Systematic Escalation of diuREtics With Natriuresis in Heart Failure Patients: SERENA Trial (SERENA)

The present is a multicenter, prospective, randomized, open-label, blinded end-point trial aiming to investigate the clinical benefit of a stepwise, natriuresis-driven diuretic strategy versus standard diuretic treatment in patients with acute decompensated heart failure with reduced ejection fraction (HFrEF) and low early urinary sodium excretion. The study will focus on patients at increased risk of resistance to diuretic therapy. In particular, patients admitted to the emergency department and cardiac intensive care unit due to an on-chronic or de-novo acute decompensated HF episode with a predominantly "wet" profile and low early spot urinary sodium (UNa+) excretion will be considered. Spot natriuresis is a low-cost, non-demanding laboratory test in use to identify diuretic-resistant patients with an inherent poor prognosis. Whether the early identification of diuretic resistant patients and the consequent more aggressive treatment may lead to a better outcome has not been demonstrated by randomized studies. This trial aims to assess if an intensive stepwise diuretic approach guided by systematic urinary output assessment including natriuresis evaluation versus a standard diuretic strategy based on urinary output alone effectively leads to faster euvolemia achievement and better prognosis in a real-world setting.

Ask patient to empty bladder. Start treatment (step 1). Re-evaluate patient every 6 hours; if therapeutic goal is not met, treat according to the following step. Therapeutic goal: Spot Urinary Sodium > 70 mEq/L AND mean diuresis > 1,5 ml/kg/h Step 1 Furosemide i.v. continuous infusion (2 times oral daily dose; minimum dose: 240 mg die) Step 2 Double furosemide i.v. continuous infusion (maximal dose: 720 mg die) Step 3 Add oral metolazone 5 mg b.i.d. Step 4 Add oral acetazolamide 250 mg b.i.d.

Ask patient to empty bladder. Start treatment (step 1). Re-evaluate patient every 12 hours; if therapeutic goal is not met, treat according to the following step. Therapeutic goal: mean diuresis > 1,5 ml/kg/h Step 1 Furosemide i.v. continuous infusion (2 times oral daily dose; minimum dose: 240 mg die) Step 2 Double furosemide i.v. continuous infusion (maximal dose: 720 mg die) Step 3 Add oral metolazone 5 mg b.i.d. Step 4 Add oral acetazolamide 250 mg b.i.d.

Evidence of significant reduction of congestion defined as absolute reduction of at least 1 point in wet score grading of congestion after 48 hours of treatment

Treatment failure, defined as persistent congestion (graded by wet score ≥12/20) after 24, 48 and 72 hours of diuretic treatment or need for renal replacement therapy.

Freedom from congestion at 48 hours, defined as jugular venous pressure of <8 cm, with no orthopnea and with trace peripheral edema or no edema

worsening heart failure symptoms or failure of the patient's condition to improve with treatment requiring the initiation of intravenous inotropic therapy and/or the implementation of mechanical circulatory or ventilatory support up until 48 hours

Composite endpoint of all-cause mortality, urgent LVAD implant or Heart Transplantation at 30 and 90 days.

including myocardial infarction, irreversible heart failure, cardiogenic shock, fatal arrhythmic events

absolute increase in serum creatinine > 0.3 mg/dl or > 1,5-fold from baseline at any time from randomization to 48 hours

Incidence of severe hypokalemia, severe hyponatremia or symptomatic electrolytes disorders during treatment protocol

Inclusion Criteria: Admission for acute decompensate chronic heart failure or acute de novo heart failure Ejection Fraction <40% Severe signs and symptoms of congestion with modified wet score ≥ 12 Spot urinary sodium excretion ≤ 70 mEq/L at 2 hours from first intravenous loop diuretic administration Systolic blood pressure ≥90 mmHg Exclusion Criteria: Reversible etiology of acute heart failure (including acute coronary syndromes, myocarditis, acute pulmonary embolism, acute rhythm disorders, severe organic valve disease) Cardiogenic shock at admission or sign of hypoperfusion needing inotropic agents or mechanical circulatory support. eGFR lower than 15 ml/min/1.73m2 or dialysis Pregnancy or breastfeeding