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

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator), Dose Comparison, Factorial Assignment, Safety/Efficacy Study

Study Primary Completion Date: November 2009

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.

Intervention(s) in this Clinical Trial

• Drug: Furosemide
  • High intensification (2.5 x oral dose) IV furosemide by either Q12 hours bolus or continuous infusion; low intensification (1 x oral dose) IV furosemide by either Q12 hours bolus or continuous infusion
• Drug: Placebo
  • To maintain blinding, all participants will receive placebo (a salt solution) via the method to which they were not assigned to receive furosemide.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Participants will receive high dose furosemide administered via IV bolus every 12 hours and placebo via continuous IV infusion.
• Experimental: 2
  • Participants will receive high dose IV furosemide administered via continuous infusion and placebo every 12 hours via IV bolus.
• Experimental: 3
  • Participants will receive low dose furosemide administered via IV bolus every 12 hours and placebo via continuous infusion.
• Experimental: 4
  • Participants will receive low dose IV furosemide administered via continuous infusion and placebo every 12 hours via IV bolus.

Primary Measures

• Patient well being, as determined by a visual analog scale
  • Time Frame: Measured over 72 hours
    Safety Issue?: No
• Change in serum creatinine
  • Time Frame: Measured at baseline and after 72 hours
    Safety Issue?: Yes

Secondary Measures

• Weight loss
  • Time Frame: Measured at 24, 48, 72, and 96 hours
    Safety Issue?: No
• Proportion of patients free of congestion
  • Time Frame: Measured at 72 hours
    Safety Issue?: No
• Change in the bivariate relationship of creatinine versus weight loss
  • Time Frame: Measured at 72 hours
    Safety Issue?: Yes
• Dyspnea, as determined by visual analog scales
  • Time Frame: Measured at 24, 48, and 72 hours
    Safety Issue?: No
• Patient global assessment, as determined by visual analog scales
  • Time Frame: Measured at 24 and 48 hours
    Safety Issue?: No
• Change in serum creatinine
  • Time Frame: Measured at baseline, Hours 24, 48, and 96, and Days 7 and 60
    Safety Issue?: Yes
• Change in cystatin C
  • Time Frame: Measured at baseline, 72 hours, and Days 7 and 60
    Safety Issue?: No
• Worsening or persistent heart failure, defined as a need for rescue therapy
  • Time Frame: Measured over 72 hours
    Safety Issue?: No
• Development of cardio-renal syndrome, defined as an increase in the serum creatinine level greater than 0.3 mg/dl
  • Time Frame: Measured over 72 hours
    Safety Issue?: Yes
• Net fluid loss
  • Time Frame: Measured at 24, 48, and 72 hours
    Safety Issue?: No
• Time from study entry to discharge during index hospitalization
  • Time Frame: Measured over 72 hours
    Safety Issue?: No
• Death or total days hospitalized for heart failure
  • Time Frame: Measured over the 60 days following study entry
    Safety Issue?: No
• Death or re-hospitalization
  • Time Frame: Measured at Day 60
    Safety Issue?: No

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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Overall Clinical Trial Officials and Contacts

Kerry L. Lee, PhD Principal Investigator Duke University  

Information obtained from ClinicalTrials.gov on January 08, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00577135

Study ID Number: 523

ClinicalTrials.gov Identifier: NCT00577135

Health Authority: United States: Federal Government