Randomization and Treatment Assignments

ORIGINAL ARTICLE

Diuretic Strategies in Patients with Acute Decompensated Heart Failure

G. Michael Felker, M.D., M.H.S., Kerry L. Lee, Ph.D., David A. Bull, M.D., Margaret M. Redfield, M.D., Lynne W. Stevenson, M.D., Steven R. Goldsmith, M.D., Martin M. LeWinter, M.D., Anita Deswal, M.D., M.P.H., Jean L. Rouleau, M.D., Elizabeth O. Ofili, M.D., M.P.H., Kevin J. Anstrom, Ph.D., Adrian F. Hernandez, M.D., Steven E. McNulty, M.S., Eric J. Velazquez, M.D., Abdallah G. Kfoury, M.D., Horng H. Chen, M.B., B.Ch., Michael M. Givertz, M.D., Marc J. Semigran, M.D., Bradley A. Bart, M.D., Alice M. Mascette, M.D., Eugene Braunwald, M.D., and Christopher M. O'Connor, M.D., for the NHLBI Heart Failure Clinical Research Network^*

N Engl J Med 2011; 364:797-805March 3, 2011DOI: 10.1056/NEJMoa1005419

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Acute decompensated heart failure is the most common cause of hospital admissions among patients older than 65 years of age and is responsible for more than 1 million hospitalizations annually in the United States.1 Intravenous loop diuretics are an essential component of current treatment and are administered to approximately 90% of patients who are hospitalized with heart failure.2 Despite decades of clinical experience with these agents, prospective data to guide the use of loop diuretics are sparse, and current guidelines are based primarily on expert opinion.3,4 As a result, clinical practice varies widely with regard to both the mode of administration and the dosing.

High doses of loop diuretics may have harmful effects, including activation of the renin–angiotensin and sympathetic nervous systems, electrolyte disturbances, and worsening of renal function.5 In addition, observational studies have shown associations between high doses of diuretics and adverse clinical outcomes, including renal failure, progression of heart failure, and death.6-8 Such observations are confounded, however, because high doses of diuretics may be a marker for greater severity of illness rather than a mediator of adverse outcomes.

In addition to uncertainty about dosing, there is uncertainty about the optimal mode of administration. Pharmacokinetic and pharmacodynamic data suggest that there are potential benefits of continuous infusion as compared with intermittent boluses. Although several small studies have evaluated the role of continuous infusion of loop diuretics in patients with heart failure, these studies have been underpowered to address clinical questions.9-16

In light of these uncertainties, the National Heart, Lung, and Blood Institute Heart Failure Clinical Research Network conducted the Diuretic Optimization Strategies Evaluation (DOSE) trial, a clinical trial of various diuretic strategies for patients with acute decompensated heart failure.

METHODS

Study Design

The DOSE study was a prospective, randomized, double-blind, controlled trial.5 The study was designed and conducted by the Heart Failure Clinical Research Network (see the Supplementary Appendix, available with the full text of this article at NEJM.org) and was funded entirely by the National Heart, Lung, and Blood Institute. The data coordinating center (Duke Clinical Research Institute) was responsible for data management and statistical analysis. The study protocol, including the statistical analysis plan, is available at NEJM.org. The decision to submit the manuscript for publication was made by the members of the Heart Failure Clinical Research Network Steering Committee, who vouch for the data and the analysis and for the fidelity of the study to the protocol. The study was approved by the institutional review board at each site, and all patients provided written informed consent.

Study Participants

Patients were eligible for enrollment if they had presented within the previous 24 hours with acute decompensated heart failure, diagnosed on the basis of the presence of at least one symptom (dyspnea, orthopnea, or edema) and one sign (rales, peripheral edema, ascites, or pulmonary vascular congestion on chest radiography) of heart failure. Additional eligibility criteria were a history of chronic heart failure and receipt of an oral loop diuretic for at least 1 month before hospitalization, at a dose between 80 mg and 240 mg daily in the case of furosemide and an equivalent dose in the case of a different loop diuretic (20 mg of torsemide or 1 mg of bumetanide was considered to be equivalent to 40 mg of furosemide). Thiazide diuretics were permitted if the patient had been taking them on a long-term basis. There was no prespecified inclusion criterion with respect to ejection fraction. Patients with systolic blood pressure of less than 90 mm Hg or a serum creatinine level that was greater than 3.0 mg per deciliter (265.2 μmol per liter) and patients requiring intravenous vasodilators or inotropic agents (other than digoxin) for heart failure were excluded.

Randomization and Treatment Assignments

The trial used a 2-by-2 factorial design. Patients were randomly assigned, in a 1:1:1:1 ratio, to either a low-dose strategy (total intravenous furosemide dose equal to their total daily oral loop diuretic dose in furosemide equivalents) or a high-dose strategy (total daily intravenous furosemide dose 2.5 times their total daily oral loop diuretic dose in furosemide equivalents) and to administration of furosemide either by intravenous bolus every 12 hours or by continuous intravenous infusion. Randomization was performed with the use of permuted blocks, stratified according to clinical site. A double-blind, double-dummy design was used so that all patients received both intravenous boluses every 12 hours and a continuous infusion, one of which contained furosemide and the other a saline placebo.

The study treatment, with group assignments concealed, was continued for up to 72 hours. At 48 hours, the treating physician had the option of adjusting the diuretic strategy on the basis of the clinical response. At this time, the physician could increase the dose by 50% (with the study treatment remaining concealed), maintain the same strategy (with the study treatment remaining concealed), or discontinue intravenous treatment and change to open-label oral diuretics. After 72 hours, all treatment was open-label at the discretion of the treating physician, who did not have knowledge of the prior study-treatment assignment. An assessment of biomarkers, including creatinine, cystatin C, and N-terminal pro-brain natriuretic peptide, was performed at a central core laboratory at baseline, 72 hours, and 60 days. Patients were followed for clinical events to day 60.

End Points

The trial had two coprimary end points. The primary efficacy end point was the patient's global assessment of symptoms, measured with the use of a visual-analogue scale and quantified as the area under the curve (AUC) of serial assessments from baseline to 72 hours (see Section 3 in the Supplementary Appendix for a description of the method used for quantification of the area under the curve).17 For this assessment, patients were asked to evaluate their general well-being by marking a 10-cm vertical line, with the top labeled “best you have ever felt” and the bottom labeled “worst you have ever felt.” We scored the patients' markings on a scale of 0 to 100 by measuring the distance in millimeters from the bottom of the line. The primary safety end point was the change in the serum creatinine level from baseline to 72 hours. See Section 3 in the Supplementary Appendix for more detailed definitions of the study end points.

Prespecified secondary end points included the following: patient-reported dyspnea (as assessed with the use of a visual-analogue scale such as that described above and quantified as the AUC of serial assessments from baseline to 72 hours); changes in body weight and net fluid loss; the proportion of patients who were free from congestion (defined as jugular venous pressure of <8 cm, with no orthopnea and with trace peripheral edema or no edema) at 72 hours; worsening renal function (defined as an increase in the serum creatinine level of more than 0.3 mg per deciliter) at any time from randomization to 72 hours; worsening or persistent heart failure; treatment failure (see Section 3 in the Supplementary Appendix); changes in biomarker levels at 72 hours, day 7 or discharge, and day 60; and clinical end points, including the composite of death, rehospitalization, or an emergency room visit within 60 days, as well as the composite of total number of days hospitalized or dead during the 60 days after randomization.

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