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

Study Overview
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Brief Summary
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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.

Official Title
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Systematic Escalation of diuREtics With Natriuresis in Heart Failure Patients: SERENA Trial

Conditions
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Heart Failure

Intervention / Treatment
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* Other: Intensive sodiuria-guided diuretic treatment
* Other: Standard diuretic treatment


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: UNa+ Driven Intensive Therapy<br>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. | Other: Intensive sodiuria-guided diuretic treatment<br>* Intensive stepwise diuretic treatment based on combined diuresis and urinary sodium assessment<br>|
| Active Comparator: Standard Therapy<br>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. | Other: Standard diuretic treatment<br>* Stepwise diuretic therapy based on diuresis assessment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Assessment of WET score (Gheorghiade et al, EJHF 2010) | 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. |  | 24,48 and 72 hours | 
| 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 |  | 48 hours | 
| Worsening or persistent heart failure | 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 | 48 hours | 
| Composite endpoint of all-cause mortality, urgent LVAD implant or Heart Transplantation at 30 and 90 days. |  | 30 and 90 days | 
| All-cause mortality |  | 30 and 90 days | 
| Cardiac cause mortality | including myocardial infarction, irreversible heart failure, cardiogenic shock, fatal arrhythmic events | 30 and 90 days | 
| Rehospitalization for heart failure |  | 30 and 90 days | 
| Worsening renal function | absolute increase in serum creatinine > 0.3 mg/dl or > 1,5-fold from baseline at any time from randomization to 48 hours | 48 hours | 
| Incidence of severe hypokalemia, severe hyponatremia or symptomatic electrolytes disorders during treatment protocol | hypokalemia <3 mEq/L, severe hyponatremia <125 mEq/L | 72 hours | 
| Severe symptomatic hypotension | Systolic arterial pressure < 80 mmHg | 72 hours |