Mechanisms of Diuretic Resistance in Heart Failure, Aim 3

Prior treatment

• On Lithium therapy

Other illness

• History of flash pulmonary edema or a "brittle" volume sensitive HF phenotype such as amyloid cardiomyopathy
• Cirrhosis or known liver disease
• History of metabolic or respiratory acidosis within 30 days
• Diagnosis of liver failure
• Contraindications or allergy to sulfonamides
• Any contraindication to thiazide diuretic or allergy to thiazide or bendroflumethiazide

Lab values

• Glomerular filtration rate (GFR) \<20 ml/min/1.73m2
• Hemoglobin \< 8 g/dL
• Patients who are on metformin may be enrolled if their metformin can be safely discontinued for the randomized treatment periods in each arm. Any participants who have consistently elevated blood glucose readings \> 200 mg/dL while inpatient will not be enrolled.
• Serum bicarbonate level \<24mmol/L at screening visit

Other

• Use of any non-loop type diuretic in the last 7 days with the exclusion of low dose aldosterone antagonist (e.g., spironolactone ≤50 mg)
• Pregnant or breastfeeding
• Use of metformin, acetazolamide, or any other agent that could predispose to acidosis
• Venous potential of hydrogen(pH) \<7.35 at screening visit
• Inability to give written informed consent or comply with study protocol or follow-up visits
• On pimozide or thioridazine

• Clinical diagnosis of heart failure
• No plan for titration/change of heart failure medical or device therapies during the study period.
• Absence of non-elective hospitalizations in the previous 2 months.
• At optimal volume status by symptoms, exam, and dry weight.
• Serum potassium ≤ 5.0 mmol/L
• Serum sodium ≥ 130 milliequivalents/ liter (mEq/L)
• Hemoglobin ≥8 g/dL
• Age \>18 years
• Objective evidence of diuretic resistance to a 10mg bumetanide challenge (screening visit may occur under this protocol or HIC2000032328 or HIC2000034315) defined as:
  • FENa \<10% and total sodium output \<150mmol
  • And at least one of the following criteria:
  • Chronic home furosemide dose greater than or equal to 80mg furosemide equivalents
  • eGFR \< 60ml/min
  • Serum chloride \<100mmol/L
  • FENa \<5% and total sodium output \<75mmol on the 2 hour