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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

Tracking Information
First Submitted Date April 13, 2016
First Posted Date April 26, 2016
Last Update Posted Date November 6, 2017
Study Start Date August 2016
Actual Primary Completion Date July 31, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: April 21, 2016)
Natriuretic responsiveness [ Time Frame: First 6 hours of diuretic administration ]
Defined by urine sodium output
Original Primary Outcome Measures Same as current
Change History
Current Secondary Outcome Measures
 (submitted: April 21, 2016)
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)
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Identifying Diuretic Resistance in Patients With Acute Heart Failure
Official Title Identifying Diuretic Resistance in Patients With Acute Heart Failure
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.
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.

Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples Without DNA
Description:
Serial urine at 1, 2, 4, and 6 hours
Sampling Method Non-Probability Sample
Study Population Adult ED patients diagnosed with HF
Condition Heart Failure
Intervention Not Provided
Study Groups/Cohorts Usual Care
All patients will receive a dose of intravenous furosemide.
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Completed
Actual Enrollment
 (submitted: October 31, 2017)
75
Original Estimated Enrollment
 (submitted: April 21, 2016)
60
Actual Study Completion Date July 31, 2017
Actual Primary Completion Date July 31, 2017   (Final data collection date for primary outcome measure)
Eligibility 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
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT02751242
Other Study ID Numbers 151931
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement
Plan to Share IPD: No
Responsible Party Jin H. Han, Vanderbilt University
Study Sponsor Vanderbilt University
Collaborators Novartis Pharmaceuticals
Investigators
Principal Investigator: Jin Han, MD Vanderbilt University
PRS Account Vanderbilt University Medical Center
Verification Date October 2017