total urinary volume starting from initiation of intravenous (IV) therapy for 6 hours | 1st week visit (time zero) | 
| Urine Volume | Total urinary volume starting from initiation of intravenous (IV) therapy for 6 hours | 1 week after 1st visit | 
| Urine Volume | Total urinary volume starting from initiation of intravenous (IV) therapy for 6 hours | 2 weeks after 1st visit | 
| Rate of symptomatic hypotension events | Systolic BP <90mmhg with symptoms | A week after 1st visit | 
| Rate of symptomatic hypotension events | Systolic BP <90mmhg with symptoms | 2 weeks after 1st visit | 
| Rate of symptomatic hypotension events | Systolic BP <90mmhg with symptoms | 3 weeks after 1st visit | 
| rate of worsening renal function events | WRF defined as a >0.3 mg/dL increase in serum Cr, or a >20% decrease in eGFR by the CKDEPI formula | A week after 1st visit | 
| rate of worsening renal function events | WRF defined as a >0.3 mg/dL increase in serum Cr, or a >20% decrease in eGFR by the CKDEPI formula | 2 weeks After 1st visit | 
| rate of worsening renal function events | WRF defined as a >0.3 mg/dL increase in serum Cr, or a >20% decrease in eGFR by the CKDEPI formula | 3 weeks after 1st visit | 
| Rate of hyponatremia during treatment phase | Hyponatremia <133mmol/dl | A week after 1st visit | 
| Rate of hyponatremia during treatment phase | Hyponatremia <133mmol/dl | 2 weeks after 1st visit | 
| Rate of hyponatremia during treatment phase | Hyponatremia <133mmol/dl | 3 weeks after 1st visit | 
| Rate of dyskalemia events during treatment phase | Dyskalemia defined as <3.5 or >5.6mmol/dl | A week after 1st visit | 
| Rate of dyskalemia events during treatment phase | Dyskalemia defined as <3.5 or >5.6mmol/dl | 2 weeks after 1st visit | 
| Rate of dyskalemia events during treatment phase | Dyskalemia defined as <3.5 or >5.6mmol/dl | 3 weeks after 1st visit | 
| Rate of metabolic acidosis events requiring NaHCO3 supplements | Rate of Metabolic acidosis (requiring NaHCO3 supplements) events | A week after 1st visit | 
| Rate of metabolic acidosis events requiring NaHCO3 supplements | Rate of Metabolic acidosis (requiring NaHCO3 supplements) events | 2 weeks after 1st visit | 
| Rate of metabolic acidosis events requiring NaHCO3 supplements | Rate of Metabolic acidosis (requiring NaHCO3 supplements) events | 3 weeks after 1st visit |