Clinical trial NCT00577135: Determining Optimal Dose and Duration of Diuretic Treatment in People With Acute Heart Failure (The DOSE-AHF Study)
Official title: Diuretic Optimal Strategy Evaluation in Acute Heart Failure (The DOSE-AHF Study)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Heart Failure
Keywords: Loop Diuretics
Furosemide
Fluid Overload
Cardio Renal Failure
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2007-12-19
Enrollment: 308
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Patient Well Being, as Determined by a Visual Analog Scale
timeFrame: Measured at 72 hours
measure: Change in Serum Creatinine
timeFrame: Measured at baseline and 72 hours
Secondary outcomes:
measure: Change in Weight
timeFrame: baseline and 96 hours
measure: Proportion of Patients Free of Congestion
timeFrame: Measured at 72 hours
measure: Dyspnea, as Determined by Visual Analog Scales
timeFrame: Measured at 24 hours
measure: Change in Serum Creatinine
timeFrame: baseline and 24 hours
measure: Change in Cystatin C
timeFrame: baseline and 72 hours
measure: Change in Serum Creatinine
timeFrame: baseline and 48 hours
measure: Change in Serum Creatinine
timeFrame: baseline and 96 hours
measure: Change in Serum Creatinine
timeFrame: baseline and day 7
measure: Change in Serum Creatinine
timeFrame: baseline and day 60
measure: Patient Well Being, as Determined by a Visual Analog Scale
timeFrame: Measured at 24 hours
measure: Patient Well Being, as Determined by a Visual Analog Scale
timeFrame: 48 hours
measure: Dyspnea VAS
timeFrame: 48 hours
measure: Dyspnea VAS
timeFrame: 72 hours
measure: Change in Cystatin C
timeFrame: baseline and day 7
measure: Change in Cystatin C
timeFrame: baseline and day 60
measure: Change in Uric Acid
timeFrame: baseline and 72 hours
measure: Change in Uric Acid
timeFrame: baseline and day 7
measure: Change in Uric Acid
timeFrame: baseline and Day 60
measure: Change in B-type Natriuretic Peptide
timeFrame: baseline and 72 hours
measure: Change in NTproBNP
timeFrame: baseline and Day 7
measure: Change in NTproBNP
timeFrame: baseline and Day 60
measure: Presence of Cardiorenal Syndrome
timeFrame: Within 72 hours
measure: Treatment Failure
timeFrame: Within 72 hours
measure: Net Fluid Loss
timeFrame: Through 24 hours
measure: Net Fluid Loss
timeFrame: Through 48 hours
measure: Net Fluid Loss
timeFrame: Through 72 hours
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Morehouse School of Medicine
state: Georgia
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: Minnesota Heart Failure Network
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Murray
country: United States
facility: University of Utah Health Sciences Center
state: Utah
city: Burlington
country: United States
facility: University of Vermont - Fletcher Allen Health Care
state: Vermont
city: Montreal
country: Canada
facility: Montreal Heart Institute
state: Quebec
Study officials:
affiliation: Duke Clinical Research Institute
name: Kerry L. Lee, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Harvard University
name: Eugene Braunwald, MD
role: STUDY_CHAIR
References:
citation: Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, Goldsmith SR, LeWinter MM, Deswal A, Rouleau JL, Ofili EO, Anstrom KJ, Hernandez AF, McNulty SE, Velazquez EJ, Kfoury AG, Chen HH, Givertz MM, Semigran MJ, Bart BA, Mascette AM, Braunwald E, O'Connor CM; NHLBI Heart Failure Clinical Research Network. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011 Mar 3;364(9):797-805. doi: 10.1056/NEJMoa1005419.
citation: Kelly JP, Cooper LB, Gallup D, Anstrom KJ, Chen HH, Redfield MM, O'Connor CM, Mentz RJ, Hernanadez AF, Felker GM. Implications of Using Different Definitions on Outcomes in Worsening Heart Failure. Circ Heart Fail. 2016 Aug;9(8):e003048. doi: 10.1161/CIRCHEARTFAILURE.116.003048.
citation: de Denus S, Rouleau JL, Mann DL, Huggins GS, Cappola TP, Shah SH, Keleti J, Zada YF, Provost S, Bardhadi A, Phillips MS, Normand V, Mongrain I, Dube MP. A pharmacogenetic investigation of intravenous furosemide in decompensated heart failure: a meta-analysis of three clinical trials. Pharmacogenomics J. 2017 Mar;17(2):192-200. doi: 10.1038/tpj.2016.4. Epub 2016 Mar 1.
citation: Lala A, McNulty SE, Mentz RJ, Dunlay SM, Vader JM, AbouEzzeddine OF, DeVore AD, Khazanie P, Redfield MM, Goldsmith SR, Bart BA, Anstrom KJ, Felker GM, Hernandez AF, Stevenson LW. Relief and Recurrence of Congestion During and After Hospitalization for Acute Heart Failure: Insights From Diuretic Optimization Strategy Evaluation in Acute Decompensated Heart Failure (DOSE-AHF) and Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARESS-HF). Circ Heart Fail. 2015 Jul;8(4):741-8. doi: 10.1161/CIRCHEARTFAILURE.114.001957. Epub 2015 Jun 3.
citation: Mentz RJ, Stevens SR, DeVore AD, Lala A, Vader JM, AbouEzzeddine OF, Khazanie P, Redfield MM, Stevenson LW, O'Connor CM, Goldsmith SR, Bart BA, Anstrom KJ, Hernandez AF, Braunwald E, Felker GM. Decongestion strategies and renin-angiotensin-aldosterone system activation in acute heart failure. JACC Heart Fail. 2015 Feb;3(2):97-107. doi: 10.1016/j.jchf.2014.09.003. Epub 2014 Oct 31.
citation: Kociol RD, McNulty SE, Hernandez AF, Lee KL, Redfield MM, Tracy RP, Braunwald E, O'Connor CM, Felker GM; NHLBI Heart Failure Network Steering Committee and Investigators. Markers of decongestion, dyspnea relief, and clinical outcomes among patients hospitalized with acute heart failure. Circ Heart Fail. 2013 Mar;6(2):240-5. doi: 10.1161/CIRCHEARTFAILURE.112.969246. Epub 2012 Dec 18.
citation: Shah RV, McNulty S, O'Connor CM, Felker GM, Braunwald E, Givertz MM. Effect of admission oral diuretic dose on response to continuous versus bolus intravenous diuretics in acute heart failure: an analysis from diuretic optimization strategies in acute heart failure. Am Heart J. 2012 Dec;164(6):862-8. doi: 10.1016/j.ahj.2012.08.019. Epub 2012 Oct 29.