The DOSE trial: Loop diuretic strategies in acute decompensated heart failure [Classics Series]

1. The use of loop diuretics in acute decompensated heart failure is commonplace, but clinical practice varies widely with regards to the dosage and administration of therapy.

2. This study found that mode of administration (bolus vs. continuous infusion) and dosage (low vs. high) of loop diuretics had no significant effect on the primary endpoints of overall effectiveness or safety of therapy.

3. Higher doses of loop diuretics led to significantly greater diuresis, improved dyspnea, and fewer adverse events than lower doses.

Original Date of Publication: March 2011

This study summary is an excerpt from the book 2 Minute Medicine’s The Classics in Medicine: Summaries of the Landmark Trials, 2e (The Classics Series).

Study Rundown: Loop diuretics were first approved by the U.S. Food and Drug Administration (FDA) in 1966 and had become widely prescribed for patients with congestive heart failure. However, in the intervening decades, scant prospective data was generated to guide the optimal administration of these drugs. There remained concern that higher doses of loop diuretics, while generating greater diuresis, could worsen renal function and activate the sympathetic nervous system, thereby leading to worse outcomes. Additionally, limited pharmacokinetic data suggested that continuous infusions of intravenous (IV) loop diuretics were superior to boluses. In this setting of clinical uncertainty, the Diuretic Optimization Strategies Evaluation (DOSE) trial was conducted in 2008 to gauge the safety and effectiveness of different dosing strategies of loop diuretics for patients with acute decompensated heart failure.

This study compared bolus doses vs. infusions and also compared low vs. high doses of loop diuretics. There were no differences in the primary effectiveness endpoint (72-hour qualitative symptom improvement) or the primary safety endpoint (72-hour increase in serum creatinine) when comparing bolus or continuous infusion administration of loop diuretic. While there were also no differences in the primary endpoints between patients receiving low doses or high doses of loop diuretics, higher doses were associated with greater total diuresis, greater relief of dyspnea, and fewer adverse events overall. Additionally, there were no differences between the low or high dose regimens when it came to 60-day mortality or rehospitalization.

In summary, among patients with acute decompensated heart failure, the mode of administration (bolus vs. infusion) and dosage of IV loop diuretics had no significant effect on the overall effectiveness or safety of therapy, though higher doses may be preferable to lower doses with regards to various secondary endpoints.

Click to read the study in NEJM

In-Depth [randomized controlled trial]: This prospective, double-blind, randomized trial was conducted at 26 institutions in the United States and Canada. A total of 308 patients meeting the inclusion criteria (history of congestive heart failure on an oral daily dose of furosemide between 80-240 mg or equivalent, admission to hospital for an acute decompensation within the previous 24 hours) were randomized to bolus vs. continuous infusion and low vs. high dose IV administration of loop diuretics in a 2×2 factorial design. Low doses were equivalent to each patient’s baseline oral loop diuretic dose prior to hospitalization, while high doses were set at 2.5 times the level of baseline oral dosages. Dosage of the loop diuretic could be adjusted based on clinical factors at 48 hours, and at 72 hours all patients were made open-label for continued management. Co-primary endpoints of effectiveness (qualitative symptom assessment improvement) and safety (change in serum creatinine) were quantified in serial assessments over the first 72 hours. Because of its dual nature, for both primary endpoints a p-value of <0.025 was considered significant. Several secondary endpoints were also measured at 72 hours, and a composite clinical outcome of mortality and rehospitalization was assessed at 60 days.

There were no differences between the continuous dosing and bolus dosing when it came to the primary measures of overall symptom improvement (p = 0.47) and creatinine change (p = 0.45). Though there was a non-significant trend towards improvement of overall symptoms with higher loop diuretic doses, there were also no significant differences between low and high dosing strategies with regards to the co-primary endpoints (p = 0.06 and p = 0.21). With regards to secondary endpoints, the higher dosing strategy was associated with improvement in qualitative dyspnea (p = 0.04), greater total diuresis (p = 0.001), and fewer adverse events (p = 0.03). There was additionally no difference in the length of hospital stay or the number of days patients remained alive and out of the hospital for the different administrations and dosages.

Image: PD

©2016 2 Minute Medicine, Inc. All rights reserved. No works may be reproduced without expressed written consent from 2 Minute Medicine, Inc. Inquire about licensing here. No article should be construed as medical advice and is not intended as such by the authors or by 2 Minute Medicine, Inc.