Investigating Diuretic Resistance in Heart Failure

Mechanisms of Diuretic Resistance in Heart Failure, Aim 2

This study is testing different combinations of diuretic medications to see if they can help people with heart failure who have trouble getting rid of excess fluid.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 50 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Yale University (Academic / other)
• Locations: 1 site (New Haven, Connecticut)
• Trial ID: NCT05753059 on ClinicalTrials.gov

What this trial studies

This study aims to explore the mechanisms behind diuretic resistance in patients with heart failure by employing a randomized, placebo-controlled, double-blind, double-dummy, crossover design. Participants will receive various combinations of medications, including bendroflumethiazide and amiloride, alongside bumetanide, to assess their effectiveness. The study will also involve co-enrollment in an ancillary study for the administration of bendroflumethiazide. The goal is to better understand how these combinations can improve treatment outcomes for heart failure patients.

Who should consider this trial

Good fit: Ideal candidates include adults over 18 with chronic heart failure and an ejection fraction of less than 40%, who are stable on guideline-directed medical therapy.

Not a fit: Patients with severely impaired kidney function or those who have recently used non-loop diuretics may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could lead to improved treatment strategies for patients with heart failure who experience diuretic resistance.

How similar studies have performed: Other studies have explored diuretic resistance in heart failure, but this specific combination approach is novel.

Eligibility criteria

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

Where this trial is running

New Haven, Connecticut

• Yale University — New Haven, Connecticut, United States (Recruiting)

Study contacts

• Principal investigator: Jeffrey Testani — Yale University
• Study coordinator: Veena Rao

Conditions Heart Failure