Diagnosing and Targeting Mechanisms of Diuretic Resistance in Heart Failure

NCT02546583 | Completed Phase 1 DMC

• 2 other identifiers: 15050158051R01HL128973-01
• Study Type: interventional
• Target: 458
• Locations: 1 country
• Sites: 1

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

Conditions

Heart Failure

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (1)

• Prediction of mechanistic sub types of DR

  6 hours

Study Arms (3)

Increased Intravenous Loop Diuretic (Bumetanide or Furosemide)

EXPERIMENTAL

2.5x Visit 1 dose

Drug: Increased Intravenous Bolus Loop Diuretic Dose (Bumetanide or Furosemide)

Loop Diuretic (Bumetanide or Furosemide) + IV Chlorothiazide

EXPERIMENTAL

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

Observational Arm

NO INTERVENTION

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.

Interventions

Increased Intravenous Bolus Loop Diuretic Dose (Bumetanide or Furosemide) DRUG

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

Increased Intravenous Loop Diuretic (Bumetanide or Furosemide)

IV Chlorothiazide DRUG

Loop Diuretic (Bumetanide or Furosemide) + IV Chlorothiazide

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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:
• 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
• 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

Sponsors & Collaborators

• Yale University: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

Yale University

New Haven, Connecticut, United States

Location

Related Publications (2)

• Rao VS, Cox ZL, Ivey-Miranda JB, Moreno-Villagomez J, Ramos-Mastache D, Maulion C, Bellumkonda L, Turner J, Wilson FP, Shilpak MG, Estrella MM, Welling P, Wilcox CS, Ellison DH, Forbush B, Testani JM. Loop Diuretic Dose Intensification versus Adjuvant Thiazide for Diuretic Resistance in Acute Heart Failure: Mechanistic Randomized Controlled Trial. J Am Soc Nephrol. 2025 Sep 12. doi: 10.1681/ASN.0000000887. Online ahead of print. No abstract available.

  PMID: 40938670 DERIVED

• Ivey-Miranda JB, Rao VS, Cox ZL, Moreno-Villagomez J, Mahoney D, Maulion C, Bellumkonda L, Turner JM, Collins S, Wilson FP, Krumholz HM, Testani JM. In-Hospital Observation on Oral Diuretics After Treatment for Acute Decompensated Heart Failure: Evaluating the Utility. Circ Heart Fail. 2023 Apr;16(4):e010206. doi: 10.1161/CIRCHEARTFAILURE.122.010206. Epub 2023 Mar 10.

  PMID: 36896716 DERIVED

MeSH Terms

Conditions

Heart Failure

Interventions

Bumetanide; Furosemide; Chlorothiazide

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; meta-Aminobenzoates; Aminobenzoates; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Sulfanilamides; Aniline Compounds; Amines; Benzothiadiazines; Thiazides; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Jeffrey Testani, MD

  Yale University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 27, 2015
• First Posted: September 11, 2015
• Study Start: August 31, 2015
• Primary Completion: January 23, 2020
• Study Completion: January 23, 2020
• Last Updated: August 17, 2025

Record last verified: 2025-08

Locations

US (1)