Diuretic Therapy for Heart Failure

(ESCALATE Trial)

Recruiting at 1 trial location

Overseen By Karen F. Miller, RN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Vanderbilt University Medical Center

Must be taking: Diuretics

Must not be taking: Ototoxic medications

Disqualifiers: ESRD, Intubation, Coronary syndrome, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 14 days

474 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method of using diuretics, medications that help the body eliminate excess fluid, in individuals with acute heart failure (a sudden worsening of heart function). The researchers compare a structured approach, known as protocolized diuretic therapy based on urine tests, to the usual care based on guidelines. Suitable candidates for this trial include those diagnosed with acute heart failure in the emergency department, exhibiting symptoms like leg swelling or difficulty breathing, and who are scheduled to receive diuretics. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant medical advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are using certain ototoxic medications (drugs that can damage the ear) like intravenous aminoglycosides and cisplatin.

What prior data suggests that this protocol is safe for heart failure patients?

Research has shown that using a specific plan for diuretic treatment, guided by urine sodium levels, is generally safe for people with sudden heart failure. Past studies found this approach practical and well-tolerated, with no major safety issues reported. It effectively removed excess fluid from the body. This suggests the treatment is fairly safe based on current evidence. However, as it is still under clinical trial evaluation, monitoring safety remains important. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores a new, personalized approach to diuretic therapy for heart failure. Unlike traditional treatments that follow a one-size-fits-all guideline, this protocolized method tailors diuretic doses based on individual patient needs. This is achieved by using spot urine sodium and creatinine measurements to guide dosing decisions, aiming for specific daily goals in urine output and fluid balance. This tailored strategy could lead to more effective fluid management and improved patient outcomes compared to the current standard of care.

What evidence suggests that protocolized diuretic therapy might be an effective treatment for heart failure?

This trial will compare two approaches to diuretic therapy for heart failure. Research has shown that a structured method of adjusting diuretic doses based on urine sodium levels can help remove excess fluid in patients with acute heart failure (AHF). Participants in the trial's "Protocolized spot urine sodium guided diuretic therapy" arm will follow this method, which has been shown to increase sodium removal through urine, thereby reducing extra fluid in the body. Another study confirmed that this approach is safe and practical for patients with AHF. The goal is to relieve fluid buildup, which is crucial in treating heart failure. Overall, these findings suggest that this structured diuretic therapy could improve outcomes for those with AHF by better managing fluid levels. ^{1 2 3 6 7}

Who Is on the Research Team?

Sean P. Collins, MD

Principal Investigator

Vanderbilt University Medical Center

Are You a Good Fit for This Trial?

The ESCALATE trial is for adults over 18 with Acute Heart Failure (AHF) diagnosed in the Emergency Department. They must have symptoms like edema, chest X-ray or ultrasound showing AHF, jugular vein swelling, lung crackles, S3 heart sound, or significant weight gain from fluid. Patients already on IV diuretics may qualify but not if they've had more than two doses before screening.

Inclusion Criteria

I am scheduled to receive IV diuretics during my first day in the hospital.

The doctor thinks you have more than 10 pounds of extra fluid in your body, or you have a previous weight that the doctor knows you should be at.

I was diagnosed with Acute Heart Failure in the Emergency Department.

Exclusion Criteria

You have very low or high levels of certain minerals in your blood that haven't been treated.

Lack of informed consent

I am not taking medications that can harm my hearing.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive protocolized diuretic therapy guided by urinary sodium or structured usual care

14 days

Daily assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days

Extended Follow-up

Monitoring for long-term outcomes such as all-cause death and readmission

180 days

What Are the Treatments Tested in This Trial?

Interventions

• Protocolized diuretic therapy

Trial Overview This study tests a new way to use diuretics based on urine sodium levels against usual care in patients with acute heart failure. Participants are randomly assigned to either the test protocol or standard treatment after their initial emergency department evaluation.

How Is the Trial Designed?

Group I: Protocolized spot urine sodium guided diuretic therapy Active Control 1 Intervention

Patients will have a spot urine sodium and urine creatinine obtained. The urine and creatinine results will be input into the diuretic calculator and the diuretic dose will be chosen based on daily goals for urine output and net negative fluid balance. Performed 3 times per day, diuretic dosing will be individualized based on the proportion of 24-hour diuresis achieved since the prior IV diuretic dose. Every 24 hours new goals for urine output and net negative fluid balance are established based on the study and treatment team's assessment of residual congestion until protocol completion.

Group II: Guideline-based care Active Control 1 Intervention

Patients will be placed on guideline-based diuretic dosing consistent with usual practice. The initial dose will be two times their home dose and will be subsequently adjusted by the treating team based on renal function and symptom severity. The treating team can increase or decrease the frequency and dose of diuretic based on urine output and clinical assessment. Patients in this arm also have urine collected 3 times per day by the bedside nurse to mirror the intervention arm.

Protocolized diuretic therapy is already approved in United States, European Union for the following indications:

Approved in United States as Protocolized diuretic therapy for:

• Acute heart failure

Approved in European Union as Urinary sodium-guided diuretic therapy for:

• Acute heart failure

Who Is Running the Clinical Trial?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

Published Research Related to This Trial

A systematic review of 9 studies, including 5 randomized trials, suggests that a flexible diuretic dosing regimen may lead to fewer emergency room visits and hospitalizations, as well as improved quality of life for heart failure patients with reduced ejection fraction.

However, only 2 of the studies specifically focused on the effects of flexible diuretic titration alone, highlighting a significant gap in research, especially for heart failure patients with preserved ejection fraction, and indicating a need for more rigorous clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Flexible diuretic titration in chronic heart failure: where is the evidence? Piano, MR., Prasun, MA., Stamos, T., et al.[2018]

Diuretic therapy is crucial in managing heart failure, with specific recommendations based on the severity of sodium retention, including the use of thiazide and loop diuretics combined with ACE inhibitors for optimal effectiveness.

Despite their importance, diuretics have not been as thoroughly studied as other heart failure treatments, highlighting the need for better assessment methods, such as sodium retention scores, to improve understanding of their role and limitations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approaches to diuretic therapy and electrolyte imbalance in congestive heart failure. Cody, RJ., Pickworth, KK.[2007]

Diuretic therapy is commonly used to treat congestion in heart failure patients, but it can lead to complications such as diuretic resistance and worsening renal function.

The article discusses the mechanisms behind diuretic resistance and offers strategies to optimize diuretic therapy, highlighting the need for careful management in heart failure treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Diuretic therapy in patients with congestive heart failure: an update]. Aspromonte, N., Ria, P., Bonello, M.[2012]

The PUSH-AHF study aims to determine if a natriuresis-guided therapy approach can improve diuretic response and clinical outcomes in 310 patients with acute heart failure requiring intravenous loop diuretics.

By adjusting diuretic treatment based on urinary sodium levels, the study will assess whether this method leads to better sodium excretion and reduces the risk of all-cause mortality or heart failure rehospitalization within 6 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Natriuresis-guided therapy in acute heart failure: rationale and design of the Pragmatic Urinary Sodium-based treatment algoritHm in Acute Heart Failure (PUSH-AHF) trial. Ter Maaten, JM., Beldhuis, IE., van der Meer, P., et al.[2022]

In a study of 116 patients with acute decompensated heart failure, continuous infusion of furosemide combined with low-dose dopamine resulted in improved renal function, as indicated by lower creatinine levels and increased glomerular filtration rate, compared to intermittent bolus therapy.

Patients receiving continuous furosemide had shorter hospital stays and significantly lower readmission rates at 30 days, suggesting that this method is not only effective but also safer for renal health in heart failure management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Continuous infusion of furosemide combined with low-dose dopamine compared to intermittent boluses in acutely decompensated heart failure is less nephrotoxic and carries a lower readmission at thirty days. Aziz, EF., Alviar, CL., Herzog, E., et al.[2018]

In a study of 13,898 patients with acute decompensated heart failure, the use of metolazone was linked to significant adverse effects, including increased rates of hyponatremia, hypokalemia, worsening renal function, and a 20% higher risk of mortality compared to those not using metolazone.

In contrast, high-dose loop diuretics were associated with some electrolyte imbalances but did not show an increased risk of mortality, suggesting that increasing loop diuretic doses may be a safer strategy than adding metolazone for managing inadequate diuresis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes Associated With a Strategy of Adjuvant Metolazone or High-Dose Loop Diuretics in Acute Decompensated Heart Failure: A Propensity Analysis. Brisco-Bacik, MA., Ter Maaten, JM., Houser, SR., et al.[2022]

Diuretic therapy is essential for managing congestive heart failure (CHF) by helping to reduce salt and water retention, which alleviates congestive symptoms.

Combining diuretics, such as metolazone with furosemide, can enhance the effectiveness of treatment while also minimizing potential complications associated with diuretic use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diuretics in congestive heart failure. Sica, DA., Gehr, T.[2013]

This randomized clinical trial will evaluate the effectiveness of the Diuretic Treatment Algorithm (DTA) in managing heart failure patients, focusing on improving clinical stability and reducing hospital readmissions within 90 days, involving 270 participants in total.

Participants in the intervention group will receive tailored diuretic adjustments and weekly phone support for nonpharmacological management, while the control group will only have initial physician-guided adjustments, allowing for a comparison of outcomes between the two approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of a diuretic adjustment algorithm and nonpharmacologic management in patients with heart failure: study protocol for a randomized controlled trial. Feijó, MK., Biolo, A., Ruschel, KB., et al.[2018]

In a study involving 310 patients with acute heart failure, natriuresis-guided diuretic therapy significantly increased urinary sodium excretion compared to standard care, indicating a potential benefit in monitoring treatment response.

However, despite improved natriuresis, there were no significant differences in clinical outcomes such as all-cause mortality or heart failure rehospitalization between the natriuresis-guided and standard care groups, suggesting that while the approach may enhance sodium excretion, it does not necessarily translate to better overall patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Natriuresis-guided diuretic therapy in acute heart failure: a pragmatic randomized trial. Ter Maaten, JM., Beldhuis, IE., van der Meer, P., et al.[2023]

In a study of 22,239 emergency room patients, the use of diuretics was not associated with increased mortality within 28 days, indicating that diuretic therapy may not pose a significant risk in this context.

While certain diuretics like spironolactone, torasemide, and chlortalidone showed initial associations with mortality in univariate analysis, these associations did not hold in a multivariate model, suggesting that factors like age and creatinine levels are more critical risk factors for mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of Diuretics is not associated with mortality in patients admitted to the emergency department: results from a cross-sectional study. Haider, DG., Lindner, G., Wolzt, M., et al.[2018]

In a study of 17,068 hospitalized patients, 13.9% received furosemide, primarily for congestive heart failure, indicating its common use in managing cardiovascular conditions.

While 10.1% of furosemide recipients experienced adverse reactions, serious life-threatening effects were rare, suggesting that furosemide is generally safe, especially when potassium supplements are used to mitigate hypokalemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical toxicity of furosemide in hospitalized patients. A report from the Boston Collaborative Drug Surveillance Program. Greenblatt, DJ., Duhme, DW., Allen, MD., et al.[2019]

Citations

1. ahajournals.org ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.123.011105

The Multicenter ENACT-HF Study | Circulation: Heart Failure A standardized natriuresis-guided diuretic protocol to guide decongestion in acute heart failure was feasible, safe, and resulted in higher natriuresis and ...

2. nature.com nature.com/articles/s41591-023-02532-z

Natriuresis-guided diuretic therapy in acute heart failure In this article, the Pragmatic Urinary Sodium-based algoritHm in Acute Heart Failure (PUSH-AHF) randomized clinical trial investigated the ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38179728/

The Multicenter ENACT-HF Study A standardized natriuresis-guided diuretic protocol to guide decongestion in acute heart failure was feasible, safe, and resulted in higher natriuresis and ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11455821/

The utility of urine sodium–guided diuresis during acute ... Diuresis to achieve decongestion is a central aim of therapy in patients hospitalized for acute decompensated heart failure (ADHF).

5. sciencedirect.com sciencedirect.com/science/article/pii/S1071916424009552

Point: Natriuresis Guided Diuresis in Patients Admitted to ... In the recent OSPREY-AHF (Oral Sodium to Preserve Renal Efficiency In Acute Heart Failure) trial, 6 g of oral NaCl for 5 days alongside a high-dose IV loop ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10579092/

Natriuresis-guided diuretic therapy in acute heart failure In patients with acute heart failure, personalized dosing of a diuretic led to treatment intensification in the majority of patients and improved natriuresis.

7. journals.lww.com journals.lww.com/10.1097/CRD.0000000000001093

Natriuresis-Guided Diuretic Therapy for Acute Heart Failure Natriuresis-Guided Diuretic Therapy for Acute Heart Failure: A Systematic Review and Meta-Analysis of Diuretic Efficacy. Shah, Syed Wajihullah MBBS *; Khan, ...