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Identifying Diuretic Resistance in Patients With Acute Heart Failure

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ClinicalTrials.gov Identifier: NCT02751242
Recruitment Status : Completed
First Posted : April 26, 2016
Last Update Posted : November 6, 2017
Sponsor:
Collaborator:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Jin H. Han, Vanderbilt University

Brief Summary:
The study team hypothesizes patients at risk for diuretic resistance can be identified early in their Emergency Department (ED) or hospital stay by evaluating their urine sodium and potassium concentration after an initial dose of IV loop diuretic. The goal of this pilot study is to prospectively study urinary electrolyte excretion and determine patterns of diuretic responsiveness. This study would be utilized to power an interventional study which aims to study alternative methods of treating patients who are identified as having a poor response to diuretics in the ED and hospital. This would be expected to have a significant impact on a patient's hospital course, length of stay and adverse events.

Condition or disease
Heart Failure

Detailed Description:

Most patients hospitalized with acute heart failure (AHF) respond to intravenous (IV) loop diuretic therapy, which results in symptom improvement and discharge from the hospital after a 3-5 day stay. However, up to 20% of these patients do not respond to IV loop diuretics, and are found to be "diuretic resistant". The treatment pathway for this cohort of patients is unclear. As a result, they experience significantly longer hospital lengths of stay, consume more healthcare resources, and experience an increased proportion of adverse events. Clinicians currently do not have a reliable method of predicting who will become diuretic resistant. The diagnosis is made after hospitalization, based on poor response to diuretics resulting in escalation of therapy. The standard approach to AHF therapy is to treat all patients with IV loop diuretics, not knowing who will become diuretic resistant. When diuretics are effective in promoting diuresis and natriuresis the urinary sodium rises and the urinary potassium falls. Those patients with continued low urinary sodium despite IV diuretic administration are at risk for developing diuretic resistance. Defining diuretic resistance based on urinary electrolytes before it becomes clinically apparent would facilitate an earlier change in therapy, with an aim of preventing a prolonged hospitalization.

Recently, a method to determine diuretic responsiveness based on measurements of urinary sodium in the first 6 hours after diuretic administration has been reported. This is a novel concept, and suggests the HF provider could identify poor diuretic responsiveness within 1-2 hours of diuretic administration. This study was conducted in the inpatient setting, where subjects were enrolled up to 4 days after admission. Conducting a similar ED-based study at the time of initial diuretic administration would be important to determine if early diuretic responsiveness can also be predicted using their formula for urinary sodium output. The fractional sodium excretion, (FeNa %), represents the amount of sodium excretion (mmol/time) as a percentage of filtered load [plasma sodium concentration to glomerular filtration rate]. FeNa has been used in several studies to assess diuresis in HF patients. Baseline FeNa has been shown to be reduced to less than 1% in patients with HF and a baseline FeNa of less than 0.2% is associated with diuretic resistance. Identifying effective therapies to mitigate diuretic resistance will improve symptoms, decrease hospital length of stay, conserve healthcare resources and possibly improve morbidity and mortality.

Sodium reabsorption is finely tuned in the distal portion of the nephron by the sodium-chloride cotransporter (NCC) in the distal convoluted tubule and the epithelial sodium channel (ENaC) in the collecting duct. Although only 5-10% of filtered urinary sodium typically reaches these portions of the nephron, this represents roughly 15-times the average daily dietary sodium intake. Nearly 100% of sodium is reabsorbed in the setting of sodium depletion, hypovolemia, or certain pathogenic conditions (congestive heart failure, decompensated cirrhosis). The aldosterone-sensitive collecting duct is largely responsible for this fine regulation by its ability to maximally active ENaC-dependent sodium reabsorption. Although ENaC activity and expression can be measured in vitro (patch clamp) and animal studies (micropuncture, Western blot), assessment in clinical studies is very limited due to the inability to access adequate tissue. Therefore, investigators have used the urinary sodium/potassium ratio as an index of ENaC activity. The study team has recently developed a mass spectrometric assay for urinary exosomal epithelial sodium channel (γENaC), demonstrating a 15-fold increase during low sodium diet or during aldosterone administration. This method represents a significant technical advance and provides clinical investigators a tool to measure ENaC expression in future clinical studies. The study team anticipates that a similar approach will enable clinicians to measure the expression of additional relevant transporters and channels.


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Study Type : Observational
Actual Enrollment : 75 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Identifying Diuretic Resistance in Patients With Acute Heart Failure
Study Start Date : August 2016
Actual Primary Completion Date : July 31, 2017
Actual Study Completion Date : July 31, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Group/Cohort
Usual Care
All patients will receive a dose of intravenous furosemide.



Primary Outcome Measures :
  1. Natriuretic responsiveness [ Time Frame: First 6 hours of diuretic administration ]
    Defined by urine sodium output


Secondary Outcome Measures :
  1. Formula to predict natriuretic responsiveness [ Time Frame: 1 and 2 hours after diuretic administration ]
    Na output (mmol) = Estimated Glomerular Filtration Rate (eGFR) x (BSA/1.73) x (Cr serum/Cr urine) x 60 min x 2.5 hours x (Na urine/1000ml)


Biospecimen Retention:   Samples Without DNA
Serial urine at 1, 2, 4, and 6 hours


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Adult ED patients diagnosed with HF
Criteria

Inclusion Criteria:

  • Adults over age 18
  • Diagnosed with AHF in the ED
  • Patient or surrogate provided informed consent

Exclusion Criteria:

  • Systolic Blood pressure < 90 mmHg
  • Intravenous diuretic administration prior to enrollment
  • Allergy to furosemide and bumetanide
  • Currently receiving any form of dialysis

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02751242


Locations
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United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Vanderbilt University
Novartis Pharmaceuticals
Investigators
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Principal Investigator: Jin Han, MD Vanderbilt University

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Responsible Party: Jin H. Han, Principal Investigator, Vanderbilt University
ClinicalTrials.gov Identifier: NCT02751242     History of Changes
Other Study ID Numbers: 151931
First Posted: April 26, 2016    Key Record Dates
Last Update Posted: November 6, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Jin H. Han, Vanderbilt University:
Diuretic Resistance
Emergency Medicine

Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases
Diuretics
Natriuretic Agents
Physiological Effects of Drugs