Mechanisms of Diuretic Resistance in Heart Failure, Aim 2

Mechanisms of Diuretic Resistance in Heart Failure, Aim 2

Randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations placebo/placebo, bendroflumethiazide/placebo, amiloride/placebo, and bendroflumethiazide/amiloride added to bumetanide.

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:

1. Clinical diagnosis of HF

2. No plan for titration/change of heart failure medical or device therapies during the study period.

3. Absence of non-elective hospitalizations in the previous 2 weeks

4. At optimal volume status by symptoms, exam, and dry weight.

5. Serum potassium ≤ 5.0 mmol/L

6. Serum sodium ≥ 130 mEq/L

7. Age > 18 years

8. Hemoglobin ≥8 g/dL

9. Objective evidence of diuretic resistance to a 10mg bumetanide challenge, defined as:

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

1. 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:

1. GFR <20 ml/min/1.73m2 using the CKD-EPI equation or use of renal replacement therapies
2. 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,
3. 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).
4. Hemoglobin < 8 g/dL or symptomatic anemia
5. Pregnant or breastfeeding
6. Inability to give written informed consent or comply with study protocol or follow-up visits
7. Chronic urinary retention limiting ability to perform timed urine collection procedures
8. On Lithium therapy
9. On pimozide or thioridazine
10. Diagnosis of liver failure
11. Contraindications or allergy to sulfonamides
12. Any contraindication to thiazide diuretic or allergy to thiazide or bendroflumethiazide