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

Sponsor

Chiang Mai University (Other)

Overall Status

Recruiting

CT.gov ID

NCT04465123

Collaborator

(none)

100

Enrollment

Location

Arms

28.6

Anticipated Duration (Months)

3.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Heart Failure Acute Kidney Injury	Drug: Spironolactone or hydrochlorothiazide Drug: Placebo	Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

100 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Aug 13, 2020

Anticipated Primary Completion Date :

Jul 31, 2022

Anticipated Study Completion Date :

Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Furosemide with spironolactone or hydrochlorothiazide 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 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. Other Names: Aldactone HCTZ Thiazide
Active Comparator: Furosemide with placebo 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 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.

Arm

Intervention/Treatment

Experimental: Furosemide with spironolactone or hydrochlorothiazide

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

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.

Other Names:

Aldactone

HCTZ

Thiazide

Active Comparator: Furosemide with placebo

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

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.

Outcome Measures

Primary Outcome Measures

Urine volume [72 hours]
Total urine volume after randomisation

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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