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

Trial Summary

What is the purpose of this trial?

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

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.

What evidence supports the effectiveness of the drug bendroflumethiazide for heart failure?

Research shows that bendroflumethiazide, when used with other diuretics like bumetanide, has a strong effect in increasing the removal of sodium and water from the body, which is beneficial for patients with heart failure. It is as effective as other diuretics like furosemide for maintaining treatment in mild to moderate heart failure. ^{1 2 3 4 5}

How do diuretics for heart failure differ from other treatments?

Diuretics like slow-release furosemide and bendroflumethiazide are used to manage heart failure by helping the body remove excess fluid, which reduces the workload on the heart. Slow-release furosemide offers a longer duration of action compared to other diuretics, which can be beneficial for maintaining consistent fluid balance in heart failure patients. ^{1 2 3 4 6}

Research Team

Jeffrey Testani, MD

Principal Investigator

Yale University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

A comparison of three diuretic regimens in heart failure. [2019]

2. United States 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. [2019]

3. Germany pubmed.ncbi.nlm.nih.gov

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

4. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Therapeutic use of amiloride and its combinations with hydrochlorothiazide and furosemide in chronic circulatory insufficiency]. [2017]

5. Sweden 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. [2019]

6. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[The place of diuretics in the treatment of chronic heart failure. Part I]. [2018]