Diagnosing and Targeting Mechanisms of Diuretic Resistance in Heart Failure

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

Study Overview

• Status: Completed
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Increased Intravenous Bolus Loop Diuretic Dose (Bumetanide or Furosemide); Drug: IV Chlorothiazide

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.

• Study Type: Interventional
• Enrollment (Actual): 458
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States
      • Yale University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
Change in total 6-hour sodium output between observational and randomized intervention study days, compared between intervention groups	Sodium output in response to a dose of diuretics will be measured via urine collection.	6 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Jeffrey Testani, MD, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): August 31, 2015
• Primary Completion (Actual): January 23, 2020
• Study Completion (Actual): January 23, 2020

Study Registration Dates

• First Submitted: August 27, 2015
• First Submitted That Met QC Criteria: September 8, 2015
• First Posted (Estimated): September 11, 2015

Study Record Updates

• Last Update Posted (Actual): August 17, 2025
• Last Update Submitted That Met QC Criteria: August 14, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Failure; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Natriuretic Agents; Antihypertensive Agents; Sodium Chloride Symporter Inhibitors; Furosemide; Bumetanide; Diuretics; Sodium Potassium Chloride Symporter Inhibitors; Chlorothiazide
• Other Study ID Numbers: 1505015805; 1R01HL128973-01 (U.S. NIH Grant/Contract)