Diuretic Treatment in Acute Heart Failure With Volume Overload Guided by Serial Spot Urine Sodium Assessment

Overview

This is a pragmatic, multicenter, interventional, parallel-arm, randomized, open-label trial to investigate whether a diuretic regimen, based on serial assessment of sodium concentration (UNa) on spot urine samples after diuretic administration and with low-threshold use of combination diuretic therapy, improves decongestion versus usual care in acute heart failure (AHF), potentially leading to better clinical outcomes.

Study Type

• Study Type: Interventional
• Study Design
  • Allocation: Randomized
  • Intervention Model: Parallel Assignment
  • Primary Purpose: Treatment
  • Masking: None (Open Label)
• Study Primary Completion Date: July 31, 2023

Detailed Description

Key interventions are: – Assessment of UNa in spot urine samples after every bolus administration of loop diuretics with continuation of intravenous diuretics until resolution of clinical signs of fluid overload AND UNa <80 mmol/L – Dosing of loop diuretic bolus according to estimated glomerular filtration rate (eGFR) – Upfront use of intravenous acetazolamide 500 mg OD unless hypernatremia (>145 mmol/L) or metabolic acidosis (bicarbonate <22 mmol/L) – Upfront use of oral chlorthalidone 50 mg OD if eGFR <30 mL/min/1.73m² OR hypernatremia (>145 mmol/L) – Switch to full nephron blockade with intravenous acetazolamide 500 mg OD, intravenous bumetanide 4 mg TID, oral chlorthalidone 100 mg OD, and intravenous canrenoate 200 mg OD in case of diuretic resistance, defined as UNa <80 mmol/L and persistent clinical signs of fluid overload – Provision of 500 mL intravenous Dextrose 5% with 3 g MgSO4 and 40 mmol KCl daily during diuretic therapy with intravenous diuretics

Interventions

• Diagnostic Test: UNa measurement after intravenous loop diuretic bolus
  • Sodium concentration is measured on a urine spot sample, collected 30-120 min after administration of every protocol-specified intravenous bumetanide dose.
• Drug: Intravenous acetazolamide 500 mg OD
  • Upfront use of intravenous acetazolamide 500 mg OD as part of the diuretic treatment, unless hypernatremia (>145 mmol/L) or metabolic acidosis (bicarbonate <22 mmol/L) is present at the moment of the scheduled administration.
• Drug: Intravenous bumetanide TID
  • An intravenous bolus of bumetanide is administered TID, with dosing according to eGFR: 2 mg for an eGFR >45 mL/min/1.73m²; 3 mg for an eGFR 30-45 mL/min/1.73m²; and 4 mg for an eGFR <30 mL/min/1.73m². At any time diuretic resistance is encountered (persistent clinical signs of fluid overload with UNa <80 mmol/L), a dose of 4 mg TID is used.
• Drug: Oral chlorthalidone OD
  • In case of hypernatremia (>145 mmol/L) or low eGFR (<30 mL/min/1.73m²), oral chlorthalidone 50 mg OD is added to the diuretic treatment. At any time diuretic resistance is encountered (persistent clinical signs of fluid overload with UNa <80 mmol/L), oral chlorthalidone is provided at a dose of 100 mg OD. Chlorthalidone is never administered in case of hypotonic hyponatremia with serum sodium concentration <135 mmol/L.
• Drug: Intravenous canrenoate 200 mg OD
  • At any time diuretic resistance is encountered (persistent clinical signs of fluid overload with UNa <80 mmol/L), intravenous canrenoate 200 mg OD is provided. Canrenoate is never administered in case of hypotonic hyponatremia with serum sodium concentration <135 mmol/L or if serum potassium levels are >5.5 mmol/L. If canrenoate is administered, oral mineralocorticoid receptor drugs are temporarily withhold until switch to oral diuretic treatment.
• Other: Maintenance infusion
  • A maintenance infusion with 500 mL dextrose 5% and 3 g MgSO4 is started at an infusion rate of 20 mL/h upon the moment of first protocol-specified administration of intravenous diuretics and continued until switch to oral diuretic therapy. 40 mmol KCl is added if serum potassium levels are <4 mmol/L. In case of hypotonic hyponatremia with serum sodium concentration <130 mmol/L, dextrose 5% will not be provided and MgSO4 will be administered in 50 mL of normal saline (NaCl 0.9%).
• Drug: Oral potassium supplements
  • If serum potassium levels are <3.5 mmol/L at any time during the administration of intravenous diuretics, oral potassium supplements are provided as needed to keep serum potassium levels >4 mmol/L
• Other: Intravenous hypertonic saline
  • In case of hypotonic hyponatremia with serum sodium concentration <125 mmol/L, a bolus of 150 mL hypertonic saline 3% is administered and repeated OD if necessary, until sodium levels are ≥135 mmol/L.
• Other: Switch to oral diuretic therapy
  • Upon complete resolution of clinical signs of fluid overload with UNa <80 mmol/L, intravenous diuretics are switched to an oral schedule including: Loop diuretics with dose & frequency at the discretion of the treating physician Chlorthalidone 50 mg if added for diuretic resistance at any time during the intravenous diuretic phase Spironolactone 25 mg or another equivalent mineralocorticoid receptor antagonist
• Other: Usual AHF care
  • It is recommended to administer an intravenous loop diuretic dose at least BID (or through continuous infusion), with the aim of achieving a urine output 3-5 L per day until the patient is considered in an optimal volume status as is recommended by current guidelines.

Arms, Groups and Cohorts

• Experimental: Intervention arm
  • Application of a standardized diuretic schedule with following key components: UNa assessment in spot urine sample after every bolus of loop diuretics with continuation of intravenous diuretics until absence of clinical signs of fluid overload AND UNa <80 mmol/L Loop diuretic dosing according to estimated glomerular filtration rate (eGFR) with higher dose for lower eGFR Upfront use of intravenous acetazolamide 500 mg OD unless hypernatremia or metabolic acidosis Upfront use of oral chlorthalidone 50 mg OD if eGFR <30 mL/min/1.73m² OR hypernatremia Full nephron blockade with intravenous acetazolamide 500 mg OD, intravenous bumetanide 4 mg TID, oral chlorthalidone 100 mg OD, and intravenous canrenoate 200 mg OD in case of diuretic resistance, defined as UNa <80 mmol/L and persistent clinical signs of fluid overload Provision of 500 mL intravenous Dextrose 5% with 3 g MgSO4 and 40 mmol KCl daily during intravenous diuretics
• Active Comparator: Control arm
  • Usual care for AHF. It is recommended to administer an intravenous loop diuretic dose at least BID (or through continuous infusion), with the aim of achieving a urine output 3-5 L per day until the patient is considered in an optimal volume status as is recommended by current guidelines. Urine electrolyte assessment in the control arm is not allowed as it is a key component of the studied intervention.

Clinical Trial Outcome Measures

Primary Measures

• Mortality, days in hospital & decongestion
  • Time Frame: 30 days
  • Win ratio for a hierarchically composed endpoint of mortality, days in hospital and relative decrease in N-terminal pro-hormone of B-type natriuretic peptide (NT-proBNP) levels after 30 days.

Secondary Measures

• Renal safety endpoint
  • Time Frame: 30 days
  • Doubling of the serum creatinine or plasma cystatin C value compared to baseline with an absolute value >2 mg/dL or >2 mg/L, respectively, or the need for ultrafiltration and/or renal replacement therapy during the index hospital admission.
• Hemodynamic safety endpoint
  • Time Frame: 30 days
  • Systolic blood pressure <90 mmHg or mean arterial pressure <65 mmHg or need for vasopressors and/or inotropes during the index hospital admission.
• Natriuretic peptide change after 30 days
  • Time Frame: 30 days
  • Relative NT-proBNP change from baseline to 30 days after randomisation [%].
• Cancer antigen 125 (CA125) change after 30 days
  • Time Frame: 30 days
  • Relative cancer antigen 125 (CA125) change from baseline to 30 days after randomisation [%].
• Number of participants with successful clinical decongestion
  • Time Frame: 30 days
  • Number of participants with no more than trace edema, absence of jugular venous distension and no rales upon the moment of transition from intravenous diuretics to oral diuretic therapy according to the protocol.
• Length of intravenous diuretic therapy
  • Time Frame: 30 days
  • Number of consecutive days from randomization during the index admission on which intravenous diuretic therapy was administered.
• Overall well-being after decongestion
  • Time Frame: 30 days
  • Five-point Likert scale for overall well-being upon the moment of transition from intravenous diuretics to oral diuretic therapy according to the protocol and compared with the moment of randomisation (5: much improved/4: slightly improved/3: neutral/2: slightly worse/1: much worse).
• Length of the index hospital admission
  • Time Frame: 30 days
  • Length of the index hospital admission [days].
• Number of participants who are death, or have a non-elective hospital admission or non-elective medical contact
  • Time Frame: 30 days
  • Number of participants who are death, or have a non-elective hospital admission or non-elective medical contact
• Number of participants who are death or have a non-elective hospital admission
  • Time Frame: 30 days
  • Number of participants who are death or have a non-elective hospital admission

Participating in This Clinical Trial

Inclusion Criteria

• At least 18 y/o and able to provide informed consent – Hospital admission (anticipated stay >24 h after randomisation) with diagnosis of acute heart failure according to the treating physician – At least one of the following three signs of volume overload: 1. bilateral oedema 2+, indicating clear pitting 2. ascites that is amenable for drainage, confirmed by echography (no obligation to perform abdominal echocardiography, but necessary when presence of ascites is used as an entry criterion for the study) 3. uni- or bilateral pleural effusions that are amenable for drainage, confirmed by chest X-ray or lung ultrasound (no obligation to perform chest X-ray, but necessary when presence of pleural effusions is used as an entry criterion for the study) – Plasma NTproBNP level >1,000 ng/L Exclusion criteria:

• No possibility to collect reliable urine spot samples after diuretic administration – Administration of any diuretic within 6 h before randomisation, except for a mineralocorticoid receptor antagonist or sodium glucose co-transporter-2 inhibitor as part of the patient's maintenance treatment for heart failure. Patients can still be included after withholding these diuretics for 6 h, after which randomisation can be performed if they qualify all other criteria. – Severe kidney dysfunction, defined as an eGFR <15 mL/min/1.73m² calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula and/or previous, current, or planned future renal replacement therapy – Systolic blood pressure <90 mmHg, mean arterial pressure <65 mmHg, or need for inotropes/vasopressor therapy at randomisation – Any acute coronary syndrome within 30 days prior to enrolment, defined as typical chest pain with a troponin rise above the 99th percentile of normal and/or electrocardiographic changes suggestive of cardiac ischemia – History of heart or kidney transplantation – History of mechanical circulatory support – Known obstructive hypertrophic cardiomyopathy, congenital heart disease, acute mechanical cause of acute heart failure (e.g., papillary muscular rupture), acute myocarditis, or constrictive pericarditis according to the treating physician – Pregnant or breastfeeding woman – Concomitant participation in another interventional study

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 99 Years

Are Healthy Volunteers Accepted: No

Investigator Details

• Lead Sponsor
  • Vrije Universiteit Brussel
• Collaborator
  • Roche Diagnostics
• Provider of Information About this Clinical Study
  • Principal Investigator: Frederik Hendrik Verbrugge, MD PhD, Head of Clinic/Clinical Professor – Vrije Universiteit Brussel
• Overall Official(s)
  • Frederik H Verbrugge, M.D.; Ph.D., Principal Investigator, Vrije Universiteit Brussel
• Overall Contact(s)
  • Simon Vanhentenrijk, M.D.; Pharm.D., +32 2 474 9060, simon.vanhentenrijk@uzbrussel.be