RecruitingPhase 1NCT05753059

Mechanisms of Diuretic Resistance in Heart Failure, Aim 2

Sponsor

Yale University

Enrollment

50 participants

Start Date

Aug 10, 2023

Study Type

INTERVENTIONAL

Conditions

Heart Failure

Summary

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

Eligibility

Min Age: 18 Years

Inclusion Criteria12

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 Criteria12

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

Interventions

DRUGPlacebo

This study will employ a randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations placebo/placebo, bendroflumethiazide/placebo, amiloride/placebo, added to bumetanide on Days 0, 7, 14 and 21

DRUGAmiloride

This study will employ a randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations of amiloride/placebo, and bendroflumethiazide/amiloride added to bumetanide on Days 0, 7, 14 and 21

DRUGBendroflumethiazide

This study will employ a randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations of bendroflumethiazide/placebo and bendroflumethiazide/amiloride added to bumetanide on Days 0, 7, 14 and 21