Diuretics vs Afterload Reduction for Congestive Heart Failure

(DART-HA Trial)

Overseen By COO

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Heart Center Research, LLC

Must not be taking: Inotropes, Diuretics

Disqualifiers: Renal failure, Heart transplant, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 37

Duration: Up to 90 days

80 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate how different treatments can assist people with congestive heart failure who exhibit certain heart changes but lack new symptoms. It will compare standard care, diuretics (medications that help the body eliminate excess fluid, such as Bumetanide, Furosemide, and Torsemide), and afterload reduction drugs (medications that ease heart pumping, such as Hydralazine and Isosorbide Dinitrate). Individuals using a Boston Scientific heart device without significant heart failure symptoms might be suitable candidates. As a Phase 4 trial, the treatments are already FDA-approved and proven effective, with the goal of understanding how they benefit more patients.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that participants should not have standard contraindications to certain heart failure medications, which might imply some restrictions. It's best to discuss your specific medications with the trial team.

What is the safety track record for these treatments?

Research shows that the treatments in this trial have been safe in earlier studies.

Bumetanide, a water pill for heart failure, helps when the heart doesn't pump enough blood. The FDA has approved it for several conditions, including heart failure. Studies have found it effective, though it might slightly increase the risk of death compared to some other water pills.

Furosemide, another water pill for heart failure, is generally safe if used carefully, but higher doses can lead to worse outcomes. Patients need regular blood tests to monitor mineral levels and prevent problems.

Torsemide is safe and well-tolerated. Some studies suggest it may result in fewer hospital stays compared to furosemide, without increasing the risk of death.

Sacubitril/valsartan, another medication in this trial, has reduced death rates and hospital visits for heart failure patients. It is generally safe and helps improve quality of life for many.

Hydralazine and isosorbide dinitrate are often used together for heart failure. Research indicates this combination can improve heart function and may lower death rates in some patients. They are usually used when other treatments aren't enough and have a good safety record.

Overall, these medications are well-researched and have proven safety in managing heart failure. Participants should discuss any concerns with the trial team to feel comfortable with the treatments involved. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about this clinical trial because it explores different strategies for managing congestive heart failure (CHF) by comparing diuretics and afterload reduction methods. The trial investigates if adjusting diuretics like Bumetanide, Furosemide, and Torsemide, which help remove excess fluid, can be more effective than increasing afterload reduction drugs like Sacubitril/valsartan, Hydralazine, and Isosorbide Dinitrate that help the heart pump more efficiently. This approach is unique because it directly compares the effectiveness of these strategies in preventing heart failure decompensation, which could lead to more personalized and effective treatment plans for patients. Researchers hope to determine which protocol best prevents heart failure symptoms from worsening, offering insights that could improve patient outcomes.

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

This trial will compare the effectiveness of diuretics and afterload reduction treatments for managing congestive heart failure. Research has shown that diuretics help manage heart failure by removing excess fluid from the body. Participants in the diuretic protocol may receive treatments like Furosemide, which provides quick relief in urgent situations. Studies suggest that Torsemide might reduce hospital visits more effectively than Furosemide, while Bumetanide also helps reduce swelling and improve physical activity, though it may carry a slightly higher risk of death compared to other diuretics.

In the afterload reduction protocol, participants may receive Sacubitril/valsartan, which has significantly lowered hospital visits and deaths in patients with heart failure who have a reduced ability to pump blood. It also improves their health over time. Additionally, the combination of Hydralazine and Isosorbide Dinitrate effectively reduces symptoms and death rates, especially in Black patients with heart failure. Overall, these treatments offer different benefits for managing heart failure, with some being more effective for certain groups or outcomes. ^{1 3 4 6 7}

Who Is on the Research Team?

Jay Dinerman

Principal Investigator

Heart Center Research, LLC

Are You a Good Fit for This Trial?

This trial is for people with a Boston Scientific device monitoring heart failure who don't have new symptoms but show diagnostic feature abnormalities. They can't have severe kidney issues, ongoing heart failure symptoms, recent arrhythmia changes, or be pregnant. Stable blood pressure and no history of certain drug reactions are required.

Inclusion Criteria

I don't have conditions that would make taking Sacubitril/valsartan unsafe for me.

Boston Scientific device with HeartLogic enabled

Exclusion Criteria

The subject is implanted with unipolar RA or RV leads

My kidney function is very low, and water pills don't work for me or I'm on dialysis.

I have severe heart failure symptoms even when resting.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Remote Monitoring

Subjects with CHF are remotely monitored for HeartLogic score elevations

Ongoing

Treatment

Participants are randomized to observation, diuretic, or afterload reduction therapy based on HeartLogic alerts

Up to 90 days

Recheck HeartLogic index 7 days after initiation of treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment

90 days

Visits at 30, 60, and 90 days

What Are the Treatments Tested in This Trial?

Interventions

• Bumetanide
• Furosemide
• Hydralazine
• Isosorbide Dinitrate
• Sacubitril/valsartan
• Torsemide

Trial Overview

The DART-HA study compares standard treatments for congestive heart failure: observation alone versus diuretics (like Furosemide) or afterload reducers (like sacubitril/valsartan). It's to see which treatment works best when HeartLogic alerts occur without new symptoms.

How Is the Trial Designed?

Group I: Observation protocol Active Control 1 Intervention

Standard therapy offered until development of symptoms of heart failure decompensation occurs. Patients will be monitored until out of alert and at 30, 60, and 90 days.

Group II: Diuretic protocol Active Control 3 Interventions

If asymptomatic at time of HeartLogic(HL) alert, will add or increase diuretic based on current medications. If currently taking ≤ 20 mg. furosemide, begin furosemide 40mg orally daily until recovery from alert or re-alert. If currently taking ≥ 40mg furosemide begin torsemide 20 mg orally daily or bumetanide 1 mg orally daily. If patient unable to obtain torsemide or bumetanide double furosemide daily dose (maximum 480mg daily). If currently taking ≥ 20mg torsemide or ≥ 1mg bumetanide, double daily dose. Recheck HeartLogic index 7 days following initiation of diuretic protocol. If patient recovers from alert consider reducing dose or stopping diuretic. If HeartLogic index is lower but still in alert continue current diuretic dose. If HeartLogic index is the same or higher double diuretic dose and/or add metolazone 2.5mg for 1-2 days.

Group III: Afterload reduction protocol Active Control 3 Interventions

If asymptomatic at time of HL alert, increase afterload reduction drugs based on current medications. If on Sacubitril/valsartan, double the dose. If on maximum Sacubitril/valsartan, add Hydralazine 10mg and Isordil10 mg both three times a day. If on Angiotensin Receptor Blocker (ARB) at low dose (less than or equal to Valsartan 160mg daily or equivalent) then stop ARB and start sacubitril/valsartan 24-26mg twice a day. If on ARB at high dose (greater than Valsartan 160mg daily or equivalent) then immediately stop ARB and start Sacubitril/valsartan 49-51mg twice a day. If on Angiotensin-converting enzyme (ACE) inhibitor at low dose (less than or equal to 10mg daily or equivalent) then immediately stop ACE inhibitor and start Sacubitril/valsartan 24-26mg twice a day after 48hours. If on ACE inhibitor at high dose (greater than Enalapril 10mg daily or equivalent) stop ACE inhibitor and start Sacubitril/valsartan 49-51mg twice a day after 48hours. Cut diuretic in half for all.

Bumetanide is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Bumetanide for:

• Edema secondary to cardiac failure
• Edema secondary to hepatic disease
• Edema secondary to renal disease
• Nephrotic syndrome
• Hypertension

Approved in European Union as Bumetanide for:

• Oedema associated with congestive heart failure
• Oedema associated with hepatic cirrhosis
• Oedema associated with a nephrotic syndrome
• Hypertension

Approved in Canada as Bumetanide for:

• Edema secondary to congestive heart failure
• Edema secondary to hepatic cirrhosis
• Edema secondary to nephrotic syndrome
• Hypertension

Who Is Running the Clinical Trial?

Heart Center Research, LLC

Lead Sponsor

Trials

1

Recruited

80+

Boston Scientific Corporation

Industry Sponsor

Trials

758

Recruited

867,000+

Michael F. Mahoney

Boston Scientific Corporation

Chief Executive Officer since 2016

MBA from Wake Forest University, BBA in Finance from the University of Iowa

Kenneth Stein

Boston Scientific Corporation

Chief Medical Officer since 2020

MD from Harvard Medical School, MMSc in Clinical Investigation from Harvard-MIT Division of Health Sciences and Technology

Published Research Related to This Trial

In a study involving 319 dogs with new onset congestive heart failure (CHF) due to degenerative mitral valve disease, torasemide was found to be noninferior to furosemide in reducing pulmonary edema and cough after 14 days of treatment.

Dogs treated with torasemide had a significantly longer time to cardiac-related death or premature withdrawal from the study compared to those treated with furosemide, indicating a better safety profile and potential for improved outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of oral torasemide in dogs with degenerative mitral valve disease and new onset congestive heart failure: The CARPODIEM study. Besche, B., Blondel, T., Guillot, E., et al.[2021]

Torasemide is an effective diuretic for treating congestive heart failure (CHF) at doses of 5 to 20 mg/day, with a higher bioavailability and longer half-life compared to furosemide.

At non-diuretic doses of 2.5 to 5 mg/day, torasemide effectively lowers diastolic blood pressure below 90 mm Hg in 70 to 80% of patients, making it a viable alternative to thiazide diuretics for managing essential hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Torasemide is the effective loop diuretic for long-term therapy of arterial hypertension]. Preobrazhenskiĭ, DV., Nekrasova, NI., Khoseva, EN., et al.[2018]

A 47-year-old patient with myeloma developed severe congestive cardiac failure after receiving bortezomib, highlighting a rare but serious side effect of this treatment.

Bortezomib inhibits the proteasome, which can lead to the accumulation of damaged proteins in heart cells, suggesting that patients should be closely monitored for cardiac function during treatment, regardless of their prior heart health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute severe cardiac failure in a myeloma patient due to proteasome inhibitor bortezomib. Hacihanefioglu, A., Tarkun, P., Gonullu, E.[2021]

Pomalidomide combined with low-dose dexamethasone was effective in maintaining disease stability in a 67-year-old male patient with relapsed multiple myeloma, even while undergoing hemodialysis.

Careful dose adjustments were necessary due to side effects like pancytopenia, indicating that pomalidomide can be a viable treatment option for patients with advanced myeloma and renal failure, but requires close monitoring and supportive care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of pomalidomide in a multiple myeloma patient requiring hemodialysis. Kida, M., Hirao, M., Iizuka, H., et al.[2017]

In a study of 234 patients with chronic heart failure, those treated with torsemide had significantly lower rates of hospital readmission for heart failure (17% vs. 32% for furosemide) and for all cardiovascular causes (44% vs. 59%).

Patients on torsemide also experienced fewer hospital days for heart failure (106 days vs. 296 days for furosemide) and reported greater improvements in fatigue, suggesting that torsemide may be a more effective diuretic for managing chronic heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-label randomized trial of torsemide compared with furosemide therapy for patients with heart failure. Murray, MD., Deer, MM., Ferguson, JA., et al.[2019]

A retrospective analysis of 2509 patients treated with bortezomib for multiple myeloma showed low incidences of serious cardiac events, such as congestive heart failure (CHF) and arrhythmias, with no significant differences compared to control groups.

Bortezomib treatment was associated with a higher incidence of mild edema, but overall, the cardiac safety profile indicates that bortezomib has a low risk of serious cardiac complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma: towards providing a benchmark for the cardiac safety profile of proteasome inhibition in multiple myeloma. Laubach, JP., Moslehi, JJ., Francis, SA., et al.[2019]

A 66-year-old woman with end-stage renal disease experienced acute left ventricular dysfunction after receiving bortezomib, indicating a potential risk of cardiotoxicity associated with this drug, despite it being less common than with other chemotherapy agents.

The Naranjo adverse drug reaction probability scale suggested a probable link between bortezomib and her cardiac issues, highlighting the need for careful monitoring of heart function in patients treated with proteasome inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Partially reversible bortezomib-induced cardiotoxicity: an unusual cause of acute cardiomyopathy. Meseeha, MG., Kolade, VO., Attia, MN.[2020]

In a study involving 7 dogs with stable congestive heart failure (CHF), torsemide was found to be as effective as furosemide in controlling clinical signs of CHF, with indications of greater diuresis.

Torsemide treatment led to significant changes in several laboratory parameters, suggesting it may have a different impact on kidney function and electrolyte balance compared to furosemide, but did not affect the quality of life of the dogs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of torsemide and furosemide on clinical, laboratory, radiographic and quality of life variables in dogs with heart failure secondary to mitral valve disease. Peddle, GD., Singletary, GE., Reynolds, CA., et al.[2018]

Diuretics, especially loop diuretics like torasemide, are crucial for providing quick relief in patients with congestive heart failure (CHF) by promoting sodium and water excretion, which helps reduce fluid overload and improve heart function.

Torasemide has a longer duration of action and better bioavailability compared to furosemide, and both medications effectively reduce symptoms of heart failure and improve cardiac function, with torasemide being well tolerated and showing only mild side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute and long term effects of loop diuretics in heart failure. Krück, F.[2018]

High-output heart failure can occur in patients with multiple myeloma due to extensive bone involvement, leading to the formation of arteriovenous fistulas, and traditional diuretic therapy is ineffective in this scenario.

Treatment with dexamethasone combined with lenalidomide or thalidomide resulted in significant symptom improvement and fluid balance in two patients, suggesting a novel approach to managing high-output heart failure in multiple myeloma through 'pharmacologic fistula ligation'.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple myeloma presenting with high-output heart failure and improving with anti-angiogenesis therapy: two case reports and a review of the literature. Robin, J., Fintel, B., Pikovskaya, O., et al.[2021]

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