Overview
Randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations placebo/placebo, bendroflumethiazide/placebo, amiloride/placebo, and bendroflumethiazide/amiloride added to bumetanide.
Description
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.
Eligibility
Inclusion Criteria:
- Chronic clinical diagnosis of HF with a documented ejection fraction <40%.
- Use of beta blocker, ACE, ARB or neprilysin inhibitor (sacubitril/valsartan), aldosterone antagonist, and SGLT2 inhibitor at ≥50% guideline directed doses for 30 days with no plan for titration/change during the study period.
- Chronic stable use of ≥80mg furosemide equivalents per day for ≥ 30 days
- Peak FENa < 5% following 10mg IV bumetanide challenge at the screening visit
- Absence of hospitalizations in the previous 3 months.
- At optimal volume status by symptoms, exam, and dry weight.
- Serum potassium ≤ 5.0 mmol/L
- Serum sodium ≥ 130 mEq/L
- Age > 18 years
Exclusion Criteria:
- GFR <20 ml/min/1.73m2
- Use of any non-loop type diuretic in the last 14 days with the exclusion of low dose aldosterone antagonist (e.g., spironolactone ≤50 mg)
- History of flash pulmonary edema or a "brittle" volume sensitive HF phenotype such as amyloid cardiomyopathy
- Hemoglobin < 8 g/dL
- Pregnant or breastfeeding
- Inability to give written informed consent or comply with study protocol or follow-up visits