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Diagnosing and Targeting Mechanisms of Diuretic Resistance in Heart Failure

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ClinicalTrials.gov Identifier: NCT02546583
Recruitment Status : Active, not recruiting
First Posted : September 11, 2015
Last Update Posted : July 1, 2020
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Yale University

Brief Summary:

Effective diuresis is the primary goal of most acute decompensated heart failure hospitalizations, but diuretic resistance is common and our ability to detect it is limited. Further, there are therapeutically distinct groups of diuretic-resistant patients. These are not easily distinguished using currently available methods, leading to trial-and-error based treatment that promotes lengthy hospitalizations.

The aims of this study are:

  1. To develop inexpensive and efficient tools to predict diuretic response
  2. To understand the prevalence of therapeutically targetable mechanisms of diuretic resistance using endogenous lithium clearance
  3. To develop methodology to differentiate diuretic resistance mechanisms using common/inexpensive laboratory tests
  4. To provide proof of concept that mechanistically tailored diuretic therapy can improve natriuresis

Condition or disease Intervention/treatment Phase
Heart Failure Drug: Increased Intravenous Bolus Loop Diuretic Dose (Bumetanide or Furosemide) Drug: IV Chlorothiazide Phase 1

Detailed Description:

This study is a minimal-risk observational open-label single center study with randomization between two standard of care interventions. Approximately 500 patients admitted to the hospital (Yale New Haven Health System) with a clinical diagnosis of heart failure will be enrolled in the overall study.

Patients will undergo sampling of their blood and collection of urine at a minimum of 4 timepoints (called "visits"), or a minimum of 5 in the interventional arm. Patients with a low urine sodium output (<100 mmol) on Visit 1 will be eligible for 1:1 randomization to either an increased dose of their Visit 1 loop diuretic or addition of IV chlorothiazide to their Visit 1 loop diuretic.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 458 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Diagnosing and Targeting Mechanisms of Diuretic Resistance in Heart Failure
Actual Study Start Date : August 31, 2015
Estimated Primary Completion Date : July 31, 2023
Estimated Study Completion Date : July 31, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arm Intervention/treatment
Experimental: Increased Intravenous Loop Diuretic (Bumetanide or Furosemide)
2.5x Visit 1 dose
Drug: Increased Intravenous Bolus Loop Diuretic Dose (Bumetanide or Furosemide)
An increase to 2.5x the Visit 1 dose of loop diuretic (bumetanide or furosemide).

Experimental: Loop Diuretic (Bumetanide or Furosemide) + IV Chlorothiazide
Loop diuretic (Bumetanide or Furosemide) dose remains the same as visit 1 dose but now with the addition of 500-1000 mg IV chlorothiazide
Drug: IV Chlorothiazide
No Intervention: Observational Arm
Subjects taking an IV loop diuretic (Bumetanide or Furosemide) that have sodium output greater than 100 mmol. These subjects will continue to be followed and have data collected on them.



Primary Outcome Measures :
  1. Accuracy of sodium prediction equation in predicting suboptimal natriuretic response to a dose of diuretics [ Time Frame: 6 hours ]
    Suboptimal Natriuretic Response is defined as a measured sodium output of <100 mmol in the 6 hours following the dose of diuretic

  2. Prevalence of mechanistic sub types of Diuretic Resistance (DR) as defined by cutoff values of change in fractional excretion of lithium [ Time Frame: 6 hours ]
    Descriptions of the prevalence of the DR mechanisms at the different time points in the study will be reported.

  3. Accuracy of prediction of mechanistic sub types of DR using universally available laboratory tests [ Time Frame: 6 hours ]
    The relationship between the change in fractional excretion of potassium and sodium and the change in fractional excretion of endogenous lithium will be assessed in order to develop methodology to identify the etiology of DR using universally available laboratory tests.

  4. Change in total 6-hour sodium output between observational and randomized intervention study days [ Time Frame: 6 hours ]
    Sodium output in response to a dose of diuretics will be measured via urine collection.


Secondary Outcome Measures :
  1. Prediction of mechanistic sub types of DR [ Time Frame: 6 hours ]
    Relationship between the fractional excretion of magnesium or calcium with the fractional excretion of endogenous lithium will also be assessed



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

For all patients:

Inclusion criteria:

  • Age ≥ 18 years
  • Clinical diagnosis of ADHF with at least one objective sign of volume overload: rales, edema, elevated JVP, preadmission weight gain
  • Current use of bolus IV loop diuretic therapy and projected need by the treating clinician for continued treatment with IV diuretics for at least 3 days with the goal of significant fluid removal (>1L net fluid loss/day)

Exclusion criteria:

  • Inability to perform informed consent or comply with the serial urine collection procedures
  • Significant bladder dysfunction or urinary incontinence
  • Hematocrit less than 21% or active bleeding

For patients in the interventional arm:

Inclusion criteria:

  • Cumulative 6-hour sodium output < 100 mmol following Visit 1 IV loop diuretic dose
  • Visit 1 IV loop diuretic dose ≤ 160 mg of furosemide equivalents
  • Serum sodium > 125 mmol/L
  • At least 6 hours since last dose of diuretic

Exclusion criteria:

  • Current use or projected future requirement by the treating physician for thiazide diuretics
  • Use of high dose mineralocorticoid receptor antagonist therapy (>50mg of spironolactone or >100mg of eplerenone) or amiloride

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): NCT02546583


Locations
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United States, Connecticut
Yale University
New Haven, Connecticut, United States
Sponsors and Collaborators
Yale University
National Heart, Lung, and Blood Institute (NHLBI)
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Responsible Party: Yale University
ClinicalTrials.gov Identifier: NCT02546583    
Other Study ID Numbers: 1505015805
1R01HL128973-01 ( U.S. NIH Grant/Contract )
First Posted: September 11, 2015    Key Record Dates
Last Update Posted: July 1, 2020
Last Verified: June 2020
Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases
Chlorothiazide
Furosemide
Bumetanide
Diuretics
Sodium Potassium Chloride Symporter Inhibitors
Natriuretic Agents
Physiological Effects of Drugs
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents
Sodium Chloride Symporter Inhibitors