Diagnosing and Targeting Mechanisms of Diuretic Resistance in Heart Failure

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.

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