Determining Optimal Dose and Duration of Diuretic Treatment in People With Acute Heart Failure (The DOSE-AHF Study)

Study Overview
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Brief Summary
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Heart failure is a disorder in which the heart does not pump blood adequately. This can lead to several serious problems, including reduced blood flow throughout the body, congestion of blood in the veins and lungs, and fluid accumulation in various organs and limbs. Diuretics are often used to address the problem of fluid accumulation, but the optimal dose and the amount of time over which to administer each dose are unclear. This study will compare high and low doses of diuretics administered over longer and shorter periods of time to determine the safest and most effective combination.

Detailed Description
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Heart failure is a common disorder in which the heart cannot pump enough blood to meet the needs of the rest of the body. Heart failure symptoms include shortness of breath, swelling, and fatigue. Standard treatment for the swelling associated with heart failure includes the use of diuretic medications, such as furosemide, which cause urination and the removal of excess fluids in the body. Although furosemide has been used to treat heart failure patients for many years, it is still unclear how much of the drug to use, and over what time period the drug should be given. This study will evaluate whether furosemide treatment is safer and more effective when the drug is given in high doses versus low doses and in two to three separate doses versus one continuous infusion. Participants in this study will begin study procedures within the first 24 hours of their hospital admission for heart failure. Participants will be randomly assigned to receive one of the following four treatments: high dose furosemide via continuous intravenous (IV) infusion and placebo every 12 hours via IV bolus; low dose furosemide via continuous IV infusion and placebo every 12 hours via IV bolus; high dose furosemide every 12 hours via IV bolus and placebo via continuous IV infusion; and low dose furosemide every 12 hours via IV bolus and placebo via continuous IV infusion. Each participant will receive treatment for the first 72 hours of his or her hospital stay. Participants will answer questionnaires and undergo physical examinations and blood tests during the first 96 hours of hospitalization and again before hospital discharge or on Day 7, if that occurs first. Participants will be asked to return to their doctors 60 days following hospital discharge to evaluate their responses to treatment.

Official Title
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Diuretic Optimal Strategy Evaluation in Acute Heart Failure (The DOSE-AHF Study)

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: Furosemide-Q12 hour bolus
* Drug: Furosemide-Continuous Infusion
* Drug: Furosemide-Low Intensification
* Drug: Furosemide-High Intensification


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Prior clinical diagnosis of heart failure that was treated with daily oral loop diuretics for at least 1 month Current diagnosis of heart failure, as defined by the presence of at least 1 symptom (dyspnea, orthopnea, or edema) AND 1 sign (rales on auscultation, peripheral edema, ascites, pulmonary vascular congestion on chest radiography) Daily oral dose of furosemide between 80 mg and 240 mg (or equivalent) Identified within 24 hours of hospital admission Current treatment plan includes IV loop diuretics for at least 48 hours Exclusion Criteria: Brain natriuretic peptide (BNP) less than 250 mg/mL or N-terminal prohormone brain natriuretic peptide (NT-proBNP) less than 1000 mg/mL Received IV vasoactive treatment or ultra-filtration therapy for heart failure since initial presentation Treatment plan during current hospitalization includes IV vasoactive treatment or ultra-filtration for heart failure Substantial diuretic response to pre-randomization diuretic dosing such that higher doses of diuretics would be medically inadvisable Systolic blood pressure less than 90 mm Hg Serum creatinine level greater than 3.0 mg/dL at baseline or currently undergoing renal replacement therapy Hemodynamically significant arrhythmias Acute coronary syndrome within 4 weeks prior to study entry Active myocarditis Hypertrophic obstructive cardiomyopathy Severe stenotic valvular disease Restrictive or constrictive cardiomyopathy Complex congenital heart disease Constrictive pericarditis Non-cardiac pulmonary edema Clinical evidence of digoxin toxicity Need for mechanical hemodynamic support Sepsis Terminal illness (other than heart failure) with expected survival time of less than 1 year History of adverse reaction to the study drugs Use of IV iodinated radiocontrast material within 72 hours prior to study entry or planned during hospitalization Enrollment or planned enrollment in another randomized clinical trial during this hospitalization Inability to comply with planned study procedures

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Q12 hour bolus<br>Furosemide-Q12 hour bolus | Drug: Furosemide-Low Intensification<br>* 1x oral dose<br>* Other names: Loop diuretic;Drug: Furosemide-High Intensification<br>* 2.5x oral dose<br>* Other names: loop diuretic;|
| Experimental: Continuous Infusion<br>Furosemide-Continuous Infusion | Drug: Furosemide-Low Intensification<br>* 1x oral dose<br>* Other names: Loop diuretic;Drug: Furosemide-High Intensification<br>* 2.5x oral dose<br>* Other names: loop diuretic;|
| Experimental: Low Intensification<br>Furosemide-Low Intensification | Drug: Furosemide-Q12 hour bolus<br>* Q12 hours bolus<br>* Other names: Loop diuretics;Drug: Furosemide-Continuous Infusion<br>* Continuous infusion<br>* Other names: Loop diuretic;|
| Experimental: High Intensification<br>Furosemide-High Intensification | Drug: Furosemide-Q12 hour bolus<br>* Q12 hours bolus<br>* Other names: Loop diuretics;Drug: Furosemide-Continuous Infusion<br>* Continuous infusion<br>* Other names: Loop diuretic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Well Being, as Determined by a Visual Analog Scale | Global Visual Analog Scale Scale Range 0-7200; higher score is better | Measured at 72 hours | 
| Change in Serum Creatinine |  | Measured at baseline and 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Weight |  | baseline and 96 hours | 
| Proportion of Patients Free of Congestion |  | Measured at 72 hours | 
| Dyspnea, as Determined by Visual Analog Scales | Global Visual Analog Scale Scale Range 0-2400; higher score is better | Measured at 24 hours | 
| Change in Serum Creatinine |  | baseline and 24 hours | 
| Change in Cystatin C |  | baseline and 72 hours | 
| Change in Serum Creatinine |  | baseline and 48 hours | 
| Change in Serum Creatinine |  | baseline and 96 hours | 
| Change in Serum Creatinine |  | baseline and day 7 | 
| Change in Serum Creatinine |  | baseline and day 60 | 
| Patient Well Being, as Determined by a Visual Analog Scale | Global Visual Analog Scale Scale Range 0-2400; higher score is better | Measured at 24 hours | 
| Patient Well Being, as Determined by a Visual Analog Scale | Global Visual Analog Scale Scale Range 0-4800; higher score is better | 48 hours | 
| Dyspnea VAS | Dyspnea Visual Analog Scale Scale Range 0-4800; higher score is better | 48 hours | 
| Dyspnea VAS | Dyspnea Visual Analog Scale Scale Range 0-7200; higher score is better | 72 hours | 
| Change in Cystatin C |  | baseline and day 7 | 
| Change in Cystatin C |  | baseline and day 60 | 
| Change in Uric Acid |  | baseline and 72 hours | 
| Change in Uric Acid |  | baseline and day 7 | 
| Change in Uric Acid |  | baseline and Day 60 | 
| Change in B-type Natriuretic Peptide | Change in NTproBNP | baseline and 72 hours | 
| Change in NTproBNP |  | baseline and Day 7 | 
| Change in NTproBNP |  | baseline and Day 60 | 
| Presence of Cardiorenal Syndrome |  | Within 72 hours | 
| Treatment Failure | Treatment failure is defined as the patient met cardiorenal syndrome endpoint, worsening or persistent heart failure endpoint, patient died, or there was clinical evidence of overdiuresis requiring intervention within first 72 hours after randomization | Within 72 hours | 
| Net Fluid Loss |  | Through 24 hours | 
| Net Fluid Loss |  | Through 48 hours | 
| Net Fluid Loss |  | Through 72 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Loop Diuretics, Furosemide, Fluid Overload, Cardio Renal Failure