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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

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

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 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 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.

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.

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 yo

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

Owing to the use of two coprimary end points (an efficacy and a safety end point), the prespecified threshold for significance for each end point was a P value of less than 0.025.

The patient population had several high-risk features, including a history of hospitalization for heart failure within the previous 12 months (74% of the patients), moderate renal dysfunction (mean serum creatinine level, 1.5 mg per deciliter [132.6 μmol per liter]), and elevated natriuretic peptide levels (mean N-terminal pro-brain natriuretic peptide level, 7439 pg per milliliter).

A total of 130 patients (42%) died, were rehospitalized, or had an emergency department visit within the 60-day follow-up period, but there was no significant difference in this composite end point between the continuous-infusion group and the bolus group (67 events and 63 events, respectively; hazard ratio with continuous infusion, 1.15; 95% confidence interval [CI], 0.83 to 1.60; P=0.41) or between the high-dose group and the low-dose group (63 events and 67 events, respectively; hazard ratio

With respect to the comparison of bolus with continuous infusion, there was no significant difference between the treatment groups across a broad range of efficacy and safety end points.

One possible explanation for the absence of a significant difference in outcomes between boluses and continuous infusion in our study is the use of a continuous placebo infusion in the patients assigned to boluses; this feature of the study design may have served to increase the time the patients were supine, a position that has been shown to enhance diuresis.22 In addition, it should be noted that the bolus group tended to receive a higher total dose of diuretic than did the continuous-infusion

This observation is consistent with other recent data suggesting that transient worsening of renal function during hospitalization for heart failure may not affect the outcomes after discharge from the hospital.25,26