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

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.

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:

1. Conducted in an established, protocol-operated setting
2. Essential only recruitment restrictions
3. Without any additional testing to the day care standard of care
4. Have minimal or no additional expected risk for the patient (comparison between standard diuretic regimens)
5. Have very clinically meaningful endpoints.

Therefore, this study should be considered a 'Low-intervention clinical trial' as:

1. 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.
2. 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.
3. 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.

Eligibility Criteria:
Inclusion Criteria:

1. Signed written informed consent must be obtained before any study assessment is performed.
2. Male or female patients 18 years of age or older
3. Confirmed Diagnosis of Heart Failure (per ESC guidelines 20212)
4. 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).
5. 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:

1. History of myocardial infraction in the last 14 days prior to patient randomization.
2. History of a cardiac transplantation and/or ventricular assist device.
3. Mean blood pressure \<60 mmHg at screening
4. Simultaneous use of intravenous inotropes, vasopressors or nitroprusside due to acute decompensated heart failure in the last 14 days.
5. Estimated glomerular filtration rate \<20ml/min/1.73m2 at screening
6. Any circumstances where urine collection is not possible.
7. Use of renal replacement therapy or ultrafiltration 30 days prior to patient randomization.
8. Subjects who are pregnant or breastfeeding