NEJM: Dose optimization of diuretics for HF does not alter outcomes

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Researchers found no significant differences in acute decompensated heart failure patients’ global assessment of symptoms or renal function when diuretic therapy was administered by bolus as compared with continuous infusion of intravenous furosemide or a low-dose strategy compared with a high-dose strategy, according to the DOSE trial published in the March 3 issue of the New England Journal of Medicine.

“Loop diuretics are an essential component of therapy for patients with acute decompensated heart failure, but there are few prospective data to guide their use,” the authors wrote. Intravenous loop diuretics are administered to an estimated 90 percent of patients hospitalized for heart failure (HF), but high doses of loop diuretics may have harmful effects—activation of the renin angiotensin and symptomatic nervous systems, electrolyte disturbances and worsening renal functions—however, there is still uncertainty regarding dosing.

To add to this sparse data and better understand global assessment of symptoms, G. Michael Felker, MD, from Duke University School of Medicine and Duke Heart Center in Durham, N.C., and colleagues assigned 308 acute decompensated HF patients to receive either a low (equivalent to the patient’s previous oral dose) or high (2.5 times the previous amount) dose of furosemide administered intravenously via either bolus every 12 hours or continuous infusion during the DOSE (Diuretic Optimization Strategies Evaluation) trial.

The patients were enrolled at 26 clinical sites in the U.S. and Canada between March 2008 and November 2009 and patients all had a mean age of 66 years, 27 percent were women and 25 percent were black. The researchers quantified patients’ global assessment of symptoms as the area under the curve (AUC) of the score on a visual-analogue scale over the course of 72 hours, along with the change in serum creatinine level from baseline to 72 hours.

Patients who were assigned to intravenous boluses every 12 hours were more likely to require a dose increase at 48 hours compared with the patients assigned to continuous intravenous infusion, 21 percent versus 11 percent.

Felker et al reported no statistical differences in patients’ global assessment of symptoms or mean change in the creatinine level. However, there was a nonsignificant trend toward greater improvement in patients’ global assessment of symptoms in the high-dose group compared with the low-dose strategy, 4,430 versus 4,171.

In addition, there was no significant difference between the groups in terms of the mean change in creatinine levels—7.1 umol per liter for the high-dose strategy and 3.5 umol per liter for the low-dose strategy.

“The high-dose strategy was associated with greater diuresis and more favorable outcomes in some secondary measures but also with transient worsening of renal function,” the authors wrote.

The researchers reported that patients assigned to the high-dose strategy were more likely to change to oral diuretics at 48 hours than were the patients assigned to the low-dose strategy, 31 percent versus 17 percent. However, patients in the low-dose group were more likely to require a 50 percent increase in the dose at 48 hours compared with those in the high-dose group, 24 percent versus 9 percent.

Over the course of the 72-hour period, the median dose of loop diuretics was 358 mg in the low-dose strategy and 773 mg in the high-dose strategies.

“The high-dose strategy was … associated with greater relief of dyspnea, greater fluid loss and weight loss, and fewer serious adverse events,” the authors wrote. And although worsening renal function was found more frequently with the high-dose strategy, there was no evidence at 60 days of worse outcomes in the high-dose arm compared to the low-dose arm.

Limitations stem from the fact that the study is most likely not applicable to patients with newly diagnosed HF or those with more modest diuretic requirements.

The study was funded by the National Heart, Lung and Blood Institute.