Diagnosing and Targeting Mechanisms of Diuretic Resistance in Heart Failure

Heart Failure Clinical Trial

Official title:

Diagnosing and Targeting Mechanisms of Diuretic Resistance in Heart Failure

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02546583
• Other study ID #: 1505015805
• Secondary ID: 1R01HL128973-01
• Status: Completed
• Phase: Phase 1
• Start date: August 31, 2015
• Est. completion date: January 23, 2020

Study information

• Verified date: November 2023
• Source: Yale University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 458
• Est. completion date: January 23, 2020
• Est. primary completion date: January 23, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Heart Failure

Intervention

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).
• IV Chlorothiazide

Locations

Country	Name	City	State
United States	Yale University	New Haven	Connecticut

Sponsors (2)

Lead Sponsor	Collaborator
Yale University	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	6 hours
Primary	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.	6 hours
Primary	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.	6 hours
Primary	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.	6 hours
Secondary	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	6 hours