Mechanisms of Diuretic Resistance in Heart Failure, Aim 2

This study will employ a randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations placebo/placebo, bendroflumethiazide/placebo, amiloride/placebo, and bendroflumethiazide/amiloride added to bumetanide.

Patients will be co-enrolled in this study and an ancillary study for administration of Bendroflumethiazide. Administration of bendroflumethiazide will take place under an ancillary protocol.

Inclusion criteria

• Clinical diagnosis of HF
• 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 weeks
• At optimal volume status by symptoms, exam, and dry weight.
• Serum potassium ≤ 5.0 mmol/L
• Serum sodium ≥ 130 mEq/L
• Age > 18 years
• Hemoglobin ≥8 g/dL
• Objective evidence of diuretic resistance to a 10mg bumetanide challenge, defined as:

• FENa <10% and total sodium output <150mmol and
• At least one of the following criteria:

• Chronic home furosemide dose > or equal to 80mg furosemide equivalents daily 2. eGFR < 60ml/min 3. Serum chloride <100mmol/L 4. FENa <5% and total sodium output <75mmol on the 2 hour screening

Exclusion criteria

• GFR <20 ml/min/1.73m2 using the CKD-EPI equation or use of renal replacement therapies
• Use of any non-loop type diuretic in the last 7 days or 5 half lives, with the exclusion of low dose aldosterone antagonist (e.g., spironolactone or eplerenone ≤50 mg). Examples of non-loop diuretics include but may not be limited to acetazolamide (oral or IV, not ophthalmic), metolazone, HCTZ, chlorthalidone, chlorothiazide, indapamide, triamterene, amiloride, finerenone, spironolactone dose > 50mg day, eplerenone > 50mg/day,
• History of flash pulmonary edema requiring hospitalization and treatment with biphasic positive airway pressure or mechanical ventilation or a "brittle" volume sensitive HF phenotype such as an infiltrative or restrictive cardiomyopathy (i.e. amyloid cardiomyopathy, etc).
• Hemoglobin < 8 g/dL or symptomatic anemia
• Pregnant or breastfeeding
• Inability to give written informed consent or comply with study protocol or follow-up visits
• Chronic urinary retention limiting ability to perform timed urine collection procedures
• On Lithium therapy
• On pimozide or thioridazine
• Diagnosis of liver failure
• Contraindications or allergy to sulfonamides
• Any contraindication to thiazide diuretic or allergy to thiazide or bendroflumethiazide