Exploring Diuretics Effective Management in Acute Decompensated Heart Failure, EDEMA Trial (EDEMA)

1. Evaluate efficacy and safety of continuous infusion of IV Frusemide compared to IV shots in acute decompensated heart failure ADHF
2. Evaluate superiority of time-adjusted metolazone to morning frusemide IV shots compared to irrespective administration (at random times) to overcome diuretic resistance

Study Overview

• Status: Recruiting
• Conditions: Acute Decompensated Heart Failure; Diuretics Resistance
• Intervention / Treatment: Other: Frusemide IV shots; Other: Frusemide IV infusion

Detailed Description

After admission for acute decompensated heart failure and ensuring eligibility to participate in the study, accepting patients will be randomized by a pre-prepared tables into 2 equal groups (A = shots, B = infusion): - Patients randomized to the Frusemide IV shots arm (group A) will be started on 80 mg frusemide daily (or at the least equal to their prior oral dose if was on >80 mg oral frusemide or equivalent doses of other loop diuretics). Dose will be allowed to be modified by judging the urine output in every 3 hours.

Patients randomized to continuous IV infusion arm (group B) will receive 84 mg Frusemide daily (40 mg bolus followed by 2 mg/ hour starting infusion rate). An extra bolus and/or modification of the infusion rate will be allowed after judging the urine output in 3 hours. The same regimen would be continued for at least 72 hours, or more than 72 hours if needed till switching to oral diuretics.

In patients who develop diuretic resistance defined as failure to achieve therapeutically desired urine output despite maximal doses of loop diuretics will be managed by adding thiazide type diuretic "Metolazone" to the regimen to achieve sequential nephron blockade. Metolazone (2.5 - 10 mg /day) addition will be allowed in both arms when deemed indicated, however, in the IV shots arm, there will be further 1:1 randomization for either giving metolazone timed 60 minutes before the morning IV frusemide shot (group A.T) or metolazone at random time irrespective of the frusemide dose timing (group A.R).

Variables that will be assessed in the patients to evaluate the prespecified end-points are:-

• Urine output in L/day as absolute volume and indexed volume to body weight.
• Weight loss in Kg as absolute number and in percentage of initial body weight.
• Diuretic efficiency defined as amount of urine output per 40mg frusemide.
• Impact on hemodynamics assessed by change in mean arterial pressure, inducing hypotension (systolic below 80 mmHg or requiring denovo vasopressors), or new clinical signs of hypoperfusion.
• Cumulative dose of IV frusemide per 72 hours.
• Improvement of NYHA class as judged by the treating physician.
• Number of days to introduction/restoring dose of betablockade therapy.
• Number of days to switch to oral diuretics as judged by the treating physician.
• Duration of ICU stay and of hospital stay.
• Change in serum creatinine (either rising or falling) in absolute value and percentage from baseline creatinine, as well as in eGFR equated by Cockcroft-Gold equation.
• Occurrence of worsening renal function (WRF) as defined by rise of serum creatinine by ≥ 0.3 mg/dl.
• Occurrence of 50% and or 100% rise in serum creatinine or indication to renal replacement therapy.
• Change in serum potassium as absolute value from baseline or below target range (between 4.0 - 5.0 mEq/dl). Serum potassium level will be routinely checked twice daily in the first 72 hours then once daily or every 48 hours as seen necessary.
• Inducing denovo hypomagnesemia (below 1.8mg/dl) or hyponatremia (below 135 mEq/dl)
• Rehospitalization within 30 days for new heart failure decompensation, and hospitalization for any cause.

VI. Study outcomes

1. Primary outcome

   • Time (in hours) to improvement of NYHA class when frusemide is given as shots compared to infusion.
   • Urine output (in ml/kg/h) per 40 mg of frusemide given as shots vs continuous infusion.

2. Secondary outcome(s)

   • Assessment of additive benefit of addition of metolazone to frusemide in ADHF.
   • Evaluating superiority of timely adjusted metolazone compared to given at random in overcoming resistance to IV frusemide (IV shots arm).

• Study Type: Interventional
• Enrollment (Anticipated): 400
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ahmad Samir, MD; Phone Number: 00201002647275; Email: ahmad.samir@kasralainy.edu.eg
• Study Contact Backup: Name: Salma Sallam; Phone Number: 00201223359622; Email: salma.sallam91@gmail.com

Study Locations

• Egypt
  • Cairo, Egypt
    • Recruiting
    • Faculty of Medicine, Cairo University Hospitals
    • Contact: Salma Sallam

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age more than 18 years.
• Chronic heart failure prior diagnosis, based on signs and or symptoms of heart failure, presenting with acute decompensation as judged by the physician to require hospitalization for IV diuretics

Exclusion Criteria:

• Refusal to participate in the study.
• Allergy to IV frusemide.
• Severe renal impairment defined as eGFR<30ml/m.
• Cardiogenic shock or hemodynamic instability judged by the treating physician to be unsuitable to participate.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Frusemide IV shots = group A; Frusemide as IV shots	Other: Frusemide IV shots; giving frusemide by IV shots And if developed diuretic resistance (diminishing diuretic effect despite incremental dose of IV loop diuretic), adjuvant oral Metolazone will be given for sequential nephron blockade comparing its administration timed 60 minutes prior to the morning Frusemide shot versus given after. (This will be in a second level of randomization)
Active Comparator: Frusemide IV infusion = group B; Frusemide as continuous IV infusion	Other: Frusemide IV infusion; giving frusemide by continuous IV infusion And if developed diuretic resistance (diminishing diuretic effect despite incremental dose of IV loop diuretic), adjuvant oral Metolazone will be given for sequential nephron blockade

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to improvement of NYHA class	Time (in hours) to improvement of NYHA class	within 5 days
Diuretic efficiency	Urine output (in ml/kg/h) per 40 mg of frusemide given as shots vs continuous infusion.	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
effectiveness of sequential nephron block	Assessing improvement of diuresis by adding of metolazone to frusemide in ADHF.patients who had developed diuretic resistance.	within 5 days of adding metolazone
Evaluating superiority of timely adjusted metolazone compared to given at random in overcoming resistance to IV frusemide (only in IV shots arm)	Evaluating superiority of timely adjusted metolazone given 60 minutes prior to IV frusemide compared to when given at random in overcoming diuretic resistance (only in IV shots arm)	within 5 days of adding metolazone

Collaborators and Investigators

• Sponsor: Cairo University
• Collaborators: Kasr El Aini Hospital
• Investigators: Study Chair: Ahmed Shehata, MD, Cairo University; Study Director: Magdy Abdelhamid, MD, Cairo University

Publications and helpful links

General Publications

• Damman K, Testani JM. The kidney in heart failure: an update. Eur Heart J. 2015 Jun 14;36(23):1437-44. doi: 10.1093/eurheartj/ehv010. Epub 2015 Apr 2.

Helpful Links

• Felker GM, Lee KL, Bull DA, et al. Diuretic Strategies in Patients with Acute Decompensated Heart Failure. N Engl J Med. 2011. doi:10.1056/NEJMoa1005419
• Hoorn EJ, Ellison DH. Diuretic Resistance. Am J Kidney Dis. 2017;69(1):136-142. doi:10.1053/j.ajkd.2016.08.027

Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2019
• Primary Completion (Anticipated): December 1, 2021
• Study Completion (Anticipated): December 1, 2021

Study Registration Dates

• First Submitted: February 23, 2019
• First Submitted That Met QC Criteria: March 4, 2019
• First Posted (Actual): March 5, 2019

Study Record Updates

• Last Update Posted (Actual): January 27, 2021
• Last Update Submitted That Met QC Criteria: January 26, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium Potassium Chloride Symporter Inhibitors; Furosemide
• Other Study ID Numbers: N-166-2018

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No