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

Trial Summary

What is the purpose of this trial?

The DART-HA study is a single-center, open label, trial intended to evaluate the clinical efficacy of standard treatment options for congestive heart failure (observation, diuretic or afterload reduction therapy) in patients without new symptoms who have developed abnormalities of the HeartLogic heart failure diagnostic feature.

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 data supports the effectiveness of the drug torasemide for treating congestive heart failure?

Research shows that torasemide, a loop diuretic, is effective in treating congestive heart failure by reducing symptoms like fluid retention and improving heart function. It has a longer duration of action and better absorption compared to furosemide, making it a reliable option for managing heart failure symptoms. ^{1 2 3 4 5}

What makes the drug combination in the trial unique for treating congestive heart failure?

This drug combination is unique because it includes both diuretics like Bumetanide, Furosemide, and Torsemide, which help remove excess fluid from the body, and afterload reducers like Hydralazine and Isosorbide Dinitrate, which help relax blood vessels and reduce the heart's workload. This dual approach targets both fluid overload and high blood pressure, which are common issues in congestive heart failure. ^{6 7 8 9 10}

Research Team

Jay Dinerman

Principal Investigator

Heart Center Research, LLC

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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 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]

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]

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]

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]

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]

References

1. United States 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. [2021]

2. Netherlands 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. [2018]

3. New Zealand pubmed.ncbi.nlm.nih.gov

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

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

[Torasemide is the effective loop diuretic for long-term therapy of arterial hypertension]. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Open-label randomized trial of torsemide compared with furosemide therapy for patients with heart failure. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Partially reversible bortezomib-induced cardiotoxicity: an unusual cause of acute cardiomyopathy. [2020]

7. England 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. [2021]

8. Japan pubmed.ncbi.nlm.nih.gov

Efficacy of pomalidomide in a multiple myeloma patient requiring hemodialysis. [2017]

9. Japan pubmed.ncbi.nlm.nih.gov

Acute severe cardiac failure in a myeloma patient due to proteasome inhibitor bortezomib. [2021]

10. England 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. [2019]