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Diagnosing and Targeting Mechanisms of Diuretic Resistance in Heart Failure

Primary Purpose

Heart Failure

Status

Active

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Increased Intravenous Bolus Loop Diuretic Dose (Bumetanide or Furosemide)

IV Chlorothiazide

About this trial

This is an interventional diagnostic trial for Heart Failure

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Yale University

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

No Intervention

Arm Label

Increased Intravenous Loop Diuretic (Bumetanide or Furosemide)

Loop Diuretic (Bumetanide or Furosemide) + IV Chlorothiazide

Observational Arm

Arm Description

2.5x Visit 1 dose

Loop diuretic (Bumetanide or Furosemide) dose remains the same as visit 1 dose but now with the addition of 500-1000 mg IV chlorothiazide

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.

Outcomes

Primary Outcome Measures

Accuracy of sodium prediction equation in predicting suboptimal natriuretic response to a dose of diuretics

Suboptimal Natriuretic Response is defined as a measured sodium output of <100 mmol in the 6 hours following the dose of diuretic

Prevalence of mechanistic sub types of Diuretic Resistance (DR) as defined by cutoff values of change in fractional excretion of lithium

Descriptions of the prevalence of the DR mechanisms at the different time points in the study will be reported.

Accuracy of prediction of mechanistic sub types of DR using universally available laboratory tests

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.

Change in total 6-hour sodium output between observational and randomized intervention study days

Sodium output in response to a dose of diuretics will be measured via urine collection.

Secondary Outcome Measures

Prediction of mechanistic sub types of DR

Relationship between the fractional excretion of magnesium or calcium with the fractional excretion of endogenous lithium will also be assessed

Full Information

NCT ID

NCT02546583

First Posted

August 27, 2015

Last Updated

July 21, 2022

Sponsor

Yale University

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

1. Study Identification

Unique Protocol Identification Number

NCT02546583

Brief Title

Diagnosing and Targeting Mechanisms of Diuretic Resistance in Heart Failure

Official Title

Diagnosing and Targeting Mechanisms of Diuretic Resistance in Heart Failure

Study Type

Interventional

2. Study Status

Record Verification Date

July 2022

Overall Recruitment Status

Active, not recruiting

Study Start Date

August 31, 2015 (Actual)

Primary Completion Date

July 31, 2023 (Anticipated)

Study Completion Date

July 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Yale University

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Heart Failure

7. Study Design

Primary Purpose

Diagnostic

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

458 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Increased Intravenous Loop Diuretic (Bumetanide or Furosemide)

Arm Type

Experimental

Arm Description

2.5x Visit 1 dose

Arm Title

Loop Diuretic (Bumetanide or Furosemide) + IV Chlorothiazide

Arm Type

Experimental

Arm Description

Loop diuretic (Bumetanide or Furosemide) dose remains the same as visit 1 dose but now with the addition of 500-1000 mg IV chlorothiazide

Arm Title

Observational Arm

Arm Type

No Intervention

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

Increased Intravenous Bolus Loop Diuretic Dose (Bumetanide or Furosemide)

Intervention Description

An increase to 2.5x the Visit 1 dose of loop diuretic (bumetanide or furosemide).

Intervention Type

Drug

Intervention Name(s)

IV Chlorothiazide

Primary Outcome Measure Information:

Title

Accuracy of sodium prediction equation in predicting suboptimal natriuretic response to a dose of diuretics

Description

Suboptimal Natriuretic Response is defined as a measured sodium output of <100 mmol in the 6 hours following the dose of diuretic

Time Frame

6 hours

Title

Prevalence of mechanistic sub types of Diuretic Resistance (DR) as defined by cutoff values of change in fractional excretion of lithium

Description

Descriptions of the prevalence of the DR mechanisms at the different time points in the study will be reported.

Time Frame

6 hours

Title

Accuracy of prediction of mechanistic sub types of DR using universally available laboratory tests

Description

Time Frame

6 hours

Title

Change in total 6-hour sodium output between observational and randomized intervention study days

Description

Sodium output in response to a dose of diuretics will be measured via urine collection.

Time Frame

6 hours

Secondary Outcome Measure Information:

Title

Prediction of mechanistic sub types of DR

Description

Relationship between the fractional excretion of magnesium or calcium with the fractional excretion of endogenous lithium will also be assessed

Time Frame

6 hours

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jeffrey Testani, MD

Organizational Affiliation

Yale University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Yale University

City

New Haven

State/Province

Connecticut

Country

United States

12. IPD Sharing Statement

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Diagnosing and Targeting Mechanisms of Diuretic Resistance in Heart Failure

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