Early Sequential Nephron Blockade in Acute Heart Failure Patients: A Randomised, Controlled Study

Study Overview
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Brief Summary
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This study aims to demonstrate the efficacy of sequential nephron blockade by adding hydrochlorothiazide or spironolactone on intravenous furosemide compared to intravenous furosemide alone in the treatments of volume overload in patients with acute heart failure who have diuretic resistance from furosemide stress test.

Detailed Description
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This study is a randomised, double-blinded, double-dummy, placebo-controlled study to demonstrate the efficacy of oral hydrochlorothiazide or spironolactone in combination with intravenous furosemide compared to intravenous furosemide in combination with placebo. Dosage of intravenous furosemide will be adjusted according to pre-defined protocol. The primary outcome is urine volume during 72 hours after randomisation.

Official Title
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Furosemide With Early Sequential Nephron Blockade Versus Furosemide Alone in Acute Heart Failure Patients With Furosemide-guided Diuretic Resistance: A Double-blinded, Randomized, Placebo-controlled Study

Conditions
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Acute Heart Failure, Acute Kidney Injury

Intervention / Treatment
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* Drug: Spironolactone or hydrochlorothiazide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Diagnosis of acute heart failure which is defined by 2 of the 3 following features: ≥2+ leg edema, jugular venous pressure >10 cm from physical examination or central venous pressure >10 mmHg, and bilateral pulmonary edema or bilateral pleural effusion from chest radiography Patients consent to participate into the study Exclusion Criteria: Patients who receive furosemide ≥500 mg/day or hydrochlorothiazide ≥100 mg/day or spironolactone ≥100 mg/day or tolvaptan of any doses Patients who have systolic blood pressure <100 mmHg or who need vasoactive drugs inotropic agents (except dobutamine) Patients with intravascular volume depletion from clinical evaluation Patients with chronic kidney disease stage 5 (estimated glomerular filtration rate <15 ml/min/1.73 m2) or patients who receive maintenance dialysis Patients who require renal replacement therapy at the time of admission Patients whom diagnosed hypertrophic obstructive cardiomyopathy, severe valvular stenosis or complex congenital heart disease Patients with sepsis or systemic infection Pregnant women Patients who have history of furosemide, spironolactone or hydrochlorothiazide allergy

Ages Eligible for Study
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Minimum Age: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Furosemide with spironolactone or hydrochlorothiazide<br>IV furosemide dosage will be adjusted according to the protocol as follows. Level 1: previous oral furosemide dose ≤80 mg/day; furosemide 80 mg IV bolus every 6 hours Level 2: previous oral furosemide dose 81-160 mg/day; furosemide 160 mg IV bolus every 6 hours Level 3: previous oral furosemide dose >160 mg/day; furosemide 250 mg IV bolus every 6 hours Furosemide dosage will be adjusted to keep urine output between 3,000 and 5,000 ml/day and >600 ml during 6 hours after furosemide administration. If the urine output <3,000 ml/day or <600 ml per 6 hours, furosemide dosage will be increase 1-level up per protocol above. If the urine output >5,000 ml/day, furosemide dosage will be reduced 1-level down per protocol above. Patients will be received spironolactone or hydrochlorothiazide in combination with intravenous furosemide according to patients' serum potassium levels. | Drug: Spironolactone or hydrochlorothiazide<br>* Patients will be received spironolactone or hydrochlorothiazide in combination with intravenous furosemide according to patients' serum potassium levels. If serum potassium levels ≤4 mEq/L, patients will be received spironolactone 100 mg every 12 hour for 72 hours. If serum potassium levels >4 mEq/L, patients will be received hydrochlorothiazide 50 mg every 12 hour for 72 hours.<br>* Other names: Thiazide;|
| Active Comparator: Furosemide with placebo<br>IV furosemide dosage will be adjusted according to the pre-defined protocol as shown in the experimental group. Patients will be received spironolactone placebo or hydrochlorothiazide placebo in combination with intravenous furosemide according to patients' serum potassium levels. | Drug: Placebo<br>* Patients will be received spironolactone placebo or hydrochlorothiazide placebo in combination with intravenous furosemide according to patients' serum potassium levels. If serum potassium levels ≤4 mEq/L, patients will be received spironolactone placebo every 12 hour for 72 hours. If serum potassium levels >4 mEq/L, patients will be received hydrochlorothiazide placebo every 12 hour for 72 hours.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urine volume | Total urine volume after randomisation | 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urine volume | Total urine volume after randomization | 24 and 48 hours | 
| Body weight | Changes of patient's body weight | 72 hours after randomisation | 
| Length of hospital admission | Number of days that patients need to stay in the hospital | During hospital admission period | 
| Furosemide dose | Total dosage of intravenous furosemide | 72 hours after randomisation | 
| Levels of B-type atrial natriuretic peptide (BNP) | levels of pro-BNP | 72 hours and 7 days after randomisation | 
| Number of participants with adverse events | All adverse events during hospital admission | During hospital admission | 
| Dyspnea score assessed by visual analogue scale | The scale is between 0 and 100. The higher scale represents lower level of dyspnea | At randomization, and 6, 12, 24, 48 and 72 hours after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute heart failure, Diuretic resistance, Sequential nephron blockade, Diuretic combination