Background - Volume overload is an important clinical target in acute heart failure management (AHF), typically addressed using loop diuretics. An important and challenging subset of heart failure patients exhibit fluid overload despite significant doses of loop diuretics. One approach to overcome loop diuretic resistance is the addition of a thiazide-type diuretic to produce diuretic synergy via "sequential nephron blockade". Although potentially able to induce diuresis in patients otherwise resistant to high doses of loop diuretics, this strategy has not been subjected to large-scale clinical trials to establish safety and clinical efficacy.

Methods - Our trial is a multicentric, double blind, randomized clinical study, aiming to recruit 310 patients with AHF and clinically evident volume overload. Study participants are randomized to receive a standard diuretic therapy (intravenous loop diuretics as recommended by current guidelines plus placebo) or SNB therapy (loop diuretics plus oral metolazone at the dose of 5/10 mg once daily) on top of standard medical therapy. Mineralocorticoid antagonists will be used in association with the two regimens according to blood potassium level and kidney function at the discretion of the treating physician. The primary endpoint is defined as the change in the serum creatinine level and the change in weight, considered both as a bivariate response and with their single components, between the time of randomization and 72 hours after randomization. Secondary endpoints include global well-being and dyspnoea assessed by a visual-analogue scale, changes in body weight and net fluid loss, proportion of patients free from congestion, treatment failure, changes in biomarker levels and the composite of death, rehospitalization, or an emergency room visit within 60 days, as well as the composite of total number of days hospitalized or death during the 60 days after randomization.

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
• An elective or emergency hospital admission with clinical diagnosis of decompensated HF with at least one clinical sign of volume overload (e.g. oedema (score 2 or more), ascites confirmed by echography or pleural effusion confirmed by chest X-ray or echography) Plasma NT-proBNP levels >1000 ng/mL or BNP levels >250 ng/mL at the time of screening.

Assessed LVEF by any imaging technique; i.e. echocardiography, catheterization, nuclear scan or magnetic resonance imaging within 12 months of inclusion

Exclusion Criteria:

• Concurrent diagnosis of an acute coronary syndrome defined as typical chest pain in addition to a troponin rise above the 99th percentile and/or electrocardiographic changes suggestive of cardiac ischemia
• History of congenital heart disease requiring surgical correction
• History of a cardiac transplantation and/or ventricular assist device
• Systolic blood pressure <90 mmHg or mean arterial pressure <65 mmHg at the moment of admission
• Estimated glomerular filtration rate <20 mL/min/1.73m² at screening
• Use of renal replacement therapy or ultrafiltration at any time before study inclusion
• Treatment with metolazone during the index hospitalization and prior to randomization
• Exposure to nephrotoxic agents (i.e. contrast dye) anticipated within the next 3 days
• Use of any non-protocol defined diuretic agent with the exception of mineralocorticoid receptor antagonists.
• Current use of sodium-glucose transporter-2 inhibitors
• Subjects who are pregnant or breastfeeding