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.

Study Overview

• Status: Not yet recruiting
• Conditions: Heart Failure
• Intervention / Treatment: Other: Intensive sodiuria-guided diuretic treatment; Other: Standard diuretic treatment

• Study Type: Interventional
• Enrollment (Anticipated): 198
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Simone Frea, MD; Phone Number: +390116335570; Email: frea.simone@gmail.com

Study Locations

• Italy
  • To
    • Torino, To, Italy, 10126
      • A.O.U. Città della Salute e della Scienza di Torino
      • Contact: Simone Frea, MD; Phone Number: 0116335570; Email: frea.simone@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: UNa+ Driven Intensive Therapy; 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; Intensive stepwise diuretic treatment based on combined diuresis and urinary sodium assessment
Active Comparator: Standard Therapy; 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; Stepwise diuretic therapy based on diuresis assessment

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to oral switch of diuretic treatments	days	90 days
Time to discharge from hospital	days	90 days
Total Urinary output and urine output/40 mg furosemide	ml/mg furosemide	24 and 48 hours
Variation of body weight and body weight/40 mg furosemide	kg/mg furosemide	24 and 48 hours
Variation of NT-proBNP at 48 hours		48 hours
Variation of wet score at 24 and 72 hours		24 and 72 hours
Dyspnea severity variation at 24 and 48 hours assessed by dyspnea Visual Assessment Scale (VAS).		24 and 48 hours
Fluid balance	In/out fluid balance	24, 48 and 72 hours
Time spent in Intensive Cardiac Intensive Care Unit	days	90 days

Collaborators and Investigators

• Sponsor: University of Turin, Italy
• Investigators: Principal Investigator: Simone Frea, MD, A.O.U. Città della Salute e della Scienza, Torino, Italia

Study record dates

Study Major Dates

• Study Start (Anticipated): October 1, 2021
• Primary Completion (Anticipated): October 1, 2024
• Study Completion (Anticipated): January 1, 2025

Study Registration Dates

• First Submitted: May 25, 2021
• First Submitted That Met QC Criteria: May 25, 2021
• First Posted (Actual): May 28, 2021

Study Record Updates

• Last Update Posted (Actual): May 28, 2021
• Last Update Submitted That Met QC Criteria: May 25, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Natriuretic Agents; Diuretics
• Other Study ID Numbers: SERENA trial

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No