Diuretics for Heart Failure

(MsDR 2 Trial)

Overseen By Kara Otis

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Yale University

Must be taking: Beta blockers, ACE, ARB, SGLT2

Must not be taking: Non-loop diuretics

Disqualifiers: Low GFR, Pulmonary edema, others

Compensation: Varies

Number of Visits: 4

Duration: 3 weeks

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to identify the best combination of diuretics (medications that help the body eliminate excess fluid) for treating heart failure. Researchers will test different combinations of two diuretics, bendroflumethiazide and amiloride, alongside a standard treatment called bumetanide, to determine which is most effective. People with heart failure who haven't had recent hospital stays and struggle with fluid retention despite taking diuretics might be suitable candidates for this study.

As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking medical research.

Will I have to stop taking my current medications?

The trial requires that you continue taking certain heart failure medications like beta blockers, ACE inhibitors, ARBs, or neprilysin inhibitors, aldosterone antagonists, and SGLT2 inhibitors at stable doses. However, you must not have used any non-loop diuretics in the last 14 days, except for low-dose aldosterone antagonists.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of bendroflumethiazide and amiloride is generally well-tolerated. Studies have not found a significant increase in the risk of death or hospital visits when using these diuretics together for heart failure, suggesting the treatment is relatively safe for managing fluid buildup in these patients.

Monitoring blood potassium levels and kidney function is important with amiloride, as the medication can affect these. Some studies have shown it can be effective without causing severe side effects if these factors are carefully managed.

Bendroflumethiazide alone has effectively managed fluid retention without causing major side effects. It helps reduce fluid buildup, a common issue in heart failure. Overall, available evidence suggests these treatments are safe when used carefully, though individual responses can vary. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using amiloride and bendroflumethiazide for heart failure because they offer a unique approach compared to standard diuretics like furosemide or hydrochlorothiazide. Amiloride works by blocking sodium channels in the kidneys, which helps reduce fluid buildup without affecting potassium levels as much as other diuretics. Bendroflumethiazide, on the other hand, enhances the effect of other diuretics like bumetanide by increasing sodium and water excretion. This combination could potentially provide a more balanced and effective way to manage fluid retention in heart failure patients.

What evidence suggests that this trial's treatments could be effective for heart failure?

In this trial, participants will receive different treatment combinations to assess their effectiveness in managing heart failure. Research has shown that using bendroflumethiazide and amiloride together can help reduce fluid buildup in people with heart failure. Studies indicate that bendroflumethiazide, when combined with other diuretics, increases the removal of excess salt and water from the body. This combination may improve exercise ability and lower blood lactate levels, suggesting better heart function. Amiloride helps manage heart failure by stabilizing potassium levels, which is crucial for heart health. This combination has effectively managed symptoms like swelling and shortness of breath in heart failure patients. Participants in this trial may receive bendroflumethiazide with amiloride, amiloride with placebo, bendroflumethiazide with placebo, or placebo alone to evaluate these effects. ^{1 2 6 7 8}

Who Is on the Research Team?

Jeffrey Testani, MD

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

This trial is for adults over 18 with heart failure and an ejection fraction below 40%. They should be on stable doses of certain heart medications, have no recent hospitalizations, and not plan to change their medication during the study. People with very low kidney function, recent use of other diuretics (except low-dose aldosterone antagonists), or those who are pregnant can't participate.

Inclusion Criteria

I am older than 18 years.

My body's fluid levels are balanced according to my doctor.

My heart's pumping ability is less than 40%.

Exclusion Criteria

Inability to give written informed consent or comply with study protocol or follow-up visits

I have had sudden lung swelling or a sensitive heart condition like amyloid cardiomyopathy.

Your hemoglobin level is less than 8 grams per deciliter.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive combinations of placebo/placebo, bendroflumethiazide/placebo, amiloride/placebo, and bendroflumethiazide/amiloride added to bumetanide in a crossover design

3 weeks

4 visits (in-person) on Days 0, 7, 14, and 21

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Amiloride
• Bendroflumethiazide
• Placebo

Trial Overview The study tests how well different combinations of drugs help people whose bodies resist water pills (diuretics) in heart failure. It compares Bendroflumethiazide and Amiloride—both added to Bumetanide—with a placebo in a randomized, controlled manner where neither doctors nor patients know who gets which treatment.

How Is the Trial Designed?

Group I: Bendroflumethiazide/ Amiloride Active Control 2 Interventions

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 on Days 0, 7, 14 and 21

Group II: Placebo/ Amiloride Active Control 2 Interventions

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 on Days 0, 7, 14 and 21

Group III: Placebo/ Bendroflumethiazide Active Control 2 Interventions

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 on Days 0, 7, 14 and 21

Group IV: Placebo/ Placebo Placebo Group 1 Intervention

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 on Days 0, 7, 14 and 21

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Published Research Related to This Trial

In a controlled study involving 86 patients with mild to moderate congestive heart failure, slow-release furosemide (30 mg or 60 mg daily) was found to be as effective as bendroflumethiazide (2.5 mg daily) for maintenance treatment over a 12-week period.

Both medications had few and minor adverse effects, indicating a good safety profile for both treatment options in managing congestive heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicentre comparison between slow-release furosemide and bendroflumethiazide in congestive heart failure. Pehrsson, SK.[2019]

In a study involving 8 patients with mild heart failure, different diuretic treatments showed that the timing and dosage of bumethanide and bendroflumethiazide affected blood volume and heart performance during exercise.

Treatment with 5 mg bendroflumethiazide resulted in a significantly higher heart rate-pressure product during exercise and lower plasma lactate levels compared to the other treatments, indicating better heart function and oxygen demand adjustment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of three diuretic regimens in heart failure. Andreasen, F., Eriksen, UH., Guul, SJ., et al.[2019]

In a study comparing the effects of theophylline ethylenediamine and bendroflumethiazide in patients with advanced congestive heart failure, both medications showed similar natriuretic and diuretic effects while patients were on long-term bumetanide treatment.

Theophylline ethylenediamine is suggested as a viable alternative to thiazide diuretics for additional natriuretic treatment, emphasizing the importance of maintaining potassium balance during combined diuretic therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative natriuretic and diuretic efficacy of theophylline ethylenediamine and of bendroflumethiazide during long-term treatment with the potent diuretic bumetanide. Permutation trial tests in patients with congestive heart failure. Sigurd, B., Olesen, KH.[2019]

In patients with advanced congestive heart failure, a single dose of bendroflumethiazide (5 mg) significantly increased sodium and chloride excretion compared to additional bumetanide (4 mg), indicating its superior natriuretic effect.

The combination of bendroflumethiazide and bumetanide produced a greater effect on sodium and chloride excretion than either drug alone, suggesting a supra-additive interaction that may require monitoring for potential side effects like hypokalemia and alkalosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The supra-additive natriuretic effect addition of bendroflumethiazide and bumetanide in congestive heart failure. Permutation trial tests in patients in long-term treatment with bumetanide. Sigurd, B., Olesen, KH., Wennevold, A.[2019]

Amyloride, a diuretic studied in 60 patients with circulatory insufficiency, effectively increases sodium excretion (natriuresis) without causing potassium loss, making it a potassium-sparing option for treatment.

The drug enhances the effects of other diuretics like furosemide and hydrochlorothiazide without increasing potassium loss, and it is well-tolerated by patients, suggesting its suitability for broader clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Therapeutic use of amiloride and its combinations with hydrochlorothiazide and furosemide in chronic circulatory insufficiency]. Sidorenko, BA., Kharchenko, VI., Evsikov, EM.[2017]

Long-acting loop diuretic torasemide has been shown to improve symptoms and functional class in patients with congestive heart failure (CHF) more effectively than the commonly used furosamide, based on long-term comparative studies.

Indapamide, a thiazide-like diuretic, not only acts as a diuretic but also helps to reduce the heart's workload by acting as a vasodilator; however, it must be used cautiously due to its potential to prolong the Q-T interval, which can lead to serious heart rhythm issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The place of diuretics in the treatment of chronic heart failure. Part I]. Sidorenko, BA., Preobrazhenskiĭ, DV., Batyraliev, TA., et al.[2018]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/6399889/

Frusemide/amiloride combination ('Frumil') in heart failure Abstract. A total of 95 patients seen in general practice with oedema associated with heart failure took part in an open study of the efficacy and tolerability ...

2. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK542303/

Amiloride - StatPearls - NCBI Bookshelf - NIH Monitoring serum potassium and renal function is integral to managing heart failure and hypertension when receiving amiloride. In addition, managing ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT01210365?term=LASIX&viewType=Table&rank=9

Safety and Efficacy of Furosemide 40mg + Amiloride ... General physical examination and measure of potassium level in blood will be used for measuring the improvement of CHF symptoms and decrease in peripheral edema ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1053077019311097

Loop Diuretics—Analysis of Efficacy Data for the ... P. Martens et al. Changes in loop diuretic dose and outcome after cardiac resynchronization therapy in patients with heart failure and reduced left ventricular ...

5. link.springer.com link.springer.com/article/10.1007/s11897-024-00643-3

Diuretic Treatment in Patients with Heart Failure: Current ... Fluid retention or congestion is a major cause of symptoms, poor quality of life, and adverse outcome in patients with heart failure (HF).

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10924023/

Diuretic Treatment in Patients with Heart Failure Fluid retention or congestion is a major cause of symptoms, poor quality of life, and adverse outcome in patients with heart failure (HF).

7. mayoclinic.org mayoclinic.org/drugs-supplements/amiloride-oral-route/description/drg-20071527

Amiloride (oral route) - Side effects & dosage If high blood pressure is not treated, it can cause serious problems such as heart failure, blood vessel disease, stroke, or kidney disease . It is best to take ...

8. immattersacp.org immattersacp.org/weekly/archives/2025/05/20/2.htm

Amiloride may be effective for resistant hypertension, timing of ... ... heart failure, occurred in 2.3 per 100 patient-years in the bedtime group and 2.4 per 100 patient-years in the morning group (adjusted ...