Diagnosing and Targeting Mechanisms of Diuretic Resistance in Heart Failure

Phase 1

Completed

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

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

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.

Recruitment & Eligibility

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Arm && Interventions

Group	Intervention	Description
Increased Intravenous Loop Diuretic (Bumetanide or Furosemide)	Increased Intravenous Bolus Loop Diuretic Dose (Bumetanide or Furosemide)	2.5x Visit 1 dose
Loop Diuretic (Bumetanide or Furosemide) + IV Chlorothiazide	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

Primary Outcome Measures

Name	Time	Method
Accuracy of sodium prediction equation in predicting suboptimal natriuretic response to a dose of diuretics	6 hours	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	6 hours	Descriptions of the prevalence of the DR mechanisms at the different time points in the study will be reported.
Change in total 6-hour sodium output between observational and randomized intervention study days	6 hours	Sodium output in response to a dose of diuretics will be measured via urine collection.
Accuracy of prediction of mechanistic sub types of DR using universally available laboratory tests	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.

Secondary Outcome Measures

Name	Time	Method
Prediction of mechanistic sub types of DR	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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